Project I:  Evolution of cholinergic deficits within multisensory, cognitive, and motor integration brain regions and development of PIGD features in people with Parkinson’s disease

PI: Nicolaas Bohnen MD, PhD

[18F]FEOBV PET delineates specific cortical regions and deep brain structures, including striatum and thalamic subnuclei. PD subjects with falls vs those with falls and gait freezing exhibit distinct abnormal patterns, highlighted by reduced striatal [18F]FEOBV as a shared dysfunctional node. Dr. Bohnen and his team will prospectively test the hypothesis that the cholinergic AMI network dysfunctions they describe are core features of PD gait and balance dysfunction, and that distinct patterns of cholinergic pathology predict specific features of PD gait dysfunction. The serial assessments proposed will allow unique within-subject analysis for the temporal dissection of distinct and converging elements of mobility control deficits of gait-balance motor features in PD. Unlike the prior grant cycle where longitudinal assessment was limited, esp. for PwP converting from non-fallers/freezers to fallers/freezers, the current cycle will allow clinically meaningful follow-up assessments of up to 5-6 years of PwP who completed baseline [18F]FEOBV PET. Hypotheses to test: 1) whether incident fallers exhibit [18F]FEOBV defects in the caudate, visual thalamus, and prefrontal cortex (compared to non-converters), and 2) whether the subsequent emergence of gait freezing involves additional and more widespread cholinergic vulnerability of the striatum, limbic archicortex, including the cingulo-opercular and insular cortices. The existence of the unique PD subject cohort developed in the currently funded cycle, together with newly recruited subjects, will allow study of an enriched sample of those converting to falls and/or to gait freezing. The focus on visual thalamus, based on the repeated association of falls with cholinergic dysfunction (found with both [11C]PMP and [18F]FEOBV), is another important and novel element. Many thalamic nuclei are primarily interconnected with association cortices with these thalamic nuclei are increasingly viewed as partners and/or modulators of cortical functions. Emerging evidence supports critical roles of visual thalamus in mediating visual attention. LGN function is modulated by attention, indicating a key role for this relay structure in bottom-up attention. Dr. Bohnen has new data implicating cholinergic denervation of additional regions driving non-episodic PIGD deficits preceding falls and FoG. This data indicates that cholinergic deficits within the MGN and entorhinal cortex (EC) are robustly associated with non-episodic PIGD, independent of nigrostriatal dopaminergic deficits. MGN is involved in processing multi-sensory (auditory, vestibular and proprioceptive) inputs, implying a significant role of impaired sensorimotor integration underlying early PIGD features in PwP. EC is associated with visuospatial maps, suggesting deficient attention-visuomotor integration.  Complementary work will be performed in the Catalyst Research Project. The analysis of cholinergic system changes of the evolution of balance and gait disturbances will be complemented by exploratory mechanistic multisensory and attentional-motor integration studies.  These studies will identify the key patterns of cholinergic systems dysfunction underlying treatment-refractory gait and balance disorders in PwP.