Plaques and tangles as well as Lewy-type alpha synucleinopathy are associated with formed visual hallucinations

Objective: Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer's disease pathology often co-occurs with LTS, we questioned whether this pathology - amyloid plaques and neurofibrillary tangles - might also be linked to VH. Methods: We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB). 173 subjects - including 50 with VH and 123 without VH - were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. Results: A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p=.003 for plaque and p=.004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects+VH than subjects-VH (p<.001). Conclusion: These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis.