A 76-year-old woman presented with progressive left-sided motor incoordination, dystonia, and instability, clinically concerning for atypical parkinsonism. MRI showed Fazekas grade 1 chronic microvascular changes. ¹⁸F-FDG brain PET revealed asymmetric right cerebral hemisphere, sensorimotor cortex, and basal ganglia hypometabolism, suggestive of corticobasal degeneration. ¹⁸F-Florbetapir PET was negative. ¹⁸F-Flortaucipir PET demonstrated asymmetric right basal ganglia uptake, corresponding to hypometabolic regions and contralateral to left-sided symptoms. Although ¹⁸F-Flortaucipir demonstrates limited affinity for pure 4R tau and known off-target subcortical binding, the pronounced asymmetry in this Aβ-negative case of atypical parkinsonism supports a 4R tauopathy phenotype, illustrating potential utility beyond the current FDA-approved indication.

FDG PET in Movement Disorders and Parkinsonian Syndromes.

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) comprise the majority of 4-repeat (4R) tauopathy cases of frontotemporal lobar degeneration (FTLD-tau). Both pathologic entities can underlie clinical syndromes such as primary progressive aphasia (PPA), characterized by an isolated, progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), marked by progressive personality changes and more symmetric frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of neuronal and glial tau inclusions in CBD and PSP to establish clinicopathologic concordance between tau pathology and the aphasic versus behavioral phenotype. Twenty-eight right-handed cases with autopsy-confirmed CBD (n=14) or PSP (n=14) were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PPA, n=16; bvFTD, n=12). Paraffin-embedded sections were immunohistochemically stained with AT8 to visualize tau pathology, and modified unbiased stereological analysis was performed in up to eight regions, including the middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG), CA1 of the hippocampus, and primary visual cortex (V1). In PPA, pathology was significantly left-lateralized, with the ATL showing the highest overall tau burden, while bvFTD cases showed more symmetric or rightward distributions with peak pathology in the MFG. Across both syndromes, CBD cases exhibited greater neuronal tau pathology, and PSP cases exhibited greater glial tau pathology, with this double-dissociation reaching significance across neocortex. Hippocampal regions, particularly CA1, showed higher neuronal tau burden than neocortical regions regardless of clinical phenotype, and DG tau burden was significantly greater in CBD than PSP (p<0.01). Inclusion-to-neuron analyses revealed disproportionately higher tau burden in the DG compared to neocortex, especially in CBD (p<0.001). These findings reveal syndrome- and pathology- specific patterns of selective cellular and regional vulnerability in 4R-tauopathies and support clinicopathologic concordance in PPA and bvFTD.

REM sleep behavior disorder as a shared motor phenotype: A multidimensional clinical study.

Neurodegenerative parkinsonisms are phenotypically diverse disorders including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. These currently incurable diseases are characterized by overlapping but also distinct clinicopathological and molecular features, and largely unknown pathogenesis. Transcriptomic studies have offered insights, but are limited by small sample sizes, technical variability, and limited reproducibility. Here, we present a large comparative bulk transcriptomic analysis of parkinsonian syndromes, comprising n = 977 post-mortem prefrontal cortex samples from pathologically-confirmed Parkinson's disease (n = 448), dementia with Lewy bodies (n = 80), multiple system atrophy (n = 35), progressive supranuclear palsy (n = 42), corticobasal degeneration (n = 17), Alzheimer's disease (n= 72), and neurologically healthy controls (n = 283). Accounting for key covariates including age, sex, RNA integrity (RIN), brain bank origin, and cell type composition, we identify convergent and divergent gene expression and pathway profiles across parkinsonisms and Alzheimer's disease. All diseases showed neuronal transcript loss and enrichment of glial signatures, consistent with neurodegeneration. Across the parkinsonian spectrum, we identified consistent downregulation of pathways related to protein homeostasis, mitochondrial energy metabolism, RNA processing, and DNA repair, highlighting core processes associated with neurodegeneration. Lewy body diseases (Parkinson's disease, dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy and corticobasal degeneration) formed distinct similarity clusters, while multiple system atrophy occupied an intermediate position, possibly reflecting its glial pathology. To facilitate further research and discovery, we provide an open-access interactive web resource (https://parkdb.decode-pd.org) enabling researchers to query, visualize, and compare differential gene and pathway expression across disorders. This study establishes the most comprehensive comparative transcriptomic map of neurodegenerative parkinsonisms to date, identifies shared and distinct molecular mechanisms in α-synucleinopathies and tauopathies, and provides a resource for hypothesis generation and therapeutic target discovery.

To advance the precise diagnosis and treatment of Parkinson's disease (PD) and related movement disorders, standardize the clinical application of integrated PET/MRI, enhance diagnostic efficacy, and optimize patient management, the Clinical Practice Guideline for Integrated PET/MRI in Parkinson's Disease (2026 Edition) was developed jointly by multiple expert groups. This initiative was led by the Chinese Society of Medical Imaging Technology, the Radiological Society of Chinese Medical Association, the Chinese Society of Nuclear Medicine, the Beijing Society of Nuclear Medicine, and the Beijing Society of Radiology, in collaboration with a multidisciplinary panel of experts from Nuclear Medicine, Radiology, Neurology, and Functional Neurosurgery, following several rounds of consensus meetings. Compared to previous consensus statements or technical specifications, the key updates of this guideline include: in the clinical application pathway, it clarifies the advantages and appropriate scenarios for utilizing integrated PET/MRI over single-modality imaging when the clinical diagnosis of PD is uncertain; it emphasizes the value of simultaneous acquisition and fusion analysis in assessing both the function of the nigrostriatal dopaminergic pathway (e.g., via PET tracers) and structural alterations (e.g., via MRI neuromelanin imaging, diffusion tensor imaging, etc.). With the development and validation of novel tracers, the guideline provides a hierarchical recommendation for the differential diagnosis between PD and atypical parkinsonian syndromes (such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration), based on multimodal imaging biomarkers. Based on the premise of the accessibility of current integrated PET/MRI equipment and tracers in China, and grounded in the latest international and domestic evidence-based research, this guideline is meticulously aligned with the realities of Chinese clinical practice. It systematically delineates the technical specifications, clinical indications, and image interpretation criteria for the use of integrated PET/MRI in the diagnosis, differential diagnosis, disease severity assessment, and therapeutic decision support for PD. The aim is to provide systematic and practical evidence-based guidance for clinicians and imaging specialists involved in the care of patients with Parkinson's disease.

Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychotic symptoms. In this narrative review, we synthesize clinical, neuroanatomical, and molecular evidence linking MBI to the spectrum of tauopathies, including Alzheimer's disease (AD), frontotemporal spectrum disorders (FTSDs), and primary four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Emerging evidence suggests that early behavioral symptoms associated with MBI may reflect the selective vulnerability of frontolimbic, salience, default mode, and frontostriatal networks to tau-mediated neurodegeneration. Mechanistically, converging findings support roles for tau-related synaptic dysfunction, including synaptotoxic soluble tau species, cytoskeletal and axonal transport disruption, monoaminergic neurotransmitter imbalance in brainstem systems, and neuroinflammatory and glial pathways. We also highlight genotype-related behavioral profiles in genetic frontotemporal lobar degeneration and discuss how scalable blood-based biomarkers, including neurofilament light chain, glial fibrillary acidic protein, and plasma phospho-tau species, may complement MBI-based phenotyping for differential diagnosis and prognostic stratification in clinical research.

BackgroundFour-repeat (4R)-tauopathies cause variable clinical profiles leading to clinical misdiagnosis. While sex differences are reported in Alzheimer’s disease (AD), Lewy body disease (LBD), and clinically-defined frontotemporal dementia (FTD), little is known in 4R-tauopathies.MethodsNational Alzheimer’s Coordinating Center data were used for pathologically-defined 4R-tauopathies: progressive supranuclear palsy (PSP, n = 175), corticobasal degeneration (CBD, n = 114), argyrophilic grain disease (AGD, n = 230), Other-4R (n = 67). Sex differences for clinical presentation and co-pathologies were assessed adjusting for age and multiple comparisons.ResultsMost common clinical diagnosis was PSP (41%) for PSP; unspecified FTD (36%) for CBD; AD for AGD (57%) and Other-4R groups (48%), without sex differences. Females had less cognitive decline, apathy, motor symptoms; were older at cognitive, behavioral change onset. Males were more likely to demonstrate LBD co-pathology and clinical profile.ConclusionBoth females and males have low clinical diagnostic accuracy for 4R-tauopathies. Females with 4R-tauopathies may experience less severe clinical presentations and less co-pathology.

Corticobasal degeneration (CBD) is a four-repeat tauopathy with heterogeneous clinical manifestations. Armstrong's criteria involve a two-step diagnostic approach: first, classifying patients into five clinical phenotypes-probable/possible corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), non-fluent/agrammatic variant primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS); second, determining whether they meet the clinical research criteria for probable CBD (cr-CBD) or the clinical criteria for possible CBD (p-CBD), which are distinct from the initial CBS classifications. To investigate how real-world patients with suspected CBD fulfill Armstrong's clinical phenotypes and diagnostic criteria, and to compare clinical and imaging features between the Alzheimer's disease (AD) group and the non-AD group defined by CSF amyloid biomarkers. We retrospectively reviewed 137 patients undergoing differential diagnosis for CBS, frontotemporal dementia, primary progressive aphasia, or PSPS. Of these, 78 met the criteria for cr-CBD (n=36) or p-CBD (n=42). CSF was examined in 32 patients, and based on the CSF Aβ42/40 ratio, patients were classified into an AD-group (AD-CBS; n=6) and a non-AD group (n=26). Among patients classified as cr-CBD or p-CBD, 79% fulfilled two or more clinical phenotypes, with FBS and PSPS most commonly. Compared with the AD group, the non-AD group showed more parkinsonian features and frontal hypoperfusion on [123I]-IMP SPECT. Armstrong's criteria captured a spectrum of overlapping clinical features. While helpful in clinical phenotyping, further validation with biomarkers is essential to distinguish CBD from AD and related disorders. Prospective studies with pathological confirmation are warranted.

Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy. We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data. Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation. Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy. This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.

Myelin oligodendrocyte basic protein (MOBP) is an abundant oligodendrocyte gene implicated in multiple neurodegenerative diseases. Genetic variation at theMOBPlocus has been associated with risk for progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), corticobasal degeneration (CBD), Alzheimer’s disease (AD), Lewy body dementia (LBD), and Creutzfeldt–Jakob disease (CJD). Epigenetically,MOBPpromoter hypermethylation and reduced expression have been reported in multiple system atrophy (MSA). AlthoughMOBPis thought to play a role in oligodendrocyte morphology and myelin structure, how genetic and epigenetic variation at this locus influences gene regulation and contributes to disease risk remains poorly understood across neurodegenerative disorders.Here, we investigated whether shared or disease-specific genetic mechanisms atMOBPconverge on altered DNA methylation and expression across neurodegenerative disorders. We analysedMOBPvariants using summary statistics from recent GWAS for ALS, PSP, FTD, LBD, PD, MSA, AD, and CJD. Colocalisation (COLOC and SuSiE-coloc) was used to test whether disease-associated variants overlapped between diseases, and with oligodendrocyte expression quantitative trait loci (eQTLs) and bulk brain methylation quantitative trait loci (mQTLs). To further investigate mQTL effects at this locus, rs1768208, a variant previously associated with PSP, was genotyped in an overlapping brain methylation cohort, allowing direct testing of genotype–methylation associations in frontal white matter tissue.ALS and PSP GWAS demonstrated strong association atMOBP, with most strongly associated SNPs (e.g. rs631312, rs616147, rs1768208) shared between both disorders. Colocalisation analyses indicated high posterior probability that ALS and PSP share the same causal variant, with weaker overlap with FTD. mQTL colocalisation highlighted cg15069948, located near an exon junction withinMOBP, as strongly colocalising with the ALS/PSP risk variants. In complementary tissue analyses, rs1768208-T carriers showed hypomethylation at cg15069948 in PSP brains. No genotype-methylation effects were detected in MSA or Parkinson’s disease.Together with prior evidence of promoter hypermethylation and reduced expression in MSA, our findings identify cg15069948 as a regulatory methylation site linking ALS/PSP risk variants to alteredMOBPmethylation, and supportMOBPdysregulation as a shared feature of neurodegeneration. However, the underlying mechanisms appear disease-specific, highlighting the complexity of involvement of this gene across neurodegenerative disorders.

We performed a narrative review of the literature of amyloid and tau co-pathology in Parkinson Disease and atypical parkinsonism in Pubmed database, including articles published between January 2020 to July 2025. In the last decade, different multicenter research efforts have worked to improve the accuracy of clinical-pathological diagnosis in neurogenerative disease. In this search, growing evidence from neuropathology, neuroimaging and fluid biomarkers have highlighted the role of Alzheimer's disease (AD) co-pathology in Parkinson's disease (PD) and atypical parkinsonism (AP) disorders potentially affecting progression, motor phenotype and cognitive status. Regarding studies of structural and functional imaging evidencing the presence of Amyloid-β (Aβ), tau, as co-pathologies contribute to α-synuclein-related profile of cortical atrophy, network disruption, as well as clinical heterogeneity in PD and AP disorders. In AP fluid biomarkers have shown limited diagnostic accuracy. Neuropathological evidence from systematic post-mortem surveys confirmed that diffuse and neuritic Aβ plaques are uncommon in non-demented PD (10%), intermediate in PD-dementia (30-40%), and frequent in Dementia with Lewy Bodies (60-80%). The evidence in PD and DLB showed that Aß fluid biomarkers may predict clinical trajectory and cognitive decline, while Aβ-imaging would help stratifying patients and directing therapeutic pipeline designs. In AP disorders, including progressive supranuclear palsy and corticobasal degeneration, a combined multimodal assessment of molecular imaging, structural and functional magnetic resonance with fluid biomarkers shall guarantee future differential diagnosis and prediction of clinical outcomes. Although there are no currently accepted biomarkers for PD or AP, the recent design of plasma tau biomarkers and seed-amplification assays are promising approaches which are also reviewed here.

Mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer's disease (AD) by enhancing cerebral accumulation of amyloid-β (Aβ) peptides and microtubule-associated protein tau (MAPT). How PS mutations affect Aβ generation is well characterized, but the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology are not fully understood. Here, we investigated the mechanisms linking PS/γ-secretase-dependent tau pathology and autophagy/proteasome by employing pathological, imaging and molecular approaches in human brains, fibroblasts and induced pluripotent stem cells (iPSC)-derived neurons from PSEN1-linked familial AD carriers, and in a novel neuronal PS-deficient tauopathy transgenic mouse. We found enhanced levels and colocalization of pathological phosphorylated tau (pTau) and ubiquitin factor p62 in the hippocampus of dementia patients with familial AD-linked PSEN1 mutations, corticobasal degeneration and Pick's disease, suggesting disrupted proteasomal degradation in tauopathies. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers showed elevated LC3-I and autolysosomes indicating autophagy flux alterations. Human iPSC-derived neurons harboring the familial-AD linked PSEN1 G206D mutation showed increased aggregated tau and reduced secreted tau, whereas pharmacological proteasome inhibition reduced significantly total and pTau (Ser396/404) while increasing its release. Consistently, proteasomal inhibition decreased intracellular tau and pTau and promoted tau release in human tau-expressing neurons through a mechanism that partially depends on PS. In the hippocampus of neuronal PS-deficient mice, Akt activation and GSK3β inhibition were associated with elevated levels of phosphorylated and aggregated tau and the ubiquitin-binding protein p62. In conclusion, PS function is required for autophagy/proteasome-mediated tau elimination in neurons, whereas that FAD-linked PSEN1 mutations cause progressive tau pathology by disrupting the proteasome and autophagy/lysosomal pathways.

ObjectivePre‐mortem diagnosis of parkinsonism is often challenging due to atypical presentations, overlapping syndromes, and co‐pathologies. This study aimed to develop a machine learning‐based algorithm predicting neuropathology in parkinsonism using chronological clinical presentations, which has previously been underexplored.MethodsClinical information was automatically abstracted from medical records of the Mayo Clinic Brain Bank using fine‐tuned Generative Pre‐trained Transformer 4 models. Patients who developed parkinsonism within 3 years of disease onset were included. Six machine learning models were trained with age, sex, family history, and 197 clinical presentations paired with onset information to predict neuropathologic diagnoses, including co‐pathologies.ResultsAmong 7,825 donors, 949 met inclusion criteria, representing 9 neuropathologic categories: Lewy body disease (LBD; n = 128), LBD with Alzheimer's disease (AD; n = 136), progressive supranuclear palsy (PSP; n = 303), PSP with AD (n = 56), PSP with LBD (n = 27), multiple system atrophy (MSA; n = 120), corticobasal degeneration (CBD; n = 99), AD (n = 43), and frontotemporal lobar degeneration (FTLD; n = 37). The CatBoost algorithm achieved an area under the receiver operating characteristic curve of 0.83 across the 9 diagnostic categories at 3 years after onset. Important predictors included age at onset, restricted eye movement, and tremor. The model remained robust to incomplete data, requiring only 23 of 200 parameters for reliable predictions with an area under the curve of 0.80. The algorithm was implemented into a user‐friendly program providing diagnostic probabilities with visualizations of parameter contributions.InterpretationThis neuropathology‐confirmed diagnostic algorithm provides a cost‐effective and interpretable screening tool for parkinsonism, bridging biomarker testing and molecular‐targeted therapies. ANN NEUROL 2026;99:1405–1414

Although the clinical features of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are well documented, their early clinical presentations from the perspective of initial clinical consultation remain less well understood. This study aimed to characterize the early clinical features of PSP and CBD to inform clinicians on diagnostic assessment and management strategies. Data were obtained from the National Alzheimer's Coordinating Center (NACC) database (2005-March 2025 data freeze). Neuropathologically confirmed cases of PSP (n = 278) and CBD (n = 149) were included. Analyses were restricted to first clinical visits, focusing on demographic, neuropsychiatric, neurological, and neuropsychological variables. Memory symptoms were reported in more than half of both groups, whereas language impairment was more common in CBD (> 70%) and associated with higher odds of CBD diagnosis. Depression was frequent (~ 50%), with PSP showing higher odds for depressive symptoms but lower odds for disinhibition. Although 20-30% of both PSP and CBD patients exhibited no parkinsonian signs at presentation, gait disturbance, falls, and slowness were common and strongly associated with PSP. Approximately half of both groups presented with cognitive-predominant onset, and nearly one-fifth were initially misdiagnosed as Alzheimer's disease. A substantial proportion of PSP and CBD patients lack parkinsonian signs at first presentation, and cognitive-onset presentations are frequent, leading to early diagnostic uncertainty. Clinicians should recognize these overlapping features when evaluating early atypical parkinsonian or cognitive syndromes.

Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are increasing worldwide. Early differential diagnosis is challenging due to overlapping symptoms and the often delayed appearance of pathognomonic signs. Presentation of the role of structural magnetic resonance imaging (MRI) in the differential diagnosis of neurodegenerative Parkinsonian syndromes. Literature review of current guidelines and studies on T1-weighted and T2-weighted sequences, susceptibility-weighted imaging (SWI), diffusion-weighted imaging, volumetry and multiparametric approaches. The focus was on disease-specific atrophy patterns, quantitative methods and automated analyses. Structural changes in PD are usually subtle; the nigrosome‑1 (swallowtail) sign on SWI can provide diagnostic clues. The PSP shows pronounced midbrain atrophy, MSA demonstrates putaminal, pontine and cerebellar atrophy and CBD exhibits asymmetric cortical atrophy. Volumetric and multiparametric analyses increase the diagnostic accuracy, especially in early disease stages, although widespread clinical implementation remains limited. Structural MRI provides early indicators of APS and aids the differential diagnosis. Quantitative and multiparametric methods improve objectivity and sensitivity, particularly for subtle or rare syndromes and could play an increasingly more important role in clinical practice.

Transcranial sonography is one of the methods of examination used in atypical parkinsonian syndromes. The assessment is not indicated in the diagnostic criteria of entities in this group e.g., Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy and Dementia with Lewy Bodies. Atypical parkinsonisms are a group of diseases affected by diverse pathologies including alpha-synuclein or tau among others. Recently broader attention was brought to less common atypical parkinsonisms as Perry syndrome. Atypical parkinsonisms are related to poor response to levodopa treatment, rapid deterioration and unfavorable prognosis. Additionally, the entities often overlap in terms of clinical manifestation, especially in the early stages. Though atypical parkinsonisms are affected by the lack of possibility of obtaining definite in vivo diagnosis, growing interest is associated to supplementary evaluations including neuroimaging. Among these methods could be mentioned magnetic resonance imaging, positron emission tomography, single photon emission computed tomography and transcranial sonography. Transcranial sonography is associated with high accessibility and low cost. The goal of this paper is to highlight the strengths and weaknesses of transcranial sonography in the examination of atypical parkinsonisms.

Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often cause severe, early-onset disease with pathology that is distinct yet partially overlapping with sporadic cases. Here, we evaluated post-mortem tissue from a patient with FTLD-tau due to MAPT S305I showing neuropathology most consistent with argyrophilic grain disease (AGD), a prevalent limbic tauopathy of aging. Structures determined by cryo-electron microscopy reveal tau filament folds that differ from those found in sporadic AGD or other tauopathies and feature a 4-layer architecture stabilized by the Ile substitution within its core. Comparative structural analysis reveals conserved motifs are shared among AGD, corticobasal degeneration, and MAPT P301T. A well-defined density stacks along a cationic cleft, indicative of a bound RNA-like polyanion or small-molecule. In vitro analysis shows the S305I mutation promotes fibrilization relative to normal tau. These results demonstrate that MAPT S305I stabilizes a distinct aggregation-prone tau fold that likely contributes to disease pathology and heterogeneity beyond its known splicing defects, and underscore potential limitations of using the most pathologically similar genetic form as a model for sporadic FTLD-tau.

Von Economo neurons (VENs) are unique spindle-shaped neurons that primarily reside in the anterior cingulate (ACC) and fronto-insular (FI) cortices. They are more numerous in species with affiliative behaviors and may support social-emotional functions. VENs are reduced in the ACC and FI of individuals with behavioral variant frontotemporal dementia (bvFTD), marked by personality changes and socially inappropriate behavior. Neuropathologies underlying bvFTD include frontotemporal lobar degenerations (FTLD) with tauopathy (FTLD-tau) or TDP-43 (FTLD-TDP). This study examined VEN density across three FTLD-tau subtypes: the 4R tauopathies of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and the 3R tauopathy known as Pick's disease (PiD). Twenty-six right-handed bvFTD-FTLD-tau cases were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PiD n= 9; CBD n= 11; PSP n= 6). Paraffin sections were cresyl violet-stained to visualize VENs in the ACC and analyzed using unbiased stereology. Wilcoxon rank-sum tests showed significantly lower VEN density in PiD than CBD (P< 0.05). No significant differences were found between PiD and PSP or CBD and PSP. Across isoforms, VEN density was over fourfold higher in 4R than 3R cases (P< 0.01). Overall, stereology indicates VENs are more vulnerable to 3R PiD than 4R CBD, both causes of bvFTD. The clinical implications of this differential vulnerability warrant further study.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by tremors, rigidity, and bradykinesia. This is primarily attributed to loss of nigrostriatal dopaminergic neurons to varying degrees. Many conditions that present similar classic motor symptoms of PD, known as atypical parkinsonian syndromes (APS), have also been identified. These encompass multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). On the other hand, causes of non-neurodegenerative parkinsonism include vascular parkinsonism, drug-induced parkinsonism, and essential tremors. Neuroimaging plays a significant role in discriminating PD from its mimics which may represent a significant challenge in clinical practice. This article aims to review recent developments in imaging technologies, particularly magnetic resonance imaging (MRI) and nuclear medicine imaging techniques, that have the potential to unravel characteristic morphological and metabolic changes in the brain and would aid in the early diagnosis of PD and its differentiation from its potential mimickers.Learning objectivesTo identify the peculiar structural imaging features of atypical parkinsonian syndromes and recognize the role of the current state-of-the-art neuroimaging modalities (particularly MRI and nuclear medicine techniques) in discriminating Parkinson's disease from its mimics.