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Background: Spinocerebellar ataxia type 1 (SCAl) is one of the autosomal dominant neurodegenerative disorders commonly linked to pathological expansion of the CAG repeat of the relevant gene. Nuclear inclusions and [...]

The article presents a case study of a Japanese patient with familial amyotrophic lateral sclerosis (FALS) with p.N352S mutation in TARDBP. The patient experienced weakness in the muscles of both hand and he underwent in extraction of genomic DNA and neuronal cytoplasmic inclusions (NCIs). The clinical features of the autopsy-confirmed FALS cases with TARDBP mutations.

Background: The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P)., Methods: This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model., Results: Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients (p = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p < 0.001 and p = 0.046, respectively)., Conclusion: Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

A heterozygous CGG repeat expansion in 5' untranslated region (5' UTR) of GIPC1 is one of the causative factors of oculopharyngodistal myopathy (OPDM), an adult-onset hereditary muscle disease characterized by progressive ptosis, ophthalmoplegia, and facial, bulbar, and distal limb muscle weakness. CGG repeat expansion in GIPC1 has also been reported to be associated with Parkinson's disease, but these patients did not exhibit myopathic symptoms. We experienced two unrelated cases of oculopharyngeal type myopathy with CGG repeat expansion in GIPC1 presenting parkinsonism after exhibiting myopathic symptoms. Both cases showed p62-positive intranuclear inclusions in the skin, similar to those in NOTCH2NLC-related disorders. Our cases suggest that GIPC1-related repeat expansions may be associated with a broad spectrum and tissue-differential neuromuscular manifestations, indicating a common mechanism between OPDM2 and other CGG-repeat expansion diseases. It is important to note OPDM2 patients' central neurological symptoms, as myopathic symptoms may obscure central nervous system manifestations., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Neuronal intranuclear inclusion disease (NIID) is a neurological disorder characterized by eosinophilic intranuclear inclusions (INI) in systemic organs and various cell types. High-intensity signals along the corticomedullary junction on diffusion-weighted imaging and presence of cellular p62-INI in skin biopsy are known indicators for NIID. Furthermore, GGC repeat expansion in NOTCH2NLC is a characteristic genetic alteration in patients with NIID. This report presents the clinical and detailed pathological features of a male older adult with NIID. We also confirmed the presence of fluid-attenuated inversion recovery high-intensity signals in the cerebellar paravermal area, showing similar pathological changes in high-intensity signals along the corticomedullary junction on diffusion-weighted imaging.

Background: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients., Methods: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients., Results: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum., Conclusions: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aims: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM&#95;NOTCH2NLC) GIPC1 (OPDM&#95;GIPC1), or LRP12 (OPDM&#95;LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy., Methods: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM&#95;NOTCH2NLC [n = 2], OPDM&#95;GIPC1 [n = 6] and OPDM&#95;LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2)., Results: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM&#95;NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM&#95;GIPC1, and all in three cell types in one of the three patients with OPDM&#95;LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy., Conclusion: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes., (© 2021 British Neuropathological Society.)

Physiological changes including altered nutritional status influence disease progression and survival in patients with amyotrophic lateral sclerosis (ALS). Ghrelin affects the nutritional status by regulating appetite and energy expenditure, and also has neuroprotective effects. To investigate the association between ghrelin and ALS prognosis, we analyzed plasma acylated-ghrelin levels in 33 patients with ALS. Compared among ALS patients, male had lower plasma ghrelin levels than female, although disease specificity is unknown. ALS patients, especially male ALS patients, with low plasma ghrelin levels (<15 fmol/mL) had significantly shorter post-examination survival times than those with high plasma ghrelin levels (≥15 fmol/mL). Univariate and multivariate analyses revealed a significant effect of ghrelin levels on post-examination survival. Immunohistochemical study of autopsied stomach samples from 8 of 33 patients revealed that the population of ghrelin-positive cells tended to be reduced in the low-plasma ghrelin group than in the high-plasma ghrelin group. Our findings suggest that ghrelin levels are an independent predictor of survival in ALS, especially male ALS patients, and the ghrelin-positive cells may decrease in ALS with low plasma ghrelin. Thus, reduced ghrelin secretion may be associated with poor prognosis among patients with ALS., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: Concentrations of soluble amyloid precursor proteins-α (sAPPα) and -β (sAPPβ) in cerebrospinal fluid (CSF) may reflect the neuropathology of Alzheimer's disease (AD). We previously reported that the concentrations of both sAPPα and sAPPβ were significantly higher in patients with mild cognitive impairment (MCI) due to AD (MCI-AD) than in control subjects without cognitive impairment. The present study analyzed whether these sAPPs are useful in the differential diagnosis of MCI., Methods: A modified and sensitive method was used to analyze concentrations of sAPPα and sAPPβ in CSF of patients with MCI-AD (n = 30) and MCI due to other causes (MCI-others) (n = 24). Phosphorylated tau (p-tau) and amyloid β-protein 42 (Aβ42) were also analyzed using standard methods., Results: CSF concentrations of sAPPα and sAPPβ were significantly higher in the MCI-AD than in the MCI-others group (p < 0.001). Furthermore, concentrations of both sAPPα and sAPPβ were highly correlated with the concentration of p-tau, consistent with our previous report., Conclusions: Measurement of both sAPPs in CSF using sensitive methods can be helpful in the precise differential diagnosis of patients with MCI., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and severe syndrome characterized by rigidity of the limb and truncal muscles, brainstem signs, myoclonus, and hyperekplexia. Iliopsoas hematoma is a serious complication of bleeding disorders that occurs most commonly in patients with hemophilia and also in association with anti-coagulant drug treatment. We herein present a case of PERM complicated with bilateral iliopsoas hematomas. His neurological symptoms improved after immunotherapy, and thereafter the iliopsoas hematomas disappeared. Neurologists should consider iliopsoas hematomas as a serious potential complication of PERM.

Competing Interests: The authors have no potential conflicts of interest to disclose.

Based on the hypothesis that autoimmunity plays a role in the pathogenesis of neuralgic amyotrophy (NA), immunotherapy is sometimes administered. Early intervention is recommended for a good prognosis. We herein report the case of a 55-year-old man who presented with neuralgia, weakness, and muscle atrophy in his right shoulder girdle and upper arm, which progressed for ten months following a marine sports accident. The patient was diagnosed with NA. His neurological deficits gradually improved after several courses of immunotherapy, suggesting that in addition to being effective for treating early-stage disease, immunotherapy may be effective for treating chronic cases.

Background: Because soluble (or secreted) amyloid precursor protein-β (sAPPβ) and -α (sAPPα) possibly reflect pathological features of Alzheimer's disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPβ in CSF as diagnostic biomarkers of dementia disorders., Methods: We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD ( N  = 33), MCI-AD ( N  = 17), non-AD dementia ( N  = 27), and disease controls ( N  = 19). Phosphorylated tau (p-tau), total tau, and Aβ42 were also analyzed using standard methods., Results: A strong correlation was observed between sAPPα and sAPPβ, consistent with previous reports. Both sAPPα and sAPPβ were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPβ were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPβ have good discriminative power for the diagnosis of MCI-AD., Conclusions: Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs.

Appropriate nutritional therapy has not been established for patients with amyotrophic lateral sclerosis (ALS). Our objective was to measure the total energy expenditure (TEE) and determine an equation to estimate the energy requirements for Japanese patients with ALS. Twenty-six Japanese patients with ALS participated in the study. The TEE was measured using the doubly labelled water (DLW) method for a 14-day period. Using a range of clinical parameters and multiple regression analyses, we determined an adequate equation to calculate TEE. Results showed that the median value of total energy intake (TEI) was 1581 (interquartile 1278-1782) kcal/d. TEE and TEE/body weight were 1628 kcal/d (1352-1865) and 31.3 kcal/kg (29.2-34.4), respectively. The ratio of TEE/estimated TEE by the Harris-Benedict equation was 1.14 (1.09-1.26). The difference between TEI and TEE was -63 kcal (-221 - 122), and 15 patients (57.7%) showed a negative balance. From regression analyses, we determined an equation to estimate TEE using the resting metabolic rate estimated by the Harris-Benedict equation (RMR-HB) and scores of the revised ALS Functional Rating Scale (ALSFRS-R): TEE = (1.67 × RMR-HB) + (11.8 × ALSFRS-R) - 680 (p < 0.0001). In conclusion, energy expenditure of Japanese patients with ALS was higher than expected, and we proposed a preliminary equation to estimate TEE for future nutritional intervention.

Advanced multiple system atrophy (MSA) patients exhibit malnutrition with hypocholesterolemia and hypoalbuminemia, similar to patients with other neurodegenerative disorders, but also display unexpected fat accumulation. To understand this paradox, we herein examined the relationship between fat accumulation, measured by triceps skinfold thickness (TSF), and plasma leptin in 29 MSA patients at three clinical stages: activities of daily living (ADL) 1: ambulatory with/without wheelchair; ADL2: bedridden/communicable; and ADL3: bedridden/non-communicable. TSF and leptin were higher while cholesterol and albumin were lower in advanced stage ADL3 than in ADL1 or ADL2. Although a correlation was observed between leptin and TSF, a stepwise regression analysis identified the first significant positive predictor of leptin as the duration of autonomic symptoms (p < 0.005) rather than TSF. Leptin/TSF strongly correlated with the duration of autonomic symptoms (p < 0.001). These results implicate leptin resistance through autonomic dysfunction in the paradoxical fat accumulation observed in patients with advanced MSA, but not to be seen in the cholesterol metabolism.

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Our objective was to describe cases of hyperosmolar hyperglycemic state (HHS) in advanced amyotrophic lateral sclerosis (ALS) patients and discuss its pathophysiology. Five ventilator-dependent patients with ALS, with no previous history of diabetes, showed development of marked hyperglycemia (plasma glucose levels of 755-1544 mg/dl) after preceding infectious episodes. All patients had severe generalized muscle wasting and tetraplegia. The initial manifestations of HHS were fever, drowsiness, or polyuria. Hydration and intravenous insulin therapy were markedly effective, resulting in favorable recovery without the necessity of chronic medication for hyperglycemia in all cases. Seventy-five grams oral glucose tolerance tests performed via feeding tubes in two patients after the successful treatment of HHS revealed increased insulin resistance and diminished early-phase insulin secretion with preserved total insulin secretion. In conclusion, a marked loss of skeletal muscle, the largest glucose consumer of the human body, with background abnormality of early-phase insulin secretion, might be a causative factor of HHS in advanced ALS.

The clinical benefits of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) remain controversial. We performed a comprehensive study to examine whether rTMS is a safe and effective treatment for PD. Twelve PD patients received rTMS once a week. The crossover study design consisted of 4-week sham rTMS followed by 4-week real rTMS. The Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr Stage, Schwab and England ADL Scale, Actigraph, Mini-Mental State Examination, Hamilton Depression Scale, Wechsler Adult Intelligence Scale-revised, and cerebral blood flow (CBF) and cerebrospinal fluid (CSF) examinations were used to evaluate the rTMS effects. Under both drug-on and drug-off conditions, the real rTMS improved the UPDRS scores significantly, while the sham rTMS did not. There were no significant changes in the results of the neuropsychological tests, CBF and CSF. rTMS seems to be a safe and effective therapeutic option for PD patients, especially in a wearing-off state.

We investigated nutritional states of 28 patients with multiple system atrophy (MSA) by measuring body mass index (BMI), arm muscle circumference (% AMC) and triceps skin fold thickness (% TSF). We also analyzed retrospectively chronological changes of nutritional status in 13 MSA patients surviving more than 10 years. BMI and % AMC were significantly reduced in patients having tube feeding compared with patients who had oral intake, whereas % TSF was increased in some patients with tube feeding. From the chronological study, patients at the stage of respiratory or swallowing deterioration showed marked malnutrition, whereas patients during the advanced, but stable stages with tracheostomy and gastrostomy showed much fat accumulation even under low calorie intake less than 1,000 kcal/day. Daily amount of calorie intake should be sufficient during respiratory or swallowing deterioration, but it should be restricted at the advanced stable stage to avoid fat accumulation.

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.

Huntington's disease is a progressive neurodegenerative disorder that is associated with a CAG repeat expansion in the gene encoding huntingtin. We found that a 60-kDa protein was increased in Neuro2a cells expressing the N-terminal portion of huntingtin with expanded polyglutamine. We purified this protein, and, using mass spectrometry, identified it as p62, an ubiquitin-associated domain-containing protein. A specific p62 antibody stained the ubiquitylated polyQ inclusions in expanded polyglutamine-expressing cells, as well as in the brain of the huntingtin exon 1 transgenic mice. Furthermore, the level of p62 protein and mRNA was increased in expanded polyglutamine-expressing cells. We also found that p62 formed aggresome-like inclusions when p62 was increased in normal Neuro2a cells by a proteasome inhibitor. Knock-down of p62 does not affect the formation of aggresomes or polyglutamine inclusions, suggesting that p62 is recruited to the aggresome or inclusions secondary to their formation. These results suggest that p62 may play important roles as a responsive protein to a polyglutamine-induced stress rather than as a cross-linker between ubiquitylated proteins.

Amplification with catalyzed reporter deposition (CARD) greatly enhances peroxidase signals, which has been utilized to amplify immunohistochemical labelings including fluorochromes. Here we describe a strategy to amplify each of two immunofluorescent signals without crosstalk on double-stained histological sections from human autopsied brains with Alzheimer's disease (AD). One of the two primary antibodies (anti-Abeta or anti-PHF-tau) was probed by a species-specific secondary antibody conjugated with horseradish peroxidase (HRP), which was visualized by FITC-labeled tyramide. After inactivation of HRP, the other primary antibody was probed by another species-specific secondary antibody conjugated with HRP. Amplification with biotinylated tyramide was followed by streptavidin-conjugated Cy-5, which specifically labeled the latter epitope. It was found that Abeta and PHF-tau were localized to senile plaques and neurofibrillary tangles (NFTs), respectively, which verified lack of crosstalk on the double-stained section. Localization of ubiquitin and PHF-tau was looked for at higher magnification in NFT-bearing neurons. Although these two epitopes were colocalized in some neurons, ubiquitin was not always present in PHF-tau positive NFTs. Discrepancy between PFH-tau and ubiquitin, verified inter- and intracellularly, may represent different stages of NFT formation. This is the first report of successful CARD amplification of two different fluorescent signals on double-labeling immunohistochemistry, which is now proved to be powerful in detecting epitopes in relation to AD-related lesions. Improved intensity over tenfold of the two fluorescent signals without crosstalk will expand the application of the multilabeling method with fluorochromes.

We report a 72-year-old man with Creutzfeldt-Jakob disease. He showed a progressive dementia, myoclonus, and other neurological symptoms. DNA analysis showed a normal variation of prion gene (codon 129, Met/Met: codon 219, Glu/Glu). He had periodic synchronous discharge on electroencephalogram and brain atrophy on CT scan and MRI. Diffusion images on his brain MRI revealed a marked increase in signal intensity in the caudate nuclei, putamen, and cerebral cortices. These changes may represent spongy changes of the brain and seem to be a feature of brain MRI in Creutzfeldt-Jakob disease.

Acute ophthalmoparesis (AO) is a monophasic disease characterized by acute onset of paresis of the extraocular muscles without ataxia or areflexia. Here we report a case of AO with gadolinium enhancement in the cisternal portion of the abducens nerves using contrast-enhanced three-dimensional magnetic resonance imaging.

In order to explore molecular mechanisms for factor XIII deficiency, a patient (Nagoya I) was examined at the DNA and RNA levels. Nucleotide sequence analysis of the patient's DNA amplified by PCR revealed that he had a 20 bp deletion at the boundary of exon I/intron A, and an insertion of T in the invariant GT dinucleotide at the splicing donor site of exon IV/intron D. The presence of these heterozygous mutations was confirmed by restriction digestion of the amplified fragments of the proband and his parents. RT-PCR analysis demonstrated that only one kind of mRNA without exon IV was detected in Nagoya I, although its level was greatly reduced to less than 5% of normal. The other detective allele of the A subunit gene containing the 20 bp deletion was not detected. Thus, both mutations impaired normal processing of mRNA for the A subunit, resulting in his severe factor XIII deficiency.