PROJECT I: SUMMARY/ABSTRACT Postural instability and gait difficulty (PIGD) motor features are common in Parkinson disease (PD), and a significant cause of treatment-refractory disability. Accumulating evidence implicates cholinergic systems dysfunctions as significant contributors to gait and balance impairment. During the initial funding period, we established the vesicular acetylcholine transporter (VAChT) ligand [18F]FEOBV, which uniquely assesses cholinergic terminal density in high density regions such as the striatum. Our recent cross- sectional findings suggest that PwP participants with isolated falls and those with freezing of gait (FoG) status share common cholinergic deficits in the thalamus (lateral geniculate nucleus [LGN]) and striatum (caudate) with more extensive striatal, limbic, and prefrontal VAChT reductions in PwP with FoG. Consistent with Project II preclinical data indicating a critical role for striatal cholinergic interneurons (SChI) in integration of attentional and motor functions, these data suggest that SChI deficits are a common denominator in the etiology of falls and FoG. These results emphasize the need to understand PIGD, falls, and FoG as products of cholinergic projection dysfunctions within the framework of failing Attentional-Motor Integration (AMI) combined with failures of additional multisensory and cognitive integration. Episodic mobility disturbances (falls, FoG) are typically preceded by insidiously developing non- episodic PIGD features. We have novel preliminary data that cholinergic deficits of the medial geniculate nucleus (MGN) and the entorhinal cortex (ERC) are robustly associated with non-episodic PIGD deficits, These results imply a significant role of impaired sensorimotor integration underlying non-episodic PIGD motor features in PwP. The overarching goal of this project is to investigate the evolution of cholinergic deficits within multisensory, cognitive and motor integration brain regions and development of PIGD features in PwP. We hypothesize that this progresses from the MGN and ERC, then LGN and caudate nucleus, and then more diffuse striatal, limbic and cortical (prefrontal followed by anterior cingulum and insula) cholinergic deficits. To assess our hypotheses, we propose to perform a prospective cohort study with [18F]FEOBV brain PET at baseline and 2-year follow-up in PD subjects at risk of conversion to non-episodic and episodic (falls and FoG) PIGD motor features. Novel insights in cholinergic changes underlying incident development of PIGD may inform new therapeutic interventions to treat these debilitating motor complications. Project I is highly integrated thematically with Project II and the Catalyst Research Project, complementary to Project III, and will interact extensively with all Cores. Our work is based on a unique, deeply phenotyped cohort of PD participants developed in the prior funding cycle allowing us to recruit an enriched sample of patients likely to convert to fall and FoG status, allowing longitudinal within-subject assessments.