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The study determines the frequency of glucocerebrosidase ("GBA") mutations in an ethnically diverse group of patients with Parkinson's disease. Findings indicate a strong relation between "GBA" mutations and Parkinson's disease.

Despite documented cross-cultural variability in autonomy and relatedness, relatively little is known about how these characteristics of self are socialized. This study, a secondary analysis (Dennis et al., 2002), explored this question by examining sequential verbal exchanges between Japanese and U.S. mothers and children during play and a challenging wait (N = 60, M age = 55.8 months, SD = 4.9). The likelihood that mothers would contingently encourage child autonomy or relatedness by matching, responding positively, or reducing directives was tested. There was greater encouragement of relatedness among Japanese mothers but few cultural differences in encouraging autonomy. Effects depended on the context of interaction, with greater cultural differences during the challenging wait. Culturally distinct gender effects also emerged: U.S. mothers bolstered girls' autonomy and showed consistent encouragement of boys' relatedness whereas Japanese mothers bolstered autonomy in boys only. Implications for cross-cultural patterns in the socialization of self are discussed. [ABSTRACT FROM AUTHOR]

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common monogenic cerebral small vessel diseases. Our previous observational study suggested that lomerizine hydrochloride, a calcium channel blocker approved in Japan in 1999 for the prevention of migraine headaches, is also effective for preventing recurrent ischemic stroke in CADASIL patients. The aim of this study (LOMCAD trial) is to verify the efficacy of lomerizine hydrochloride., Materials and Methods: This is a multicenter, prospective, single-arm trial, using a historical control for comparison. CADASIL patients with a history of two or more cerebral ischemic events within the last two years will be administered lomerizine hydrochloride (5-mg tablet twice daily) for 24 months. The primary endpoint is symptomatic cerebral ischemic events during the 24-month period. Using our historical data and Bayesian sample size calculation based on a prior predictive distribution, the planned sample size was determined as 20 subjects., Conclusion: We have planned a clinical trial to verify the effectiveness of lomerizine hydrochloride as prophylaxis to prevent recurrent cerebral ischemic events in CADASIL patients., Registration: The LOMCAD trial has been registered in the Japan Registry of Clinical Trials (jRCTs051220072, https://jrct.niph.go.jp/latest-detail/jRCTs051220072)., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to this study., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Recent advancements in genome research have revealed not only the importance of variants associated with cerebrovascular diseases but also a notably high frequency of carriers harboring multiple variants, presenting with an elusive blended phenotype. In this study, we report the case of a 66-year-old man who experienced 3 stroke episodes over a 4-year period, starting at the age of 62 years. The patient presented with isolated infarcts in the left temporal pole with progressive stenosis in the ipsilateral middle cerebral artery based on large and small artery crosstalk., Methods: Exons 2-24 of the NOTCH3 gene were analyzed by direct genomic DNA sequencing. The presence of the p.Arg4810Lys variant of the ring finger protein 213 ( RNF213 ) gene was evaluated using real-time PCR., Results: Diagnoses of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and RNF213 -related vasculopathy were made based on the early-onset recurrent stroke episode, progressive intracranial artery stenosis, and presence of the heterozygous NOTCH3 p.Cys1250Arg and RNF213 p.Arg4810Lys variants., Discussion: Temporal pole infarcts could represent a blended phenotype of both variants. This case highlights the importance of large and small artery crosstalk and the pivotal role of genetic analysis in determining the pathogenesis of stroke and dementia., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation., Methods: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations., Results: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations., Interpretation: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

This report presents a case of Alexander disease showing clinical characteristics mimicking progressive supranuclear palsy (PSP). A 67-year-old woman complaining of motor disturbance exhibited severe atrophy of medulla, spinal cord, and midbrain tegmentum, as well as periventricular hyperintensity on cerebral MRI. Genetic analysis identified a novel in-frame deletion/insertion mutation in the exon 3 of the GFAP gene. Interestingly, neurological findings and decreased striatal uptake in dopamine transporter SPECT were suggestive of PSP. A novel GFAP gene mutation found in the present case may cause the unique clinical phenotype, which should be differentiated from PSP., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Notch signaling is conserved in C. elegans , Drosophila , and mammals. Among the four NOTCH genes in humans, NOTCH1 , NOTCH2 , and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH -related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.

Background: Although RNF213 p.R4810K, a genetic susceptibility variant for moyamoya disease (MMD), is associated with intracranial artery stenosis/occlusion (ICASO), the impact of this variant on ischemic stroke patients in non-young adults is unclear. We aimed to determine the characteristics of non-young adult stroke patients with RNF213 p.R4810K., Methods: We retrospectively identified acute ischemic stroke patients ≥50 years who were admitted to our hospital and underwent intracranial vascular imaging. We reviewed the patients with RNF213 p.R4810K and compared stroke characteristics and the frequency and location of ICASO between patients with and without the variant., Results: Among 341 patients, RNF213 p.R4810K was identified in 7 patients (2.1%). Five of the 7 patients with the variant (71%) had multiple ICASO without any finding of MMD and remaining 2 patients had no ICASO. The presumed etiologies of ICASO were atherosclerosis in 3 cases, vasculitis in 1, and undetermined vasculopathy in 1. ICASO in the anterior circulation was more common in patients with the variant than in those without (71% vs. 25%). The internal carotid artery, the M1 segment of the middle cerebral artery, the A1 segment of the anterior cerebral artery, and the P1 segment of the posterior cerebral artery, which were the most frequently affected arteries in MMD, were more often affected in the variant group., Conclusions: Non-young adult stroke patients with RNF213 p.R4810K are more likely to have ICASO in arterial segments commonly affected in MMD. The etiology of their ICASO exhibited diverse mechanisms, possibly depending on vascular risk and other environmental factors., (Copyright © 2023. Published by Elsevier B.V.)

Background: Impaired cerebrovasoreactivity is thought to play an important role in the pathophysiology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to clarify the association between cerebrovascular reactivity and stroke in patients with CADASIL., Methods: We retrospectively recruited 14 patients with CADASIL, eight of whom had symptomatic stroke. They underwent quantitative single-photon emission computed tomography using an autoradiographic method at rest and after acetazolamide (ACZ) administration. Regional cerebral blood flow (rCBF) in the cerebral cortex, lenticular nucleus, thalamus, and cerebellum was measured. We compared the rCBF parameters between patients with and without stroke., Results: The baseline characteristics and magnetic resonance imaging findings were similar between the two groups, except for a higher frequency of pyramidal tract sign (75% vs. 0%) and a larger number of old lacunes (15.4 ± 8.8 vs. 2.2 ± 1.8) in the patients with stroke. Of the rCBF parameters measured, significantly lower flow (mL/100 g/min) was observed in ACZ-rCBF in the thalamus (35.6 ± 9.4 vs. 51.1 ± 7.6, p = 0.01) and ΔrCBF in the thalamus (10.6 ± 3.7 vs. 21.0 ± 7.9, p = 0.02) in the patients with stroke., Conclusion: Cerebrovasoreactivity in the thalamus was significantly associated with stroke in patients with CADASIL., Competing Interests: IY reports grants from KAKENHI, AMED, and Health, Labor and Welfare Policy Research Grants, a research fund from Nihon Medi-Physics, and speaker fees from Chugai Pharmaceutical Co, AstraZeneca plt, Japan Tobacco Pharmaceutical Division, and Nippon Shinyaku Co., outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mukai, Hamano, Mizuta, Yokota, Watanabe-Hosomi, Matsuura, Koizumi, Matsuura, Ohara, Matsushima, Teramukai, Yamada and Mizuno.)

Background: This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan., Methods: This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests for NOTCH3 and HTRA1 , whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups., Results: Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients had NOTCH3 mutations, 11 patients had HTRA1 mutations, 6 patients had ABCC6 mutations, 1 patient had a TREX1 mutation, 1 patient had a COL4A1 mutation and 1 patient had a COL4A2 mutation. The total frequency of mutations in NOTCH3 , HTRA1 and ABCC6 was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134)., Conclusions: More than 90% of mgCSVDs were diagnosed by screening for NOTCH3 , HTRA1 and ABCC6 . The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients., Competing Interests: Competing interests: OO is a speaker honorarium for Kyowa Hakko Kirin, Bristol-Myers Squibb, Ono Pharmaceutical, Mitsubishi Tanabe Pharm, Takeda, Daiichi-Sankyo, FUJIFILM, SANOFI, FP-pharm. The other authors have no conflicts of interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) show various clinical symptoms, including migraine, recurrent stroke, and cognitive impairment. We investigated the associations between magnetic resonance imaging (MRI) markers of small vessel disease and neuropsychological tests and identified the MRI characteristics for predicting cognitive impairment in patients with CADASIL., Methods: Subjects included 60 CADASIL patients diagnosed with genetic tests and registered in the Japanese CADASIL REDCap database between June 2016 and December 2020. Patient information including clinical data, modified Rankin Scale (mRS); MRI findings of small vessel disease including periventricular and deep white matter lesions (WML), lacunar infarcts, and cerebral microbleeds (CMBs); and neuropsychological tests, including the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), and the Frontal Assessment Battery (FAB), were evaluated., Results: Data from 44 CADASIL patients were eligible for this study, compared between patients with and without dementia. Regarding the neuroimaging findings, the Fazekas score of periventricular and deep WML was higher in patients with dementia (periventricular, p = 0.003; deep, p = 0.009). The number of lacunar infarcts was higher in patients with dementia ( p = 0.001). The standardized partial regression coefficient (SPRC) in MoCA-J was 0.826 (95% CI, 0.723-0.942; p = 0.005) for the number of CMBs. The SPRC in MMSE was 0.826 (95% CI, 0.719-0.949; p = 0.007) for the number of CMBs. The SPRC for FAB decreased significantly to 0.728 (95% CI, 0.551-0.960; p = 0.024) for the number of lacunar infarcts. Receiver operating characteristic (ROC) curves for dementia showed that in the number of lacunar infarcts, a cut-off score of 5.5 showed 90.9% sensitivity and 61.1% specificity. For the number of CMBs, a cut-off score of 18.5 showed 45.5% sensitivity and 100% specificity., Conclusion: The characteristic MRI findings were that CADASIL patients with dementia had severe WML, both periventricular and deep, and a larger number of lacunar infarcts than those without dementia. The risk of dementia may be associated with ≥ 6 lacunar infarcts, ≥19 CMBs, or a Fazekas scale score of 3 in periventricular and deep WML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Taniguchi, Shindo, Tabei, Onodera, Ando, Urabe, Kimura, Kitagawa, Miyamoto, Takegami, Ihara, Mizuta, Mizuno and Tomimoto.)

Background: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes., Method: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined., Results: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (β = -0.34, P = 0.0005) and age (β = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment., Conclusions: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes., (© 2022 Japanese Psychogeriatric Society.)

Background: Alexander disease (ALXDRD) affects a wide range of ages from infancy to adulthood. However, only a few cases involving patients with older-adult onset over 65 years of age have been reported. In contrast, regarding in-house data, 10.6% of 85 cases with the identification of GFAP mutations demonstrated older-adult onset. This discrepancy may be due to poor awareness of such cases., Methods: The subjects included 9 older-adult-onset cases, with an onset age of 65 years or older. We characterized older-adult-onset ALXDRD by assessing neurological findings and several magnetic resonance imaging (MRI) parameters., Results: The age at onset, mean age at diagnosis, and mean period from onset to diagnosis were 68.2 years, 70.4 years, and 2.2 years, respectively. The main neurological features at diagnosis included pyramidal signs with muscle weakness and/or cerebellar ataxia. Two-thirds of cases were dependent, and the dependence was significantly correlated with a longer period from onset to diagnosis. Quantitative MRI evaluation for brainstem atrophy demonstrated distinctive morphological features of bulbospinal ALXDRD. The corpus callosum index tended to be negatively correlated with the period from onset to diagnosis., Conclusions: Although neurological and MRI findings of older-adult-onset ALXDRD patients showed typical features of bulbospinal ALXDRD, their disease progression was more severe than that in younger-adult-onset ALXDRD, and patients developed dependence within 2 years from onset. Cerebral white matter damage tended to progress in proportion to the duration of illness. Our case study may help to advance understanding of the clinical spectrum of ALXDRD., (© 2021 European Academy of Neurology.)

Background and Objective: Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein ( GFAP ) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation., Methods: Genetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed., Results: The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5' end of the exon 4., Discussion: GFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.

We herein report a case of corticobasal syndrome (CBS) due to asymmetric degeneration of the motor cortex and substantia nigra with transactivation response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, associated with Alzheimer's disease (AD) pathology. An 85-year-old man initially noticed that he had difficulty in walking and had trouble in moving his right hand and lower limb one year later. His gait disturbance was aggravated, and at the age of 87 years, his neurological examination revealed parkinsonism and positive frontal lobe signs. Brain magnetic resonance imaging (MRI) revealed atrophy of the left frontotemporal lobe and cerebral peduncle, and cerebral blood flow scintigraphy revealed hypoperfusion of the left frontotemporal lobe, leading to a possible diagnosis of CBS. At the age of 89 years, he was bedridden, and rarely spoke. He died of aspiration pneumonia five years after the onset of initial symptoms. At the autopsy, the brain weighed 1280 g and showed left-sided hemiatrophy of the cerebrum and cerebral peduncle. Neuropathological examination revealed AD pathology (Braak AT8 stage V, Braak stage C, CERAD B, Thal classification 5). Phosphorylated TDP-43 (p-TDP-43) immunohistochemistry revealed widespread deposits of dystrophic neurites (DNs), glial cytoplasmic inclusions (GCIs), and neuronal cytoplasmic inclusions (NCIs), which were most remarkable in layers II/III of the motor cortex and predominant on the left hemisphere of the frontal cortex, these neuropathology being consistent with frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) type A. Interestingly, neuronal loss in the substantia nigra was more severe on the left than the right side, with a few phosphorylated tau (p-tau) and p-TDP-43 deposits. It is highly likely that asymmetric TDP-43 pathology rather than symmetric tau pathology contributed to the laterality of degeneration of the cerebral cortex, substantia nigra, and pyramidal tract, which led us to suggest that TDP-43 proteinopathy might be a primary cause., (© 2021 Japanese Society of Neuropathology.)

Purpose: The purpose of this study is to increase awareness of the importance of considering neuromyelitis optica spectrum disorder (NMOSD) as a differential diagnosis for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: We report two NMOSD patients demonstrating magnetic resonance imaging (MRI) abnormalities resembling those of CADASIL., Results: Brain MRIs of both patients showed symmetrical hyperintense signals in the temporal poles and cerebral hemispheres on T2 weighted images. One case also involved the bilateral external capsule. The chief complaint of both patients was loss of visual acuity, and neurologic examination showed no other apparent neurological signs or symptoms. Anti-aquaporin-4 antibodies were detected on serological examination, and NMOSD was subsequently diagnosed. Visual acuity improved following intravenous methylprednisolone therapy. One patient refused further immunological treatment. Although she remained clinically stable, gradual radiographic deterioration was observed. This deterioration then stabilized after the patient commenced oral prednisolone therapy. The other patient was treated with prednisolone and azathioprine. She is clinically stable, but we have observed gradual radiographic deterioration over the past 5 years., Conclusion: MRI findings in patients with NMOSD may resemble those of CADASIL, namely symmetrical hyperintensities in the temporal poles, external capsules and cerebral hemispheres. NMOSD is a differential diagnosis for CADASIL, and testing for anti-AQP4 antibodies should be considered., (Copyright © 2020 Elsevier B.V. All rights reserved.)