The goal of this proposal is to define the signature phenotypic profiles of the two most common genetically defined forms of early onset Parkinson s Disease (PD), parkin (Park2) and glucocerebrosidase (GBA), cross-sectionally (Aim 1), longitudinally (Aim 2), and before motor manifestations that define PD occur (Aim 3). We will recruit 75 PD probands who carry parkin mutations, 100 PD probands who carry GBA mutations, and 100 noncarrier (idiopathic PD) probands and their first-degree relatives (3 per family). The majority of these families have participated in the Consortium on Risk for Early Onset PD (CORE PD) study, which has enrolled 1062 PD probands with age at onset (AAO) < 50.
In Aim 1, we will compare the range of cognitive psychiatric and motor manifestations among the three groups using the CORE PD battery. To enhance detection of cognitive and psychiatric impairment, we will use state-of-the-art computerized assessments of cognition, including interval timing, and lifetime psychopathology.
In Aim 2, to refine our understanding of the prognosis for carriers of parkin and GBA, we will compare the range of cognitive, psychiatric and motor manifestations at baseline, 1.5 years and 3 years. We hypothesize that GBA PD and Parkin PD define extremes of disease progression and that GBA PD will manifest more cognitive and psychiatric impairment at baseline (Aim1) and will decline more rapidly and develop the cognitive and psychiatric features that may lead to Parkinson s disease dementia (PDD) significantly more frequently than parkin PD and IPD (Aim 2).
In Aim 3, we will use our family history interview, video, and new web-based cognitive assessments to describe the development of motor and non-motor manifestations in first-degree relatives. We will determine the age dependent risk of developing PD (penetrance) in asymptomatic relatives who carry GBA mutations and will refine our penetrance estimates in parkin carrier relatives, particularly among Caribbean Hispanics who may have increased penetrance compared to non-Hispanic Whites. This proposal will provide medical professionals and families vital information on progression that is essential for individual treatment decisions. The penetrance estimates will help individuals decide whether to pursue genetic testing and will provide more accurate interpretation of results. Lastly, longitudinal examination of these genetic forms of PD will reduce the marked reported heterogeneity of disease progression. This will lead to improved design of clinical trials that target parkin and GBA carriers for mechanistically-driven treatments.

Public Health Relevance

Determining what it means clinically to carry a mutation in one of the two most common genetic forms of early onset Parkinson?s disease (PD), parkin or glucocerebrosidase (GBA), will aid in medical decision making for symptomatic individuals, and decisions about genetic testing for asymptomatic carriers of these mutations. Describing the clinical course of genetic forms of PD will explain some of the marked differences in reported progression of motor and non-motor signs and will lead to more accurate design of clinical trials for idiopathic PD. Identification of genetic causes of neuropsychiatric impairment in PD may lead to treatments applicable to all individuals who have PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56NS036630-10
Application #
8150561
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Sutherland, Margaret L
Project Start
1998-07-01
Project End
2013-11-30
Budget Start
2010-09-30
Budget End
2013-11-30
Support Year
10
Fiscal Year
2010
Total Cost
$500,000
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Alcalay, R N; Wolf, P; Levy, O A et al. (2018) Alpha galactosidase A activity in Parkinson's disease. Neurobiol Dis 112:85-90
Lee, Annie J; Wang, Yuanjia; Alcalay, Roy N et al. (2017) Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov Disord 32:1432-1438
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Terrelonge Jr, Mark; Marder, Karen S; Weintraub, Daniel et al. (2016) CSF ?-Amyloid 1-42 Predicts Progression to Cognitive Impairment in Newly Diagnosed Parkinson Disease. J Mol Neurosci 58:88-92
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Alcalay, Roy N; Levy, Oren A; Wolf, Pavlina et al. (2016) SCARB2 variants and glucocerebrosidase activity in Parkinson's disease. NPJ Parkinsons Dis 2:
Alcalay, Roy N; Mejia-Santana, Helen; Mirelman, Anat et al. (2015) Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. Parkinsonism Relat Disord 21:106-10
Alcalay, Roy N; Levy, Oren A; Waters, Cheryl C et al. (2015) Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain 138:2648-58
Huntington Study Group Reach2HD Investigators (2015) Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 14:39-47

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