Koga, Shunsuke

AbstractBackgroundPerry disease (or Perry syndrome [PS]) is a hereditary neurodegenerative disorder inevitably leading to death within few years from onset. All previous cases with pathological confirmation were caused by mutations within the cytoskeleton‐associated protein glycine‐rich (CAP‐Gly) domain of the DCTN1 gene.ObjectivesThis paper presents the first clinicopathological report of PS due to a novel DCTN1 mutation outside the CAP‐Gly domain.MethodsClinical and pathological features of the new variant carrier are compared with another recently deceased PS case with a well‐known pathogenic DCTN1 mutation and other reported cases.Results and ConclusionsWe report a novel DCTN1 mutation outside the CAP‐Gly domain that we demonstrated to be pathogenic based on clinical and autopsy findings.

Abstract Background: As part of the CurePSP brain donation program, a questionnaire was developed to capture basic information from the next-of-kin or someone familiar with the brain donor with respect to symptoms and clinical course. The usefulness of information from the questionnaire has not been assessed. Objective: To assess the value of information from the brain donation questionnaire as it relates to differential diagnosis of parkinsonian disorders. Methods: We reviewed 150 questionnaires, including 50 patients, each with a neuropathologic diagnosis of Lewy body disease (LBD), multiple system atrophy (MSA), or progressive supranuclear palsy (PSP). The frequency of clinical features recorded in the questionnaires was compared for the three disorders, and machine learning algorithm, XGBoost, was applied to tabulated information from the questionnaires to identify features that had predictive value with respect to neuropathologic diagnosis. Results: The information from the questionnaires correlated with core clinical features for each disorder - hallucinations for LBD, autonomic dysfunction for MSA, and early falls for PSP. Age at onset and early falls were identified as the key variables that contributed most to prediction of neuropathology. Conclusion: While less optimal than prospectively collected information, a questionnaire can provide useful clinical information for clinicopathological correlative studies.

Abstract Neuropathological assessment at autopsy is the gold standard for diagnosing neurodegenerative disorders. We aimed to develop a pipeline for diagnosing Alzheimer's disease and other tauopathies, including corticobasal degeneration, globular glial tauopathy, Pick’s disease, and progressive supranuclear palsy. We used deep learning (DL)-based approach called clustering-constrained-attention multiple instance learning (CLAM) on whole slide images (WSIs) of tau immunohistochemistry in three brain regions from 120 patients. We also augmented gradient-weighted class activation mapping (Grad-CAM) to the model for visualizing cellular-level evidence in the model’s decisions. The model using the sections of cingulate and superior frontal gyri achieved the highest area under the curve (0.970±0.037) and diagnostic accuracy (0.873±0.087). Grad-CAM showed the highest attention in known pathognomonic tau lesions for each disease (e.g., Pick bodies for Pick’s disease). Our findings supported the feasibility of the DL-based approach for the classification task on WSIs, which encouraged further investigation, especially focusing on clinicopathological correlation studies.

Abstract Neuropathological assessment at autopsy is the gold standard for diagnosing neurodegenerative disorders. We aimed to develop a pipeline for diagnosing Alzheimer's disease and other tauopathies, including corticobasal degeneration, globular glial tauopathy, Pick’s disease, and progressive supranuclear palsy. We used deep learning (DL)-based approach called clustering-constrained-attention multiple instance learning (CLAM) on whole slide images (WSIs) of tau immunohistochemistry in three brain regions from 120 patients. We also augmented gradient-weighted class activation mapping (Grad-CAM) to the model for visualizing cellular-level evidence in the model’s decisions. The model using the sections of cingulate and superior frontal gyri achieved the highest area under the curve (0.970±0.037) and diagnostic accuracy (0.873±0.087). Grad-CAM showed the highest attention in known pathognomonic tau lesions for each disease (e.g., Pick bodies for Pick’s disease). Our findings supported the feasibility of the DL-based approach for the classification task on WSIs, which encouraged further investigation, especially focusing on clinicopathological correlation studies.

AbstractBackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar syndromes. Although consensus criteria have been widely used to diagnose MSA, accurate clinical diagnosis remains challenging. Other neurodegenerative disorders, such as Lewy body disease, can mimic MSA.ObjectivesWe described clinical and neuropathologic findings of two patients with Creutzfeldt–Jakob disease (CJD) who had antemortem clinical diagnoses of MSA.MethodsThe brain bank for neurodegenerative disorders was queried for cases with a clinical diagnosis of MSA, but neuropathologic findings of CJD.ResultsCase 1 was a 55‐year‐old man with a 6‐month history of orthostatic hypotension, parkinsonism, cerebellar ataxia, bradyphrenia, and memory impairment. Case 2 was a 65‐year‐old man who had a 5‐year history of cerebellar ataxia, parkinsonism, and cognitive impairment, as well as a 7‐year history of dream enactment behavior. Neither case had characteristic α‐synuclein immunoreactive neuronal or glial inclusions typical of MSA. Instead, they had spongiform encephalopathy with neuronal loss and gliosis with prion protein‐immunoreactive kuru‐like plaques. Genetic analyses in case 1 had wild‐type PRNP, whereas case 2 revealed a 4‐octapeptide repeat insertion in PRNP.ConclusionsEven when clinical features suggest MSA, CJD should also be considered if the progression is rapid or the disease course is atypical, such as the absence of autonomic dysfunction for an extended period.

ABSTRACTBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP.ObjectivesThis paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations.MethodsThe index case was a 30‐year‐old male who presented with gait difficulty, followed by cognitive decline and incontinence.ResultsNeurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work‐up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations.ConclusionsWe draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease‐modifying therapy is already available for ALSP‐CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

ABSTRACTBackgroundLoss‐of‐function mutations in GRN are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimer's disease and Parkinson's disease. Although TDP‐43‐positive inclusions are characteristic of GRN‐related neurodegeneration, Lewy body copathology has also been observed in many GRN mutation carriers.ObjectiveThe objective of this study was to assess a Lewy body dementia (LBD) case–control cohort for pathogenic variants in GRN and to test whether there is an enrichment of damaging mutations among patients with LBD.MethodsWe analyzed whole‐genome sequencing data generated for 2591 European‐ancestry LBD cases and 4032 neurologically healthy control subjects to identify disease‐causing mutations in GRN.ResultsWe identified six heterozygous exonic GRN mutations in seven study participants (cases: n = 6; control subjects: n = 1). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of GRN loss‐of‐function mutations in patients with LBD compared with control subjects (Optimized Sequence Kernel Association Test P = 0.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP‐43‐positive neuronal inclusions.ConclusionsOur findings suggest that deleterious GRN mutations are a rare cause of familial LBD. © 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.