Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

AIMS: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. METHODS: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. RESULTS: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. CONCLUSIONS: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Novel Homozygous Variant in the MCOLN1 Gene Associated With Severe Oromandibular Dystonia and Parkinsonism.

BACKGROUND: Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the MCOLN1 gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function. OBJECTIVES AND METHODS: Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum. RESULTS AND CONCLUSIONS: Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the MCOLN1 gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the MCOLN1 variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.

Molecular Behavior of α-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin-Proteasome Pathways in Lewy Body Disease.

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer's disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin-proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.

Towards a biological diagnosis of PD.

Since the original description by James Parkinson, Parkinson's disease (PD) has intrigued us for over 200 years. PD is a progressive condition that is incurable so far, and affects millions of people worldwide. Over the years, our knowledge has expanded tremendously, and a range of criteria have been put forward and used to try to define PD. However, owing to the complexity of the problem, it is still not consensual how to diagnose and classify a disease that manifests with diverse features, and that responds differently to existing therapies and to those under development. We are now living a time when 'biological' information is becoming abundant, precise, and accessible enabling us to attempt to incorporate different sources of information to classify different forms of PD. These refinements are essential for basic science, as they will enable us to develop improved models for studying PD, and to implement new findings into clinical practice, as this will be the path towards effective personalized medicine.

Lesion network of oculogyric crises maps to brain dopaminergic transcriptomic signature.

Oculogyric crises are acute episodes of sustained, typically upward, conjugate deviation of the eyes. Oculogyric crises usually occur as the result of acute D2-dopamine receptor blockade, but the brain areas causally involved in generating this symptom remain elusive. Here, we used data from 14 previously reported cases of lesion-induced oculogyric crises and employed lesion network mapping to identify their shared connections throughout the brain. This analysis yielded a common network that included basal ganglia, thalamic, and brainstem nuclei, as well as the cerebellum. Comparison of this network with gene expression profiles associated with the dopamine system revealed spatial overlap specifically with the gene coding for dopamine receptor type 2 (DRD2) as defined by a large-scale transcriptomic database of the human brain. Furthermore, spatial overlap with DRD2 and DRD3 gene expression was specific to brain lesions associated with oculogyric crises when contrasted to lesions that led to other movement disorders. Our findings identify a common neural network causally involved in the occurrence of oculogyric crises and provide a pathophysiological link between lesion locations causing this syndrome and its most common pharmacological cause, namely DRD2 blockade.

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study.

INTRODUCTION: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases. METHODS: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance. RESULTS: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume. DISCUSSION: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition. HIGHLIGHTS: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes.

Using artificial intelligence to identify drugs for repurposing to treat l-DOPA-induced dyskinesia.

Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready. We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l-DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability. In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline.

Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.

BACKGROUND AND OBJECTIVES: Sensitive, reliable, and scalable biomarkers are needed to accelerate the development of therapies for Parkinson disease (PD). In this study, we evaluate the biomarkers of early PD diagnosis, disease progression, and treatment effect collected in the SPARK. METHODS: Cinpanemab is a human-derived monoclonal antibody binding preferentially to aggregated forms of extracellular α-synuclein. SPARK was a randomized, double-blind, placebo-controlled, phase 2 multicenter trial evaluating 3 cinpanemab doses administered intravenously every 4 weeks for 52 weeks with an active treatment dose-blind extension period for up to 112 weeks. SPARK enrolled 357 participants diagnosed with PD within 3 years, aged 40-80 years, ≤2.5 on the modified Hoehn and Yahr scale, and with evidence of striatal dopaminergic deficit. The primary outcome was change from baseline in the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale total score. Secondary and exploratory biomarker outcomes evaluated change from baseline at week 52 relative to placebo. Dopamine transporter SPECT and MRI were used to quantify changes in the nigrostriatal dopamine pathway and regional atrophy. CSF and plasma samples were used to assess change in total α-synuclein levels, α-synuclein seeding, and neurofilament light chain levels. SPARK was conducted from January 2018 to April 2021 and terminated due to lack of efficacy. RESULTS: Approximately 3.8% (15/398) of SPECT-imaged participants did not have evidence of dopaminergic deficit and were screen-failed. Binary classification of α-synuclein seeding designated 93% (110/118) of the enrolled CSF subgroup as positive for α-synuclein seeds at baseline. Clinical disease progression was observed, with no statistically significant difference in cinpanemab groups compared with that in placebo. Ninety-nine percent of participants with positive α-synuclein seeding remained positive through week 52. No statistically significant changes from baseline were observed between treatment groups and placebo across biomarker measures. Broadly, there was minimal annual change with high interindividual variability across biomarkers-with striatal binding ratios of the ipsilateral putamen showing the greatest mean change/SD over time. DISCUSSION: Biomarker results indicated enrollment of the intended population with early PD, but there was no significant correlation with disease progression or clear evidence of a cinpanemab treatment effect on biomarker measures. Suitable biomarkers for evaluating disease severity and progression in early PD trials are still needed. TRIAL REGISTRATION INFORMATION: NCT03318523 (clinicaltrials.gov/ct2/show/NCT03318523); Submitted October 24, 2017; First patient enrolled January 2018.

Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus.

BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Concomitant Medications for Progressive Supranuclear Palsy: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial examines changes in the progression of progressive supranuclear palsy (PSP) associated with 31 concomitant medication classes used by study participants over 1 year.

Arm Swing while Walking and Running: A New Clinical Feature to Separate Parkinson's Disease from Functional Parkinsonism.

BACKGROUND: Functional parkinsonism is an important differential diagnosis of Parkinson's disease (PD). Based on anecdotal experience, we hypothesized that arm swing while walking and running could differentiate these two conditions, but this assumption has not been previously explored systematically. OBJECTIVES: To examine differences in arm swing while walking and running between patients with PD and functional parkinsonism. METHODS: We analyzed blinded video assessments of arm swing and other gait parameters in patients with asymmetrical PD (n = 81) and functional parkinsonism (n = 8) while walking and running. The groups were matched for age, sex and disease duration. RESULTS: In contrast to those with PD, patients with functional parkinsonism (i) were more likely to have a marked asymmetry in arm swing while walking (5/8 vs. 25/81; P = 0.06), (ii) were less likely to improve arm swing while running with full effort (3/8 vs. 72/81; P < 0.001) and (iii) demonstrated normal passive arm swing even when asymmetry of arm swing was marked during running/walking (6/6 vs. 9/33; P = 0.002). CONCLUSIONS: Assessment of arm swing while walking and running and passive arm swing could be important differentiating clinical features between functional parkinsonism and PD.

A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria.

With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.

Estimation of Ambulation and Survival in Neurodegeneration with Brain Iron Accumulation Disorders.

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.

The molecular spectrum of amyloid-beta (Aß) in neurodegenerative diseases beyond Alzheimer's disease.

This study investigated the molecular spectrum of amyloid-beta (Aß) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aß deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aß deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD-TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aß epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi-quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aß deposition, particularly Aß42 and Aß43 , along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aß peptides in the LBD group revealed an association with the APOE-ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aß deposition in cases with LBD (N = 15), AD without α-synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan-Aß antibody (6F/3D)-immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aß43 , was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aß peptides on a case-by-case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aß deposition, impacted also by sex and APOE genotypes.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy.

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the peripheral nervous system (PNS) are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases (progressive supranuclear palsy: PSP, n = 15; Alzheimer's disease: AD, n = 18; chronic traumatic encephalopathy: CTE, n = 5; and corticobasal degeneration: CBD, n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy, LNT, n = 1) using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88 %), IX/X: 10/11 (91 %), XII: 6/6 (100 %); anterior spinal roots: 10/10 (100 %). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE, and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

Neuronal SNCA transcription during Lewy body formation.

Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson's disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.