An autopsy case of diffuse atypical argyrophilic grain disease (AGD) with presenile onset and three-year course of motor and cognitive impairment.

We report a case of argyrophilic grain disease (AGD) with unique clinical and pathological presentations. A 52-year-old man presented with spastic quadriparesis, bulbar palsy, and mild cognitive decline. His condition deteriorated rapidly and he died of pneumonia three years from onset. Pathologically, neuronal degeneration was involved severely in the amygdala, ambient gyrus, midbrain tegmentum, and reticular formation. The neurons of the temporal lobe, cingulate gyrus, brainstem, and spinal gray matter were also lost moderately. There was diffuse 4-repeat tau-pathology with argyrophilic grains. There were pretangles, globose-type neurofibrillary tangles, and coiled bodies in the cerebral cortices, basal ganglia, thalami, brainstem, and the spinal cord except for the cerebellar cortices. There was no pathologic mutation in MAPT.

Spinal muscular atrophy type 2 patient who survived 61 years: an autopsy case report.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness due to degeneration of lower motor neurons in the anterior horn of the spinal cord. We analyzed autopsy findings of a male patient with SMA type 2 who survived until 61 years of age. Genetic analysis revealed a homozygous deletion of the survival motor neuron (SMN) gene 1 (SMN1) exon 7, confirming the diagnosis of SMA. Results of further analyses indicated that the patient had two copies of the genuine SMN gene 2 (SMN2) and one copy of a hybrid gene containing SMN2 exon 7 and SMN1 exon 8. Pathological examination revealed moderate neuronal loss of the anterior horn and appearance of heterotopic neurons in the lateral funiculus, whereas a few achromatic neurons were notably localized in the anterior horn of the lumbar segment. Microdysgenesis as a consequence of migration disturbance was found in the white matter of the frontal lobe, postulating the possibility of the maldevelopment of the nervous system.

Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein.

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson's disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-ß structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-ß sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-ß structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-ß structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

Knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism.

Mitochondrial dysfunction in the nigrostriatal dopaminergic system is a critical hallmark of Parkinson's disease (PD). Mitochondrial toxins produce cellular and behavioural dysfunctions resembling those in patients with PD Causative gene products for familial PD play important roles in mitochondrial function. Therefore, targeting proteins that regulate mitochondrial integrity could provide convincing strategies for PD therapeutics. We have recently identified a novel 13-kDa protein (p13) that may be involved in mitochondrial oxidative phosphorylation. In the current study, we examine the mitochondrial function of p13 and its involvement in PD pathogenesis using mitochondrial toxin-induced PD models. We show that p13 overexpression induces mitochondrial dysfunction and apoptosis. p13 knockdown attenuates toxin-induced mitochondrial dysfunction and apoptosis in dopaminergic SH-SY5Y cells via the regulation of complex I. Importantly, we generate p13-deficient mice using the CRISPR/Cas9 system and observe that heterozygous p13 knockout prevents toxin-induced motor deficits and the loss of dopaminergic neurons in the substantia nigra. Taken together, our results suggest that manipulating p13 expression may be a promising avenue for therapeutic intervention in PD.

A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy.

We report an autopsy case of amyotrophic lateral sclerosis with L126S mutation in the superoxide dismutase 1 (SOD1) gene (SOD1). The patient was a 69-year-old Japanese man without relevant family history, who initially presented with slow progressive muscle weakness of the lower extremities without upper motor neuron signs, and died of respiratory failure 6 years after the onset. Neuropathological examination revealed a loss of lower motor neurons and degeneration of Clarke's column commensurate with that of the posterior spinocerebellar tract and the middle root zone of the posterior column. The primary motor area was minimally affected. Characteristic SOD1-immunopositive neuronal intracytoplasmic inclusions, mixed with neurofilament accumulation, were present in the affected areas. Isolated inferior olivary hypertrophy was observed, but did not involve the contralateral dentate nucleus, or the ipsilateral red nucleus and central tegmental tract, where no neuronal inclusions were found. In combination with data from a previous autopsy case, this study suggests that the L126S mutation may cause focal neuronal degeneration in the brainstem.

Increased number of mitochondria in capillaries distributed in stroke-like lesions of two patients with MELAS.

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) using immunohistochemical staining with an anti-mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42-year-old man with a disease duration of 53 days, and in case 2, the patient was a 62-year-old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke-like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke-like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.

Early use of donepezil against psychosis and cognitive decline in Parkinson's disease: a randomised controlled trial for 2 years.

OBJECTIVES: Brain acetylcholine is decreased even in patients with cognitively preserved Parkinson's disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients. METHODS: A double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson's Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping. RESULTS: Kaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11-0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers. CONCLUSIONS: Although donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil. TRIAL REGISTRATION NUMBER: UMIN000005403.

Autism spectrum disorders are prevalent among patients with dystrophinopathies.

Recent studies have reported a higher prevalence of autism spectrum disorders among patients with dystrophinopathies. The aim of this study was to investigate the prevalence of autism spectrum disorder (ASD) among those with dystrophinopathies. The possible role of dystrophin isoforms in patients was also explored. Fifty-six patients recruited from Toneyama National Hospital were included in this study (mean age = 12.9 years, SD = 5.2 years). Autistic symptoms were evaluated using the Pervasive Developmental Disorders/Autism Spectrum Disorders Rating Scale (PARS), a clinician rating scale. Eleven patients (19.6%; 95% confidence interval 10.2-32.4) met the criteria for ASD based on their PARS scores. Patients were separated into two groups based on the cumulative loss of dystrophin isoforms predicted from the mutation location. The prevalence of ASD was examined between these groups. Infantile and current autistic symptoms did not differ between the groups, except on one subscale of the PARS. This study revealed that there was a high prevalence of ASD in patients with dystrophinopathies.

An autopsy case of neuronal intermediate filament inclusion disease with regard to immunophenotypic and topographical analysis of the neuronal inclusions.

We report an autopsy case of neuronal intermediate filament inclusion disease (NIFID), in which pyramidal motor dysfunction preceded cognitive disturbance for 3 years from the onset. A 41-year-old Japanese man presented progressive spastic tetraparesis followed by cognitive impairment. His neurological symptoms gradually deteriorated and he died of pneumonia 16 years from the onset. His brain showed severe generalized atrophy with enlargement of ventricles. The microscopic examination revealed severe neuronal loss with gliosis and sponginess predominantly in the fronto-temporal cortices, caudate and putamen. Many hyaline conglomerate inclusions (HC) without immunoreactivity for 'fused in sarcoma' protein (FUS) and some granular and small round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were observed in the remaining neurons. Some neurons with HC had small basophilic inclusions which showed positive FUS-ir, attached to HC in the cytoplasm. Otherwise, FUS-ir large compact inclusions (so-called Pick-like) were also observed but were scarce. In the cerebral cortex and the neostriatum, frequency of the inclusions was well correlated with neuronal loss. In the brainstem, neuronal loss was mild and FUS-ir inclusions dominated. In the subthalamic nucleus and red nucleus, there was no HC but there were many FUS-ir inclusions without neuronal loss. The above findings suggest that cytoplasmic mislocalization and aggregation of FUS appear at the early stage of the disease, and the FUS aggregate process may not be a direct precedent structure of HC.

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA sequencing.

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansion of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing occurs in the brains of patients with DM1, its relation to central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter defects in patients with DM1. Here, we performed RNA sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the gray matter and white matter, to investigate splicing abnormalities in the DM1 brain, especially in the white matter. Several genes showed similar levels of splicing abnormalities in both gray and white matter, with an observable trend toward an increased number of repeats in the gray matter. These findings suggest that white matter defects in DM1 stem from aberrant RNA splicing in both gray and white matter. Notably, several of the genes displaying abnormal splicing are recognized as being dominantly expressed in astrocytes and oligodendrocytes, leading us to hypothesize that splicing defects in the white matter may be attributed to abnormal RNA splicing in glial cells.

Details of treatment-related difficulties in men with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others.

[Antibody production capacity after COVID-19 vaccination in immune-mediated neuromuscular diseases under immunotherapy].

The post-vaccination antibody response in patients with immune-mediated neuromuscular diseases under immuno-suppressive therapy has not been sufficiently verified. The Japanese Society of Neurology has stated that coronavirus disease 2019 (COVID-19) vaccination should be given priority in patients with immunotherapy-associated neuromuscular diseases; however, data on antibody production to a novel mRNA vaccine are scarce in these patients. In this study, we aimed to measure residual antibody titers after the second dose and produced antibodies after the third dose of SARS-CoV-2 mRNA vaccine in 25 patients with neuromuscular diseases under immuno-suppressive therapy (disease group). We compared the disease group antibody titers with those of 829 healthy employees in our hospital (control group). The disease group included 17 patients with myasthenia gravis, 4 with multiple sclerosis, 3 with inflammatory muscle disease, and 1 with chronic inflammatory demyelinating polyneuropathies. Seven cases of the disease group showed negative antibody levels (<15.0 s/co) before the third vaccination, and antibody titers in the positive cases ranged from 16.9 to 4,589.0 s/co. Three of the seven antibody-negative cases turned positive after the third vaccination, and all but one of the antibody-positive cases showed a booster effect, with antibody titers after the third dose ranging from 245.1 to 85,374.0 s/co (1.0 to 885.0 times higher than those before vaccination). Although the immune response in the disease group was modest compared to the control group, in which antibody titers after the third vaccination ranged from 67.8 to 150,000 s/co (0.9 to 5,402.1 times higher than those before vaccination), the result indicated that a constant immune response was achieved under immuno-suppressive therapy. Even in the control group, three participants tested negative for residual antibody before the third inoculation, and four of the antibody-positive participants (27.7-24,054.0 s/co) lacked a booster effect after the third vaccination.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Guillain-Barré Syndrome Associated with COVID-19 in a Japanese Male.

April 2021 saw a widespread outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Osaka, Japan. We encountered the case of a 52-year-old man who had Guillain-Barré syndrome associated with coronavirus disease 2019 (COVID-19). After the relief of the respiratory symptoms owing to COVID-19, the patient experienced muscle weakness, which spread from his fingers to his extremities, and was unable to walk. Further examinations revealed mild protein elevation in the cerebrospinal fluid. In addition, nerve conduction studies showed demyelinating polyneuropathy, leading to the diagnosis of Guillain-Barré syndrome. After the administration of intravenous immunoglobulin and intravenous methylprednisolone, his symptoms drastically improved, and he was able to walk unaided 21 days after the onset of symptoms. On day 40, the patient was discharged with minimal muscle fatigue. Because Guillain-Barré syndrome associated with COVID-19 is expected to have a good prognosis, early diagnosis and treatment are important. Therefore, Guillain-Barré syndrome should be considered as a possible factor for muscle weakness during and after COVID-19 treatment.

[Encephalitis associated with positive anti-GluR antibodies showing abnormal appearance in basal ganglia, pulvinar and gray matter on MRI--case report].

We treated a 25-year-old woman with encephalitis. Following delivery, the patient developed fever, consciousness disturbance, cognitive dysfunction, and progressive motor dysfunction. In addition, mycobacterium tuberculosis was found in the lung, though there was no evidence of such infection in the central nervous system. Cerebrospinal fluid analysis revealed a slight elevation of mononuclear cells with a normal protein level indicating a possible viral infection. We could not find the origin of the infection, though the serum anti-glutamate epsilon2 receptor antibody was positive. Intravenous administration of methylprednisolone (1000 mg/day for 3 days) was temporarily effective for improvement of the clinical signs and symptoms. However, she finally demonstrated rapid deterioration resulting in death. Diffusion-weighted brain magnetic resonance imaging demonstrated abnormal high intensity lesions in the bilateral pulvinar and gray matter, with an abnormal appearance mimicking pulvinar sign.

[A longitudinal cause-of-death analysis of patients with Duchenne muscular dystrophy].

Mechanical ventilation (MV) and cardiac protective therapy have improved the prognosis and quality of life of patients with Duchenne muscular dystrophy (DMD). To understand how these therapies have changed prognosis, we performed a cause-of-death analysis in DMD patients. Mean age at death before initiation of MV (January 1977-July 1984) was 18.9±4.1 years. After the introduction of MV, from August 1984 to December 1993 (1(st) term), it was 20.0±4.5 years, from January 1994 to December 2003 (2(nd) term), it was 25.2±4.6 years, and from January 2004 to December 2010 (3(rd) term), it was 31.1±5.4 years. Almost half of all deaths before MV were due to respiratory failure (RF). Because MV was performed by a tracheostomy in the initial stage, some patients were reluctant to use it, and as a result, RF accounted for 43% of deaths in the 1(st) term. Over time, patients started to accept non-invasive ventilation and home mechanical ventilation, which became available in the 1990s. Consequently, no DMD patients have died from RF since 2000. Respiratory physiotherapy and risk management became important tools, because many patients undergo decades of respiratory managements at home. Cardiac treatments for patients with DMD consisted mainly of diuretics and digitalis in the 1(st) term, angiotensin-converting enzyme inhibitors (ACEI) in the 2(nd) term, and a combination of ACEIs and beta blockers in the 3(rd) term. Compared to the 2(nd) term, the ratios of severe cardiac dysfunction (fractional shortening <10%, left ventricle diastolic dimension >75mm, plasma brain natriuretic peptide >1,000pg/ml) were reduced in the 3(rd) term. In the 3(rd) term, 14% of patients died from renal failure nevertheless their cardiac indices remained mildly abnormal or normal. We should pay enough attention for cardio-renal association.

Clinical trajectory of a patient with filaminopathy who developed arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors.

We report a case of a patient presenting with arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors. A 41-year-old woman with a history of hypertrophic cardiomyopathy, diagnosed at 6 years of age, developed scoliosis after puberty. Following spinal surgery to address the scoliosis, she developed recurrent severe arrhythmia and heart failure. She developed hypoventilation at age 29 years. Proximal dominant weakness and mild elevation of serum creatine kinase indicated possible myopathy. Myofibrillar myopathy was diagnosed by muscle biopsy at age 30 year. Acute abdomen was repeatedly reported from age 33 years, eventually leading to a diagnosis of gastric polyp and erosive ulcer. A urinary bladder tumor was found at age 35 years, and breast cancer was diagnosed at age 40 years. Whole exome sequencing detected a heterozygous missense mutation in Filamin C. Recent evidences suggest that filamins are associated with tumors, and this case further highlights the clinical spectrum of filaminopathy.

Transcriptome alterations in myotonic dystrophy frontal cortex.

Myotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.

Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling.

Age-related regeneration failure in the central nervous system can occur as a result of a decline in remyelination efficacy. The responsiveness of myelin-forming cells to signals for remyelination is affected by aging-related epigenetic modification; however, the molecular mechanism is not fully clarified. In the present study, we report that the apelin receptor (APJ) mediates remyelination efficiency with age. APJ expression in myelin-forming cells is correlated with age-associated changes in remyelination efficiency, and the activation of APJ promotes remyelination through the translocation of myelin regulatory factor. APJ signaling activation promoted remyelination in both aged mice with toxin-induced demyelination and mice with experimental autoimmune encephalomyelitis. In human cells, APJ activation enhanced the expression of remyelination markers. Impaired oligodendrocyte function in aged animals can be reversibly reactivated; thus, the results demonstrate that dysfunction of the apelin-APJ system mediates remyelination failure in aged animals, and that their myelinating function can be reactivated by APJ activation.