18F-PI-2620 Tau PET is associated with cognitive and motor impairment in Lewy body disease

Co-pathology is frequent in Lewy body disease, which includes clinical diagnoses of both Parkinson's disease and dementia with Lewy bodies. Measuring concomitant pathology <i>in vivo</i> can improve clinical and research diagnoses and prediction of cognitive trajectories. Tau PET imaging may serve a dual role in Lewy body disease by measuring cortical tau aggregation as well as assessing dopaminergic loss attributed to binding to neuromelanin within substantia nigra. We sought to characterize ¹⁸F-PI-2620, a next generation PET tracer, in individuals with Lewy body disease. We recruited 141 participants for ¹⁸F-PI-2620 PET scans from the Stanford Alzheimer's Disease Research Center and the Stanford Aging and Memory Study, most of whom also had β-amyloid status available (139/141) from PET or cerebrospinal fluid. We compared ¹⁸F-PI-2620 uptake within entorhinal cortex, inferior temporal cortex, precuneus and lingual gyrus, as well as substantia nigra, across participants with Lewy body disease [Parkinson's disease (<i>n</i> = 29), dementia with Lewy bodies (<i>n</i> = 14)] and Alzheimer's disease (<i>n</i> = 28), in addition to cognitively unimpaired healthy older adults (<i>n</i> = 70). Mean bilateral signal was extracted from cortical regions of interest in ¹⁸F-PI-2620 standard uptake value ratio (inferior cerebellar grey reference) images normalized to template space. A subset of participants received cognitive testing and/or the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III motor exam (off medication). ¹⁸F-PI-2620 uptake was low overall in Lewy body disease and correlated with β-amyloid PET in temporal lobe regions and precuneus. Moreover, inferior temporal ¹⁸F-PI-2620 uptake was significantly elevated in β-amyloid positive relative to β-amyloid negative participants with Lewy body disease. Temporal lobe ¹⁸F-PI-2620 signal was not associated with memory in Lewy body disease, but uptake within precuneus and lingual gyrus was associated with worse executive function and attention/working memory performance. Finally, substantia nigra ¹⁸F-PI-2620 signal was significantly reduced in participants with Parkinson's disease, and lower substantia nigra signal was associated with greater motor impairment. These findings suggest that although levels are lower than in Alzheimer's disease, small elevations in cortical tau are associated with cognitive function in Lewy body disease relevant domains, and that reduced ¹⁸F-PI-2620 binding in substantia nigra may represent loss of dopaminergic neurons. Cortical tau and neuromelanin binding within substantia nigra represent two unique signals in the same PET image that may be informative in the context of cognitive and motor deficits, respectively, in Lewy body disease.