Longitudinal Comparison of the Nature and Evolution of Mild Cognitive Impairment in Individuals With and Without Parkinson's Disease Characterized by Neuroimaging, Clinical Assessments and Genotyping

Parkinson's disease (PD) is the second most frequent chronic neurodegenerative disorder, affecting up to 2% among persons older than 65 years of age and nearly 10% of people over 80. The cardinal symptoms of PD include tremor, rigidity and bradykinesia originating from the loss of dopaminergic neurons in the striatum. It has recently been shown that the non-motor symptoms in PD such as cognitive and behavioural impairment are highly prevalent and have a severe and direct negative effect on health-related and perceived quality of life. It is now well established that 25 to 40% of persons with PD will develop cognitive deficits early in the disease. Moreover, the risk of developing dementia is almost six times higher in PD patients than in age-matched controls. The nature and evolution of cognitive deficits in PD remain poorly understood, so is their relationship with neuropsychiatric features often observed in the disease including depression, anxiety and apathy. Furthermore, the medication treatment of cognitive deficits in PD yields very modest results. PD neuropathology is associated with alpha-synuclein-containing Lewy-Bodies whereas that of Alzheimer's disease (AD) is usually associated with Aß-amyloid plaques and tau-containing neurofibrillary lesions. However, recent post-mortem studies suggest that between 30 and 45% of PD patients with dementia also meet neuropathologic diagnostic criteria for AD. With such a high proportion of demented PD patients with concurrent AD, it would be valuable, from a therapeutic standpoint, to identify those with AD earlier. In the context of the present proposal the investigators will be able to follow different groups of PD patients longitudinally and compare them to non-PD patients with mild cognitive impairment who are at risk of developing a medio-temporal lobe dementia such as Alzheimer's disease.

The three major aims for this longitudinal study are:

1. Identify anatomical and functional neuroimaging, neuropsychological and neuropsychiatric profiles that can serve as markers for the early prediction of dementia in PD.
2. Uncover the cognitive and neural characteristics that are specific to PD-MCI subjects vs. characteristics shared by all MCI subjects whether due to PD or other aetiology such as Alzheimer's disease.
3. Identify the effect of specific genotypes that can influence the cognitive profile and evolution in PD.

The investigators will recruit 100 PD and 100 non-PD individuals. None of them will have dementia. Participants will be selected in order to obtain about 65% MCI and 35% cognitively intact individuals in each cohort (PD, non-PD). At study start they will be asked to consent to a blood draw for genotyping purposes. At each time point, they will receive a neuropsychological evaluation to determine whether and which domain(s) of cognition is (are) affected and whether the participant meets the criteria for dementia. Neuropsychiatric symptoms which are often present before the onset of cognitive symptoms will be assessed at each time point using the Mild Behavioural Impairment-Checklist (MBI-C). At Time points 1 and 2 they will also undergo two MRI sessions containing anatomical acquisitions as well as BOLD functional series while performing an executive (set-shifting) task that the investigators have shown to rely on fronto-striatal regions and an (associative) memory task that solicits the medial temporal lobe. At Time point 3 they will undergo just one MRI session not containing any task. This will allow the investigators to identify markers that can distinguish subgroups with respect to their possible evolution towards dementia. This multi-faceted, longitudinal project promises to enhance the understanding of the nature and evolution of cognitive dysfunction in PD relative to general aging. To the investigators' knowledge, this is the first time that PD and non-PD patients stratified according to cognitive profile will be studied longitudinally using neuropsychological evaluation, anatomical and functional neuroimaging measures as well as genotyping. This information has the potential to yield markers that can be used in clinics to determine the diagnosis and prognosis of cognitive dysfunction in PD, allowing for an early prediction of dementia in the disease. This will ultimately yield intervention and treatment strategies tailored to different patient subtypes, aimed at improving cognitive deficits and decelerating the decline.