Dickson, Dennis W

ObjectivesThe four‐repeat (4R) tauopathies are a group of neurodegenerative diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and globular glial tauopathy (GGT). This study aimed to characterize spatiotemporal atrophy progression using structural magnetic resonance imaging (MRI) and to examine its relationship with clinical course and neuropathology in a cohort of autopsy‐confirmed 4R tauopathies.MethodsThe study included 85 autopsied patients (54 with PSP, 28 with CBD, and 3 with GGT) who underwent multiple 3T MRI scans, as well as neuropsychological, neurological, and speech/language examinations, and standardized postmortem neuropathological evaluations. An unsupervised machine‐learning algorithm, Subtype and Stage Inference (SuStaIn), was applied to the cross‐sectional brain volumes to estimate spatiotemporal atrophy patterns and data‐driven subtypes and stages in each patient. The relationships among estimated subtypes, pathological diagnoses, and longitudinal changes in clinical testing were examined.ResultsThe SuStaIn algorithm identified 2 distinct subtypes: (1) the subcortical subtype, in which atrophy progresses from the midbrain to the cortex, and (2) the cortical subtype, in which atrophy progresses from the frontal cortex to the subcortical regions. The subcortical subtype was more associated with typical PSP, whereas the cortical subtype was more associated with atypical PSP with a cortical distribution of pathology and CBD (p < 0.001). The cortical subtype had a faster rate of change on the PSP Rating Scale than the subcortical subtype (p < 0.05).InterpretationSuStaIn analysis revealed 2 MRI‐driven subtypes with distinct spatiotemporal atrophy patterns, clinical courses, and neuropathology. Our findings contribute to a comprehensive and improved understanding of disease progression and its relationship to tau pathology in 4R tauopathies. ANN NEUROL 2025;98:492–507

Abstract INTRODUCTION Robust plasma-based biomarkers to distinguish Lewy body disease (LBD) and Alzheimer’s disease (AD) are currently lacking. We applied track-etch magnetic nanopore (TENPO) sorting for enrichment of brain-derived extracellular vesicle (EV) signatures as potential biomarkers to address this gap. METHODS We analyzed plasma from 137 autopsy-confirmed patients [30 LBD, 31 AD, 30 AD/LBD, 19 AD with amygdala Lewy bodies (AD/ALB), and 27 controls], sequencing miRNAs from TENPO-isolated GluR2-positive (neuron-enriched) and GLAST-positive (astrocyte-enriched) EVs, and measuring plasma proteins (Aβ40, Aβ42, tau, p-Tau181, p-Tau231) via SIMOA. RESULTS We identified 16 GluR2+, 8 GLAST+, and 4 protein biomarkers with differential expression (false discovery rate-corrected P value < .1) between LBD and AD. A multimodal 15-feature panel classified LBD versus AD with 10-fold cross-validated accuracy = 0.95 and area under the curve (AUC) = 0.96. DISCUSSION Brain-derived EVs offer accurate and accessible miRNA biomarkers for the differential diagnosis of LBD and AD.

ObjectiveTo determine whether a machine learning model of voxel level [18f]fluorodeoxyglucose positron emission tomography (PET) data could predict progressive supranuclear palsy (PSP) pathology, as well as outperform currently available biomarkers.MethodsOne hundred and thirty‐seven autopsied patients with PSP (n = 42) and other neurodegenerative diseases (n = 95) who underwent antemortem [18f]fluorodeoxyglucose PET and 3.0 Tesla magnetic resonance imaging (MRI) scans were analyzed. A linear support vector machine was applied to differentiate pathological groups with sensitivity analyses performed to assess the influence of voxel size and region removal. A radial basis function was also prepared to create a secondary model using the most important voxels. The models were optimized on the main dataset (n = 104), and their performance was compared with the magnetic resonance parkinsonism index measured on MRI in the independent test dataset (n = 33).ResultsThe model had the highest accuracy (0.91) and F‐score (0.86) when voxel size was 6mm. In this optimized model, important voxels for differentiating the groups were observed in the thalamus, midbrain, and cerebellar dentate. The secondary models found the combination of thalamus and dentate to have the highest accuracy (0.89) and F‐score (0.81). The optimized secondary model showed the highest accuracy (0.91) and F‐scores (0.86) in the test dataset and outperformed the magnetic resonance parkinsonism index (0.81 and 0.70, respectively).InterpretationThe results suggest that glucose hypometabolism in the thalamus and cerebellar dentate have the highest potential for predicting PSP pathology. Our optimized machine learning model outperformed the best currently available biomarker to predict PSP pathology. ANN NEUROL 2025;98:410–420

Pick’s disease (PiD) is a rare neurodegenerative disorder defined by dementia, frontotemporal lobe atrophy, and 3-repeat tau inclusions. To elucidate PiD pathobiology, we performed the first bulk transcriptomics study on PiD using short- and long-read sequencing on the parietal cortex of 28 PiD and 15 control samples. We identified several significantly differentially expressed genes, with CCL2 displaying the strongest association with 3-repeat tau pathology and increased burden in PiD compared to those in 4-repeat tau progressive supranuclear palsy (PSP) cases. Investigation of co-expressed genes and pathways suggested the involvement of mRNA processing, mitochondrial function, and immune processes in disease pathobiology. Long-read RNA sequencing on a subset of samples (eight PiD and four control) proposed novel, potentially disease-associated transcripts for AZGP1 , CD44 , HSD11B2 , and WIF1 , predicted to result in truncated proteins. In conclusion, we observed transcriptomic changes in the parietal cortex of patients with PiD that may inform into clinically relevant biomarkers and therapeutic strategies.

Abstract Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinson’s disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease. Teaser Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractINTRODUCTIONParkinsonism in patients with Alzheimer's disease (AD) is often attributed to Lewy‐related pathology, given its high comorbidity. In the era of anti‐amyloid therapy, recognizing parkinsonism caused by AD pathology is needed to optimize the treatment.METHODSThis study aimed to quantitatively characterize parkinsonism and nigral neuropathology in AD without Lewy bodies (LB). Nigral neurons were counted automatically. Fine‐tuned ChatGPT collected structured clinical data.RESULTSAmong 635 AD patients without LB, 62 (9.7%) presented parkinsonism, which correlated with reduced nigral neuron density (p < 0.01). Tau burden did not explain the nigral neuronal loss. TAR DNA‐binding protein 43 (TDP‐43) pathology correlated with reduced nigral pigmented neuron density (p = 0.03).DISCUSSIONOur findings suggest that parkinsonism in AD without LB is related to nigral neuronal loss in association with TDP‐43 pathology. Recognition of parkinsonism in AD without LB is crucial for appropriate therapy.Highlights One in 10 Alzheimer's disease (AD) patients without Lewy bodies had parkinsonism. Parkinsonism in AD was correlated with reduced nigral neuron density. TAR DNA‐binding protein 43 pathology was associated with nigral degeneration in AD. AD should be included in the differential diagnosis of dementia with parkinsonism.