БОЛЕЗНЬ ПАРКИНСОНА (биомаркеры нейродегенеративного

БОЛЕЗНЬ ПАРКИНСОНА
(биомаркеры нейродегенеративного процесса)
2010–2015 гг.
АННОТИРОВАННЫЙ КАТАЛОГ
ОТЕЧЕСТВЕННЫХ И ЗАРУБЕЖНЫХ НАУЧНО-МЕДИЦИНСКИХ ПУБЛИКАЦИЙ
Настоящий каталог «БОЛЕЗНЬ ПАРКИНСОНА (биомаркеры нейродегенеративного
процесса)
2010–2015
гг.»
представляет
собой
аннотированный
указатель
библиографических описаний публикаций, посвященных биологическим маркерам
нейродегенеративного
процесса
при
болезни
Паркинсона,
и
включающий
библиографические описания документов по теме, вышедших за 5 лет, в 2010–2015 гг.,
общим количеством 85 наименований. Библиографические описания даются в алфавитном
порядке заглавия или фамилия первого автора. После каждого описания приводится
соответствующая аннотация. Библиографические описания сгруппированы по годам, в
порядке хронологического убывания, от 2015 г. к 2010 г.
Ключевые слова: болезнь Паркинсона, биологические маркеры, биомаркеры, кровь,
цереброспинальная
жидкость,
генетика,
нейровизуализация,
нейротрансмиттеры,
клинические испытания.
The current catalogue PARKINSON’S DISEASE (biomarkers of neurodegenerative process) is
an annotated index of bibliographical descriptions of publications dedicated to all aspects of
biological markers of neurodegenerative process in cases of Parkinson’s disease. The index
comprises the bibliographical descriptions of documents on the theme which have been
published over the period of 5 years, 2010–2015. The index is alphabetically arranged by titles or
first author last names followed by respective annotations. The bibliographical descriptions are
grouped by years, from 2015 to 2010.
Key words: Parkinson's disease, biomarker, biological markers, blood; cerebrospinal fluid,
genetics, imaging, neurotransmitters, clinical trial.
MESH terms: Parkinson's disease, biomarker, biological markers, imaging.
СОДЕРЖАНИЕ
Вступление
Аннотированный каталог
Публикации в российских научно-медицинских изданиях
Публикации в зарубежных научно-медицинских изданиях
Клинические испытания
ВСТУПЛЕНИЕ
Согласно современным представлениям, ключевое значение в стратегии борьбы с
нейродегенеративными заболеваниями придается максимально ранней диагностике
патологического процесса и в особенности - диагностике болезни в её доклинической
стадии (Иллариошкин С.Н. Ранняя диагностика нейродегенеративных заболеваний URL:
http://www.neurology.ru/patient/a-illarioshkin2008-1.htm). Болезнь Паркинсона (БП) входит в
клиническую стадию лишь после гибели более 70% нейронов среднего мозга,
ответственных за двигательные функции.
Данные
многочисленных
клинических
и
экспериментальных
исследований
показывают, что при большинстве нейродегенеративных заболеваний доклиническая
стадия длится в среднем около 6-8 лет, а затем сравнительно быстро развивается
манифестация явных клинических проявлений болезни.
Задача диагностики доклинической стадии нейродегенерации базируется на двух
нижеследующих составляющих.
1. Выделение факторов риска и формирование групп риска - лиц с высокой
предрасположенностью к развитию болезни. Наиболее часто речь идет о генетических и
средовых факторах риска той или иной болезни.
2.
Установление
биомаркеров
ранней
и
пресимптоматической
стадии
нейродегенеративного процесса. Наиболее перспективными считаются три группы
биомаркеров:
• нейрофизиологические и нейропсихологические (изменение нормальной картины
биоэлектрической активности мозга при электроэнцефалографии, тонкие изменения
психики и профиля личности при использовании специальных тестов и др.);
• молекулярно-биохимические (например, повышение в цереброспинальной
жидкости и крови пациентов уровня некоторых белков, строго специфичных для вещества
мозга);
•
нейровизуализационные
(выявление
с
помощью
специальных
методик
рентгеновской, магнитно-резонансной или радиоизотопной компьютерной томографии тех
или иных функционально-биохимических изменений в веществе мозга либо тонких
признаков нарастающего уменьшения объема отдельных ядер - скоплений нейронов в
определенных отделах мозга).
Выявление у человека из группы риска одного или нескольких вышеуказанных
маркеров нейродегенеративного процесса позволяет с высокой степенью вероятности
(которую можно даже рассчитать специальными методами) диагностировать наличие
доклинической стадии болезни и поставить вопрос о проведении ранней терапии,
направленной на предотвращение прогрессирования (нейропротекция).
Для анализа научной литературы по теме «Болезнь Паркинсона (биологические
маркеры нейродегенеративного процесса» нами определены следующие ключевые слова и
рубрики MeSH:
Ключевые слова: болезнь Паркинсона, биологические маркеры, биомаркеры, кровь,
цереброспинальная
жидкость,
генетика,
нейровизуализация,
нейротрансмиттеры,
клинические испытания.
Key words: Parkinson's disease, biomarker, biological markers, blood; cerebrospinal
fluid, genetics, imaging, neurotransmitters, clinical trial.
MeSH Headings: Parkinson's disease, biomarker, biological markers, imaging.
Важно отметить, что болезнь Паркинсона - это гетерогенный агломерат, ярлык
патологических синдромов, имеющих различный патогенез и, естественно, различную
генетику.
Для
отражающих
иллюстрации
это
можно
многообразие.
ознакомиться
Для
со
этого
списком
в
MeSH-терминов,
поисковике
MeSH
http://www.nlm.nih.gov/mesh/2015/mesh_browser/MBrowser.html наберите Parkinson's Disease
и нажмите среднюю клавишу Find Terms with ALL Fragments.
АННОТИРОВАННЫЙ КАТАЛОГ
БОЛЕЗНЬ ПАРКИНСОНА
(биомаркеры нейродегенеративного процесса)
2010–2015 гг.
ПУБЛИКАЦИИ В РОССИЙСКИХ НАУЧНО-МЕДИЦИНСКИХ ИЗДАНИЯХ
Поиск
на
информационном
портале
«Научная
электронная
библиотека
eLIBRARY.RU» выявил 23 публикации по теме за последние 5 лет.
В каталоге «Электронной библиотеки диссертаций dslib.net» найдено 56
диссертаций. Для аннотированного каталога нами отобраны 12 наиболее релевантных
диссертационных исследований.
2015
Белок альфа-синуклеин как биомаркер болезни Паркинсона / Андоскин П.А., Емельянов
А.К., Николаев М.А., Шилин В.П. // Фундаментальная наука и клиническая медицина —
Человек и его здоровье: Тезисы XVIII Международной медико-биологической конференции
молодых исследователей, посвященной двадцатилетию медицинского факультета
СПбГУ. — СПб.: Изд-во СПбГУ, 2015. — С. 31–32. [Фундам. наука клин. мед. — 2015. — Т.
18. — С. 31–32].
В исследование были включены группа пациентов с БП (n = 18, ср. возраст 67 ± 8,7
лет, от 56 до 82 лет), не получающих лечение препаратами Л-ДОФА, и контрольная группа
(n = 23, от 44 до 86 лет ср. возраст 65,67 ± 11,27). Плазма была получена из цельной
венозной крови путем центрифугирования 20 мин., 3000 g. Выделение CD45+ клеток
проведено методом магнитного сортинга из незамороженной периферической крови.
Использованы образцы клеточных лизатов, выравненные по концентрации общего белка
(по 6 мкг в образце). Оценка уровня общего и олигомерного альфа-синуклеина
проводилась методом иммуноферментного анализа (ИФА). Исследования каждого образца
проводились в трех повторах. Определение уровня мРНК гена SNCA проводилось
методом количественной ПЦР в режиме реального времени. Оценка экспрессии гена
SNCA и референсного гена была проведена с использованием метода 2-ΔΔCt. В качестве
референсного был использован конститутивно экспрессирующийся в клетках ген GNB2L1
(guanine nucleotide binding protein (G protein), beta polypeptide 2-like). Статистическая
обработка результатов проводилась с использованием программы SPSS версия 12.0.
Оценка общего, а также олигомерного альфа-синуклеина в плазме периферической крови
у пациентов с БП и в контроле статистически значимых различий не выявила (р = 0,8, p =
0,65 соответственно). Было показано некоторое увеличение уровня общего альфасинуклеина CD45+ клеток крови в группе пациентов с БП по сравнению с контрольной
группой (р = 0,04), в то время как относительный уровень мРНК гена SNCA между
группами не различался (p > 0,05).
В ходе исследования получены данные, свидетельствующие о возможном
увеличении уровня общего альфа-синуклеина CD45+ клеток крови при отсутствии
увеличения экспрессии гена SNCA у пациентов, что могло бы свидетельствовать о
нарушении деградации белка в клетке при БП. Предполагается, что в случае
подтверждения полученных данных на большей выборке, уровень общего альфасинуклеина CD45+ клеток крови можно будет рассматривать в качестве потенциального
маркера развития заболевания. Исследование поддержано грантами РФФИ № 13-04-01510;
№ 14-04- 31665.
Работа выполнена сотрудниками ФГБУ «ПИЯФ им. Б. П. Константинова».
ПСПБГМУ им. акад. И. П. Павлова.
Клинические показатели и уровень цитокинов в крови и цереброспинальной жидкости
пациентов с болезнью Паркинсона. Милюхина И.В., Карпенко М.Н., Клименко В.М. //
Клиническая медицина. 2015. Т. 93. № 1. С. 51-55.
Цель исследования - выявление особенностей цитокинового статуса у пациентов с
БП с учетом длительности, стадий и клинических проявлений заболевания. При
исследовании содержания цитокинов в сыворотке крови и цереброспинальной жидкости
больных БП выявлено, что у пациентов с БП вне зависимости от степени тяжести
заболевания в крови наблюдается изменение содержания интерлейкинов (IL): повышен
уровень IL-1β и IL-6 и снижен уровень IL-1RA по сравнению с показателями в
контрольной группе. Для пациентов с преимущественно правосторонней клинической
латерализацией БП характерен повышенный уровень фактора некроза опухолей a (TNFa) в
крови. Впервые обнаружено, что цитокиновый профиль у пациентов с БП изменяется в
зависимости от скорости прогрессирования заболевания: уровень TNFa в ликворе у
пациентов с быстрым темпом прогрессирования БП выше, чем у пациентов с медленным
темпом прогрессирования, уровень IL-1β в крови выше, чем у пациентов с умеренным и
медленным темпом прогрессирования. У пациентов с БП обнаружена связь уровня IL-10 в
крови и тяжести тревоги и депрессии, уровня TNFa в крови и выраженности когнитивного
дефицита.
Авторы
–
сотрудники
ФГБУ
«Научно-исследовательский
институт
экспериментальной медицины» СЗО РАМН и ФГБОУ ВПО «Санкт-Петербургский
государственный политехнический университет».
Исследование
методом
оптической
когерентной
томографии
толщины
слоя
ганглионарных клеток у пациентов с болезнью Паркинсона. Дынин П.С., Литвиненко И.В.,
Исаева Г.Е. // Бюллетень медицинских интернет-конференций. 2015. Т. 5. № 3. С. 171.
Цель исследования: оценить изменение толщины слоя ганглионарных клеток
сетчатки глаза у пациентов с болезнью Паркинсона методом оптической когерентной
томографии. Материалы и методы: исследование проводилось на аппарате ОКТ RTVue100, протокол GCC, с оценкой общей толщины слоя, верхнего и нижнего участков слоя
ганлионарных клеток. Обследованы 50 пациентов с установленным диагнозом болезнь
Паркинсона, средний возраст которых составил 62,2±4,2 лет и контрольная группа,
состоявшая из 20 пациентов соответствующего возраста. Стадия заболевания у пациентов
с болезнью Паркинсона составляла от 2,0 до 3,0 по Хен и Яру. Результаты и обсуждение:
подсчет достоверности производился с использованием критерия Манна-Уитни. Средняя
толщина слоя у пациентов составила 89,59 нм в сравнении со средней толщиной слоя у
контрольной группы 94,98 нм (p<0,05). При этом достоверно значимое истончение
определялось не только по значению общей толщины, но и по результатам измерения его
наружного (89,78 нм у пациентов с болезнью Паркинсона и 95,83 нм у контрольной
группы (p<0,05)) и внутреннего участков (89,68 нм у пациентов с болезнью Паркинсона и
95,38 нм у контрольной группы (p<0,05)). Таким образом по результатам оптической
когерентной томографии у пациентов с болезнью Паркинсона, отмечается достоверно
значимое истончение как общей толщины слоя ганглионарных волокон сетчатки глаза, так
и его наружного и внутреннего участков.
2014
Диссертации
Белоцерковская Екатерина Васильевна. Роль минисателлитного повтора UPS29 В
модуляции экспрессии гена ACAP3 при эпилепсии и болезни Паркинсона: диссертация ...
кандидата биологических наук: 03.01.04 / Белоцерковская Екатерина Васильевна;[Место
защиты: Научно-исследовательский институт экспериментальной медицины].- СанктПетербург, 2014.- 124 с.
URL:
http://www.dslib.net/bio-ximia/rol-minisatellitnogo-povtora-ups29-v-moduljacii-
jekspressii-gena-acap3-pri.html (дата обращения: 17.04.2015.).
Цель работы – оценить влияние минисателлитного повтора UPS29 на экспрессию
гена ACAP3 при эпилепсии и болезни Паркинсона в сравнении с модельными
экспериментами на культуре клеток.
Результаты. Выявлено снижение частоты метилированных форм UPS29 в
лейкоцитах периферической крови у женщин с эпилепсией и отсутствие связи между
статусом
метилирования
UPS29
и
болезнью
Паркинсона.
Показано,
что
при
симптоматической эпилепсии и болезни Паркинсона наблюдается повышение уровня
мРНК гена ACAP3 в лейкоцитах периферической крови по сравнению с контролем. Изучен
уровень мРНК гена CSTB при симптоматической эпилепсии и болезни Паркинсона и
показано, что при этих заболеваниях уровень мРНК CSTB значительно снижается по
сравнению с контролем. В модельных экспериментах обнаружено, что короткий аллель
минисателлита UPS29 обладает супрессорными свойствами в отношении экспрессии
репортерного гена EGFP в клеточной линии F9.
Сапронова Маргарита Рафаильевна. Эпидемиологическая и клинико-генетическая
характеристика болезни Паркинсона (на примере закрытого административнотерриториального образования Железногорск): автореферат дис. ... кандидата
медицинских наук: 14.01.11 / Сапронова Маргарита Рафаильевна;[Место защиты:
Красноярский государственный медицинский университет имени профессора В.Ф.ВойноЯсенецкого Министерства здравоохранения и социального развития Российской
Федерации].- Красноярск, 2014. - 124 с.
URL:
http://www.dslib.net/bolezni-nervov/jepidemiologicheskaja-i-kliniko-geneticheskaja-
harakteristika-bolezni-parkinsona.html (дата обращения: 17.04.2015.).
Цель
исследования
особенностей
болезни
–
изучение
Паркинсона
на
эпидемиологии
территории
и
клинико-генетических
закрытого
административно-
территориального образования Железногорск Красноярского края для совершенствования
лечебно-диагностической и медико-социальной помощи больным.
Результаты. Впервые в Красноярском крае (на примере ЗАТО Железногорск)
проведено
сплошное
эпидемиологическое
исследование
БП;
пациентам
с
БП,
проживающим на территории ЗАТО, проведено молекулярно-генетическое исследование
ОНП-маркеров гена LRRK2: rs7966550, rs1427263, rs11176013, rs11564148, тесно
сцепленных с локусом PARK8 на хромосоме 12q12, и уточнена их роль в этиологии БП на
исследуемой территории; создан банк ДНК пациентов с БП. Показано, что исследование
генетического маркера rs7966550, сцепленного с мутацией гена LRRK2 в локусе PARK8 на
хромосоме 12q12 (6055G>T), может применяться для прогнозирования болезни
Паркинсона у населения Закрытого административно-территориального образования
Железногорск.
Статьи
Анализ мутаций у пациентов с предполагаемой аутосомно-доминантной формой болезни
Паркинсона. Филатова Е.В., Алиева А.Х., Шадрина М.И., Шульская М.В., Федотова Е.Ю.,
Иллариошкин С.Н., Лимборская С.А., Сломинский П.А. // Молекулярная генетика,
микробиология и вирусология. 2014. № 1. С. 3-4.
Настоящая работа посвящена анализу мутаций, приводящих к развитию
моногенных форм БП, у пациентов с предполагаемой аутосомно-доминантной формой БП
с помощью множественной лигазной полимеразной реакции (МЛПР). Выявлены мутации
(G2019S в LRRK2, гетерозиготные делеции 2 и 3, 3 и 4 экзонов и гетерозиготная
дупликация экзонов 2-4 гена PARK2, делеция экзона 3 в гене PARK7 ), приводящие к
развитию БП, только у 7 (18,4%) человек из 70, что говорит о необходимости дальнейшего
поиска новых мутаций, например, с помощью методов экзомного секвенирования.
Исследование однонуклеотидного полиморфизма гена SNCA при болезни Паркинсона в
Северо-Западном регионе России. Эмануэль В.С., Емельянов А.К., Андоскин П.А. //
Клинико-лабораторный консилиум. 2014. № 2 (49). С. 45-49.
В результате
нескольких ассоциативных исследований (GWAS - Genome-Wide
Association Studies) для ряда Европейских популяций была обнаружена высоко
достоверная ассоциация однонуклеотидного полиморфизма (ОНП) в генах небольшого
пресинаптического белка альфа-синуклеина (rs356165, SNCA), а также белка дардарина
(rs1491942, LRRK2) с БП. С целью оценить ассоциации ОНП гена LRRK2 (rs1491942) с
риском Болезни Паркинсона в Северо-Западном регионе России, а также отработать
условия стабильной ПЦР для детекции ОНП гена SNCA (rs356165): 1) разработаны
методы детекции ОНП генов SNCA (rs356165) и LRRK2 (rs1491942) на основе ПЦР и
рестрикционного анализа; 2) для ОНП гена SNCA (rs356165) разработан оригинальный
метод на основе ПЦР и последующего рестрикционного анализа с искусственным
введением в последовательность праймера сайта рестрикции: отработаны температурный
режим оптимального отжига наиболее специфичной пары праймеров из трех и условия
проведения полимеразной цепной реакции; 3) для ОНП LRRK2 (rs1491942) отработаны
условия проведения полимеразной цепной реакции и рестрикционного анализа.
Статистически значимой ассоциации в распределении генотипов по исследуемому ОНП
гена LRRK2 (rs1491942) с БП не выявлено.
Исследование частоты встречаемости полиморфных аллельных вариантов гена LRRK2
(PARK8) у пациентов с болезнью Паркинсона. Сапронова М.Р., Шнайдер Н.А., Муравьева
А.В., Трикман О.П., Ломакин А.И., Касперович Н.А. // Вестник Новосибирского
государственного университета. Серия: Биология, клиническая медицина. 2014. Т. 12.
№ 1. С. 19-25.
Исследована частота встречаемости кандидатных маркеров (rs7966550, rs1427263,
rs11176013 и rs11564148) в группе пациентов с болезнью Паркинсона (БП) и здоровых
добровольцев (Железногорск, Россия). Детекцию однонуклеотидных полиморфизмов
осуществляли с использованием синтезированных праймеров методом ПЦР в режиме
реального времени. Установлена суммарная частота встречаемости диких и мутантных
полиморфных аллельных вариантов у пациентов с БП и в группе контроля, причем
значения оказались выше, чем у здоровых лиц. Сходная ситуация прослеживалась при
анализе частот встречаемости компаунд-гетерозиготы по исследованным аллельным
вариантам экзонов гена LRRK2 в группе пациентов с БП и у здоровых добровольцев.
Молекулярные основы болезни Паркинсона, обусловленной мутациями в гене LRRK2.
Пчелина С.Н., Емельянов А.К., Усенко Т.С. // Молекулярная биология. 2014. Т. 48. № 1. С. 3.
При семейных формах болезни Паркинсона наиболее часто обнаруживают мутации
в гене LRRK2, кодирующем протеинкиназу 2, обогащенную лейциновыми повторами,
однако механизм возникновения заболевания у носителей мутаций в этом гене не
установлен. Изучение сигнальных каскадов, регулируемых этой киназой, существенно
затрудняется отсутствием знаний о физиологических субстратах LRRK2. Наличие
основной мутации в гене LRRK2 – G2019S – значительно облегчает выявление больных с
LRRK2-ассоциированной формой болезни Паркинсона в различных популяциях. В обзоре
обсуждаются данные о влиянии мутаций в гене LRRK2 на формирование белковых
агрегатов, в частности агрегатов
-синуклеина, динамику цитоскелета, развитие
воспаления и индукцию апоптоза, полученные как в опытах in vitro, так и при
обследовании больных.
Роль D-аминокислот в патогенезе нейродегенеративных заболеваний и при нормальном
старении. Червяков А.В., Захарова М.Н., Пестов Н.Б. // Анналы клинической и
экспериментальной неврологии. 2014. Т. 8. № 2. С. 51-58.
Недавние исследования показали, что D-аминокислоты широко представлены в
тканях высших организмов, в том числе человека. Определены специфические функции
отдельных D-аминокислот в здоровом организме: так, D-серин играет важную роль в
нейропластичности, процессах памяти, обучения, а D-аспартат вовлечен в процессы
развития
и
эндокринные
функции.
Патогенность
D-аминокислот
связана
с
гиперактивацией NMDA-рецепторов глутамата, изменением конформации нормальных
белковых молекул при встраивании в полипептидную цепь, повышением концентрации
активных форм кислорода при оксидазном метаболизме D-аминокислот. Оценка уровня Dаминокислот в биологических жидкостях, а также определение активности ферментов их
метаболизма и мутаций кодирующих их генов могут служить диагностическим маркером
при некоторых заболеваниях ЦНС (болезнь Альцгеймера, болезнь Паркинсона, боковой
амиотрофическитй склероз и др.).
Эпидемиологическая и клинико-генетическая характеристика болезни Паркинсона (на
примере Железногорска). Сапронова М.Р., Шнайдер Н.А. // Неврология, нейропсихиатрия,
психосоматика. 2014. № 4. С. 59-64.
В статье представлены результаты 4-летнего эпидемиологического исследования
БП на территории г. Железногорска (Красноярский край). Цель - изучение эпидемиологии
и клинико-генетических особенностей БП. Пациенты и методы. Были сформированы три
группы наблюдения: первая группа - 135 пациентов с БП, из них 72,6% с ранее
диагностированной БП и 27,4% - с впервые выявленной БП, вторая группа - 44 пациента с
БП, принявших участие в молекулярно-генетическом исследовании (75% женщин и
25%мужчин), третья (контрольная) группа – 30 здоровых добровольцев (66,7% женщин и
33,3% мужчин). Группы наблюдения были сопоставимы по полу и возрасту (р>0,05).
Исследование
включало
ретроспективный
анализ
медицинской
документации,
проспективное клинико-эпидемиологическое исследование и когортное исследование
генетических
предикторов
БП.
Результаты
и
обсуждение.
Средневзвешенная
распространенность БП на территории Железногорска составила 124,2 на 100 тыс.
населения, заболеваемость - 13,8на 100 тыс. в 2013 г., смертность была минимальной - 0
случаев на 100 тыс. населения в 2010 и 2012 гг., 1,1 на 100 тыс. - в 2012 и 2012 гг.
Генетические маркеры rs1427263, rs11176013, rs11564148, сцепленные с мутацией гена
LRRK2 в локусе PARK8 на хромосоме 12q12 (6055G>T), не ассоциировались с развитием
БП среди жителей Железногорска. Частота встречаемости генетического маркера
rs7966550 (по гомозиготному генотипу С/С) в группе пациентов с БП была выше, чем в
группе здоровых добровольцев (44,5% против 16,5%). Особенностей в характере течения и
клинической картине БП с учетом однонуклеотидных полиморфизмов не выявлено.
2013
Диссертации
Баранова, Татьяна Сергеевна. Структурные изменения головного мозга при болезни
Паркинсона по данным морфометрии (клинико-нейровизуализационное исследование):
автореферат дис. ... кандидата медицинских наук: 14.01.11 / Баранова Татьяна
Сергеевна;[Место защиты: ФГБУ "Научный центр неврологии" РАМН].- Москва, 2013. –
115 c.
URL: http://www.dslib.net/bolezni-nervov/strukturnye-izmenenija-golovnogo-mozga-pri-bolezniparkinsona-po-dannym.html (дата обращения: 17.04.2015.).
Цель работы – анализ возможностей метода воксел-ориентированная морфометрия
(ВОМ) в оценке структурных изменений головного мозга при различных формах БП, а
также его роли в качестве биомаркера нейродегенеративного процесса на фоне
прогрессирования заболевания. Результаты. Показано, что ВОМ - новый информативный
метод
нейровизуализации,
количественной
оценки
который
объема
может
атрофических
применяться
изменений
для
качественной
головного
мозга
и
при
нейродегенеративном процессе у пациентов с БП. Основные изменения когнитивной
сферы при БП характеризуются признаками лобной дисфункции, с наиболее четко
выраженными
дизрегуляторными
и
зрительно-пространственными
нарушениями,
варьирующими в зависимости от ведущего двигательного фенотипа заболевания
(акинетико-ригидный, дрожательный, смешанный). Характерным МР-морфометрическим
паттерном при дрожательных фенотипах БП является увеличение объема таламуса, а при
акинетико-ригидной форме заболевания - увеличение объема поясной извилины.
Динамические изменения МР-морфометрического паттерна характеризуются диффузным
увеличением участков атрофического церебрального процесса, без четкой асимметрии
сторон, с преобладанием изменений в лобной и теменно-затылочной коре.
Милюхина,
Ирина
Валентиновна.
Провоспалительные
и
противовоспалительные
цитокины при различных формах болезни Паркинсона : автореферат дис. ... кандидата
медицинских наук : 14.01.11, 03.03.01 / Милюхина Ирина Валентиновна; [Место защиты:
С.-Петерб. гос. мед. ун-т им. И.П. Павлова].- Санкт-Петербург, 2013.- 22 с.: ил. РГБ ОД,
9 14-1/1244
URL: http://www.dslib.net/bolezni-nervov/protivospalitelnye-i-protivovospalitelnye-citokiny-prirazlichnyh-formah-bolezni.html (дата обращения: 17.04.2015.).
Целью исследования явилось изучение особенностей цитокинового статуса и
показателей окислительного стресса при различных формах и вариантах течения БП для
усовершенствования диагностики и оптимизации терапии. Результаты. Определён уровень
цитокинов (ИЛ-1β, ИЛ-1РА, ФНОα, ИЛ-6, ИЛ-10) в сыворотке крови и ликворе пациентов
с
БП,
уровень
антиоксидантных
ферментов
(супероксиддисмутазы
(СОД)
и
церулоплазмина (ЦП) в сыворотке крови пациентов с БП. Показано, что для разных
клинических форм и вариантов прогрессирования БП характерно различное содержание
про- и противовоспалительных медиаторов в крови и ликворе: при акинетико-ригидной
форме наблюдается снижение уровня ИЛ-10 в крови и повышение уровня ФНОα в
ликворе на всех стадиях заболевания по сравнению с дрожательной формой. Выявлено,
что для больных БП с ранним началом характерно снижение уровня церулоплазмина в
крови. Получены приоритетные данные об изменении содержания показателей
нейровоспаления, характерных для аффективных и когнитивных проявлений БП, их
взаимосвязи с обменом меди, уровнем супероксиддисмутазы и церулоплазмина.
Подтверждено, что уровень про- и противовоспалительных цитокинов в крови и ликворе
связан со стадией заболевания, выраженностью моторных и немоторных нарушений при
БП. Продемонстрировано дозозависимое влияние леводопотерапии на уровни ИЛ-6 и ИЛ10 в крови и ликворе.
Хаймов, Дмитрий Александрович. Возможности многовоксельной магнитно-резонансной
морфометрии в оценке атрофии структур головного мозга у пациентов с болезнью
Паркинсона: автореферат дис. ... кандидата медицинских наук: 14.01.13 / Хаймов
Дмитрий Александрович; [Место защиты: Военно-медицинская академия им. С.М.Кирова
- Федеральное государственное военное образовательное учреждение ВПО Минобороны
России].- Санкт-Петербург, 2013. – 148 с.
URL:
http://www.dslib.net/luch-diagnostika/vozmozhnosti-mnogovokselnoj-magnitno-
rezonansnoj-morfometrii-v-ocenke-atrofii.html (дата обращения: 17.04.2015.).
Цель исследования – улучшение диагностики атрофических изменений различных
структур головного мозга у больных болезнью Паркинсона на основе применения
многовоксельной
МР-морфометрии.
Результаты.
Разработана
новая
методика
многовоксельной МР-морфометрии головного мозга с использованием программы SPM
(Statistical Parametric Mapping), при помощи которой можно провести повоксельный
анализ единичных или множественных сканов, межгрупповой или внутригрупповой
анализ и получить точное представление о локализации и степени атрофии головного
мозга
у
больных
болезнью
Паркинсона.
Многовоксельная
МР-морфометрия
-
дополнительная методика лучевой диагностики для определения прогрессирования
заболевания у пациентов с болезнью Паркинсона. Методика обработки данных МР-
морофметрии позволяет количественно и качественно оценивать атрофические изменения
в головном мозге, что является значимым критерием в определении степени вовлечения
его структур в патологический процесс и возможном прогнозировании дальнейшего
течения заболевания.
Статьи
Ингибирование нейровоспаления редуцирует дегенерацию дофаминергических нейронов
черной субстанции мозга, индуцированную гиперэкспрессией в них рекомбинантного гена
альфа-синуклеина человека. Вежеева О.А., Сергеева Т.Н., Сергеев В.Г. // Медицинский
академический журнал. 2013. Т. 13. № 3. С. 71-77.
Исследовали влияние гиперэкспрессии альфа-синуклеина в дофаминергических
нейронах
на
интенсивность
нейродегенерации
и
провоспалительной
активации
микроглиальных клеток черной субстанции мозга в рамках гипотезы о сопряженности
процессов нейровоспаления и нейродегенерации. О вкладе нейровоспаления в процессы
нейродегенерации судили по результатам эксперимента с ежедневным однократным
введением кортикостерона в течение 8 недель крысам, которым предварительно в область
черной
субстанции
мозга
инъецировали
вектор,
сконструированный
на
основе
аденоассоциированного вируса, несущий ген альфа-синуклеина человека. Обнаружено,
что введение вектора драматически редуцирует количество дофаминергических нейронов
(-86,5±16,8%), в то же время дополнительные инъекции кортикостерона значительно
повышали количество выживающих дофаминергических нейронов (+35,7±12,4%).
Иммуногистохимическое исследование продемонстрировало как повышение экспрессии
глиальными клетками иммунопозитивных провоспалительных маркеров (МНС II, IL-1),
так и выраженность глиоза. Полученные данные свидетельствуют о нейродегенеративном
эффекте повышения уровня эндогенного альфа-синуклеина в черной субстанции мозга и
его провоспалительном действии на микроглию, активация которой, в свою очередь,
усиливает интенсивность нейродегенерации.
Исследование влияния полиморфизма гена COMT на характер клинического течения
болезни Паркинсона. Хидиятова И.М., Ахмадеева Г.Н., Гилязова И.Р., Насибуллин Т.Р.,
Туктарова И.А., Байтимеров А.Р., Демчук Н.Д., Магжанов Р.В., Хуснутдинова Э.К. //
Неврологический журнал. 2013. Т. 18. № 3. С. 22-27.
Катехол-орто-метилтрансфераза (COMT) — ключевой фермент элиминации
дофамина в префронтальной коре головного мозга. Активность фермента генетически
детерминирована полиморфизмом 1947G>A (Val108Met) гена
COMT. В работе
представлены результаты анализа ассоциации полиморфных вариантов данного локуса
гена COMT с развитием болезни Паркинсона и характером проявления ее клинических
признаков. Исследование проведено в группах больных и контроля — жителей
Республики Башкортостан, с учетом этнической принадлежности (русские, башкиры,
татары) обследуемых лиц. В этнической группе татар выявлена ассоциация полиморфных
вариантов гена COMT с БП, особенно с ее акинетико-ригидно-дрожательной формой, с
тяжелым течением заболевания, а также с поздним (старше 60 лет) началом болезни.
Маркерами риска развития БП у татар являются генотип *H/*H (1947*G/*G, 108Val/Val) и
аллель *H (1947*G), детерминирующие синтез фермента с высокой активностью,
предрасполагающие также к развитию когнитивных расстройств у больных. Аналогичная
тенденция прослеживается и для популяций башкир и русских, достигая статистической
значимости при выделении выборок больных с более тяжелым течением болезни.
Современные возможности идентификации латентной стадии нейродегенеративного
процесса. Иллариошкин С.Н., Власенко А.Г., Федотова Е.Ю. // Анналы клинической и
экспериментальной неврологии. 2013. Т. 7. № 2. С. 39-50.
В
статье
представлены
современные
технологии
пресимптоматической
диагностики двух наиболее распространенных нейродегенеративных заболеваний –
болезней Альцгеймера и Паркинсона. На основании собственных и литературных данных
показано, что ведущими в выявлении лиц, имеющих высокий риск развития указанных
заболеваний, являются методы нейровизуализации (идентификация бета-амилоида в
головном мозге, феномена гиперэхогенности черной субстанции и др.) в комбинации с
рядом нейрофизиологических и молекулярно-патобиохимических тестов. Валидация
предлагаемых биомаркеров и их интеграция в единые диагностические скрининговые
алгоритмы является на сегодня одним из наиболее актуальных разделов неврологии.
Современные представления о молекулах-маркерах при болезни Паркинсона. Малиновская
Н.А. // Неврологический вестник. Журнал им. В.М. Бехтерева. 2013. Т. XLV. № 3. С. 46-56.
Рассмотрены современные представления о патогенезе болезни Паркинсона с
участием различных молекул (дисфункции митохондрий, ферментов обменов веществ,
лизосом, эндосом и ЭПР, факторов иммунного ответа и нейровоспаления, окислительного
стресса, протеасомной деградации белков, шапероны, регуляторы физиологических и
патологических процессов, структурные и транспортные белки, сигнальные молекулы,
глиальные белки и белки синаптических везикул, нейротоксические белки, молекулы
нейрон-глиальных
коммуникаций),
которые
могут
являться
геномными
и/или
протеомными биомаркерами этого вида нейродегенерации.
2012
Диссертации
Пчелина, Софья Николаевна. Молекулярно-генетические основы наследственных форм
болезни Паркинсона : диссертация ... доктора биологических наук : 03.02.07 / Пчелина
Софья Николаевна; [Место защиты: Федеральное государственное образовательное
учреждение
высшего
профессионального
образования
Санкт-Петербургский
государственный университет].- Санкт-Петербург, 2012.- 240 с.: ил.
URL:
http://www.dslib.net/genetika/molekuljarno-geneticheskie-osnovy-nasledstvennyh-form-
bolezni-parkinsona.html (дата обращения: 17.04.2015.).
Целью работы явилось молекулярно-генетическое исследование наследственных
форм БП. Результаты. Данная работа, включившая молекулярно-генетический анализ
генов SNCA, PARK2, LRRK2, GBA у пациентов с БП, является первым комплексным
исследованием генетических основ наследственных форм БП в России. Показано, что
мутация G6055A (G2019S) в гене LRRK2 является наиболее распространенной причиной
развития наследственных форм БП в Северо-Западном регионе России. В группе
пациентов с БП, обусловленной мутацией G6055A (G2019S) в гене LRRK2, наблюдается
повышенная частота побочных эффектов при применении Л-ДОФА-содержащих
препаратов. Мутации гена GBA (L444P и N370S) играют важную роль в формировании
предрасположенности к развитию БП. Наличие мутации L444P повышает риск развития
БП в возрасте до 50 лет. Мутации в гене PARK2 не являются значимой причиной развития
БП с началом заболевания в возрасте от 40 до 50 лет. Наличие мутаций в гене LRRK2
ассоциировано со снижением уровня белка альфа-синуклеина, повышением уровня мРНК
гена FAS и усилением спонтанного апоптоза в лимфоцитах периферической крови у
пациентов с БП.
Усенко, Татьяна Сергеевна. Апоптоз лимфоцитов периферической крови у пациентов с
болезнью Паркинсона, ассоциированной с мутациями в генах LRRK2 и GBA: автореферат
дис. ... кандидата биологических наук: 03.03.04 / Усенко Татьяна Сергеевна;[Место
защиты: Института цитологии РАН].- Санкт-Петербург, 2012.- 21 с.
URL:
http://www.dslib.net/citologia/apoptoz-limfocitov-perifericheskoj-krovi-u-pacientov-s-
boleznju-parkinsona.html (дата обращения: 17.04.2015.).
Целью данной работы явились исследования влияния мутаций в генах LRRK2 и
GBA у пациентов с БП на апоптоз лимфоцитов периферической крови. Результаты.
Выявлено повышение спонтанного апоптоза лимфоцитов периферической крови у
пациентов с БП, обусловленной мутациями в генах LRRK2 и GBA. Показано увеличение
экспрессии гена FAS в лимфоцитах периферической крови у пациентов с LRRK2ассоциированной БП по сравнению с группой пациентов со спорадической БП и
контролем. Исследована активация каспазы 8 и каспазы 9 в лимфоцитах периферической
крови у пациентов с LRftO-ассоциированной БП. Показана преимущественная активация
каспазы 9 лимфоцитов периферической крови при спонтанном апоптозе у пациентов с
LRRK2-ассоциированной БП по сравнению с контролем.
Статьи
Анализ однонуклеотидного полиморфизма rs12720208 в гене FGF20 у больных
спорадической формой болезни Паркинсона, проживающих в России. Устинова В.В.,
Шадрина М.И., Федотова Е.Ю., Иллариошкин С.Н., Лимборская С.А., Сломинский П.А. //
Генетика. 2012. Т. 48. № 12. С. 1437.
Для однонуклеотидного полиморфизма rs12720208 в гене FGF20 была выявлена
ассоциация с риском развития БП и установлено, что он расположен в сайте связывания 3ОНП и микроРНК-433, участвующей в регуляции экспрессии гена FGF20. В связи с этим
нами был проведен анализ распределения частот генотипов rs12720208 в гене FGF20 в
выборке больных спорадической формой БП и популяционной выборке из России.
Результаты анализа показали, что rs12720208 в гене FGF20 не влияет на риск развития БП
у пациентов из России (OR = 0.95, доверительный интервал (95% ДИ) 0.55 – 1.63, p = 0.9).
Апоптоз лимфоцитов периферической крови у пациентов с LRRK2-ассоциированной
формой болезни Паркинсона. Усенко Т.С., Емельянов А.К., Якимовский А.Ф., Боганькова
Н.А., Вавилова Т.В., Шварцман А.Л., Пчелина С.Н. // Цитология. 2012. Т. 54. № 1. С. 44-48.
У пациентов c LRRK2-ассоциированной БП по сравнению с контрольной группой
мы наблюдали методом проточной цитометрии повышенный уровень спонтанного
апоптоза лимфоцитов периферической крови в культуре через 24 (P < 0.016) и 48 (P <
0.031) ч. Кроме того, у пациентов с LRRK2-ассоциированной БП выявлено увеличение
уровня мРНК гена FAS по сравнению как с контрольной группой (P < 0.05), так и с
группой пациентов со спорадической БП (P < 0.002). Достоверные различия в уровне
экспрессии гена FAS сохранялись спустя 3 года (P < 0.03) и наблюдались также через 24 ч
(P < 0.05) культивирования лимфоцитов у пациентов с LRRK2-ассоциированной БП по
сравнению с контрольной группой. Повышенный уровень апоптоза лимфоцитов
периферической крови у пациентов наряду с увеличением уровня мРНК FAS дает
основание сделать предположение о предпочтительной активации внешнего пути апоптоза
при наличии мутации в гене LRRK2.
Метод «дозы гена» на основе количественной ПЦР в реальном времени для выявления
делеций/мультипликаций экзонов гена PARK2 и гена SNCA у пациентов с болезнью
Паркинсона. Пчелина С.Н., Емельянов А.К., Дроздова А.С., Якимовский А.Ф., Шварцман
А.Л. // Ученые записки СПбГМУ им. акад. И.П. Павлова. 2012. Т. XIX. № 1. С. 82-86.
С использованием разработанного метода оценки дозы отдельных экзонов гена
PARK2 и гена SNCA на основе количественной ПЦР в реальном времени с зондами
TaqMan проведен анализ мутаций, связанных с изменением копийности в генах PARK2 и
SNCA у пациентов с болезнью Паркинсона (БП). Делеции отдельных экзонов гена PARK2
выявлены в 5,7 % пациентов с БП (4/70), преимущественно в гетерозиготном состоянии,
что затрудняет интерпретацию их клинической значимости. Впервые в России описан
случай
аутосомно-доминантной
БП,
обусловленной
дупликацией
гена
SNCA.
Разработанный нами метод выявления мутаций с изменением копийности в генах PARK2
и SNCA может быть использован для массового скрининга данных мутаций среди
пациентов с БП.
Микро-РНК: возможная роль в патогенезе болезни Паркинсона. Обзор. Филатова Е.В.,
Алиева А.Х., Шадрина М.И., Сломинский П.А. // Биохимия. 2012. Т. 77. № 8. С. 981-988.
В настоящее время одним из наиболее интересных и активно развивающихся
направлений в области молекулярной биологии является изучение роли микро-РНК в
норме и при патологии. Микро-РНК регулируют экспрессию различных генов, а также
могут быть вовлечены в патогенез различных заболеваний. В настоящем обзоре
рассмотрены возможная роль микро РНК в патогенезе болезни Паркинсона.
2011
Диссертации
Емельянов, Антон Константинович. Экспрессия гена SNCA и уровень белка альфасинуклеина в лимфоцитах периферической крови при болезни Паркинсона, обусловленной
мутациями гена LRRK2 : диссертация ... кандидата биологических наук : 03.02.07 /
Емельянов Антон Константинович; [Место защиты: С.-Петерб. гос. ун-т].- СанктПетербург, 2011.- 123 с.: ил. РГБ ОД, 61 12-3/71.
URL:
http://www.dslib.net/genetika/jekspressija-gena-snca-i-uroven-belka-alfa-sinukleina-v-
limfocitah-perifericheskoj.html (дата обращения: 17.04.2015.).
Целью работы явилось исследование уровня белка альфа-синуклеина и мРНК гена
SNCA в лимфоцитах периферической крови у пациентов с БП. Результаты. Показано
снижение уровня белка альфа-синуклеина лимфоцитов периферической крови у
пациентов с семейной формой БП по сравнению с группой пациентов со спорадической
БП и контролем. Частота мутации G6055A (G2019S) гена LRRK2 выше среди пациентов с
семейной формой БП (7 %), чем среди пациентов со спорадической формой заболевания
(0,4 %). Частота мутации С4321Т (R1441C) среди спорадических случаев БП в северозападном регионе России составляет 0,4 %. Уровень белка альфа-синуклеина лимфоцитов
периферической крови снижен в группе пациентов с семейной БП по сравнению с
пациентами со спорадической БП и лицами с отсутствием неврологических заболеваний.
Пациенты с ранней формой БП (начало до 50 лет) характеризуются высоким уровнем
белка альфа-синуклеина по сравнению с пациентами с более поздним дебютом
заболевания. У лиц с отсутствием неврологических заболеваний наблюдается увеличение
уровня мРНК гена SNCA с возрастом.
Филатова, Елена Владиславовна. Поиск генетических и экспрессионных маркеров риска
развития болезни Паркинсона в российской популяции : диссертация ... кандидата
биологических наук : 03.01.03 / Филатова Елена Владиславовна; [Место защиты: Гос.
науч.-исслед. ин-т генетики и селекции промышленных микроорганизмов].- Москва, 2011.155 с.: ил. РГБ ОД, 61 11-3/798.
URL:
http://www.dslib.net/virusologia/poisk-geneticheskih-i-jekspressionnyh-markerov-riska-
razvitija-bolezni-parkinsona-v.html (дата обращения: 17.04.2015.).
Целью настоящей работы являлись поиск и анализ генетических и экспрессионных
маркеров риска развития болезни Паркинсона в российской популяции. Результаты. При
анализе 68 известных точковых мутаций в генах моногенных форм БП было выявлено
только три известных точковых мутаций (MIL, A82G и C253Y) в гетерозиготном
состоянии в гене PARK2 у трёх различных пациентов со спорадической формой БП с
ранним началом развития, что свидетельствует о малом вкладе известных мутаций в
патогенез спорадической формы БП в России. Была показана ассоциация полиморфизма
rs2736990 (С/Т) в гене SNCA с риском развития спорадической формы болезни
Паркинсона в российской популяции. Показано, что носительство аллеля С в ОНП
rs2736990 в гене SNCA повышает риск развития болезни Паркинсона в 1,70 раза.
Проведён анализ относительных уровней экспрессии генов GSK3B, SLC6A3, МАРТ,
PARK2, SNCA, ST13, вовлечённых в патогенез БП, в периферической крови у пациентов,
находящихся на ранних стадиях развития БП. Было показано, что уровень мРНК генов
SLC6A3, МАРТ, PARK2 крайне низок - это усложняет их использование для анализа
транскриптома при БП в периферической крови. Обнаружено, что уровни мРНК генов
GSK3B и ST13 в периферической крови пациентов с болезнью Паркинсона на ранних
стадиях не отличаются от таковых у здоровых добровольцев. Было выявлено значительное
увеличение уровня мРНК гена SNCA в периферической крови у пациентов с болезнью
Паркинсона на ранних стадиях заболевания более чем в 5 раз, у больных церебральным
атеросклерозом более чем в 2 раза и у пациентов с различными неврологическими
заболеваниями в 3 раза.
Шадрина, Мария Игоревна. Молекулярно-генетические основы болезни Паркинсона :
диссертация ... доктора биологических наук : 03.01.07 / Шадрина Мария Игоревна;
[Место защиты: Ин-т биологии гена РАН].- Москва, 2011.- 288 с.: ил. РГБ ОД, 71 12-3/60.
URL:
http://www.dslib.net/virusologia/molekuljarno-geneticheskie-osnovy-bolezni-
parkinsona.html (дата обращения: 17.04.2015.).
Целью данной работы было изучение роли генетических факторов в патогенезе
спорадической
формы
болезни
Паркинсона
и
выявление
новых
геномных
и
транскриптомных маркеров данного заболевания.
Результаты. При проведении анализа мутаций с изменением копийности в генах
PARK2 и SNCA было показано, что делеции и дупликации экзонов гена PARK2 вносят
существенный вклад в развитие спорадической формы болезни Паркинсона в российской
популяции. Обнаружено, что у людей, имеющих делеции и дупликации, риск развития
заболевания повышен в 8,53 раза (95%ДИ=1,14-63,52; p=0,0095). Вероятность развития
спорадической формы болезни Паркинсона в раннем возрасте у людей, имеющих мутации
с изменением копийности экзонов гена PARK2, повышена в 13,95 раза (95%ДИ=1,85105,96; р=0,0004). Получено подтверждение гипотезы о том, что данный тип мутаций в
гене PARK2 в гетерозиготном состоянии влияют на риск развития заболевания.
Установлено, ген PARK2 отвечает за часть фенотипической вариабельности болезни
Паркинсона в российской популяции. Показано, что наличие делеций и/или дупликаций
экзонов в гене PARK2 способствует существенному снижению возраста клинического
дебюта болезни Паркинсона (на 9 лет), развитию дистонии и симметричному протеканию
заболевания. Обнаружено, что ген POMC вовлечен в патогенез болезни Паркинсона.
Показано, что наличие аллеля Т по полиморфизмам rs28930368 и rs2071345 гена POMC
повышает риск развития заболевания в 5,01 раза (95%ДИ= 1,05-23,83; p =0,03) и приводит
к развитию клинического фенотипа с преобладанием мышечной ригидности. Показано,
что ген WFS1 вовлечен в патогенез болезни Паркинсона. Обнаружено, что наличие аллеля
Т по полиморфизму rs1801211 гена WFS1 повышает риск развития заболевания в 2,34 раза
(95%ДИ=1,29-4,24; р=0,005). Выявлена ассоциация полиморфизма rs2736990 (C/T) в гене
SNCA с риском развития спорадической формы болезни Паркинсона для российской
популяции. Показано, что носительство аллеля С по данному полиморфизму повышает
риск развития болезни Паркинсона в 1,75 раза (95%ДИ= 1,19-2,58; p=0,004). Проведено
изучение
относительных
уровней
экспрессии
генов
GSK3B,
SNCA,
ST13
в
периферической крови больных на ранних стадиях развития болезни Паркинсона и
показано, что изменение уровня мРНК каждого гена в отдельности не является
специфичным для этого заболевания.
Статьи
Анализ однонуклеотидного полиморфизма rs415430 в гене WNT3 в российской популяции
при болезни Паркинсона. Филатова Е.В., Шадрина М.И., Федотова Е.Ю., Сломинский
П.А., Иллариошкин С.Н., Иванова-Смоленская И.А., Лимборская С.А. // Молекулярная
генетика, микробиология и вирусология. 2011. № 2. С. 3-4.
Проанализировано распределение частоты генотипов ОНП rs415430 в гене WNT3
между выборкой пациентов со спорадической формой БП и популяционным контролем
(OR 0,84 при доверительном интервале (95% CI) 0,58-1,23 и достоверности р = 0,39).
Сделан вывод о том, что ОНП rs415430 в гене WNT3 не влияет на риск развития БП в
российской популяции
Влияние генотипов и активности параоксоназы 1 (PON1) на возраст начала LRRK2ассоциированной болезни Паркинсона. Пчелина С.Н., Дроздова А.С., Мирошникова В.И.,
Родыгина Т.И., Емельянов А.К., Якимовский А.Ф., Шварцман А.Л. // Ученые записки
СПбГМУ им. акад. И.П. Павлова. 2011. Т. XVIII. № 3. С. 31-34.
В настоящем исследовании авторы оценили влияние генотипов и активности
параоксоназы 1 (PON1) на возраст начала заболевания у 13 пациентов с БП,
обусловленной мутациями в гене LRRK2 (8 с мутацией G2019S, 2 - V1613A и 1- R1441C).
Отсутствие ассоциации генотипов или активности PON 1 с возрастом начала LRRK2ассоциированной БП предполагает участие множественных факторов, модифицирующих
течение заболевания, не обязательно связанных с PON1, и указывает на необходимость
продолжения
исследований
на
расширенной
выборке
пациентов
с
LRRK2-
ассоциированной БП.
Исследование влияния полиморфных вариантов гена DRD4 на развитие и течение болезни
Паркинсона. Ахмадеева Г.Н., Хидиятова И.М., Садыкова А.З., Гилязова И.Р., Байтимеров
А.Р., Магжанов Р.В., Хуснутдинова Э.К. // Известия Самарского научного центра
Российской академии наук. 2011. Т. 13. № 5-3. С. 228.
Представлено исследование влияния полиморфных вариантов гена DRD4 (120 bp
VNTR в 5’-UTR, 48 bp VNTR в экзоне 3, -616C/G) на развитие и течение болезни
Паркинсона. Установлены полиморфные варианты гена, являющиеся маркерами риска
(аллель *7 48bp-VNTR в 3-м экзоне) и протективными маркерами (аллель*2 48bp-VNTR в
3-м экзоне) в отношении развития БП для жителей Республики Башкортостан. Выявлено
модифицирующее влияние определенных генотипов и аллелей данного гена на характер
клинического течения заболевания.
Клиническое течение LRRK2-ассоциированной болезни Паркинсона. Пчелина С.Н.,
Иванова О.Н., Емельянов А.К., Якимовский А.Ф. // Журнал неврологии и психиатрии им.
C.C. Корсакова. 2011. Т. 111. № 12. С. 56-62.
Мутации в гене обогащенной лейциновыми повторами киназы 2 (LRRK2) являются
наиболее
распространенной
причиной
развития
наследственных
форм
болезни
Паркинсона (БП). Проведенное авторами ранее секвенирование кодирующей области гена
LRRK2 среди 85 пациентов с БП позволило выявить в России превалирование БП,
ассоциированной с мутацией G2019S (G2019S-БП) среди всех случаев заболевания,
обусловленных мутациями в гене LRRK2. Cкрининг распространенных мутаций LRRK2
(G2019S, R1441C, R1441G) на расширенной выборке пациентов (100 пробандов с
семейной формой БП, 14 родственников пробандов и 230 пациентов со спорадической БП)
в дополнение к ранее описанным случаям LRRK2-ассоциированной БП позволил выявить
2 новых семейных случая с G2019S-БП. Суммарно частота LRRK2-ассоциированной
формы БП среди семейных форм БП составила 8%. Наиболее распространенной являлась
мутация G2019S (7% среди семейной БП и 0,5% среди спорадической БП). При
сопоставлении возраста начала болезни и встречаемости основных неврологических
симптомов у 13 пациентов с различными мутациями в гене LRRK2 (10 с мутацией
G2019S, 2 - V1613A и 1 - R1441C) и 80 пациентов с БП, не имеющих мутаций в гене
LRRK2, различий между группами не выявлено. Однако показано, что у пациентов с
мутацией G2019S наблюдалась повышенная частота осложнений при приеме препаратов
L-ДОФА по сравнению с пациентами с БП иной этиологии (OR=6,4, p<0,02). Полученные
данные могут быть полезны как для понимания патогенеза LRRK2-ассоциированной БП,
так и для оптимизации фармакотерапии заболевания.
Молекулярно-генетические и некоторые биохимические аспекты болезни Паркинсона.
Маджидова Е.Н., Халимова Х.М., Раимова М.М., Матмурадов Р.Ж., Фахаргалиева С.Р.,
Жмырко Е.В. // Международный неврологический журнал. 2011. № 1. С. 91-94.
Проведен молекулярно-генетический анализ на наличие ассоциаций с болезнью
Паркинсона (БП) полиморфизмов генов GSTM1 (нулевая аллель), GSTT1 (нулевая аллель)
у
представителей
узбекской
национальности
и
определение
содержания
нейронспецифической енолазы (НСЕ) в сыворотке крови больных болезнью Паркинсона.
Всего исследовано 190 образцов ДНК, в том числе 140 образцов ДНК больных БП и 50
образцов ДНК здоровых лиц из группы контроля. Биохимическое исследование проведено
у 35 пациентов с длительностью заболевания от 1 года до 15 лет. Анализ полиморфизма
генов GSTT1 и GSTM1 выявил значительную гетерогенность по частотам нулевых и
ненулевых генотипов у больных БП и здоровых лиц: у больных доля нуль-генотипов гена
GSTT1 на 52 % выше, и по гену GSTM1 на 45,1 % выше, чем у здоровых лиц.
Повышенный уровень НСЕ отмечался в 69 % случаев БП, чаще у больных со смешанной и
акинетико-ригидной формой заболевания.
Мутации в гене GBA при болезни Паркинсона. Абрамычева Н.Ю., Федотова Е.Ю.,
Багыева Г.Х., Клюшников С.А., Иванова-Смоленская И.А., Иллариошкин С.Н. //
Медицинская генетика. 2011. Т. 10. № 5 (107). С. 22-27.
В российской выборке случаев спорадической БП (200 больных в возрасте от 21 до
70 лет, средний возраст 50,7±14,4 года) изучена частота пяти мажорных мутаций в гене
GBA - 84insGG, K198T, R329C, N370S и L444P. Выявлены 8 не связанных родством
пациентов, являющихся гетерозиготными носителями мутации N370F (3 случая) либо
L444P (5 случаев), тогда как в контрольной выборке здоровых лиц (n=200) исследованных
мутаций не обнаружено. Суммарная частота носительства мутаций в гене GBA у
российских больных со спорадической БП составила 4,0% (различие с контролем
статистически значимо, р=0,049, OR=17,71, 95% CI 1,02-308,89).
2010
Диссертации
Семенова, Елена Владимировна. Мутации с изменением копийности в генах PARK2 и
SNCA при болезни Паркинсона в России : диссертация ... кандидата биологических наук :
03.01.03 / Семенова Елена Владимировна; [Место защиты: Гос. науч.-исслед. ин-т
генетики и селекции промышленных микроорганизмов].- Москва, 2010.- 140 с.: ил. РГБ
ОД, 61 10-3/1256.
URL:
http://www.dslib.net/virusologia/mutacii-s-izmeneniem-kopijnosti-v-genah-park2-i-snca-
pri-bolezni-parkinsona-v.html/ (дата обращения: 17.04.2015.).
Целью настоящей работы являлось оценить вклад делеций и дупликаций экзонов
гена PARK2 и мультипликаций гена SNCA в развитие болезни Паркинсона (БП) у
пациентов из России.
Результаты. Разработан быстрый и эффективный метод выявления делеций и
дупликаций экзонов 1-12 в гене PARK2 и мультипликаций гена SNCA на основе ПЦР в
реальном времени технологии TaqMan. Проведен анализ спорадических больных с ранним
началом развития заболевания (<45 лет) из России на наличие экзонных перестроек в гене
PARK2. Установлено, что частота больных с экзонными перестройками в гене PARK2
составляет 12,4%, и показано, что наиболее подвержены экзонным перестройкам экзоны 3
и 4. Обнаружено, что относительный риск развития БП у лиц в молодом возрасте при
наличии делеций или дупликаций в гене PARK2 повышен в 12,4 раза. Получено
подтверждение гипотезы о том, что мутации в гетерозиготном состоянии в гене RARK2
влияют на риск развития заболевания. Проведен анализ представительной выборки
спорадических больных с поздним началом развития заболевания (>45 лет) из России на
наличие экзонных перестроек в гене PARK2. Установлено, что частота больных с
экзонными перестройками в гене PARK2 составляет 3,8%. Установлено, что наличие
экзонных перестроек способствует существенному снижению возраста начала БП (на 9
лет), развитию дистония и симметричному протеканию заболевания и не влияет на
скорость и тяжесть протекания болезни. Проведен анализ больных с семейной формой БП
с аутосомно-доминантным типом наследования на наличие дупликаций и трипликаций
гена SNCA. В результате анализа было показано, что мультипликации гена SNCA не вносят
существенного вклада в патогенез БП у больных из России.
Статьи
Внутриинтронный мини-сателлит человека UPS29, ассоциированный с неврологическими
заболеваниями, регулирует экспрессию репортерного гена EGFP в зависимости от
клеточного типа. Сасина Л.К., Сломинская Н.А., Сучкова И.О., Пицик Е.В., Соловьев К.В.,
Грудинина Н.А., Клинская Т.А., Паткин Е.Л. // Цитология. 2010. Т. 52. № 9. С. 715.
Ранее было установлено, что полиморфизм внутриинтронного мини-сателлита
человека UPS29 гена центаурина бета 5 (CENTB 5) ассоциирован с болезнью Паркинсона
и эпилепсией. Механизм такой связи неясен. В данной работе в модельных экспериментах
по временной трансфекции клеточных культур HeLa, эмбриональной карциномы мыши
линии F9 и астроцитов крысы было изучено, обладает ли данный мини-сателлит
регуляторными свойствами по отношению к эукариотическому промотору ROSA26
репортерного гена EGFP в зависимости от клеточного типа. Оказалось, что UPS29
обладает энхансерными свойствами в клетках нейронального типа.
Сниженный уровень альфа-синуклеина в лейкоцитах периферической крови у пациентов с
LRRK2-ассоциированной болезнью Паркинсона. Пчелина С.Н., Емельянов А.К., Якимовский
А.Ф., Миллер Д.В., Шабалина И.Г., Дроздова А.С., Шварцман А.Л. // Бюллетень
экспериментальной биологии и медицины. 2010. Т. 150. № 12. С. 619-621.
Определение уровня a-синуклеина в периферической крови неоднократно
предлагалось в качестве диагностического теста болезни Паркинсона. Тем не менее
результаты исследований остаются крайне противоречивыми. Авторы предполагают, что
эти противоречия связаны в первую очередь с присутствием в изучаемых выборках
пациентов с различной этиологией болезни Паркинсона. Для доказательства этого
предположения авторы исследовали уровень a-синуклеина в лимфоцитах периферической
крови в гомогенной по этиологии выборке пациентов с болезнью Паркинсона,
обусловленной мутациями в гене лейцинбогатой киназы 2 (LRRK2). Средний уровень aсинуклеина был достоверно снижен в группе пациентов с LRRK2-ассоциированной
болезнью Паркинсона (N=8) по сравнению с наблюдаемым у пациентов со спорадической
формой заболевания (N=33; p<0.02) и в контрольной группе (N=18; p<0.05). С другой
стороны, не было найдено отличий в уровне a-синуклеина в группе пациентов со
спорадической формой заболевания и в контроле. Предполагается, что уровень aсинуклеина в периферической крови в значительной мере зависит от этиологии
заболевания и не может быть использован как универсальный диагностический тест
болезни Паркинсона.
ПУБЛИКАЦИИ В ЗАРУБЕЖНЫХ НАУЧНО-МЕДИЦИНСКИХ ИЗДАНИЯХ
С помощью модальности композиционного поиска PubMed «Advanced Search»
найдено множество публикаций, принадлежащих логическому пересечению множеств
публикаций, относящихся к рубрикам MeSH-терминов Parkinson's disease и Biomarker.
Таким образом, выявлено 1108 публикаций, выполненных в 2010–2015 гг., из них
395 свободно доступных полнотекстовых (в том числе 67 обзоров). Для аннотированного
каталога нами отобраны 27 наиболее релевантных полнотекстовых статей.
2015
Biomarkers of Parkinson’s disease: Present and future / Miller D.B., O’Callaghan J.P. //
Metabolism, 2015. Vol. 64, No 3. P. 40-46.
URL: http://www.ncbi.nlm.nih.gov/pubmed/25510818.
The Parkinson’s Progression Markers Initiative (PPMI) (http://ppmi-ifo.org/), which
involves 20 centers in the USA and Europe, aims to combat this problem by enrolling equal
numbers of early stage (before medication) PD patients and matched controls. All involved
centers will adhere to standardized techniques for repeated biosampling (blood, CSF, urine),
clinical assessments and imaging. Strict standards for sample archiving, storage and analysis also
are part of the initiative. NINDS has followed suit with its Parkinson’s Disease Biomarkers
Program emphasizing cooperation and collaboration between consortium members, a sample
repository and a Data Management Resource. Genetic, functional, fluid and tissue, as well as
imaging biomarkers will be discussed. Finally, we will examine the conceptual and
methodological barriers to the development of useful PD biomarkers and how newer discovery
approaches may move the field forward.
Molecular neuropathology of PD. These investigational studies have focused on the
pathological hallmarks of PD, namely (1) the degeneration and death of the melanin containing
neurons of the SN, and (2) Lewy pathology — the presence of intra-cytoplasmic Lewy bodies
with inclusions containing mainly α-synuclein and ubiquitin. Neuronal projections, called Lewy
neurites, containing similar inclusions also are present.
Genetic biomarkers. These efforts have focused attention on mitochondrial dysfunction
and mutations in mitochondrial genes (e.g., SNCA) and gene products (α-synuclein). Many of
the gene products of the mutated genes in the autosomal dominant forms have been linked to
oxidative stress, mitochondrial dysfunction and mishandling of impaired or aberrant forms of the
gene products (e.g, oligometric α-synuclein). Further, these proteins because of their intimate
association with disease pathophysiology (e.g., α-synuclein) have been identified as candidate
biomarkers for PD.
Fluid and tissue biomarkers of PD — α-synuclein as an example. Although a variety of
candidates related to aspects of PD pathology have been evaluated for their suitability as fluid
biomarkers (e.g., neurofilaments, neurotransmitters, urate, DJ-1), to date α-synuclein is probably
one of the most investigated.
Imaging and other functional biomarkers of PD. Neuroimaging using single-photon
emission tomography (SPECT), positron emission tomography (PET), magnetic resonance
imaging (MRI) and transcranial sonography (TCS) can provide important information on brain
structure and function in PD and serve as an adjunct to clinical assessment. As these approaches
are non-invasive they can repeatedly assess the integrity of the DA system and provide
anatomical profiles (e.g., asymmetry of uptake, etc), as well as information about the time frame
of neuron loss. In some instances they are correlated with disease severity. All, with the
exception of TCS, are expensive, limiting their usefulness in standard diagnostic situations. MRI,
functional MRI, SPECT, PET as well as transcranial sonography all have been used in efforts to
differentiate PD from other movement disorders and can facilitate diagnostic accuracy.
Transcranial sonography can detect an echo of greater density in midbrain with good accuracy in
PD patients in both hospital-based and community settings. Voxel-based morphometry
techniques can reveal structural similarities and volume differences that aid in differentiating
between PD and other motor disorders in the early stages of the diseases where misdiagnosis is
more prevalent.
Functional/behavioral indices. Early non-motor symptoms of PD are believed to reflect
degeneration in extra-nigral areas before the loss of DA nigral neurons and include disturbances
in olfaction, sleep, visuospatial abilities, cognition including diminished executive function as
well as changes in behavior. Functional tests aimed at these symptoms may indicate PD risk, are
non-invasive and may be cost effective, are usually easy to administer and include some
evaluations which can be done at home and/or on-line by participants themselves. These include
olfaction acuity tests (e.g., the University of Pennsylvania Smell Identification Test — the
UPSIT), the REM sleep behavior disorder screening questionnaire, a keyboard tapping test, the
bradykinesia akinesia incoordination test (BRAIN), and accelerometer based exams.
The future — new approaches in disease biomarker discovery. Newer approaches
espouse casting a broader net and utilizing more global non-targeted strategies, such as omics
(e.g., genomics, proteomics, metabolomics, etc.), for identifying multiple biomarkers in tissue
from healthy and diseased individuals. For example, a metabolomics evaluation of plasma
generated a set of metabolites (i.e., a signature) able to differentiate PD patients from controls
irrespective of medication status.
Cerebrospinal fluid peptides as potential Parkinson disease biomarkers: a staged pipeline for
discovery and validation / Shi M. et al. // Mol Cell Proteomics. 2015. Vol. 14, No 3. P. 544–555.
URL: http://www.ncbi.nlm.nih.gov/pubmed/25556233.1
Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent
technical limitations associated with imaging or antibody-based protein assays. To circumvent
the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling
followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human
cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter
study consisting of training and validation sets, a total of 178 subjects were randomly selected
from a retrospective cohort, matching age and sex between PD patients, healthy controls, and
neurological controls with Alzheimer disease (AD). From ∼14,000 unique peptides displaying
differences between PD and healthy control in proteomic investigations, 126 peptides were
selected based on relevance and observability in CSF using bioinformatic analysis and MS
screening, and then quantified by highly accurate and sensitive selected reaction monitoring
(SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by
diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most
promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD
patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1,
LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of
0.873 (sensitivity = 76.7%, specificity = 80.0%) for PD versus healthy controls in the training
set. The performance was essentially confirmed in the validation set (AUC = 0.853, sensitivity =
82.5%, specificity = 82.5%). Additionally, this panel could also differentiate the PD and AD
groups (AUC = 0.990, sensitivity = 95.0%, specificity = 97.4%). Furthermore, a combination of
two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease
severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the
training (r = 0.381, p = 0.038)j and the validation (r = 0.339, p = 0.032) sets. The novel panel of
CSF peptides, if validated in independent cohorts, could be used to assist in clinical diagnosis of
PD and has the potential to help monitoring or predicting disease progression.
CSF biomarkers and clinical progression of Parkinson disease / Hall S. et al. // Neurology. 2015.
Vol. 84, No 1. P. 57–63. URL: http://www.ncbi.nlm.nih.gov/pubmed/25411441.1
To investigate whether certain CSF biomarkers at baseline can predict future progression
of motor symptoms and cognitive decline in patients with Parkinson disease (PD).
Patients and controls were recruited from hospitals in southern Sweden as part of the prospective
and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD
and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF
samples were analyzed for α-synuclein (αSyn), β-amyloid 1-42 (Aβ42), tau, phosphorylated tau,
and neurofilament light. Associations between CSF markers at baseline and change in clinical
characteristics after 2 years of follow-up were investigated using multivariate models adjusting
for age, sex, disease duration, and levodopa-equivalent daily dose.
Higher levels of αSyn within the PD group were associated with progression of motor
symptoms and cognitive decline over 2 years, indicated by significant relationships between
αSyn and change in Hoehn and Yahr (β = 0.394, p = 0.043), Unified Parkinson's Disease Rating
Scale, Part III (UPDRS-III) (β = 0.449, p = 0.013), Timed Up and Go (β = 0.406, p = 0.023), and
A Quick Test of Cognitive Speed (β = 0.423, p = 0.018). Lower levels of Aβ42 were associated
with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high
levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, β
= 0.350, p = 0.045; Hoehn and Yahr, β = 0.366, p = 0.038).
Found evidence of a link between higher levels of αSyn at baseline and worsening of
motor symptoms and cognitive speed over 2 years in PD. Increased αSyn might be a marker of
more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology
(low CSF Aβ42) is associated with memory decline.
MS-based methods for biomarkers of Parkinson's disease: what is the future? / Barkovits K.,
Helling S., Marcus K. // Bioanalysis. 2015. Vol. 7, No 2. P. 149–151. URL:
http://www.future-science.com/doi/full/10.4155/bio.14.273
Potential biomarkers, such as DJ-1, NFL, total Tau, Aβ42, urate and others, were
identified in numerous studies. However, owing to the low sensitivity, selectivity or
reproducibility, they are of limited benefit for PD. The most promising candidate for PD is alphasynuclein (ASyn), since disease progression is closely linked to the dysfunction of the
presynaptic protein ASyn.
Lymphocyte vitamin C levels as potential biomarker for progression of Parkinson's disease /
Kazuki I. et al. // Nutrition. 2015. Vol. 31, No 2. P. 406–408.
The aim of this study was to investigate the association between lymphocyte and plasma
vitamin C levels in various stages of Parkinson’s disease (PD).
Methods: Fasting blood samples were collected, and plasma and lymphocyte vitamin C
levels were measured. The association between PD severity and vitamin C levels was estimated
by ordinal logistic regression with confounding variables.
Conclusions: Our findings suggest that lymphocyte vitamin C levels in the peripheral
blood may be a potentially useful biomarker for the progression of PD.
Colonic mucosal a-synuclein lacks specificity as a biomarker for Parkinson disease / Visanji
N.P.
et
al.
//
Neurology.
2015.
Vol.
84,
No
6.
P.
609–616.
URL:
http://www.ncbi.nlm.nih.gov/pubmed/25589666.1
To determine the utility of detecting a-synuclein (aSyn) in colonic mucosal biopsy tissue
as a potential diagnostic biomarker for Parkinson disease (PD).
We used the paraffin-embedded tissue (PET) blot, which degrades physiologic nonaggregated
aSyn using proteinase K and enhances antigen retrieval allowing sensitive and selective
detection of remaining protein aggregates, to detect aSyn in colonic mucosal biopsies from 15
patients with early PD (,3 years), 7 patients with later PD (.5 years), and 11 individuals without
PD. aSyn and serine 129–phosphorylated aSyn (Ser129p-aSyn) were assessed by PET blot and
conventional immunohistochemistry.
PET blot–resistant aggregated aSyn and Ser129p-aSyn was present in 12 of 15
individuals with early PD, 7 of 7 individuals with later PD, and 11 of 11 control subjects. The
number of biopsies positive by PET blot relative to conventional immunohistochemistry was
significantly lower in both PD groups compared with the control group for both aSyn and
Ser129p-aSyn,whereas routine immunohistochemistry was positive more often in PD, but was
positive in as many as 9 of 11 control individuals.
Strong evidence of the presence of aggregated hyperphosphorylated aSyn in individuals
with and without PD, using such a sensitive and specific method as the PET blot, suggests that
colonic deposition of aSyn is not a useful diagnostic test for PD. The utility of detecting aSynin
the colon as a biomarker in combination with other assessments remains to be determined.
Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic
biomarkers for Parkinson's disease / Santiago J.A., Potashkin J.A. // Proc Natl Acad Sci U S A.
2015. Vol. 112, No 7. P. 257–262. URL: http://www.ncbi.nlm.nih.gov/pubmed/25646437.1
Environmental and genetic factors are likely to be involved in the pathogenesis of
Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the
elderly. Network-based metaanalysis of four independent microarray studies identified the
hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with
gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD
patients.
Longitudinal performance analysis demonstrated that relative abundance of HNF4A and
PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y
follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale
for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers
identified in this study may be useful for monitoring disease-modifying therapies for PD.
Phosphorylated α-synuclein in Parkinson’s disease: correlation depends on disease severity /
Stewart
T.
et
al.
//
Acta
Neuropathol
Commun.
2015;
3:
7.
URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362824/
α-Synuclein (α-syn) is a key protein in Parkinson’s disease (PD), and one of its
phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few
studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in
preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from
three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of
LRRK2 mutation carriers).
Results. Consistent with our previous observation that CSF pS129 positively correlated with
Unified Parkinson’s Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort
increased over approximately two years of disease progression (mean change 5.60 pg/ml,
p=0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores
at the baseline (R=−0.244, p=0.017), but not final point, suggesting that this association may
depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and
addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the
idea that the relationship between CSF pS129 and disease severity over a wider range of PD
stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with
worse clinical condition at early stages, but better condition at later stages.
Conclusion. The observation of a negative-to-positive transition of correlation of pS129 to
disease severity as PD progresses could have profound impact on how pS129 is used as a
biomarker clinically as well as in modeling PD experimentally.
2014
Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's Disease / Parnetti
L.
et
al.
//
Front
Aging
Neurosci.
2014.
Vol.
6:53
URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978246/
There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis
and prognosis of Parkinson's disease (PD). CSF alpha synuclein (α-syn) species, namely total
and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis.
Combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of
PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive
decline.
Neuroimaging biomarkers for Parkinson disease: facts and fantasy / Perlmutter J.S., Norris S.A.
//
Ann
Neurol.
2014.
Vol.76,
No
6.
P.
769–783.
URL:
http://www.readcube.com/articles/10.1002%2Fana.24291
In this grand rounds, we focus on development, validation, and application of
neuroimaging biomarkers for Parkinson disease (PD). We cover whether such biomarkers can be
used to identify presymptomatic individuals (probably yes), provide a measure of PD severity (in
a limited fashion, but frequently done poorly), investigate pathophysiology of parkinsonian
disorders (yes, if done carefully), play a role in differential diagnosis of parkinsonism (not well),
and investigate pathology underlying cognitive impairment (yes, in conjunction with postmortem
data). Along the way, we clarify several issues about definitions of biomarkers and surrogate
endpoints. The goal of this lecture is to provide a basis for interpreting current literature and
newly proposed clinical tools in PD. In the end, one should be able to critically distinguish fact
from fantasy.
What is the Clinical Significance of Cerebrospinal Fluid Biomarkers in Parkinson's disease? Is
the Significance Diagnostic or Prognostic? / Kim D. . et al. // Exp Neurobiol. 2014. Vol. 23, No
4. P. 352–364.
URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276806/
In this review, we describe the molecular pathogenesis of PD and discuss its implication
to develop PD biomarkers in CSF.
GENETICS. The monogenetic causes of autosomal dominant PD are mutations in
LRRK2 (leucine-rich repeat kinase 2; PARK8), SNCA (α-syn; PARK1/4), VPS35 (vacuolar
protein sorting 35 homolog), or the EIF4G1 (eukaryotic translocation initiation factor-4-gamma
1) gene. Mutations in PRKN (Parkin, E3 protein ligase, PARK2), PINK1 (PTEN-induced kinase
1, PARK6), DJ-1 (daisuke-junko-1, PARK7), ATP13A2 (lysosomal P-type ATPase, PARK9),
PLA2G6 (calcium independent phospholipase A2, PARK14), FBXO7 (F-box only protein 7,
PARK15), or DNAJC6 (neuronal-specific clathrin-uncoating co-chaperone auxilin) are
responsible to autosomal recessive forms of PD [reviewed in reference 29]. These familial forms
of PD (fPD) caused by a specific mutation only account for approximately 10% of total PD
cases. However, the discovery of genes causing fPD has provided new insights into the
molecular pathogenesis of PD. For example, fPD caused by mutations in LRRK2 encoding
dardarin is the most common fPD, and LRRK2 involves the phosphorylation of α-syn or the tau
protein and the autophagy-lysosomal pathway. The multiplication of SNCA gene causes
overproduction of α-syn followed by aggregation in connection with an LRRK2 mutation, and is
related to atypical clinical features. Moreover, a genome-wide association study revealed that the
variants of these genes were genetic risk factors of sporadic PD. Therefore, clinical studies
providing genetic implication in PD could open the discovery of novel biochemical biomarkers
in the field of PD.
Biomarkers in biological fluids for dementia with Lewy bodies / Schade S., Mollenhauer B. //
Alzheimers
Res
Ther.
2014.
.
Vol.
6,
No
5-8:72.
URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255553/
In this review, we summarize the knowledge on fluid biomarkers for Dementia with
Lewy bodies (DLB), derived predominantly from cerebrospinal fluid. We discuss the value of
well-defined markers (β-amyloid, (phosphorylated) tau, α-synuclein) as well as some promising
‘upcoming’ substances, which still have to be further evaluated.
Phosphatases of α-synuclein, LRRK2, and tau: important players in the phosphorylationdependent pathology of Parkinsonism / Taymans J.M., Baekelandt V. // Front Genet. 2014. Vol.
7, No 5: 382. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224088/
LRRK2 and α-syn have been both linked to familial forms of PD as well as associated to
sporadic PD. Another gene, microtubule associated protein tau (MAPT), has been genetically
linked to a dominant form of frontotemporal dementia and parkinsonism linked to chromosome
17 (FTDP-17) and genome-wide association studies report a strong association between MAPT
and sporadic PD. Interestingly, LRRK2, α-syn, and tau are all phosphorylated proteins, and their
phosphorylation patterns are linked to disease. In this review, we provide an overview of the
evidence linking LRRK2, α-syn, and tau phosphorylation to PD pathology and focus on studies
which have identified phosphatases responsible for dephosphorylation of pathology-related
phosphorylations. We also discuss how the LRRK2, α-syn, and tau phosphatases may point to
separate or cross-talking pathological pathways in PD. Finally, we will discuss how the study of
phosphatases of dominant Parkinsonism proteins opens perspectives for targeting pathological
phosphorylation events.
Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential
search for biomarkers for this disease / Jiménez-Jiménez F.J. et al. // Front Cell Neurosci. 2014.
Vol. 11, No 8: 369. URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227512/
This review article summarizes the studies reported on CSF levels of many potential
biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the
progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein
with the progression of PD and with the preservation of cognitive function in PD patients; (c) the
possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD
patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the
differential diagnosis between PD and other parkinsonian syndromes. Future multicentric,
longitudinal, prospective studies with long-term follow-up and neuropathological confirmation
would be useful in establishing appropriate biomarkers for PD.
References for this review were identified by searching in PubMed from 1966 until June
20, 2014. The term “Parkinson's disease” was crossed with “cerebrospinal fluid” and “blood
brain barrier,” and the related references were selected. Table summarizes a classification of the
diverse types of compounds which have been analyzed in the CSF of PD patients:
Relation and classification of compounds measured in CSF of PD.
(A) Neurotransmitters, neuromodulators, and related substances
1.
Dopamine (DA) metabolites: dihydroxyphenylacetic acid (DOPAC) and
homovanillic acid (HVA), 3-orthomethylDOPA (3-OMD)
2.
Serotonin (5-hydroxytryptamine or 5-HT) metabolites or precursors: 5-
hydroxytryptophan
(5-HTP),
5-hydroxyindoleacetic
acid
(5-HIAA),
kynurenine,
3-
hydroxykynurenine
3.
Noradrenalin (norepinephrine or NE) metabolites or precursors: 3-methoxy-4-
hydroxy-phenylethylenglycol (MHPG), dopamine-beta-hydroxylase (DBH)
4.
Acetylcholine (Ach) and related substances: choline, acetylcholine-esterase
(AchE), butiryl-cholin-esterase (BchE)
5.
Neurotransmitter amino acids: gamma-amino butyric acid (GABA), glutamate,
aspartate, glycine
6.
Neuropeptides: substantia P (SP), cholecystokinin-8 (CCK-8), met-enkephalin
(MET-ENK), leu-enkephalin (LEU-ENK), dynorphin A(1-8), somatostatin, neuropeptide Y
(NPY), beta-endorphin, arginine-vasopressine (AVP), vasoactive intestinal peptide (VIP), delta
sleep-inducing peptide (DSIP), alpha-melanocyte-stimulating hormone-like, diazepam-binding
inhibitor, neurokinin A, corticotropin-releasing hormone (CRH), adrenocorticotropin hormone
(ACTH), beta-lipotropine, angiotensin, chromogranins A and B, secretogranin II, orexinA/hypocretin-1
7.
Other neurotransmitters: endogenous cannabinoids, β-phenylethylamine
8.
Cyclic nucleotides: cyclic adenosine 3′5′ monophosphate (cAMP), cyclic
guanosine 3′5′ monophosphate (cGMP)
9.
Biopterin derivatives and other cofactors
(B) Endogenous neurotoxins
1.
Tetrahydroisoquinolin (TIQ) derivatives: 2-methyl-6,7-dihydroxy1,2,3,4-TIQ (2-
MDTIQ), 1-MDTIQ (salsolinol). 1-benzyl-1,2,3,4-TIQ
2.
β-carbolinium cations (BC+s)
(C) Oxidative stress markers
1.
Lipid peroxidation markers: Malonyl-dialdehyde (MDA) (E)-4-hydroxynonenal
(HNE) Low density lipoprotein (LDL) oxidation products Schiff bases, conjugated dienes,
oxidized proteins, and aldehyde polymers
2.
DNA
oxidation
markers:
8′-hydroxy-2′deoxyguanine
(8-OHdG)
8-
hydrosyguanosine (8-OHG) 8-OHdG/8-OHG ratio
3.
Transition metals and related proteins: iron, ferritin, transferring, copper,
cerulopasmin, ferroxidase, manganese, zinc
4.
Other metals: selenium, chromium, magnesium, calcium, aluminum, silicon,
cobalt, tin, lead, barium, bismuth, cadmium, mercury, molibdenum, nichel, antimony, strontium,
thallium, vanadium, wolfram, and zirconium
(D) Inflamatory and immunological markers
1.
Inteleukins (IL)
2.
Tumor necrosis alpha (TNF-α)
3.
Other: leukotrienes. α-1-antichymotrypsin
(E) Growth and neurotrophic factors
1.
Brain-derived neurotrophic factor (BDNF)
2.
Transforming Growth Factors: TGF-α, TGF-β1, TGF-β2
3.
Insulin-like growth factor-1 (IGF-1) and IGF-binding proteins (IGFBPs)
4.
Neuroregulins (Epidermal Growth Factor or EGF family)
(F) Proteins involved in the pathogenesis of PD
1.
Microtubular-Associated Protein Tau (MAPT)
2.
Alpha-synuclein
3.
Amiloyd beta
4.
Neurofilament proteins
5.
Other proteins: DJ-1, UCH-L1
(G) Other compounds (proteoglycan, N-acetyl neuraminic acid, insulin, corticosterone,
neuroactive steroids such as allopregnanolone (THP) and 5 α-dihydroprogesterone (DHP),
polyunsaturated fatty acid eicosapentanoic acid (EPA), 24S-hydroxycholesterol, total polyamine,
N1acetyl-cadaverine,
cadaverine
,
putrescine,
spermidine,
N1acetylputrescine,
N8-
acetylspermidine et al.)
Predicting cognitive decline in Parkinson's disease: can we ask the genes? / De Marchi F. et
al. // Front Cell Neurosci. 2014. Vol. 27, No 5: 224. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209831/?report=classic
In recent years, several studies have focused on predictive markers of cognitive decline in
PD. Clinical, neuroimaging, and molecular markers have been identified. Nonetheless, which
markers are most reliable and applicable to clinical practice to predict the long-term prognosis of
these patients still needs to be clarified.
Potential Disease Markers. Higher age at onset and gait impairment are the best clinical
predictors of PDD. Community-studies showed that gait impairment both precedes and predicts
dementia. Moreover, a direct correlation between brain atrophy and freezing of gait has been
detected.
Neuroimaging studies have demonstrated that PDD is associated with extensive cortical
atrophy, which may be quantified with structural MRI. More detailed imaging studies can
differentiate PD patients with mild cognitive impairment (PD-MCI) from PDD. Voxel based
morphometry (VBM) shows that PD-MCI patients display selective posterior cortical atrophy,
while PDD patients have a more widespread cortical atrophy involving the posterior and
temporal lobes, hippocampus, and frontal association areas. 18FDG PET in PDD patients shows
a pattern of hypometabolism targeting parietal, occipital, temporal, frontal lobes, and anterior
cingulate cortex, which is directly proportional to disease severity. DaTSCAN SPECT shows that
loss of mesolimbic and mesocortical dopaminergic function is likely to be more relevant to PDD
than DLB.
The cerebrospinal fluid (CSF) provides relevant information on the central nervous
system (CNS) biochemical environment, and its study in neurodegenerative conditions has
boosted since the discovery of changes in beta amyloid/tau concentrations in the CSF of
Alzheimer’s disease (AD) patients. Increased CSF tau protein levels are typical of AD, but they
are also observed in other neurodegenerative diseases with rapid neuronal cell loss, even
independently from tau-related pathology . Therefore, CSF tau should be considered a nonspecific marker of neuronal degeneration. CSF tau levels do not differ in PD patients and
controls, whereas PDD patients display higher levels compared to PD patients but lower than
LBD and AD patients. On the contrary, CSF levels of phosphorylated tau are not useful to
differentiate these conditions. α-synuclein, the major constituent of Lewy bodies, was found to
be decreased in the CSF of PD patients at diagnosis compared to controls. Such decrease was
particularly evident in patients with akinetic-rigid PD. On the contrary, no correlation between αsynuclein levels and disease progression was found and no specific comparison between PD and
PDD patients was performed. Aβ-peptides are the major constituents of amyloid plaques.
Decreased CSF levels of Aβ1–42 in PDD patients were strongly associated with cognitive
decline over time, in particular, with a faster decline in cognitive performances assessed by the
dementia rating scale (DRS). Osteopontin (OPN), a pro-inflammatory molecule previously found
to be associated with AD progression, has also been studied in PD and LBD. OPN serum and
CSF levels are higher in PD patients than controls, with CSF levels positively correlating with
concomitant dementia. Accordingly, similar findings were reported in LBD, where a single
nucleotide polymorphism (SNP) of the OPN gene was also shown to be associated to disease
susceptibility.
With regard to studies on serum and plasma, just a few significant associations between
levels of circulating molecules and PDD have been detected so far. In a study assessing baseline
plasma levels of 102 proteins in PD patients, only decrease of epidermal growth factor (EGF)
was found to correlate to poor cognitive scores at baseline and predict a major risk of cognitive
decline. More recent studies have also suggested association between serum levels of uric acid
and plasma homocysteine and the development of dementia, but such results need replication in
larger cohorts.
The potential markers for PDD development that we have reviewed so far have, however,
some downsides: neuroimaging studies are generally not invasive but they are very expensive
and require advanced technology, highly specialized operators and patients’ collaboration for a
long period of time.
Studies on body fluids are generally less expensive than imaging, but in case of CSF
studies, they require an invasive procedure, with potential risks, especially in the elderly.
Furthermore, circulating molecules can serve as prognostic markers only if the sample is
obtained at the time of diagnosis, when patients are drug-naive and the disease is in its early
phase. In fact, biological molecules may undergo biochemical changes during the evolution of
the disease and due to pharmacological treatment.
In recent years, proteomic techniques have been increasingly used to explore the
molecular mechanisms underlying PD and to detect biomarkers allowing early diagnosis,
prediction of disease progression, and a more targeted treatment. Proteomics can be performed
on CSF, plasma, or circulating cells. Nonetheless, it is generally quite expensive and no definite
biomarker has entered the routine clinical practice so far.
Role of Genetics. Genetic studies may provide ideal markers for predicting disease
progression as DNA sequence is not likely to undergo changes during disease course and is not
influenced by drug treatment. Preliminary prognostic correlations can be obtained with crosssectional or even retrospective data. To this respect, the genetic background of PDD has been
explored with both unbiased and candidate–gene approaches. Although most genome wide
association studies (GWAS) performed so far were focused on PD susceptibility, Chung et al.
analyzed the common variants associated with motor and cognitive progression in 443 PD
subjects. Two potential markers of progression were identified: SNP rs6482992 of CLRN3 and
SNP rs10958605 of C8orf4: the former provided the best prediction of cognitive deterioration
[hazard ratio 1.81, p = 1.81 × 10(−6)], the latter, which is likely involved in
neuroinflammatory pathways (8), was associated with both motor and cognitive outcomes.
Traditional candidate–gene approaches have mainly focused on genes involved in
pathways of neurodegeneration, such as mitochondrial transcription factor A (TFAM) or brain
derived neurotrophic factor (BDNF); alternatively, genes like apolipoprotein E (APOE) and
microtubule-associated protein Tau (MAPT), were selected among those previously associated
with AD (24).
A SNP in the gene encoding TFAM, A > G rs2306604, has been recently studied in
PDD patients compared to controls. Data showed that the A allele was associated with PDD (p = 0.024, OR = 2.092), even though such findings need to be replicated in a larger population.
Brain derived neurotrophic factor is a trophic factor that can act as synaptic modulator and
interact with dopaminergic transmission and dopamine receptor stimulation in the fronto-striatal
circuitry, whose integrity is crucial for the cognitive aspects of PD. A SNP in the BDNF gene,
namely, G196A, resulting in a methionine (Met)–valine (Val) substitution at codon 66
(Val66Met), was shown to be associated with increased susceptibility to AD. Intriguingly, PD
patients carrying AA genotype of G196A display significantly increased risk of cognitive
decline.
The ε4 allele of APOE was shown to be associated with higher prevalence of dementia in
PD patients. A meta-analysis indicated an over-representation of APOE ε4 carriers in PDD
patients compared to non-demented cases [OR 1.74 (1.36–2.23)]. To further support these
findings, two recent reports confirmed that APOE ε4 is an important predictor of cognitive
function in PD across multiple domains (i.e., recall and delayed recall, semantic verbal fluency)
and it also has a relevant influence on the memory domain.
The H1/H1 haplotype of MAPT was associated with an increased risk of several
neurodegenerative disorders. A possible association between the H1 allele and cognitive decline
in PD was explored, but the results obtained were conflicting, with some studies showing a
positive correlation between PDD and the H1 allele, in particular, with the sub-haplotype H1p
(31), and others that provided negative results.
Important insights into the relationship between genetics and the cognitive progression of
PD derive from the natural history of familial cases. PARKIN and leucine-rich repeat kinase 2
(LRRK2) mutations are associated to a lower rate of PDD compared to sporadic cases, whereas
opposite findings were shown for α-synuclein (SNCA) or glucocerebrosidase (GBA) gene
mutations.
The risk of dementia in patients with PARKIN mutations is reported to be very low (33).
Nonetheless, neuropsychiatric features are reported, including anxiety, psychosis, panic attacks,
depression, disturbed sexual behavioral, and obsessive–compulsive disorders. A recent crosssectional study, comparing outcome in 21 PARKIN mutation carriers versus 23 idiopathic PD
(IPD) patients, showed that PARKIN carriers had better performance, not only on the motor
score but also on attention, memory, and visuospatial cognitive domains compared with noncarriers.
Leucine-rich repeat kinase 2 is a common genetic cause of PD and Gly2019Ser is the
most frequent mutation. It was shown that Gly2019Ser carriers have lower PPD risk compared to
IPD patients, particularly in the first 2 years of disease.
SNCA gene point mutations (A53T, A30P, and E46K), named PARK1, as well as duplications
and triplications (PARK4), cause autosomal dominant PD with variable penetrance. Clinically,
carriers may have rapid motor progression and frequent dementia, in particular, triplications
result in earlier onset of PD and dementia. Moreover, functional SNCA SNPs are associated with
different rates of motor progression in IPD.
Heterozygous GBA mutations are over-represented in cases of both familial and sporadic
PD. Compared with IPD, patients carrying GBA mutations have been reported to have an earlier
age at onset, more symmetrical clinical signs, and an increased incidence of neuropsychiatric
disturbances. In 2012, Winder-Rhodes et al. demonstrated that in PD patients with single GBA
mutations the risk of progression to dementia is more than five times higher that the one of
GBA-negative patients, but the mechanism underlying this association has yet to be elucidated.
With the progress in genotyping and sequencing technologies, discovery of novel genetic
markers associated with disease onset, progression, and response to treatment is expected.
Nonetheless, the use of genetic markers to predict disease progression and specifically cognitive
impairment in PD patients requires a great effort in collecting accurate and reproducible clinical
data. To standardize procedures for acquisition, processing, and storage of clinical data which are
often not homogeneous, is mandatory to improve the quality of the research. It is conceivable to
collect more accurate indicators of dementia, through the systematic use of specific rating scales
(e.g., DRS) that also take into account the interference of cognitive decline with the activities of
daily living. This would eventually help in early identifying a subgroup of PD patients at risk of
dementia to be enrolled in clinical trials of novel and more specific treatments. Finally, large
collaborative studies involving several institutions will be required to prospectively validate the
utility of these markers for clinical decision making.
Neuroimaging characteristics of dementia with Lewy bodies / Mak E. . et al. // Alzheimers Res
Ther. 2014. Vol. 6, No 2: 18. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055038/
This review summarises the current imaging literature of DLB in the context of its
differentiation from other causes of dementia, discusses the increasingly important role of
imaging biomarkers in differential diagnosis, and outlines promising areas for future research.
Collectively, the imaging findings have yielded important insights into the underlying
pathophysiology of this condition while showing potential promise in improving clinical
differentiation of DLB from other types of dementia.
To date, the marked reduction of dopaminergic activity in the basal ganglia is the most
characteristic imaging finding of DLB, and has been considered as a significant step in aiding the
clinical diagnosis of DLB. Cerebral perfusion studies have also revealed a distinctive pattern of
deficits in parietal and occipital regions. At the structural level, another robust observation
concerns the relative preservation of MTL in DLB that is consistent with preserved memory
functions. Other techniques such as DTI, MRS, and fMRI coupled with novel analytical
approaches have also revealed information for differential diagnosis of DLB.
While the field has made substantial progress in delineating the imaging characteristics
associated with dementia subtypes, the ability to detect structural patterns that enable accurate
prediction of diagnosis for specific individuals ultimately determines the clinical value of MRI
and the measurements obtained from it. The reliable application of these methods in routine
radiological practice may be facilitated by non-expert-dependent, automated methods of
analysis.
In terms of practical considerations, SPECT and PET are both generally well tolerated
investigations with few contra-indications, though both involve radiation exposure, limiting the
number that any one subject should have. In most countries, SPECT is more widely available
than PET. MRI is now widely accessible but more unsuitable for those with claustrophobia,
pacemakers or metallic implants in or around the head. fMRI requires specialist stimulus
presentation, which limits its applicability to research studies. In addition, some computerized
paradigms in task-based fMRI might not be suitable for elderly dementia patients. Other
modalities, particularly DTI and MRS, require extensive post-processing analysis time, also
potentially limiting their routine application for clinical use.
It is worth mentioning the limitations of the current research. At present, the
overwhelming majority of neuroimaging studies in DLB are cross-sectional, relatively small in
size, and in participants in established stages of the disease. Therefore, larger prospective
longitudinal studies are warranted to confirm the utility of many imaging techniques and monitor
disease progression in early disease stages as well as at risk individuals and patients with mild
cognitive impairment. Furthermore, studies involving multimodal neuroimaging data and larger
cohorts are likely to make novel contributions in evaluating the utility of combined biomarkers
in DLB.
A review of the use of magnetic resonance imaging in Parkinson's disease Pyatigorskaya N. et
al. // Ther Adv Neurol Disord. 2014. Vol. 7, No 4. P. 206-220. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082302/
To date, the most frequently used Parkinson’s disease (PD) biomarkers are the brain
imaging measures of dopaminergic dysfunction using positron emission tomography and single
photon emission computed tomography. However, major advances have occurred in the
development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade.
Although conventional structural imaging remains normal in PD, advanced techniques have
shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in
PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other
quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization
transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques
such as tractography and resting state functional connectivity give access to anatomical and
functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using
non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to
metabolites concentrations. However, to date these techniques are not yet fully validated and
standardized quantitative metrics for PD are still lacking. This review presents an overview of
new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use
in PD and their potential applications to improve the clinical diagnosis of Parkinsonian
syndromes and the quality of clinical trials.
Overview of MRI methods used to study PD. Cortex: changes were detected using voxelbased techniques, cortical thickness measurements and perfusion imaging. Brain connectivity
was investigated using resting-state functional MRI (rs-fMRI) for functional connectivity and
tractography for structural connectivity. Substantia nigra (yellow contour): changes were
detected using diffusion imaging (reduced fractional anisotropy - FA), relaxometry (increased
R2* indicating increased iron load and more recently susceptibility-weighted imaging),
magnetization transfer ratio (MTR reduced) and spectroscopy. Basal ganglia: studies showed no
or mild changes in FA, R2* or MTR. Locus coeruleus area (white arroxw head): reduced signal
intensity was detected using neuromelanin imaging.
Over the last decade and a half, research in PD imaging has focused on developing
quantitative techniques in the aim of providing measurements that can be used a markers of the
disease process. In the SN, several techniques including diffusion imaging, T2* relaxometry and
MT have shown great promises for detecting pathological changes. Investigators have developed
computerized neuroanatomical techniques to study cortical changes that have been related to
specific motor and nonmotor symptoms in the disease. MRI gives also access to the anatomical
and functional connectivity changes in the brain of PD patients. MRI techniques could be used to
monitor disease progression and to detect brain changes in preclinical patients or in patients at
risk of developing PD, such as gait REM sleep behaviour disorder patients. However, to date
these techniques suffer from the lack of standardization, particularly methods for extracting
quantitative information from images, and of validation in large cohorts of subjects in
longitudinal studies. It is expected that future efforts in imaging research will provide significant
improvement in this respect.
The role of lipid peroxidation in neurological disorders / Shichiri M. // J Clin Biochem Nutr.
2014. Vol. 54, No 3. P. 151-160. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042144/
There has been much evidence demonstrating the involvement of oxidative stress in the
pathology of neurological disorders.
PD clinically manifests as resting tremors, slowness of movement, rigidity, and postural
instability. PD is pathologically defined by the loss of neurons in the substantia nigra (SN) and
by the presence of cytoplasmic protein inclusions named Lewy bodies and neuritis. (71) A small
synaptic protein, α-synuclein, is recognized to be the main component of Lewy bodies.(72) The
loss of SN cells lead to striatal dopamine deficiency and are related to the clinical severity of PD.
Three independent mutations in α-synuclein, including A53T, A30P, and E46K, are involved in
the development of familial PD. Recombinant synuclein is reported to produce hydrogen
peroxide by Electron Spin Resonance (ESR),(73) and hydrogen peroxide exposure induces αsynuclein fragmentation and accumulation in the nucleus.(74)
These results suggest that oxidized DJ-1 might be a useful biomarker for the detection
and diagnosis of PD at early-stages.
Parkinson’s disease is a progressive, age-related, neurodegenerative disorder, and
oxidative stress is an important mediator in its pathogenesis. DJ-1 is a causative gene of a
familial form of Parkinson’s disease, namely PARK7, and plays a significant role in antioxidative
defense to protect the cells from oxidative stress. DJ-1 undergoes preferential oxidation at the
cysteine residue at position 106, Cys-106, under oxidative stress. The critical role of Cys-106 in
the biological function of DJ-1 has been demonstrated, and recent studies indicate that DJ-1 acts
as a sensor of oxidative stress by regulating the gene expression of antioxidative defense.
Specific antibodies against Cys-106-oxidized DJ-1 have been developed, and the generation of
oxidized DJ-1 in cellular and animal models of Parkinson’s disease has been investigated. This
review focuses on the role of DJ-1 in antioxidative defense and the importance of oxidizable
Cys-106 in its function. The significance of the identification of early-phase Parkinson’s disease
biomarkers and the nature of oxidized DJ-1 as a biomarker for Parkinson’s disease are discussed
here.
Several studies strongly indicates a relationship between DJ-1 oxidation, oxidative stress,
and the onset and progress of PD. The importance of the prevention of oxidative stress in PD is
understood. Elucidation of the timing and site of oxidative stress in PD might be required to
develop the therapy using antioxidants. Recently, a correlation between oxDJ-1 levels in
erythrocytes and MIBG scintillation in PD patients has been discovered. The examination of
several PD biomarker candidates might lead to the diagnosis of PD in its early stages.
Cognition in movement disorders: where can we hope to be in ten years? / Burn D. et al. // Mov
Disord. 2014. Vol. 29, No 5. P. 704-711. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371593/
Toward Improved Biomarkers
Well-defined populations are critical for clinical trials, but there are no disease-specific
biomarkers for the diagnosis of nongenetic movement disorders. To evaluate targeted
interventions and prevention therapies designed to delay the cognitive decline observed in these
disorders, we need biomarkers that could increase diagnostic accuracy, predict cognitive decline,
and accurately track progression of this decline.
Diagnostic biomarkers that quantify levels of CSF beta-amyloid, tau and phosphorylated
tau, and PET imaging tracers that have high affinity for beta-amyloid are useful in the diagnosis
of AD in vivo, for which they have been recently incorporated to improve its diagnostic criteria. 12
However, whereas quantification of CSF alpha-synuclein (α-Syn) levels is a promising
biomarker for the diagnosis of PD,13 higher specificity and sensitivity are needed to allow its
adoption to refine extant diagnostic criteria. Furthermore, CSF tau levels are not helpful for
diagnosing tauopathies presenting with parkinsonism, such as PSP and corticobasal
degeneration. However, the recent development of two PET imaging tracers targeting paired
helical filament-tau, phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs) and
[(18)F]T807, that have high affinity in vitro, in animal models and in patients with AD are
encouraging and may help increase the accuracy in diagnosing these disorders. 14–16 Validation of
these biomarkers in AD is in progress. Evidence that these biomarkers will be helpful to
diagnose patients with other tauopathies is not yet available, although one report describes
increased [11C]PBB signal in areas typically affected of a patient with a corticobasal syndrome.
This new development increases the likelihood of finding tracers that could label α-Syn because
this shows us that imaging radiotracers can feasibly label intracellular protein inclusions such as
those found in PD.17 Improved biomarkers not only will increase diagnostic accuracy, but will
also allow the diagnosis of patients at earlier disease stages, thereby improving the chances of
finding successful biological therapies. PET tau and α-Syn biomarkers may also serve as
surrogate markers of disease progression. It is unlikely that PET ligands will become inexpensive
and accessible world-wide, but they could pave the way for the identification of other less-costly,
more-ubiquitous imaging approaches (e.g. single-photon emission CT), as well as less-invasive
blood or urine biomarkers that could allow an early diagnosis of movement disorders.
Moreover, in the coming years, we may also be able to use genetics to design therapeutic
trials that will target specific populations more likely to respond to therapy or with similar
disease progression, which, in turn, will increase the likelihood of finding successful therapies.
For example, if apolipoprotein E4 (ApoE4), the H1/H1 haplotype, or the α-Syn gene predispose
to the conversion of PD patients with mild cognitive impairment to dementia, stratifying or
selecting patient samples with these genes will decrease the sample size needed and may more
readily identify successful therapies.
What can biomarkers tell us about cognition in Parkinson's disease? / Mollenhauer B. et al. //
Mov Disord. 2014. Vol. 29, No 5. P. 622-633. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384332/
Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage,
and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we
discuss marker candidates for cognitive decline in PD from different angles, including functional
and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood
genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically,
imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical
metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an
increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower
plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition,
genetic variation in the apolipoprotein E (APOE), catechol-O-methyltransferase (COMT),
microtubule-associated protein tau (MAPT), and glucocerebrosidase (GBA) genes may confer
risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for
dementia. Other marker candidates have been proposed and are discussed. All of the current
studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline,
which will have to be considered in future biomarker studies.
Imaging Dementia in Parkinson's Disease
Structural Magnetic Resonance Imaging Studies
Functional Imaging of Glucose Metabolism
Functional Imaging of Dopamine Transporter
Functional Imaging of the Cholinerigic System
Visualization of Specific Pathologies
Functional Imaging of Activated Microglial Activation
Biological Fluids: CSF Biomarkers for Cognitive Impairment in PD
Aβ peptides
Tau protein
α-Synuclein
Epidermal growth factor
Other marker candidates in blood, CSF, and other biofluids
Genetic Risk Markers of Cognitive Impairment in PD
Apolipoprotein E
Catechol O-methyltransferase gene
MAPT and tau haplogroups
Glucocerebrosidase
Numerous studies have evaluated the contribution of variants or mutations in APOE,
COMT, MAPT, and GBA to the risk for cognitive impairment in PD. Although there are
conflicting reports for all of these genes, the preponderance of the data suggests that a modestly
increased risk for cognitive impairment is conferred by the APOE ∼4 allele, the COMT met
variant, the MAPT H1 haplogroup, and mutations in GBA.
Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions /
Magdalinou N. et al. // J Neurol Neurosurg Psychiatry. 2014. Vol. 85, No 10. P. 1065-1075.
URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173749/
Parkinsonian diseases comprise a heterogeneous group of neurodegenerative disorders,
which show significant clinical and pathological overlap. Accurate diagnosis still largely relies
on clinical acumen; pathological diagnosis remains the gold standard. There is an urgent need for
biomarkers to diagnose parkinsonian disorders, particularly in the early stages when diagnosis is
most difficult. In this review, several of the most promising cerebrospinal fluid candidate
markers will be discussed. Their strengths and limitations will be considered together with future
developments in the field.
Idiopathic Parkinson's disease (iPD) is a progressive neurological disorder initially
described as a clinical entity by James Parkinson and then embellished by Charcot and other
nineteenth-century physicians, including Trousseau, Gowers and Erb. It is a clinical construct,
based upon the presence of bradykinesia accompanied by at least one other characteristic feature,
such as resting tremor, rigidity and impaired postural reflexes.1 The signs and symptoms are
usually asymmetrical at onset and, typically, there is a good response to levodopa treatment.
‘Parkinson-plus’ or ‘atypical parkinsonism’ are terms that refer to a heterogeneous group of
neurodegenerative disorders that may masquerade particularly in the early stages of the disease
as Parkinson's disease (PD).2 The ‘plus’ or ‘atypical’ descriptor indicates the presence of
additional characteristics not usual in patients with iPD, such as early autonomic disturbance and
pyramidal signs exhibited by patients with multiple system atrophy (MSA), supranuclear gaze
palsy and frontal/dysexecutive syndrome by those with progressive supranuclear palsy (PSP),
dystonia and myoclonus in corticobasal degeneration (CBD) and early postural instability and
falls by all of them. Another disease that could be classified as an atypical parkinsonian disorder
is dementia with Lewy bodies (DLB), where dementia onset is before or within a year of onset of
extrapyramidal features. The earlier onset of dementia differentiates DLB from Parkinson's
disease dementia (PDD).
Atypical parkinsonian disorders account for less than 10% of all parkinsonism and rarely
respond with sustained improvement to levodopa. They usually follow a much more aggressive
disease course than iPD and are characterised by atrophy to several different cortical and
subcortical networks. Furthermore, atypical parkinsonism has been described in other conditions,
such as Alzheimer's disease (AD) and frontotemporal dementia (FTD).
Genetics. Recent advances in genetics have shed light on the underlying pathophysiology
because mutations in the gene for each misfolded protein can give rise to an inherited form of a
relevant neurodegenerative condition. For example, rare hereditary forms of PD can be caused
by mutations affecting the gene coding for α-Syn (SNCA); PARK1 (missense) and PARK4
(duplication, triplication).12 Furthermore, in both PD and to a lesser extent in MSA, population
studies demonstrated an association between disease risk and distinct single-nucleotide
polymorphisms in SNCA. DJ-1(PARK7) mutations can lead to rare forms of autosomal-recessive
PD, pointing towards mitochondrial damage/oxidative stress pathways driven pathogenesis.13
Even though PD is not a ‘tauopathy’, population studies also showed variants in tau (MAPT)
gene, particularly the H1 haplotype, as another risk factor for PD (for a review, see ref. 14).
Several tauopathies are associated with variants in MAPT, including CBD, FTD linked to
chromosome 17 (FTDP-17T) and PSP.15 The fact that the MAPT/tau haplotype also shows an
association with PD strongly suggests that the pathogenic cascades in the tauopathies may be
related to those in the synucleinopathies.
Diagnostic challenges. Accurate diagnosis of parkinsonian disorders still relies heavily on
clinical acumen, although imaging and ancillary investigations may be helpful in some
situations. In one postmortem series, 24% of patients clinically diagnosed with idiopathic PD by
a consultant neurologist during life were found to have an alternative diagnosis.1
Parkinson's Disease Biomarkers: Resources for Discovery and Validation // Frasier M., Kang
U.J. // Neuropsychopharmacology. 2014. Vol. 39, No 1. P. 241-242. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857671/
The Parkinson's Progression Marker Initiative (PPMI) is a prospective study of 400
newly diagnosed PD patients and 200 controls that will be followed over 5 years and collect
extensive clinical (motor and non-motor information), imaging, and biosample (blood,
cerebrospinal fluid, DNA/RNA from blood, urine) information from all 600 subjects at sites
around the world. PPMI expanded to include a prodromal cohort of 100 individuals at risk for
developing PD to develop biomarkers that are present prior to the onset of clinical motor
symptoms. The Fox Investigation for New Discovery of Biomarkers (BioFIND) is a study
supported in collaboration with National Institute of Neurological Diseases and Stroke (NINDS)
focused on novel biomarker discovery by enrolling 120 rigorously defined clinically typical PD
in mid-stage and 120 age- and gender-matched controls at one timepoint in US sites. BioFIND
was launched to serve as a platform to test new biomarkers in somewhat narrow spectrum of
clinically typical PD in moderate stages to maximize the chance of discovering differences in a
less heterogeneous population. The Parkinson's Disease Biomarker Program (PDBP) is a
program designed to support new and existing biomarker cohorts that collect biospecimens using
standardized protocols. Biospecimens and data from all above studies are available to the
research community. Through standardization and coordination of data and sample collection,
we are optimistic that new markers will emerge which will assist in clinical trials and ultimately
result in improved management of the disease.
Blood-based biomarkers for Parkinson's disease / Chahine L.M. et al. // Parkinsonism Relat
Disord. 2014. Suppl 1:S99-103. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070332/
In this review, we summarize these techniques and discuss the challenges and successes
of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include αsynuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral
inflammatory markers.
Table 1 Promising Blood-Based PD Biomarkers (only those in which replication in at least one
independent cohort was achieved are included)
State Biomarkers
Trait
Dementia
Diagnostic
Biomarkers
Motor
disease EGF
markers
severity
DJ-1 isoforms
DJ-1 isoforms
Uric Acid
ApoA1
Age-at-onset
ApoA1
GBA mutation
carriers
Interleukin-8
Table 2 Parkinson’s Disease Biomarker Initiatives
Initiative
Primary
Goals
Parkinson’s
Sponsors
National
Disease
Institute
Biomarkers
Neurological
Program (PDBP)
Disorders
and
 Bridge the gap between small pilot biomarker studies and
of
validation studies of well replicated biomarker candidates
 Support new and existing cohort studies that collect, into
unified databases, standardized longitudinal clinical data
Stroke
(NINDS)
and biospecimens across all stages of PD
 Support development of analytical tools that will promote
Parkinson’s
innovation around biomarker discovery
 Establish standardized protocols for acquisition, transfer
Progression
and analysis of clinical, imaging and biospecimen data
Markers Initiative
that can be used by the PD research community.
 Investigate existing and identify novel clinical, imaging
and biospecimen PD progression markers that individually
Michael
J.
or in combination will rapidly demonstrate interval change
Fox
in PD patients in comparison to healthy controls or in sub-
Foundation
sets of PD patients defined by baseline assessments,
progression milestones and/or rate of clinical, imaging or
biospecimen change.
 Optimize bioassays and conduct preliminary verification
studies on promising biological markers using stored
biospecimen
To that end, the recent advent of large multi-site consortia for PD biomarker development
such as the Michael J. Fox Foundation’s Parkinson’s Progression Marker Initiative and the
National Institutes of Neurological Disease and Stroke Parkinson’s Disease Biomarkers Program
(table 2) hold great promise for moving this nascent area of translational research forward.
Eryptosis as a marker of Parkinson's disease / Pretorius E. et al. // Aging (Albany NY) 2014. Vol.
6, No 10. P. 788-819. URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247384/
A major trend in recent Parkinson's disease (PD) research is the investigation of
biological markers that could help in identifying at-risk individuals or to track disease
progression and response to therapies. Central to this is the knowledge that inflammation is a
known hallmark of PD and of many other degenerative diseases. In the current work, we focus
on inflammatory signalling in PD, using a systems approach that allows us to look at the disease
in a more holistic way. We discuss cyclooxygenases, prostaglandins, thromboxanes and also iron
in PD. These particular signalling molecules are involved in PD pathophysiology, but are also
very important in an aberrant coagulation/hematology system. We present and discuss a
hypothesis regarding the possible interaction of these aberrant signalling molecules implicated in
PD, and suggest that these molecules may affect the erythrocytes of PD patients. This would be
observable as changes in the morphology of the RBCs and of PD patients relative to healthy
controls. We then show that the RBCs of PD patients are indeed rather dramatically deranged in
their morphology, exhibiting eryptosis (a kind of programmed cell death). This morphological
indicator may have useful diagnostic and prognostic significance.
Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease
Theuns
J.
et
al.
//
Neurology.
2014.
Vol.
83,
No
21.
P. 1906-1913.
URL:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248456/
The objective of this study is to clarify the role of (G 4C2)n expansions in the etiology of
Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's
Disease (GEO-PD) cohort.
Methods: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients
diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe,
Asia, North America, and Australia.
Results: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD
(4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia,
amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with
typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an
increasing number of (G4C2)n repeats; however, we could not detect a robust association
between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.
Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a
major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be
considered in patients with PD who have overt symptoms of frontotemporal lobar
degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative
dementia or motor neuron disease.
2013
A Systematic Review of Biomarkers for Disease Progression in Parkinson's Disease
David J.M. et al. // BMC Neurol. 2013;13(35) URL:
http://www.medscape.com/viewarticle/807328_1
Using surrogate biomarkers for disease progression as endpoints in neuroprotective
clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from
true disease-modifying effects. A systematic review was undertaken to determine what
biomarkers for disease progression in Parkinson's disease (PD) exist.
Methods: MEDLINE and EMBASE (1950–2010) were searched using five search
strategies. Abstracts were assessed to identify papers meriting review in full. Studies of
participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means
were included. We made no restriction on age, disease duration, drug treatment, or study design.
We included studies which attempted to draw associations between any tests used to investigate
disease progression and any clinical measures of disease progression. The electronic search was
validated by hand-searching the two journals from which most included articles came.
Results: 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal.
The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1–86.0) and a specificity of
97.1% (95% CI 96.5–97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1–
3.5). Included studies were generally poor quality - cross-sectional with small numbers of
participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and
simplistic statistical analyses.
Conclusion: We found insufficient evidence to recommend the use of any biomarker for
disease progression in PD clinical trials, which may simply reflect the poor quality of research in
this area. We therefore present a provisional 'roadmap' for conducting future disease progression
biomarker studies, and recommend new quality criteria by which future studies may be judged.
КЛИНИЧЕСКИЕ ИСПЫТАНИЯ (CLINICAL TRIAL)
В
международном
регистре
клинических
испытаний
Минздрава
США
ClinicalTrials.gov всего значится 105 исследований, посвященных изучению биомаркеров
при болезни Паркинсона (дата обращения: 17.04.2015).
URL:
https://clinicaltrials.gov/ct2/results?term=Parkinson
%27s+Disease+biomarkers&recr=&rslt=&type=&cond=&intr=&titles=&outc=&spons=&lead=
&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&
lup_s=&lup_e
Для аннотированного каталога нами отобраны 24 наиболее релевантных
клинических испытания:
1.
Imaging Biomarkers in Parkinson s Disease (NCT01496599) – США. Идёт
набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT01496599?term=NCT01496599&rank=1
They will have a clinical assessment, brain ultrasound (transcranial sonography or TCS),
dopamine transporter single photon emission computed tomography (DAT SPECT) scan, a
magnetic resonance (MR) scan, and magnetoencephalography (MEG). Subjects on Parkinson
medications may have 2-3 additional MR scans in the off medications condition as tolerated. Part
2: (Longitudinal study). PD and EP subjects will be asked to follow-up annually for a total of 10
visits. After a screening visit, HV subjects will be asked to follow up annually for the first 3
years, and then every 3 years for the following 6 years, for a total of 6 visits. Each follow-up will
involve a 2-3 day visit and will consist of repeat clinical evaluations and imaging studies (TCS,
SPECT, MEG, MR scans). Outcome Measures: 1. MRI: To measure the difference in
susceptibility in iron-rich structures (using susceptibility weighted imaging); the difference in
fractional anisotropy between seed and target regions of interest (using DTI); the difference in
gray and white mattervolume of brain regions (using VBM); fluctuations of the blood oxygen
level dependent (BOLD) signal during resting state (using fMRI); Permeability of the blood
brain barrier on DEC MRI; and the signal amplitude of phosphorus-containing compounds and
neurotransmitters in brain regions of interest (ROIs) (using MRS). 2. TCS: To measure
parameters such as the difference in the area of increased signal (hyperechogenicity) seen in
brain structures such as the substantia nigra (SN). 3. SPECT: To measure the amount of
dopamine reuptake in the striatal part of the brain. 4. MEG: To quantify measures such as taskrelated potentials, relative spectral power, and synchronization.
2.
Evaluation of a Biomarker Related to the GI Tract for the Diagnosis of
Parkinson's Disease (NCT01904240) – США. Испытание завершено
https://clinicaltrial.gov/ct2/show/NCT01904240?term=NCT01904240&rank=1
The pathology of PD is distributed throughout the entire nervous system including the
central, peripheral, and enteric nervous system. There is evidence that inflammation plays a
major role in neurodegeneration in PD. In both the striatum and substantia nigra of PD patients
activated microglia were found and proinflammatory cytokines (TNF, IL-1B, IL-6, iNOS) are
increased in the CSF. An inflammation-driven animal model has emerged and has been widely
accepted as a model of the disease based on lipopolysaccharide (LPS) induced neurotoxicity.
LPS is an endotoxin found on the outer membrane of gram negative bacteria and humans are
exposed to LPS through the intestinal tract. The intestinal tract and thus the enteric nervous
system serve as a conduit to the central nervous system. It has been posited that the inflammatory
process could gain access to the lower brainstem via the vagal nerve and then ascend through the
basal mid- and forebrain until it reaches the cerebral cortex, producing various pre-motor and
motor symptoms of PD along the way. LPS may be one of the inflammatory triggers involved in
this process. Systemic exposure to bacterial endotoxin can be determined by measuring plasma
LPS binding protein (LBP). A study of 9 patients with early PD (median Hoehn and Yahr stage
2) and age matched controls found that the PD subjects had a significantly lower mean level of
plasma LBP compared to control subjects. The aim of the research plan is to establish LBP as a
potential biomarker for PD across a spectrum of disease severity.
3.
Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease
Progression (NCT01141023) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT01141023?term=NCT01141023&rank=1
This is a observational, multi-center study to assess progression of clinical features,
imaging and biologic biomarkers in Parkinson disease (PD) patients compared to healthy
controls (HC) and in PD patient subtypes. The primary objective of this study is to identify
clinical, imaging and biologic markers of PD progression for use in clinical trials of diseasemodifying therapies.
PPMI will be a five-year natural history study (a minimum of 3-year involvement for
each subject) of de novo idiopathic PD patients and healthy controls. This study will also include
a SWEDD (subjects without evidence of dopaminergic deficit)and Prodromal populations. All
subjects will be comprehensively assessed at baseline and every three to six months thereafter.
Subjects will undergo clinical (motor, neuropsychiatric and cognitive) and imaging assessments
and will donate blood, urine, and cerebral spinal fluid (CSF). A blood sample for DNA will be
collected. Data will be collected by each site under uniformly established protocols and data will
be analyzed and stored at designated core facilities.
4.
Effect of 2.5 Years of Rasagiline Therapy on Progression of Cognitive Biomarkers
Assessed by MRI in Parkinson's Disease (NCT02278588) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02278588?term=NCT02278588&rank=1
In this investigator-initiated study, we will compare changes in brain cognitive
biomarkers assessed by diffusion tensor imaging over 2.5 years among 12 patients with
Idiopathic Parkinson's disease (IPD) receiving rasagiline, 20 IPD patients not receiving MAO-B
inhibitors and 25 age-matched healthy controls. Will also compare the changes in Mini-Mental
State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) scores and plasma brainderived neurotrophic factor (BDNF) with changes in brain cognitive biomarkers in all IPD
patients and HC over 2.5 years.
5.
Cholinergic Nicotinic Receptors and Cognition in PD (NCT02076295) – США.
Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02076295?term=NCT02076295&rank=1
Mild cognitive impairment and dementia are frequent non-motor complications of
moderate to advanced Parkinson's disease. Brain positron emission tomography (PET) study
findings confirm post-mortem evidence that cholinergic loss is related to cognitive impairment in
Parkinson's disease. However, current cholinergic augmentation therapy is not always effective
and it should only target those Parkinson's disease patients who have evidence of cholinergic
system impairment. The objective of this study is to study the association of a particular subtype
of cholinergic receptors, so-called nicotinic acetylcholine receptors, with cognition in
Parkinson's disease using a novel PET marker of cholinergic system integrity.
Parkinson's disease patients will undergo nicotinic acetylcholine receptor PET imaging
with the radioligand [18F]flubatine and MRI on one day and extensive neuropsychological
testing on another day. The degree of nicotinic receptor expression obtained with PET imaging
will be correlated with the neuropsychology test results. Positive [18F]flubatine PET findings in
this study would establish nicotinic receptors as an important contributor to cognitive
dysfunction in Parkinson's disease and could kindle pharmaceutical interest in pursuing these
agents for Parkinson's disease applications. We expect that lower nicotinic receptor expression is
associated with impaired cognitive functioning in Parkinson's disease. In a personalized
medicine approach the PET radioligand [18F]flubatine could serve as an important marker to
identify those patients who are expected to benefit most from nicotinic receptor drug treatment.
6.
Evaluation of [123I]MNI-420 and SPECT as a Marker of the Adenosine A2a
Receptor in PD, HD and Healthy Subjects (NCT00970229) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT00970229?term=NCT00970229&rank=1
The underlying goal of this study is to assess [123I]MNI-420 SPECT imaging as a tool to
detect A2aR density in the brain of PD and HD research participants to be compared with
similarly aged healthy subjects.
To assess the dynamic uptake and washout of [123I]MNI-420 in brain using single
photon emission computed tomography (SPECT) in Parkinson's disease (PD), Huntington's
disease (HD), and similarly aged healthy subjects as a potential imaging biomarker of adenosine
receptor type A2a (A2aR) in brain - To acquire initial safety data following injection of
[123I]MNI-420
7.
Electromyography
Signals
as
Biomarkers
for
Parkinson's
Disease
(NCT02168504) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02168504?term=NCT02168504&rank=1
This study will use the analysis of electrical activity recorded from hand muscles during
handwriting and at rest. There will be two groups of subjects: early Parkinson's disease patients
and healthy people. The researcher analyzing the recorded data will not know who is a patient
and who is healthy, as subjects will be identified only by numbers. Healthy volunteers will be of
similar age as patients. In the course of this study, various properties of hand muscle electrical
activity will be examined, and results will be verified by third party. A neurologist will accrue 10
early PD patients with mild symptoms and 10 healthy controls. Inclusion and exclusion criteria
of participants (early PD patients and healthy controls) will be described by the clients after a
discussion with the neurologist. It is important that the healthy controls should be similar to the
early PD patients in terms of age, gender, and other factors which might also cause differences in
EMG signals. The neurologist's diagnosis of the participants' disease status (early PD or health)
will be considered the "reference standard test" results, and will be kept confidential until the end
of the study. That is, only the neurologist knows the diagnosis for each participant accrued at the
end of the study. An assistant (recorder), who does not know the disease status of these
participants and does not know the study design (e.g., how many PD participants and how many
health controls), will record EMG signals of these participants following the pre-specified
protocol. The order of these participants being examined by the recorder will be randomized. The
signals will be analyzed by the software provided by the clients and results needed for diagnosis
will be outputted and saved in individual files, one for each participant. Another assistant
(reader), who has no contact with these participants and does not know the study design (e.g.,
how many PD participants and how many health controls), would then diagnose each individual
as early PD or health based on the analysis outputs, according to pre-specified rules as described
in the proposal. At the end of the study, the reader's diagnoses will be compared to the
neurologist's diagnosis by a third party. A diagnosis by the reader is defined as correct if this
diagnosis is the same as the neurologist's diagnosis. The success rate of our approach of
diagnosing early PD disease is defined by the total number of corrected diagnoses by the reader
divided by the total number of diagnoses, which equals to the total number of participants.
Statistical analysis The null hypothesis will be rejected, i.e., the client's claim about the
capability of their approach in diagnosing early PD should be accepted, if the number of correct
diagnosis equals to or exceeds 15, Otherwise, the null hypothesis will not be rejected and the
clients' claim about the capability of their approach in diagnosing early PD will not be accepted.
We claim that the success rate of their approach should be no less than 0.8. We denote P0 (= 0.5)
as the success rate under the null hypothesis, and P1 as the success rate under the alternative
hypothesis. We expect P1 >= 0.80 based on pilot study results. A sample size of 20 participants
achieves 80% power to detect a difference (P1-P0) of 0.30 using a one-sided binomial test. The
target significance level is 0.05. The actual significance level achieved by this test is 0.0207.
These results assume that the population proportion under the null hypothesis is 0.50. As a
secondary objective, the clients could also generate estimates and 95% confidence intervals of
sensitivity and specificity of this approach for diagnosing PD. However, it should be noted that
given the small sample size, we couldn't produce accurate estimate of sensitivity and specificity.
For example, with 10 PD participants, and assume that the sensitivity is about 0.9, the width of
the 95% CI for the estimated sensitivity would be as large as 0.44.
8.
Imaging Biomarkers of Progression of Mobility Impairment in Parkinson's
Disease (PD) (NCT01106976) – США. Испытание завершено.
https://clinicaltrial.gov/ct2/show/NCT01106976?term=NCT01106976&rank=1
The main purpose of the follow-up study is to determine which of the two brain
chemicals (dopamine, acetylcholine) or changes seen on brain MR called "small vessel disease"
(which is commonly seen with aging) are related to development of balance problems. The study
activities are very similar as the previous study you participated in.
9.
Development of a Novel 18F-DTBZ PET Imaging as a Biomarker to Monitor
Neurodegeneration of PARK6 and PARK8 Parkinsonism (NCT01759888) – Тайвань.
Испытание завершено.
https://clinicaltrial.gov/ct2/show/NCT01759888?term=NCT01759888&rank=1
The primary objective of this protocol is to access the utility of 18F-DTBZ PET imaging
as an in vivo biomarker to monitor neurodegeneration of both PD mouse models and PD
patients. Secondary, the investigators will analyze progression rate of genetic-proving PARK8
and PARK6 patients who have homogeneous phenotype and genotype by 18F-DTBZ PET
imaging.
Total of 60 patients, 20 LRRK2 G2385R, 20 PARK6, and 20 idiopathic PD, will be
recruited. Subjects will be evaluated sequentially with 18F-DTBZ during a 36 month period.
18F-DTBZ PET scans will be performed twice, at baseline, and 24 (21~27) months following the
start of their participation in the study. Subjects will receive a single i.v. administration of
approximately 10 mCi 18F-DTBZ immediately prior to imaging. Whitney test will be used to
compare the mean standard uptake value ratio (SUVR) values between groups. The decline rate
of VMAT2 density will be calculated by comparing the SUVRs of age-matched healthy subjects
from our previous studies. Each evaluable subject involved in this study must fulfill all the
inclusion and exclusion criteria according the subject grouping, each subject will have 3 visits in
each scan (total 6 visits in this study), as one screening visit, one imaging visit, and one safety
evaluation visit. Safety measurement will be evaluated by medical history, vital signs, physical
examinations, laboratory examinations and collecting of adverse events.
10.
LRRK2
and
Other
Novel
Exosome
Proteins
in
Parkinson's
Disease
(NCT01860118) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT01860118?term=NCT01860118&rank=1
This proposal seeks to 1) determine whether there are biomarkers associated with
Parkinson's disease (PD) susceptibility and/or progression in exosome-proteomes derived from
PD patients versus controls, and 2) to determine if LRRK2 expression and/or phosphorylation
are significantly lowered in the exosomes of individuals treated with the potent LRRK2 kinase
inhibitor sunitinib (a multi-kinase inhibitor compound), to establish an assay for on-target effects
for future LRRK2 inhibitor clinical trials.
11.
Intestinal and Nasal Microbiota of Patients With Idiopathic Parkinson's Disease
(NCT01536769) – Финляндия. Испытание активно, набор пациентов завершён.
https://clinicaltrial.gov/ct2/show/NCT01536769?term=NCT01536769&rank=1
The cause of Parkinson's disease (PD) is unknown and a reliable biomarker to identify
PD patients as early as possible is urgently needed. Nerve cells near the nose and in the gut
become first affected in PD and patients frequently suffer from loss of smell and constipation.
The nose and gut harbor very high amounts of bacteria that influence our body functions in many
ways, even in the brain. The investigators are examining a possible role of bacteria of the nose
and gut in the pathogenesis of PD. This may lead to a better understanding of what PD causes
and may open new possibilities for diagnosis and treatment. The investigators will recruit 100
PD patients and 100 control subjects. The investigators will characterize all subjects carefully
with respect to clinical symptoms. The investigators will collect bacterial samples from the nose,
mouth and stool of these subjects. Using modern genomic techniques the investigators will read
out the genetic code of all bacteria contained in these samples and will be able to identify which
species of bacteria are present in the samples. Using complex cluster computing the investigators
will compare the pattern of bacterial species between PD patients and controls and look for
specific abnormalities in PD patients. If the investigators can detect specific differences of
bacterial communities between PD patients and controls this may point to a role of bacteria as a
cause of PD. Since there are many ways to influence bacterial communities pharmacologically
(antibiotics, probiotics) it will be possible to investigate whether these therapies could alleviate
or even reverse PD symptoms. Furthermore, the investigators would be able to use these
differences as a biomarker which would enable us to develop a quick screening test for bacterial
samples that may reveal whether a person has PD or not. By doing this study the investigators
will learn whether bacteria play a role in the development of PD and whether the investigators
can use them as a biomarker or therapeutic target. So hopefully the investigators will be able in
the future to better understand what causes PD, how the investigators can diagnose it as early as
possible and how to cure patients from PD.
12.
Biomarkers in Parkinsonian Syndromes (NCT02114242) – Франция. Идёт
набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02114242?term=NCT02114242&rank=1
Parkinson disease (PD), multiple system atrophy (MSA) and progressive supranuclear
palsy (PSP) are neurodegenerative disorders. PD and MSA are alpha-synucleinopathies, which
are characterized by the abnormal accumulation of alpha-synuclein, while tau protein
accumulates in PSP. The development of biological markers for the diagnosis and prognosis in
PD, MSA and PSP remains an unmet need. Such biological markers are crucial for future
disease-modification and neuroprotection trials. Alpha-synuclein has a high potential for
biomarker development since it constitutes the pathological hallmark feature in PD and MSA.
The oligomeric alpha-synuclein seems to be particularly involved in abnormal protein
aggregation in alpha-synucleinopathies. The main objective is to compare oligomeric alphasynuclein CSF levels between PD, MSA and PSP patients. PD and MSA patients will receive
Cerebrospinal Fluid (CSF) and blood sampling at two study visits (baseline and after 12 months).
Major secondary objectives are (i) to assess potential associations between the biomarker and
clinical measures of disease severity and progression in MSA and PSP, and (ii) to assess the
variation of the biomarker and its correlation to disease severity and progression in PD, MSA
and PSP.
The differential diagnosis between Parkinson's disease, multiple system atrophy and
progressive supranuclear palsy can be very difficult in early disease. PD, MSA and PSP are
neurodegenerative disorders. PD and MSA belong to the alpha-synucleinopathies, which are
characterized by the abnormal accumulation of alpha-synuclein. Alpha-synuclein accumulates in
intraneuronal Lewy bodies in PD patients and as intracytoplasmic glial inclusions in MSA. In
PSP, tau protein accumulates in neurons and glia cells while alpha-synuclein deposits are only
found to a small extend. The development of biological markers for the diagnosis and prognosis
of PD, MSA and PSP remains an unmet need. Beyond guiding clinical decision-making, such
biological markers are crucial for future disease-modification and neuroprotection trials. Alphasynuclein has a high potential for biomarker development since it constitutes the pathological
hallmark feature of PD and MSA. The oligomeric alpha-synuclein fraction whose CSF levels are
increased in PD seems to be particularly involved in abnormal protein aggregation in alphasynucleinopathies. The main objective of the study is to compare oligomeric alpha-synuclein
CSF levels between PD, MSA and PSP patients. Secondary objectives are (i) to compare total
alpha-synuclein levels and the index total/oligomeric alpha-synuclein between PD, MSA and
PSP, (ii) to study the correlation and concordance between CSF and plasma levels of total and
oligomeric alpha-synuclein, (iii) to assess potential associations between the biomarker and
clinical measures of disease severity and progression and (iv) to assess the variation of the
biomarker over time and its correlation to disease severity and progression.
13.
Shanghai Parkinson's Study (NCT00999388) – США/КНР. Испытание
завершено.
https://clinicaltrial.gov/ct2/show/NCT00999388?term=NCT00999388&rank=1
Background: - Parkinson disease (PD) is the second most prevalent neurodegenerative
disease, affecting more than 1 percent of the elderly population in the United States and other
Western countries. Although effective treatments can alleviate symptoms in early PD, no cure or
treatment slowing disease progression has been identified, and patients will eventually develop
severe physical and mental disabilities and often die of complications. More research is needed
on the causes of and appropriate preventive strategies for PD. - The Shanghai Women s Health
Study (SWHS) was established 10 years ago by investigators from the Vanderbilt University, the
Shanghai Cancer Institute (SCI) and the National Cancer Institute (NCI) of the US. Their
primary aim was to examine several unique dietary hypotheses on cancer among Chinese
women. Researchers from the National Institute of Environmental Health Sciences and SWHS
investigators are now interested in studying PD patients from SWHS to evaluate biological and
environmental factors that may have put them at risk for PD. Objectives: - To initiate a long-term
prospective study on PD in Chinese women from the Shanghai Women s Health Study. - To
examine a set of biological and environmental factors that may raise or lower risk of developing
PD. Eligibility: - All participants of the SWHS cohort are eligible. Design: - Researchers will
contact self-reported PD cases from the SWHS, confirm (or reject) the self-report, and invite
them to a clinical examination at a coordinating hospital in Shanghai. - Cases that confirm the
self-report will be invited to visit the coordinating hospital for clinical examinations, including a
PD clinical workup, blood and urine collections, a cognitive assessment and relevant
neuropsychological testing, and an interview on additional risk factor exposures that are not
available from baseline surveys. - For those who could not participate in the clinical
examination, researchers will ask for a few details about the diagnosis and treatment history and
ask for permission to obtain medical records relevant to PD diagnosis from government or
hospital agencies. - For self-reported PD cases who are now deceased, researchers will follow a
similar procedure by asking for consent and help from the next-of-kin.
We propose to clinically examine self-reported Parkinson s disease (PD) patients from the
well established Shanghai Women s Health Study (SWHS) and thus initiate a long-term PD
research in this unique Chinese women cohort. The SWHS cohort was established in late 1990s
by Dr. Wei Zheng from Vanderbilt University in collaboration with investigators from the
Shanghai Cancer Institute (SCI) and the National Cancer Institute (NCI) of the US. Their
primary aim was to examine several unique dietary hypotheses on cancer among Chinese
women. From 1996 to 2000, the SWHS successfully recruited 74,942 Chinese women, aged 40
to 70, from selected communities in a single district in Shanghai with an overall consent rate of
92%. All participants completed a comprehensive baseline survey, 88% donated urine, 76%
donated blood, and an additional 12% donated buccal cells.1 Follow-up surveys have since been
conducted biennially with consistent participation rates of 95% or higher. Through the 3rd
follow-up, the cohort has documented 220 self-reported PD cases and we expect to identify
another 80 self-reports during the ongoing 4th follow-up survey (2007-2010). We hereby propose
to clinically examine self-reported PD patients to achieve the following two major aims. Aim #1:
To initiate a long-term prospective study on PD in this unique Chinese women cohort Aim #2: To
examine the following specific hypotheses among women 1. < TAB> Higher plasma levels of
pro-inflammatory biomarkers predict higher PD risk. 2. < TAB> Higher plasma uric acid is
associated with a lower PD risk 3. < TAB> Environmental tobacco smoke (ETS) is associated
with lower PD risk 1. Self-reported ETS exposure is associated with a lower PD risk 2. Higher
urine level of cotinine is associated with a lower PD risk We hereby propose a prospective study
on PD in a unique women-only cohort. The infrastructure and the many desirable characteristics
of this cohort offer us a rare opportunity for PD research in women, particularly on biomarkers.
We expect to establish it as a long-term and excellent resource for PD research in women in the
future. In the short term, we plan to examine several promising PD hypotheses that have not
been adequately evaluated among women. These findings will apply directly to Chinese women
and may also have implications for women in the West. PD etiological research is underrepresented in women. Therefore, research in the SPS may not only corroborate findings on
women in the west, but also lead to the identification of novel risk factors that could be
generalizable to Western women.
14.
Biomarkers of Risk of Parkinson Disease (NCT00775853) – США. Идёт набор
пациентов.
https://clinicaltrial.gov/ct2/show/NCT00775853?term=NCT00775853&rank=1
This study (https://pdrisk.ninds.nih.gov) will determine if people who have risk factors
for Parkinson disease (PD) have biomarkers (objective ways to measure a disease process) that
show that the disease process is actually going on, and if people who have abnormal biomarkers
go on to develop PD during several years of follow-up. Biomarkers of Parkinson disease (PD)
might identify people who are healthy now but may develop the disease later in life. Healthy
volunteers and people who have certain risk factors for developing PD who are between 18 and
70 years of age may be eligible for this study. People with the following risk factors are included:
- Family history of PD - Loss of sense of smell - Fall in blood pressure when standing up - REM
behavior disorder (a type of sleep disturbance) Participants undergo the following tests and
procedures: - Screening examination - Medical and neurological history and physical
examination - Tests or rating scales for movement, sense of smell, mood, attention, fatigue, pain,
and thinking. - Measurement of blood pressure and pulse rate while lying down and then
standing up - Blood draw for genetic testing - Inpatient testing at the NIH Clinical Center for 2-3
days, including: - Measurements while blowing against a resistance - Measurements of blood
pressure and pulse rate - Blood draws for levels of various chemicals - PET and MRI scanning -
Lumbar puncture (spinal tap) - Electrocardiogram - Skin electrical conduction test (test of sweat
production) - Skin and core temperature measurements - Transcranial ultrasound (sound-wave
test of the head) - Follow-up testing (up to five visits in 18-month intervals) to repeat some of the
tests listed above, excluding the genetic testing and spinal tap
Objective: This Protocol is to test whether individuals with putative risk factors for
Parkinson disease (PD) have abnormal values for biomarkers of central or peripheral
catecholaminergic innervation and whether at-risk individuals with positive biomarkers develop
PD within up to 7.5 years of follow-up. Study Population: The subjects are individuals who may
be at risk for developing PD, because of (a) genetic risk i.e., a family history of PD or genotypic
abnormalities known to be associated statistically with PD; (b) olfactory dysfunction i.e.,
decreased ability to distinguish among odors; (c) symptomatic rapid eye movement (REM) sleep
behavior disorder (RBD); or (d) orthostatic hypotension. A total of 200 at-risk subjects undergo
catecholaminergic biomarker testing by 6-[18F]fluorodopa brain and 6-[18F]fluorodopamine
cardiac scanning. At-risk subjects with positive biomarkers are compared to at-risk subjects
without positive biomarkers, in terms of development of PD during follow-up. Up to 20 control
subjects are included, to add to a database of normal values for catecholaminergic biomarkers.
Design: The study includes four phases recruitment, screening, laboratory biomarkers testing,
and follow-up. Recruitment is by advertisement and a web site questionnaire of self-reported
risk. A screening examination is done at the NIH Clinical Center, to confirm risk status. Based on
the screening examination results, subjects undergo clinical laboratory testing, to identify central
and peripheral catecholaminergic denervation. In the follow-up phase, subjects are re-tested
approximately every 18 months for a total of up to 5 re-evaluations (90 months, or 7.5 years), to
detect onset of the characteristic movement disorder in PD and follow the status of
catecholaminergic innervation. Outcome Measures: Primary: Diagnosis of PD by a board
certified neurologist who is blinded to risk factor status and the results of catecholaminergic
biomarkers testing. If PD diagnosed, time to diagnosis. Secondary: UPDRS; 6-[18F]fluorodopa
brain scanning, 6-[18F]fluorodopamine cardiac scanning; CSF and plasma neurochemicals;
neuropsychological rating scales; autonomic function testing; retrospective CSF proteomics;
retrospective DNA analyses.
15.
Measure of Microglial Activation in the Brain of Parkinson Disease Patients With
PET (NCT02319382) – Франция. Идёт набор пациентов.
(High Resolution PET Imaging of Microglial Activation in Parkinson's Disease (PD)
With a New Tracer [18F]DPA-714)
https://clinicaltrial.gov/ct2/show/NCT02319382?term=NCT02319382&rank=1
There is accumulating evidence suggesting that inflammatory processes, through
microglial activation, would play a key role in the neurodegenerative process of Parkinson's
disease (PD). It is considered that microglial activation would be part of self-propelling cycle of
neuroinflammation that fuels the progressive dopaminergic neurodegeneration. It is however
hard to evidence microglial activation in vivo, especially in the substantia nigra: first, the
investigators need very high resolution imaging tools and then, the only ligand available to date,
11C-PK11195, has a low sensitivity and specificity and provided heterogeneous results. 18FDPA-714 is a new PET ligand which labels microglial cells. The investigators aim to explore the
topography and intensity of microglial activation in several different groups of PD patients: 1) de
novo, drug-naïve subjects (n = 6); 2) non-fluctuating treated patients ("honeymoon") (n = 10); 3)
advanced drug-responsive patients motor fluctuations (wearing-off or dyskinesia) (n = 6); 4)
patients with LRRK2 gene mutation (n = 6); and 5) related to healthy patients carriers of the
mutation LRRK2(n = 6). PET imaging will be performed with a new generation tomography
having a very high resolution. This study might reveal significant neuroinflammatory process in
the midbrain of PD patients and will determine if such process is present in both sporadic and
genetic forms of PD. The results of this study might provide a new biomarker of disease
pathological progression and help as identifying subjects who might most benefit from a specific
anti-inflammatory drug.
16.
Parkinson's Diseases Susceptibility Genes and Pesticides (NCT00044590) –
США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT00044590?term=NCT00044590&rank=1
While many pathophysiologic pathways may be involved in the neurodegeneration
responsible for PD, genetic factors are likely to determine a general susceptibility to
neurodegeneration. There are a number of genetic polymorphisms of genes such as those coding
for the cytochrome p450 super-family of genes referred to as 'susceptibility genes'. However,
they are generally not sufficient to cause disease unless a person encounters exposure to an
environmental toxin: the disease is caused by a gene-environment interaction. Thus, it is
imperative to assess genetic susceptibility in individuals exposed to a toxin. We will test the
gene-environment interaction hypothesis by conducting an epidemiologic population-based casecontrol study of newly diagnosed PD patients from three rural California counties: Kern, Fresno,
and Tulare. Over a four year period, we expect to collect 400 cases referred to us by local
neurologists, farm worker clinics, and Parkinson's foundations. For each case, one population
control will be selected at random from residential parcel maps and Medicare databases and, in
addition, one unaffected sibling control and - when possible - affected siblings to avoid potential
biases and inefficiencies inherent in the use of each type of control. For each study subject, an
environmental and occupational pesticide exposure estimate will be derived using California
pesticide-use reporting (PUR) data and information about pesticide application on crops in
combination with crop patterns shown in satellite images and aerial photographs; in addition,
extensive exposure interviews will be conducted with all study subjects. In a three-tiered
approach to examine the effects of gene-environment interactions we will: 1) test for association
(and linkage) of PD to selected loci associated with PD in earlier studies using multiallelic repeat
markers and genotyping; 2) test for association using intragenic single nucleotide polymorphisms
(SNPs) of 50 candidate genes arrayed to create "the PD array"; and 3) use future technical
possibilities to screen for genome wide associations using array technology to scan 5,000-10,000
SNPs throughout the genome. Data analysis will employ hierarchical modeling procedures to
take into account multiple comparison issues and to incorporate prior knowledge such as
increased neurotoxicity due to the interaction of gene products and chemicals.
17.
Study for the Early Diagnosis of Parkinson's Disease (NCT02283073) – Израиль.
Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02283073?term=NCT02283073&rank=1
In this study, the PDx assay will be designed and validated in order to distinguish
between Idiopathic Parkinson's disease (PD) to patients with similar symptoms and healthy
controls. The differential diagnosis cohort includes patients diagnosed with Multiple System
Atrophy (MSA), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD),
Essential Tremor (ET) or Lewy Body Dementia (LBD) and Healthy Controls. This is a
prospective observational study. Blood samples and clinical data will be collected at the first and
only study visit. The expression levels of 5 to 6 genes will be analyzed by blinding technicians
concerning the diagnosis, demographic data and clinical data, which will be revealed after
sending PDx gene expression values to the clinical sites. The gene expression levels will be
compared between Parkinson's disease patients to the differential diagnosis cohort and healthy
controls. The primary aim of the study is to design and validate a clinical classifier that will aid
the physician in the diagnosis of Parkinson's disease patients. The analysis will be performed in
two stages: Stage 1) Exploration analysis and Stage 2) Validation. After one year of taking a
blood sample, the study physician will contacted to confirm the patient's diagnosis. Blood
samples will be collected at specialized movement disorder clinics. Medical history, clinical
diagnostic features, family history in regard to Parkinson's disease, use of medication and routine
imaging assessment (not mandatory) will be collected at the first and only patient visit.
18.
Using Heavy Water to Study Cell Dynamics in Parkinson's Disease
(NCT00990379) – США. Испытание активно, набор пациентов завершён.
https://clinicaltrial.gov/ct2/show/NCT00990379?term=NCT00990379&rank=1
This pilot study will assess the feasibility of using heavy water as a safe 'tracer' for
biomarker studies of diseases of the brain and spinal cord, that, together, are also called the
central nervous system (CNS). Heavy water, also called deuterated water or D20, is the same as
normal drinking water except the hydrogen atoms have been replaced by deuterium, a naturally
occurring isotope of hydrogen. In particular, this study will use heavy water to define: 1) The
rate of immune cell proliferation (growth) in the cerebrospinal fluid (CSF) compared to blood.
This study will be examining a particular type of immune cell called T lymphocytes. 2) This
study will also examine selected molecules generated by nerve cells of the CNS to understand
their rate of secretion and turnover in healthy control participants, HIV-1-infected participants
and participants with a non-HIV-related neurodegenerative disease such as Parkinson's disease
(PD). This study will involve the administration of heavy water orally for either seven days, 12
days or six weeks. Measurements will be taken by lumbar puncture (LP, also known as a spinal
tap). Blood (approximately five tablespoons per visit) will also be obtained at each of the lumbar
puncture appointments. If this method can be used to establish the rates of immune cell turnover
and the production rates of neuronal molecules using cerebrospinal fluid, it will provide unique
data that is important to understand chronic neurodegenerative conditions, like PD, and to
measure responses to targeted therapies. Hypothesis: 1. D2O, administered orally, can be used to
measure the proliferation rates of CSF T cells (and, eventually, of their major phenotypic
subsets). 2. D2O can be used to assess the turnover and production rates of CNS constituents that
are normally or pathologically shed or secreted into the CSF, including (eventually): cargo
molecules transported specifically in neurons in the CNS, such as chromogranin-A and -B,
neuregulin-1 (specifically the extracellular secreted ectodomain of neuronal differentiation factor
(NDF) isoform type α1, α2, β1, and the acetylcholine receptor inducing activity isoform (ARIA),
secreted amyloid precursor protein (sAPP), alpha-synuclein; and APP metabolites amyloid beta
(Aβ) 41 and 42.
19.
Neuroimaging of Dystonia (NCT02046447) – США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02046447?term=NCT02046447&rank=1
The main purpose of this study is to investigate primary cervical dystonia as compared to
healthy control subjects and DYT 1 dystonia as compared to healthy control subjects by
examining cognitive measures, physical measures, and structural and functional magnetic
resonance imaging (MRI). The secondary aim of this study is to investigate a specific drug
therapy for primary cervical dystonia to develop a functional MRI (fMRI) research paradigm.
The drug, trihexyphenidyl, is FDA approved to treat Parkinson's Disease and is commonly
prescribed by physicians as a treatment for symptoms of primary cervical dystonia.
To participate in this study, you will be asked to come to the University of Florida for one
testing day. For your convenience, arrangements will be made by the study coordinator. If you
have a movement disorder, you will be tested in an "off" medication condition. We do not expect
concerns or unwanted consequences arising from discontinuing medications for this duration. We
will review the informed consent and you will have the opportunity to ask questions before
signing the informed consent. During the experiment, you may be asked to complete the
following: (1) questionnaires about quality of life and depression; (2) tests to measure your
strength and motor function; (3) tests to measure your cognition; (4) functional and structural
MRI scan of your brain while performing a precision gripping task; (5) intravenous blood draw;
(6) urine pregnancy test (if applicable); (7) trial of anticholinergic therapy drug trihexyphenidyl
(if applicable - cervical dystonia only). Participants with DYT 1 dystonia and healthy controls
are not eligible to receive the trial drug. All women of childbearing potential will be given a
urine pregnancy test. The questionnaire about depression will not be given to subjects under the
age of 18. If you have any metal in your eye or eyes, the researchers may require additional
screening to ensure that it is safe for you to enter the MRI environment. If additional screening is
determined to be necessary, you will be referred to Radiology at Shands UF for an orbitofrontal
x-ray. Blood will be collected for all subjects, including healthy control subjects. The blood may
be analyzed, at the University of Florida, to assess potential biomarkers for cervical dystonia and
DYT 1 dystonia. Biomarker testing is another way to say genetic testing.
20.
Behavioural Addiction and Genetics in Parkinson's Disease (NCT02319395) –
Франция. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02319395?term=NCT02319395&rank=1
The "Behavioural Addiction and Genetics in Parkinson's Disease " study (BADGE-PD) is
a national (France), multicenter, genetic association, case-control study to identify genetic factors
associated with behavioural addiction (or Impulse Control Disorders, ICD) related to dopamine
agonists treatment in Parkinson's disease (PD). Polymorphisms of candidate genes supposed to
be involved in this adverse effect will be compared in 200 PD patients with ICD (n=200) and
200 matched PD patients without ICD (n=200).
Objective: To identify susceptibility genes to impulse control disorders in Parkinson's
Disease. Study design: Genetic association study. Primary objective: To identify the
susceptibility genes in behavior addiction in Parkinson's Disease Secondary endpoints: - To
compare the clinical, neurological and psychiatric features of parkinsonian patients with
behavior addiction compared to the control population. In case of differences between these
groups, interaction will be studied with genetic factors - Identify a psychometric profile from the
TCI-R scale corresponding to the "hyperdopaminergic" subjects with AC personality Patient
selection: Cases: patients with Parkinson's disease (PD) and impulse control disorder (ICD) as
defined by a score greater than or equal to 2 or 3 scores greater than or equal to 2 at the
"Evaluation Comportementale de la Maladie de Parkinson" scale (ECMP, Ardouin et al. 2009)
for hyperdopaminergic items. Controls: PD patients without impulse control disorder (ICD) as
defined by a score of 0 or 1 at each hyperdopaminergic items AND no more than 2 items with a
score of 1. Controls must have been treated with at least 300 mg of Levodopa equivalent daily
dose for more than 12 months. Controls will be matched for sex, age, and age at onset of PD.
Number of subjects: 200 cases and 200 controls. Clinical assessment: motor score (UPDRS),
neuropsychological assessment, diagnostic criteria for addiction and ICD (MINI), selfadministered psychometric questionnaire (TCI-R), treatment history, ICD history. Genetic
analysis: A blood sample will be taken for extraction and storage of DNA (DNA bank and PitieSalpetriere cells). Candidate genes* and polymorphisms will be selected from the literature data
(receptors, transporters and metabolizing enzymes monoamine) and the molecular signature
induced by L-DOPA in the striatum of a mice model of PD. Statistical analysis: A two-step
analysis will be performed. For the first step, a training set (36% of subjects) will be analyzed
with a logistic regression model considering an additive genetic effect. For the second step, the
top 27% of the more significant genetic markers will be analyzed by using the left over
replication set (64% of patients). Finally, a pooled analysis will be performed. Sample Size: 200
patients per group to study 50 candidate markers with a power of 83% for genotype effect of 2.0,
an additive genetic model, each allele frequency of 0.5. * candidate genes list: 20 genes from the
literature : DRD1, ANKK1, DRD2, DRD3, DRD4, DAT1, MAOA, COMT, HTR2A, HTR1B,
TPH1, TPH2, 5HTT, GRIN2B, DBH, SCL6A2, BDNF, OPMR1, OPRK1, PDYN 8 genes from
the experimentation: FosB, Arc, Nptx2, Ccrn4l, Car12, C8b, Mocs1, Mef2c
21.
Developing a Novel Imaging Biomarker in the Differential Diagnosis of
Parkinson's Disease and Parkinsonism by 18F-DTBZ PET (NCT02059733) – Тайвань. Идёт
набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT02059733?term=NCT02059733&rank=1
This study will compare the brain uptake of 18F- DTBZ in 20 patients with PD, 20
patients with MSA, 20 patients with PSP, 20 patients with CBS, and 20 patients with VaP, 20
patients with ET, and 10 patients with DT.
Study duration is expected to be completed in a period of 4 year. This study is a
uncontrolled, open-label, non-randomized, parallel, and cross-sectional study. Total 130 subjects,
including 20 patients with PD, 20 patients with MSA, 20 patients with PSP, 20 patients with
CBS, 20 patients with VaP, 20 patients with ET, and 10 patients with DT, will be enrolled. Each
evaluable subject involved in this study must fulfill all the inclusion and exclusion criteria
according the subject grouping, each subject will have 3 visits in this study, as one screening
visit, one imaging visit, and one safety evaluation visit. Safety measurement will be evaluated by
medical history, vital signs, physical examinations, laboratory examinations and collecting of
adverse events.
22.
A Biospecimen and Clinical Data Study on Patients With Alzheimer's, Multiple
Sclerosis, Parkinson's, and Huntington's, for Drug & Biomarker Discovery (NCT01592552) –
США. Идёт набор пациентов.
https://clinicaltrial.gov/ct2/show/NCT01592552?term=NCT01592552&rank=1
The purpose of this research project is to collect and store blood samples and clinical
data. Researchers can then use the stored samples in future studies. Through such studies, they
hope to find new ways to detect, treat, and maybe even prevent or cure health problems.
23.
Parkinson's Disease Biomarker Program (PDBP) (NCT01767818) – США.
Испытание активно, набор пациентов завершён.
https://clinicaltrials.gov/ct2/show/NCT01767818?term=NCT01767818&rank=1
The primary objective of this study is to obtain detailed clinical information and biologic
specimens from subjects with PD toward the ultimate end of identifying a biomarker of PD.
Because of the inherent difficulties of using clinical outcome measures to assess disease
modification, the identification of biomarkers of PD is of paramount importance. The ideal PD
biomarker would be one that is easily assayed in a convenient biological sample, varies
proportionally with disease severity, is abnormal during the pre-symptomatic phase of the illness,
and is unaffected by drugs or other interventions used to treat PD. The existence of a sensitive
biomarker with these properties would enable much more effective disease modifying research
that would likely be able to take advantage of smaller and potentially shorter trials.
24.
Research of Biomarkers in Parkinson Disease (Genepark) (NCT00465790) –
Франция. Испытание завершено.
https://clinicaltrial.gov/ct2/show/NCT00465790?term=NCT00465790&rank=1
With special emphasis on the careful clinical selection of patients and sufficient power
regarding patient numbers, as well as extensive quality control and validation of the data,
GENEPARK aims to develop a standardised approach to development and validation of
haemogenomic biomarkers of disease.
Employ innovative haemogenomic approaches to determine gene expression signatures
specific for idiopathic Parkinson's disease (PD). There is currently no specific clinical or
laboratory diagnostic test available for PD. In GENEPARK, blood samples from patients with
genetic PD and idiopathic PD will be analysed by microarrays to identify gene expression
signatures specific for PD. The specificity of the new biomarkers for PD will be tested by the
analysis of patients with atypical parkinsonisms, including multiple system atrophy (MSA),
progressive supranuclear palsy (PSP) and diffuse Lewy body disease (DLBD), as well as in
patients with other basal ganglia disorders such as Huntington's disease (HD) and dopa
responsive dystonia (DRD). The validated gene expression signatures will be utilised to develop
a new test for diagnosis of idiopathic PD. Determine correlation between gene expression
signatures and different stages of PD.
Gene expression in presymptomatic and symptomatic patients with genetic forms of PD
as well as patients in various stages of idiopathic PD will be analysed to identify gene expression
signatures specific for various stages of the disease. It should be emphasised that since no
clinical measures are present in presymptomatic genetic PD such molecular markers could serve
as surrogate markers to monitor therapeutic efficacy of possible preventive treatments in PD.
Determine correlations between gene expression signatures and morphological evidence of
neurodegenerative process in PD brain as determined by neuroimaging. Gene expression
signatures identified in blood samples will be correlated with changes in brain as detected by
neuroimaging in PD patients. Such correlations of molecular and morphological markers of
disease will facilitate the selection of blood markers in relation to disease progression. Moreover,
molecular and morphological markers of disease progression could be utilised in combination for
monitoring the effects of new neuroprotective therapies for PD. Develop standardised
approaches to development and validation of haemogenomic biomarkers.
This objective will be achieved by the special emphasis on careful clinical selection of
patients, sufficient power regarding patient numbers, as well as extensive quality control and
validation of the data. Develop new bioinformatic software tools for selection of genomic
biomarkers using microarray data. The aim of the GENEPARK is to develop the theoretical
foundations and to build the software tools for sample classification and selection of genomic
biomarkers using microarray data. The established computational tools and novel methods
developed within the GENEPARK will be applied to the patient data to study advantages and
limitations of different methodologies.
ДОПОЛНЕНИЯ
На специальном сайте американского министерства здравоохранения, содержатся в
открытом доступе большинство указаний и руководств, в т.ч. и европейских:
http://www.guideline.gov/index.aspx.
Руководство по диагностике болезни Паркинсона Европейской Федерации
неврологических обществ / Европейского отделения общества изучения расстройств
движения (European Federation of Neurological Societies/Movement Disorder Society–
European Section (EFNS/MDS–ES)) опубликовано в 2013 году:
http://www.guideline.gov/content.aspx?id=43845&search=parkinson%27s+disease.
EFNS/MDS-ES recommendations for the diagnosis of Parkinson's disease / Berardelli A.,
Wenning G.K., Antonini A. et al. // Eur. J. Neurol. 2013 Vol. 20, No 1 P. 16-34.
URL: http://onlinelibrary.wiley.com/doi/10.1111/ene.12022/epdf.
В руководстве рассмотрены следующие диагностические тесты:
1.
Clinical diagnostic criteria (Queen Square Brain Bank [QSBB])
2.
Genetic testing for the following mutations:

Alpha-synuclein (SNCA)

Leucine-rich repeat kinase 2 (LRRK2)

Glucocerebrosidase (GBA)

parkin, PINK1, and DJ-1

ATP13A2, PLA2G6, and FBXO7
3.
Olfactory tests
4.
Neuropsychological tests

Collateral history

Brief assessment of cognition

Screening for rapid eye movement (REM) sleep behavior disorder (RBD),
psychotic manifestations, and severe depression
5.
Neuroimaging

Transcranial sonography (TCS)

Conventional magnetic resonance imaging (cMRI)

Dopamine transporter-single photon emission tomography (DaTscan-SPECT)

Cardiac [123I] meta-iodobenzylguanidine (MIBG)/SPECT imaging
Note: The following interventions were considered but not recommended: autonomic function
tests, drug challenge tests, neurophysiological tests, SPECT imaging other than DaTscan-SPECT
or cardiac [123I] meta-iodobenzylguanidine (MIBG)/SPECT, positron emission tomography
(PET).