Driver‐Dunckley, Erika

Objective To investigate sex differences in Alzheimer's disease (AD) related pathology among autopsy-confirmed Parkinson's disease (PD) cases. Background AD and PD frequently co-occur in older adults, yet the influence of sex on AD pathology in the context of PD remains unexplored. Methods All subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP) and had annual standardized research clinical assessments by neuropsychologists, subspecialty behavioral and movement disorders neurologists, as well as comprehensive neuropathological examinations after death. Results Among 230 autopsy-confirmed PD cases, females exhibited greater amyloid plaque pathology burden than males, regardless of a co-occurring AD diagnosis. Specifically, females with PD had significantly higher mean cortical total plaque scores (mean 6.5/15 vs. 4.9/15, p = 0.045) and greater CERAD neuritic plaque density (mean 1.7/3 vs. 1.3/3, p = 0.035). Females were also more likely to have a higher cortical plaque burden (plaque total ≥ 5: 56.8% vs. 39.7%, p = 0.015). In multivariable logistic regression models, female subjects showed greater than twice the odds of having an amyloid plaque burden ≥5 compared to males (OR = 2.18; 95% CI = 1.17–4.06; p = 0.014), when controlling for ApoE ε4 status, Lewy body density score, and age at death. Conclusions Female sex is associated with increased amyloid plaque pathology in PD, independent of ApoE ε4 status. These findings highlight a sex-specific vulnerability to AD pathology in PD patients and support the need for sex-informed approaches to reseach in mixed neurodegenerative disease.

Abstract Background Cumulative head trauma, encompassing repetitive head impacts (RHI) and traumatic brain injury (TBI), has been associated with later‐life neurodegenerative disease. Studies on parkinsonism/Parkinson's disease (PD) have evaluated RHI and TBI in isolation, yielding mixed results. Cumulative head trauma may better predict PD risk. Objective To examine independent and cumulative effects of RHI through soccer participation and TBI history on PD diagnosis and age at diagnosis. Methods We used a cross‐sectional cohort design with data from the Fox Insight study. Participants completed self‐report questionnaires on PD diagnosis, TBI (no TBI, TBI with loss of consciousness [LOC], TBI without LOC), and sport participation. Multivariable logistic regressions examined the effects of soccer, TBI group, and their interaction on PD diagnosis. Cox proportional hazards examined associations with time to PD diagnosis. Covariates included age, sex, race, education, income, body mass index, heart disease/diabetes, and family PD history. Results Among 1231 participants (mean[SD] age = 66.12[10.60]), 278 played soccer (953 non–contact and collision sport [CCS] athletes). Participants reported no TBI (390[33%]), TBI without LOC (495[43%]), or TBI with LOC (258[23%]). Overall, 768(62%) reported a PD diagnosis (mean[SD] age at diagnosis = 59.02[9.86]). A significant soccer × TBI interaction indicated that soccer players with TBI with LOC had 2.6× higher odds of PD compared to non‐CCS athletes without TBI (OR [95% CI] = 2.600[1.085–6.305], P = 0.033). Former soccer players with TBI with LOC had a 15.6% higher hazard of early PD diagnosis (HR = 1.469, P = 0.027) compared to non‐CCS athletes with no TBI. Conclusion Cumulative head trauma (RHI + TBI) increased PD risk and lowered age at onset. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Importance Decline in olfactory function may be used as a predictor of cognitive decline, to enhance early detection models, improve risk stratification, and enable early intervention. Objective To assess the longitudinal association between olfactory decline, cognitive decline, and postmortem neuropathology. Design, setting and participants Retrospective longitudinal analysis with clinicopathological correlations of a prospective population-based cohort study using data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and its Brain and Body Donation Program. Participants included cognitively unimpaired individuals without parkinsonism that converted to mild cognitive impairment (MCI) and/or dementia or remained cognitively stable. Main Outcomes and Measures longitudinal change in olfaction, neuropsychiatric symptoms, motor function and memory, conversion to MCI/dementia, postmortem neuropathology Results Over a mean follow-up period of 7.7 ± 5.4 years, out of 922 participants who were cognitively unimpaired at the first cognitive conference, 643 remained cognitively unimpaired, 279 converted to MCI, and 82 developed dementia. Of these, 633 individuals had at least 2 olfactory tests. Converters showed reduced olfactory function (t=-12.6, p <0.0001), faster progression in neuropsychiatric symptom burden (t=3.42, p < 0.001), and faster decline in memory (t= -7.33, p <0.0001) prior to conversion while no significant differences were observed in motor scores between converters and non-converters. Using ROC analysis, olfactory decline, increased neuropsychiatric symptom burden, as well as motor and memory decline predicted conversion to MCI with a consistent accuracy of ∼ 70% up to 5 years before conversion, while UPSIT alone had an accuracy of ∼ 60%. Longitudinal decline in olfaction was associated with a higher burden of a-synuclein (t= -8.21, p <0.0005), tau tangle (t= -2.66, p < 0.01) and amyloid plaque burden (t= -2.85, p < 0.005) and a faster decline over time was associated with a higher burden of tau (t=5.66, p<0.0001). Conclusions and Relevance A reduction in olfactory identification ability is observed up to a decade prior to conversion to MCI and is associated with underlying burden of neuropathology markers, underscoring the value of incorporating olfactory testing in cognitively unimpaired individuals to identify those at-risk of future cognitive decline.

Abstract Skin biopsies analyzed with α-synuclein seed amplification assays (SAAs) are a simple way to clinically interrogate the presence of α-synuclein aggregates. We determined the accuracy of skin biopsy SAA in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Blinded SAAs were performed in 3 independent laboratories. Subjects diagnosed with PD, PDD and DLB were analyzed together as group 1, clinically unaffected subjects as group 2 and those with risk factors for LBD as group 3. Punch biopsies were taken from the posterior neck and analyzed by the 3 labs in 6 separate SAAs. Pairwise agreement between labs and assays ranged from excellent (kappa 0.82) to moderate (kappa 0.40-0.68). Sensitivity across assays ranged between 50.0% and 61.3%; specificity ranged between 68.6% and 100%. Comparisons of group 1 vs group 2 produced the greatest specificities, between 77.3% and 100%. In 17 cases that subsequently came to autopsy, 93% of SAAs were positive in those at the neocortical LBD stage but in only &lt;10% of those at lower stages. Skin biopsy α-synuclein SAA may be useful as a diagnostic and progression biomarker in Lewy body dementia clinical trials.

ABSTRACT Braak and others have proposed that Lewy body pathology (LBP) in Parkinson’s disease (PD) may arise not only in the brain but alternatively from an initial site in the gastrointestinal (GI) tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry (IHC) and RT QuIC a form of alpha synuclein seed amplification assay (SAA) to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease (ILBD) and 94 with no Lewy body IHC pathology detected (NLB). A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI-only with brain-only synucleinopathy, however, we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions: olfactory bulb, medulla, pons, and amygdala. Further SAA of brain regions is estimated, based on the proportional results to date, to potentially identify 21 additional brain-only LBP subjects, for a total of 32, if it were done on all of the NLB subjects. From this brain-only LBP is estimated to be 16 times more common than GI-only LBP. To assess the clinical impact of SAA-positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA-AUT GI related scores including those for salivation, straining, constipation, and bowel movement.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.