Visual cortical dysfunction in Parkinson Disease
Non-motor symptoms are increasingly recognized as important contributors to overall disability and quality of life in patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB). Cognitive impairment and hallucinations are defining features of DLB and are also common in PD. In both DLB and PD, impairments in visuospatial and visual perceptual functions are prominent. These functional impairments correlate with neuroimaging data showing early hypometabolism of the posterior parietal and occipital lobes and later, cortical thinning and atrophy in these same structures. Together, these findings suggest the visual cortical system is an important site of pathology in these disorders. Accumulation and aggregation of the protein a-synuclein is hypothesized to play a central role in the pathogenesis of PD and DLB. Although a-synuclein has well recognized roles in synaptic transmission, including vesicle fusion and neurotransmitter release, the effects of a-synuclein pathology on cortical circuit function are not well studied. To date, there remain significant gaps in our knowledge of how a-synuclein pathology leads to cortical dysfunction. Hypotheses include pre-synaptic denervation due to nigrostriatal degeneration, a-synuclein mediated impairment of cortical neuron activity, and direct cytotoxicity to cortical neurons.
To begin to address these possibilities, we are using longitudinal in vivo two-photon calcium imaging in mice to directly record changes in neuronal ensemble activity of visual cortical circuits throughout the progression of a-synuclein pathology. Our approach allows us to simultaneously image the formation and progression of a-synuclein inclusions and activity of individual cortical neurons longitudinally over time. We also plan to investigate the differential effects of distinct a-syn strains isolated from patients afflicted with synucleinopathies (PD/DLB or multiple system atrophy) on cortical circuit dysfunction. These studies will fill important gaps in our knowledge of the mechanisms underlying cognitive symptoms in synucleinopathies that we hope will inform future therapeutic strategies for PD and DLB.