Tomoyasu Matsubara

Background & Objectives: As recently recommended by neuropathologists, we assessed the diagnostic accuracy of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) seed amplification assay (SAA) in an autopsy cohort with systemic assessment of Lewy pathology. Methods: CSF was obtained antemortem and stored at -80 ℃. α-syn SAA and systemic Lewy pathology assessment were conducted as previously reported. Kinetic parameters, including maximum fluorescence (Fmax) and time to reach 50% of Fmax (T50), were also evaluated. Results: CSF samples were available from 30 patients (8 with symptomatic Lewy body disease [LBD], 2 with multiple system atrophy [MSA], 3 with Alzheimer's disease [AD], and 17 disease controls). Despite different clinical stages, all patients with LBD had diffuse neocortical or limbic-stage pathology at autopsy, with widespread peripheral Lewy bodies, including in the esophagus, heart, and sympathetic ganglia. Lewy pathology was not observed in disease controls. SAA was positive in all 8 with LBD, low positive in one patient with AD, and negative in all others. Fmax was significantly higher in LBD compared with cases without α-syn pathology (9091±2083 vs. 1659±113 relative fluorescence units). The low-positive case had a lower positivity rate (25% vs. 75-100%), lower Fmax, and longer T50 than LBD cases. Conclusions: In this pilot study, CSF α-syn SAA demonstrated high specificity (95%) and high sensitivity (100%) for detecting LBD; however, all LBD cases had widespread pathology, including peripheral involvement. Larger studies are needed to understand the association between CSF α-syn SAA and Lewy pathology in the body.

We report a 58‐year‐old woman with a novel splice‐site variant in the TANK‐binding kinase 1 ( TBK1 :c.993–2A>C p.Ala332TyrfsTer39) who sequentially developed primary lateral sclerosis (PLS) followed by right temporal variant frontotemporal dementia (rtvFTD). Neuroimaging demonstrated right anterior temporal atrophy before cognitive symptoms, and prosopagnosia represented the earliest manifestation of rtvFTD. Molecular analysis revealed reduced levels of correctly spliced TBK1 transcripts, consistent with haploinsufficiency. Given the shared involvement of TDP‐43 pathology in both PLS and rtvFTD, this case indicates TBK1 dysfunction as a fundamental genetic factor underlying the coexistence of these phenotypes, underscoring the clinical value of early neuroimaging and genetic evaluation.

Background: Argyrophilic grain disease (AGD) is a common yet underrecognized tauopathy that often mimics Alzheimer's disease (AD) in clinical and imaging presentations. While regional atrophy in AGD has been reported on magnetic resonance imaging (MRI), network-level structural changes remain poorly understood. Objective: We aimed to explore a gray matter volume network related to AGD. Methods: Structural MRI data were collected from 12 patients with pathologically confirmed AGD (age at MRI, 87.7 ± 5.5 years; male, 4), 12 patients with pathologically confirmed AD (83.4 ± 10.0 years; male, 4), and 9 healthy controls (HCs; 82.4 ± 1.9 years; male, 2) at Fukushimura Hospital in Japan. Scaled Subprofile Model with principal component analysis was applied to preprocessed gray matter volume data of AGD and HCs to identify an AGD-related network. Results: An AGD-related network involving relative reduction in the ambient gyrus, entorhinal cortex, hippocampus, amygdala, and thalamus was identified. Represented by principal components 1, 2, and 3, this network showed significantly higher expression in patients with AGD than HCs (p < 0.0001, permutation test). The expression of the network was also higher in patients with AD than HCs (p < 0.0001, t-test). Conclusions: This exploratory study identified a gray matter volume network related to AGD, providing a basis for future research of network-based imaging approaches.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C > T p.(Arg83Trp) variant in RAB3A, encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In the cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber–Purkinje cell synapses mediated by the Rab3A–RIM1 complex.

Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.

Background: This study aimed to evaluate Hasegawa Dementia Scale‐Revised (HDS‐R) cutoff scores that correspond to Mini‐Mental State Examination (MMSE) thresholds for identifying candidates for anti‐amyloid β (Aβ) therapies. Additionally, we conducted exploratory analyses to examine the cognitive subdomains associated with Aβ status. Methods: This retrospective cross‐sectional study included consecutive patients with amnesia who underwent neuropsychological examinations and Aβ assessment through cerebrospinal fluid analysis or positron emission tomography. Diagnostic accuracy for MMSE thresholds (≥ 20, ≥ 22 and ≥ 24) was assessed, and two HDS‐R cutoffs (high‐sensitivity, high‐specificity) were determined for each threshold. We examined differences in cognitive subdomains between Aβ‐positive and Aβ‐negative patients with MMSE score ≥ 20. Results: Of 234 patients, 143 (61.1%) were Aβ‐positive. The area under the receiver operating characteristic curve for predicting MMSE score ≥ 20, ≥ 22 and ≥ 24 was 0.92, 0.90 and 0.91, respectively. High‐sensitivity cutoffs, defined as scores that maximised specificity while maintaining sensitivity ≥ 80%, were HDS‐R score ≥ 16, ≥ 17 and ≥ 18. Conversely, high‐specificity cutoffs, defined as scores that maximised sensitivity while maintaining specificity ≥ 80%, were HDS‐R score ≥ 19, ≥ 20 and ≥ 21, respectively. Subdomain analysis of MMSE and HDS‐R showed Aβ‐positive patients had lower scores in delayed recall and higher scores in calculation than Aβ‐negative patients (all p < 0.01). In HDS‐R subdomains, visual memory scores were also lower in Aβ‐positive patients than in Aβ‐negative patients ( p < 0.01). Conclusions: The identified HDS‐R cutoff scores were associated with MMSE‐defined cognitive thresholds and may serve as a potential reference for identifying patients who could be eligible for anti‐Aβ therapies. The cognitive profile observed in Aβ‐positive patients was characterised by deficits in delayed recall and in visual memory and by relatively preserved calculation ability, suggesting a selective vulnerability pattern in early Alzheimer's disease.

Summary: This study identified a novel amyotrophic lateral sclerosis subtype with prominent astroglial phosphorylated TDP‐43 inclusions and minimal neuronal inclusions. The patients shared a clinical phenotype of flail arm variant of ALS. These observations suggest a more critical role for astroglia than previously recognised.

Argyrophilic grain disease is an age-related disorder characterized by the presence of argyrophilic grains. Argyrophilic grain disease has a sequential distribution pattern that begins in the ambient gyrus (Saito Stage I), spreads to the medial temporal lobe (Saito Stage II) and reaches the basal forebrain and cingulate gyrus (Saito Stage III). A strong association with cognitive decline, especially in cases of Saito Stage III argyrophilic grain disease, has also been reported. The main clinical feature includes cognitive decline characterized by memory disturbance, although conflicting results have been reported. Recent studies suggest an association with parkinsonism. To clarify the association between argyrophilic grain disease, cognitive decline and parkinsonism, we performed a clinicopathological study using the Brain Bank for Aging Research autopsy cohort in Japan. Approximately half (227) of the 452 consecutive autopsy cases had argyrophilic grain disease, and the frequency and stage of argyrophilic grain disease increased with age. Among the argyrophilic grain disease cases, 20 were demented without any comorbid pathology responsible for it, a condition referred to as dementia with grains. Furthermore, 6 of the 20 dementia with grains cases presented with parkinsonism, particularly postural instability, in addition to memory disturbance. Dementia with grains cases with parkinsonism had significantly more argyrophilic grains in the substantia nigra than those without parkinsonism and showed significantly decreased anti-dopamine transporter immunoreactivity in the putamen compared to control cases. Given these findings, argyrophilic grain disease is strongly associated with cognitive decline, especially in Saito Stage III cases, and parkinsonism is a new common clinical presentation. The extension of argyrophilic grain disease pathology to the nigrostriatal system may contribute to the development of parkinsonism.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C>T p.(Arg83Trp) variant in RAB3A , encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In frozen sections of the mouse cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber–Purkinje cell synapses mediated by the Rab3A–RIM1 complex.