Faculty Profiles - TAKASHIMA Hiroshi

Papers - TAKASHIMA Hiroshi

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Masayuki Wakita, Ran Takei, Fumio Miyashita, Yuki Hamada, Satoshi Ohyama, Hideki Matsuoka, Hiroshi Takashima . Carotid ultrasound features of anomalous left vertebral artery originating from the aortic arch proximal to the left subclavian artery . Neuroradiology Journal30 ( 2 ) 168 - 171 2017.4Reviewed International journal

Publisher：SAGE Publications Inc.

We present three cases of anomalous origin of the left vertebral artery (LVA) detected during the evaluation of stroke. The VA usually enters the transverse foramen of the sixth cervical vertebra (C6), but an anomalous LVA originating from the aorta frequently enters at a higher level. In our series, ultrasound of the LVA showed entry at C4 in two patients and at C5 in one patient. These findings suggested anomalous LVA origin, and three-dimensional computed tomography demonstrated the LVA arising from the aorta proximal to the left subclavian arteries. Carotid duplex ultrasound is useful for the diagnosis of this anomaly.

DOI： 10.1177/1971400916687585

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Hideaki Nishihara, Masatoshi Omoto, Masaki Takao, Yujiro Higuchi, Michiaki Koga, Motoharu Kawai, Hiroo Kawano, Eiji Ikeda, Hiroshi Takashima, Takashi Kanda . Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction. . Neurology. Genetics3 ( 4 ) e171 2017Reviewed International journal

Language：English

OBJECTIVE: To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene. METHODS: We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations. RESULTS: The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2-weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65. CONCLUSIONS: We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations.

DOI： 10.1212/NXG.0000000000000171

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Takashima Hiroshi . Diagnostic tips and treatment of autoimmune encephalopathy . Neurological Therapeutics34 ( 3 ) 160 - 162 2017Reviewed

Authorship：Lead author Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. In clinical situations, we often recognize that patients with autoimmune encephalopathy are often misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. We clinically analyzed 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with give–way weakness. About 70% of patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or fast neurologic pain. Most pain was distributed in manner that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. We observed memory loss, PNES (psychogenic non–epileptic seizure), dissociative amnesia, hyperventilation, opsoclonus, epilepsy, or autonomic symptoms amongst our patients. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.

DOI： 10.15082/jsnt.34.3_160

CiNii Research

髙嶋博, 荒田仁, 東桂子, 松浦英治 . 子宮頸がんワクチンに関連した自己免疫脳症 . 神経治療学34 ( 6 ) S136 - S136 2017

Takashima Hiroshi, Kuwabara Satoshi, Kuriyama Masaru, Iizuka Takahiro . Discussion on Clinical Diversity of Various Encephalitis/Encephalopathy . Nihon Naika Gakkai Zasshi106 ( 8 ) 1598 - 1610 2017International journal

Sato T., Tsuchimochi Y., Hamada Y., Kukihara K., Kawabata Y., Iwamoto K., Takaguchi G., Higuchi Y., Matsuoka H., Takashima H. . Severe cerebral small vessel disease burden is associated with intraventricular extension of intracerebral hemorrhage . Journal of the Neurological Sciences480 125680 2026.1

Language：Japanese Publisher：Journal of the Neurological Sciences

Objectives: Factors associated with intraventricular extension (IE) following intracerebral hemorrhage (ICH) are not fully clarified. We aimed to elucidate the correlation between IE and cerebral small vessel disease (SVD) in ICH. Materials & methods: Consecutive patients with acute ICH between July 2012 and November 2023 were screened. The inclusion criteria: 1) onset to door time within 7 days; 2) availability of SVD evaluation using total SVD score; and 3) availability of IE evaluation on admission and/or more than 24 h after admission. Total SVD score was calculated as the sum of the points for the following observations: old lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and enlarged perivascular spaces. Results: Of 608 ICH screened, 449 (234 [52 %] males, median age 75 years) were included. IE was observed in 151 (34 %). Total SVD score was independently associated with IE (prevalence ratio (PR) 1.188, 95 % confidence interval (CI) 1.063–1.329, p = 0.002). Further, a positive linear trend was observed between total SVD score and IE relative to a total SVD score of 0 (total SVD score 0: PR 1.000, total SVD score 1–2: PR 3.769, total SVD score 3–4: PR 4.109, p = 0.011 for trend). Among the items comprising the total SVD score, WMH (PR 1.406 95 % CI 1.041–1.899, p = 0.026) and CMBs (PR 1.800, 95 % CI 1.068–3.036, p = 0.027) were associated with IE. Conclusion: In acute ICH, higher total SVD score is associated with IE. In particular, WMH and CMBs might correlate with the occurrence of IE.

DOI： 10.1016/j.jns.2025.125680

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Nozuma S., Dozono M., Tanaka M., Kodama D., Yoshida T., Higuchi Y., Sakiyama Y., Matsuura E., Matsuzaki T., Takashima H., Kubota R. . HTLV-1-Specific CTL Accumulation in CSF Contributes to Neuroinflammation in HTLV-1-Associated Myelopathy . Neurology R Neuroimmunology Neuroinflammation13 ( 1 ) e200508 2026.1

Language：Japanese Publisher：Neurology R Neuroimmunology Neuroinflammation

BACKGROUND AND OBJECTIVES: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurologic disorder characterized by chronic inflammation in the CNS. HTLV-1-specific cytotoxic CD8+ T lymphocytes (CTLs) play a crucial role in the pathogenesis of HAM/TSP; however, the dynamics of CTLs in the CSF remain poorly understood. The aim of this study was to investigate the accumulation of HTLV-1-specific CTLs in the CSF of patients with HAM/TSP and to evaluate their association with neuroinflammation and neural damage. METHODS: The frequency of HTLV-1-specific CTLs was compared between paired peripheral blood (PB) and CSF from patients with HAM/TSP and asymptomatic HTLV-1 carriers (ACs) using MHC/antigen tetramers. In addition, cytokine levels and neurofilament light chain (NfL) concentration were analyzed in the CSF of patients with HAM/TSP and ACs. RESULTS: The frequency of HTLV-1-specific CTLs in PB was significantly higher in patients with HAM/TSP compared with ACs (median [interquartile range (IQR)] = 3.0 [0.9-8.3] % vs 0.3 [0.2-3.1] %, p < 0.01). Notably, this difference was even more pronounced in CSF, where patients with HAM/TSP exhibited a significantly elevated frequency compared with ACs (19.1 [7.9-33.4] % vs 6.1 [0.9-15.7] %, p < 0.01). Furthermore, the frequency of HTLV-1-specific CTLs in the CSF was considerably higher than in the PB of patients with HAM/TSP (p < 0.0001). The lack of accumulation of cytomegalovirus-specific CTLs indicates that HTLV-1-specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. These accumulated HTLV-1-specific CTLs in the CSF significantly correlated with increased levels of cytokines in patients with HAM/TSP. In addition, CSF NfL levels were significantly higher in patients with HAM/TSP than in ACs (696 [534-1,407] vs 429 [373-717] pg/mL, p < 0.05) and showed a positive correlation with HTLV-1 proviral load. DISCUSSION: HTLV-1-specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. Chronic inflammation, primarily driven by the interaction between proliferating HTLV-1-infected cells and accumulated HTLV-1-specific CTLs, may contribute to neural damage in patients with HAM/TSP.

DOI： 10.1212/NXI.0000000000200508

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Sato T, Tsuchimochi Y, Hamada Y, Kukihara K, Kawabata Y, Iwamoto K, Takaguchi G, Higuchi Y, Matsuoka H, Takashima H . Fibrosis-4 index and prognosis and hematoma volume: association with lobar and non-lobar intracerebral hemorrhage. . Hypertension research : official journal of the Japanese Society of Hypertension 2025.12

Yuan JH, Higuchi Y, Ando M, Hashiguchi A, Okamoto Y, Hiramatsu Y, Yoshimura A, Kodama K, Sakiyama Y, Mitsui J, Tsuji S, Takashima H . Respiratory complex I deficiency caused by a novel multi-exonic PUS1 deletion. . Journal of human genetics 2025.12

Yamashiro M., Yasutomi D., Ohya Y., Ohyama S., Takashima H., Tokashiki T. . A case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease . Human Genome Variation12 ( 1 ) 13 2025.12

Language：Japanese Publisher：Human Genome Variation

Hereditary cerebral small vessel diseases (CSVDs) include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by biallelic HTRA1, and heterozygous HTRA1-related CSVD. Here we report a case of a 53-year-old Japanese woman with coexisting NOTCH3 p.R75P and HTRA1 p.R166L mutations, each in the heterozygote. She presented with early-onset spastic paraparesis, frequent urination, cognitive impairment and baldness. We compared the clinical features of this case with known phenotypes of CADASIL caused by p.R75P, HTRA1-related CSVD. We reported cases with heterozygous HTRA1 p.R166L to discuss the potential synergistic effects of the coexisting variants.

DOI： 10.1038/s41439-025-00317-z

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Yuan JH, Higuchi Y, Ando M, Hiramatsu Y, Yoshimura A, Hobara T, Kojima F, Nakamura T, Sakiyama Y, Nozuma S, Ohyama S, Mitsui J, Tsuji S, Takashima H . Frameshift and Copy Number Variants in SACS-Related Neuropathy. . Neurology. Genetics11 ( 6 ) e200318 2025.12

Honkawa Yuta, Kuwagaki Shiori, Hayashida Hitoshi, Higuchi Yujiro, Takashima Hiroshi, Ikezoe Koji . A case of adult-onset Krabbe disease diagnosed by galactocerebrosidase gene mutations, presenting with an atypical phenotype . Rinsho Shinkeigaku65 ( 11 ) 808 - 812 2025.11

Language：Japanese Publisher：Societas Neurologica Japonica

Adult-onset Krabbe disease is a rare neurodegenerative disorder caused by mutations in the galactocerebrosidase (GALC) gene. It typically presents with slowly progressive central nervous system involvement, primarily characterized by pyramidal tract signs. We report the case of a 74-year-old man who presented with slowly progressive, asymmetric muscle atrophy associated with peripheral neuropathy, but without any clinical evidence of pyramidal tract involvement. Neurological examination revealed muscle wasting and weakness without spasticity or pathological reflexes. Based on the clinical presentation, differential diagnoses included motor neuron disease, Charcot–Marie–Tooth disease, and chronic inflammatory demyelinating polyneuropathy. Genetic analysis revealed a known pathogenic missense variant in the GALC gene: c.246A>G (p.I82M), confirming the diagnosis of Krabbe disease. These mutations have been previously reported in adult-onset Krabbe disease. This case lacked typical central nervous system signs and represents an atypical phenotype that may lead to delayed diagnosis. Our findings suggest that Krabbe disease should be considered in the differential diagnosis of adult patients presenting with unexplained neuropathy and marked muscle atrophy. Genetic testing plays a critical role in identifying such atypical cases, particularly when conventional diagnostic approaches fail to provide a definitive diagnosis.

DOI： 10.5692/clinicalneurol.cn-002148

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矢野直志, 髙嶋博 . 特集シャルコーを讃えて-Hommage à Charcot シャルコー･マリー･トゥース病-疾患概念の確立と現況 . BRAIN and NERVE77 ( 11 ) 1176 - 1184 2025.11

Dozono M., Nozuma S., Hirakata S., Yoshida T., Kodama D., Tanaka M., Matsuura E., Kubota R., Takashima H. . Clinical Characteristics of Parkinsonism in HTLV-1-Associated Myelopathy . Annals of Clinical and Translational Neurology12 ( 10 ) 1962 - 1970 2025.10

Language：Japanese Publisher：Annals of Clinical and Translational Neurology

Objective: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the classic neurological manifestation of HTLV-1 infection; however, this virus has also been associated with other neurological disorders. Concurrent parkinsonism is relatively rare and presents diagnostic challenges. The present study aimed to identify the clinical characteristics of HAM/TSP with parkinsonism. Methods: This retrospective study included HAM/TSP patients hospitalized in Kagoshima University Hospital from January 2000 to March 2022. Clinical and laboratory findings of the HAM/TSP patients with parkinsonism (P-HAM) were collected from the medical records and compared with HAM/TSP patients without parkinsonism (typical HAM/TSP [T-HAM]). P-HAM cases were defined as patients presenting with any combination of rigidity, resting tremor, bradykinesia, and/or postural instability, with these symptoms not attributed to HAM/TSP. Results: Of 246 HAM/TSP patients, 11 (4.5%) presented with parkinsonism. Compared with T-HAM, the age of onset was significantly older (65.0 vs. 48.8 years, p = 0.001) in patients with P-HAM. Moreover, despite a shorter illness duration (8.5 vs. 12.5 years, p = 0.151), the Osame Motor Disability Score was significantly higher in P-HAM cases than in T-HAM cases (6.3 vs. 4.6, p = 0.0132), and all P-HAM cases had scores ≥ 4. Laboratory findings showed no differences between the groups. Interpretation: In our cohort, 4.5% of HAM/TSP patients had concomitant parkinsonism, which was associated with a later age of onset and greater disease severity. The coexistence of parkinsonism in HAM/TSP may be underrecognized, and our findings expand the clinical spectrum of neurological disease with HTLV-1 infection.

DOI： 10.1002/acn3.70121

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Sato T., Tsuchimochi Y., Hamada Y., Kukihara K., Kawabata Y., Iwamoto K., Takaguchi G., Higuchi Y., Matsuoka H., Takashima H. . Lower high-density lipoprotein cholesterol level is associated with hematoma expansion in acute intracerebral hemorrhage: association with hypertensive microangiopathy . Hypertension Research48 ( 9 ) 2326 - 2338 2025.9

Language：Japanese Publisher：Hypertension Research

The correlation between lipoprotein cholesterol levels and hematoma expansion (HE) following intracerebral hemorrhage (ICH) remains unknown. We aimed to elucidate the correlation between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and HE following acute ICH in entire ICH, non-lobar ICH, and lobar ICH cohorts. Consecutive patients with ICH between July 2012 and November 2023 were screened. The inclusion criteria were: (1) onset to door time within 24 h; (2) availability of serum HDL-C and LDL-C level evaluations on admission; and (3) availability of HE evaluation. We investigated the association between HDL-C and LDL-C levels and HE using Poisson regression analyses with a robust variance estimator in three models with adjustment for various factors. Screening of 608 consecutive ICH patients revealed 409 with acute ICH (204 [50%] males, median age 75 years). HE was observed in 43 patients (11%). In the entire ICH cohort, lower HDL-C was independently associated with HE in all the study models (p < 0.05). Further, a negative linear association was observed between HDL-C quartiles and HE in reference to HDL-C Quartile 4 in all the models (p < 0.05 for trend). These significant associations were also observed in the non-lobar ICH cohort, but not in the lobar ICH cohort. LDL-C was not associated with HE in any of the cohorts. In acute ICH patients, lower HDL-C was associated with HE, especially in the non-lobar ICH cohort generally caused by hypertensive microangiopathy. HDL-C might have protective potential against HE following ICH. (Figure presented.)

DOI： 10.1038/s41440-025-02268-y

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Sato Takeo, Tsuchimochi Yuka, Hamada Yuki, Kukihara Kaishi, Kawabata Yutaro, Iwamoto Kana, Takaguchi Go, Higuchi Yujiro, Matsuoka Hideki, Takashima Hiroshi . 【Current evidence and perspectives for hypertension management in Asia】Lower high-density lipoprotein cholesterol level is associated with hematoma expansion in acute intracerebral hemorrhage: association with hypertensive microangiopathy(タイトル和訳中) . Hypertension Research48 ( 9 ) 2326 - 2338 2025.9

Hobara T., Ando M., Higuchi Y., Yuan J.H., Yoshimura A., Saito T., Shiihara T., Okuda S., Fukushima N., Awano H., Inoue T., Yano C., Kojima F., Kodama K., Hiramatsu Y., Nozuma S., Nakamura T., Sakiyama Y., Hashiguchi A., Mitsui J., Tsuji S., Takashima H. . Charcot–Marie–Tooth-like presentation in giant axonal neuropathy: clinical variability and prevalence in a large Japanese case series . Journal of Neurology272 ( 8 ) 514 2025.8

Language：Japanese Publisher：Journal of Neurology

Background: Giant axonal neuropathy 1 (GAN) is a rare neurodegenerative disorder with autosomal recessive inheritance and significant phenotypic heterogeneity, ranging from milder presentations resembling Charcot–Marie–Tooth disease (CMT) to classical presentations involving central and peripheral nervous systems. We investigated the genetic and clinical spectrum of GAN in Japanese patients with inherited peripheral neuropathies (IPNs). Methods: We conducted genetic screening of 3315 Japanese patients diagnosed with IPNs between 2007 and 2023 using targeted next-generation or whole-exome sequencing. Variant pathogenicity, clinical features, and neurophysiological and neuroimaging findings were reviewed. Results: We identified seven biallelic GAN variants in five patients from four unrelated families, including one homozygous and three compound heterozygous genotypes. Two novel pathogenic variants were identified: c.922G > T (p.Glu308*) and c.456dup (p.Ala153Cysfs*27). Two families exhibited the classical phenotype, whereas the other two exhibited a CMT-like phenotype. Mean onset age was 4.4 years (range 1.5–8), and gait disturbance was the initial symptom. The most common findings included distal weakness (n = 5), sensory impairment (n = 4), scoliosis (n = 3), autonomic dysfunction (n = 2). Neurophysiologically, all patients had sensorimotor axonal polyneuropathy. One patient with mild phenotype maintained a CMT-like state without systemic involvement until the age of 43 years and was still alive at 72, representing the longest documented survival in GAN. Conclusion: This study expands the genetic and phenotypic spectrum of GAN by identifying novel variants and a long-term survivor. These findings underscore the importance of systematic genetic screening for GAN in pediatric-onset CMT, even in the absence of classical features.

DOI： 10.1007/s00415-025-13243-5

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Kubota R., Hanada K., Saito M., Dozono M., Nozuma S., Takashima H. . High TCR Degeneracy Enhances Antiviral Efficacy of HTLV-1-Specific CTLs by Targeting Variant Viruses in HAM Patients . International Journal of Molecular Sciences26 ( 14 ) 2025.7

Language：Japanese Publisher：International Journal of Molecular Sciences

T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide–MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = −0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capacity, characterized by broadened epitope recognition and more effective suppression of HTLV-1 infection. To our knowledge, this is the first study to systematically quantify TCR degeneracy in HTLV-1-specific CTLs and evaluate its contribution to viral control in HAM patients. These findings establish TCR degeneracy as a critical determinant of antiviral efficacy and provide a novel immunological insight into the mechanisms of viral suppression in chronic HTLV-1 infection.

DOI： 10.3390/ijms26146602

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Watanabe R., Papatriantafyllou J.D., Maeda K., Aguirre G.K., Ando M., Benoit B., Grossman M., Irwin D.J., Kim B., Massimo L., McMillan C.T., Papageorgiou S.G., Phillips J.S., Shiraishi T., Sugihara Y., Suh E.R., Takashima H., Toro C., Van Deerlin V.M., Nasrallah I.M., Lee E.B. . Clinicopathological characterization of vacuolar tauopathy associated with VCP D395G . Alzheimer S and Dementia21 ( 7 ) e70427 2025.7

Language：Japanese Publisher：Alzheimer S and Dementia

INTRODUCTION: The clinical, radiological, and pathological features have not been well documented for the recently discovered autosomal-dominant vacuolar tauopathy (VT) harboring the Valosin-containing protein (VCP) p.Asp395Gly variant. METHODS: We investigated the clinical, neuropsychological, physiological, laboratory, and radiological data and neuropathological findings in five symptomatic VT cases who met the diagnostic criteria for frontotemporal dementia (FTD). Radiological data were also collected from two pre-symptomatic carriers. RESULTS: All participants had heterozygous c.1184A > G, p.Asp395Gly in VCP. All symptomatic cases exhibited cognitive, behavioral, and/or language dysfunction indicative of FTD in their 30s to 50s. Neuroimaging studies revealed marked bilateral frontal neurodegeneration and occipital lobar diffusion abnormalities. Post mortem examination of three cases and brain biopsy of one case revealed abundant three- and four-repeat tau deposition and neocortical microvacuolization. Radiological changes were not evident in two pre-symptomatic carriers in their 20s. DISCUSSION: This study reveals distinct clinical-radiological-pathological correlations in VT, expanding the spectrum of early-onset frontotemporal lobar degeneration (FTLD). Highlights: We characterized the clinical, radiological, and pathological features of vacuolar tauopathy (VT). Five VT cases exhibited a behavioral syndrome, often with aphasic features, with marked frontal lobar atrophy and hypometabolism. Magnetic resonance imaging (MRI) of VT cases revealed occipital lobar diffusion abnormalities. Diffuse neurofibrillary tangles (NFTs) and microvacuolization were observed in the neocortex, with an inverse distribution.

DOI： 10.1002/alz.70427

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Yamashiro Masataka, Yasutomi Daigo, Ohya Yuichiro, Ohyama Satoshi, Takashima Hiroshi, Tokashiki Takashi . A case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease(タイトル和訳中) . Human Genome Variation12 s41439 - 025 2025.7

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Papers - TAKASHIMA Hiroshi