Cerebellar cholinergic connections as a biomarker of dementia and gait impairment in Parkinson disease

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder characterized by tremendous clinical heterogeneity. PD with dementia is considered one of the Alzheimer disease related dementias. Dementia, afflicting up to 80% of PD patients and gait impairment cause significant morbidity and

mortality, and tremendously amplify the socioeconomic burden as effective treatments are lacking. Both these impairments are refractory to dopaminergics suggesting involvement of other neurotransmitter systems or brain regions beyond nigrostriatal pathways. Most neuroimaging studies have focused on striatal dopaminergic deficits

and fail to adequately explain gait and cognitive impairments in PD. The midbrain pedunculopontine nucleus (PPN) sends cholinergic input to the cerebellar vermis, which has much greater cholinergic innervation in humans than the cerebellar hemispheres. Degeneration of PPN, known to occur in PD could lead to cholinergic

denervation of vermis. Vermis modulates gait and cognition, but little is known about its role in PD. Recent cerebellar resting-state functional connectivity (FC) analysis demonstrates altered vermal FC with sensorimotor and association cortices in PD and their respective gait and cognitive correlates. This proposed study utilizing a

multimodal approach will extend the prior work and investigate whether longitudinal changes in vermal FC reflect decline in gait and cognition in PD and whether cholinergic denervation of the vermis, as measured by vesicular cholinergic transporter activity (VAChT) PET imaging, underlie these deficits in FC and behavior. The long term

goal is to investigate whether vermal FC and cholinergic PET measures can serve as antecedent markers of dementia and falls in PD. The proposed study serves three major objectives. The first objective is to investigate cholinergic denervation of vermis and two important aspects of vermal FC in PD: its ability to objectively reflect

progression of gait and cognitive impairment and its ties to underlying cholinergic pathology as measured by VAChT PET, the two key attributes of a reliable imaging biomarker. The second objective is to leverage the highly conducive and supportive environment, access to wealth of cross-sectional and longitudinal multimodal

imaging data and comprehensive, sophisticated behavioral measures, and an excellent diverse team of mentors to provide the candidate with training in a) PET analysis and b) conducting longitudinal studies with special emphasis on multivariate, longitudinal statistics to ensure a timely transition to independence. The final objective

for the candidate is to continue to author manuscripts especially involving PET and generate preliminary data towards a R01 application. Although with independent research aims, this study is privileged to use the data collected as a part of large scale longitudinal study with established funding. The proposed study could have

substantial clinical impact by elucidating pathophysiologic bases of dementia and falls in PD, identifying potential therapeutic targets and possible metrics of target engagement, stratifying at risk patients before these disabling symptoms progress irreversibly, potentially leading to individually tailored therapeutic options in the future.