Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study.

PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

Efficacy and Tolerability of Ivabradine for Cardiomyopathy in Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.

Familial idiopathic basal ganglia calcification with a heterozygous missense variant (c.902C>T/p.P307L) in SLC20A2 showing widespread cerebrovascular lesions.

We describe a postmortem case of familial idiopathic basal ganglia calcification (FIBGC) in a 72-year-old Japanese man. The patient showed progressive cognitive impairment with a seven-year clinical course and calcification of the basal ganglia, thalami, and cerebellar dentate nuclei. A novel heterozygous missense variant in SLC20A2 (c.920C>T/p.P307L), a type III sodium-dependent phosphate transporter (PiT-2), was subsequently identified, in addition to typical neuropathological findings of FIBGC, such as capillary calcification of the occipital gray matter, confluent calcification of the basal ganglia and cerebellar white matter, widespread occurrence of vasculopathic changes, cerebrovascular lesions, and vascular smooth muscle cell depletion. Immunohistochemistry for PiT-2 protein revealed no apparent staining in endothelial cells in the basal ganglia and insular cortex; however, the immunoreactivity in endothelial cells of the cerebellum was preserved. Moreover, Western blot analysis identified preserved PiT-2 immunoreactivity signals in the frontal cortex and cerebellum. The variant identified in the present patient could be associated with development of FIBGC and is known to be located at the large intracytoplasmic part of the PiT-2 protein, which has potential phosphorylation sites with importance in the regulation of inorganic phosphate transport activity. The present case is an important example to prove that FIGBC could stem from a missense variant in the large intracytoplasmic loop of the PiT-2 protein. Abnormal clearance of inorganic phosphate in the brain could be related to the development of vascular smooth muscle damage, the formation of cerebrovascular lesions, and subsequent brain calcification in patients with FIBGC with SLC20A2 variants.

An autopsy case of corticobasal degeneration with inferior olivary hypertrophy.

We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-to-moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau-immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato-olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

Accumulation of phosphorylated TDP-43 in the cytoplasm of Schwann cells in a case of sporadic amyotrophic lateral sclerosis.

We report for the first time the presence of phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-immunoreactive cytoplasmic inclusions in Schwann cells in an autopsy case of sporadic amyotrophic lateral sclerosis (ALS). An 81-year-old woman with no family history of neuromuscular disorders noticed difficulty in handling chopsticks due to weakness of the hands. She then developed weakness of the lower and upper limbs and dyspnea. Neurological examination at the age of 83 years revealed disorientation, severe weakness of the facial muscles, tongue, neck and extremities, and fasciculations in the thighs. She exhibited hyperactive jaw jerk and lower limb deep tendon reflexes and normal upper limb deep tendon reflexes, and left extensor plantar response was observed. The patient was diagnosed as having sporadic ALS. An autopsy performed at the age of 84 years revealed widespread p-TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions in the cerebrum, brain stem, and spinal cord, in addition to some Bunina bodies. Moreover, a small number of p-TDP-43-immunoreactive inclusions were found in the facial or accoustic nerve (indistinguishable), spinal cord anterior roots, cauda equina, and peripheral nerves in the dorsal root ganglia. Immunohistochemical staining for p-TDP-43 revealed just a few p-TDP-43-immunoreactive inclusions surrounding axons in the cervical and lumbar anterior roots. Double immunofluorescence analysis revealed that these inclusions were co-localized with S-100 protein ß, suggesting that these inclusions were localized in the cytoplasm of Schwann cells. The peripheral nervous system including Schwann cells may be involved in TDP-43 pathology in ALS.

Delusions and visual hallucinations in a patient with Parkinson's disease with dementia showing pronounced Lewy body pathology in the nucleus basalis of Meynert.

We describe an autopsy-proven case of Parkinson's disease with dementia showing early-onset delusions and hallucinations with limbic-type Lewy body pathology. A Japanese man 72 years old at time of death, developed hand tremor at the age of 45. On neurological examination at 47 years of age, parkinsonian symptoms and signs were present. Pergolide mesylate 1000 µg/day improved his motor symptoms. Then, delusional jealousy appeared and he consulted the psychiatric department in our hospital at the age of 50. Pergolide mesylate 2000 µg/day and trihexyphenidyl hydrochloride 6 mg/day were prescribed. His delusional jealousy made him hit his wife at the age of 63, and visual hallucinations were demonstrated. Brain magnetic resonance imaging (MRI) at the age of 65 revealed mild frontal lobe atrophy. At the age of 72, apparent dementia and dysphagia appeared. The total clinical course was 27 years. The brain showed mild frontal atrophy and weighed 1295 g before fixation. Depigmentation of the substantia nigra and locus ceruleus was macroscopically apparent. Neuronal loss with gliosis was noteworthy in the substantia nigra, locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert (NBM), and intermediate lateral nuclei; however, cerebral neocortex and limbic systems were relatively preserved. Widespread occurrence of Lewy bodies with a few Lewy neurites were demonstrated (limbic-type). Noticeable Lewy body pathology in the NBM was shown in contrast to that in other limbic system structures, such as the amygdala and parahippocampal gyrus, and cerebral cortex. In vivo structural imaging studies revealed that cholinergic projections from the NBM could be responsible for generation of cholinergic deficiency syndrome, including delusions and hallucinations. Furthermore, basal forebrain volume is reduced in patients with Parkinson's disease showing visual hallucinations. Prominent Lewy body pathology in the NBM could be related to not only visual hallucinations but also delusions.

Contiguous and symmetrical disease expansion and massive necrosis of the cerebral white matter in a patient with neuromyelitis optica.

The present report discusses the case of a woman with neuromyelitis optica (NMO) who exhibited bilateral optic neuritis, longitudinally extensive myelitis, serum anti-aquaporin-4 antibodies, and a unique pattern of white matter involvement. The disease duration was 26 years, and the patient died at the age of 65 years. Sequential magnetic resonance images obtained during the last 6 years of life revealed leukoencephalopathy-like lesions extending symmetrically and contiguously from the periventricular regions, which had begun to transform into multiple cavities with semi-annular partitions. This unique pattern of white matter abnormalities should thus be considered among those associated with NMO.

Somatic sprouts of the Purkinje cells in a patient with multiple system atrophy.

We describe the post mortem case of a 71-year-old Japanese woman diagnosed as having multiple system atrophy (MSA), showing somatic sprouting formation of Purkinje cells. The patient had suffered from frequent falling episodes and clumsiness of the left hand since the age of 67 years. Orthostatic hypotension and parkinsonism subsequently emerged. Typical neuropathological features of MSA, including degeneration of the striatum, pontine base and cerebellum with abundance of phosphorylated α-synuclein-positive neuronal and glial cytoplasmic and nuclear inclusions in the brain, were observed. In addition to gliosis of the cerebellar white matter and notable loss of Purkinje cells, several Purkinje cells showed somatic sprouting. Somatic sprouting of Purkinje cells has been demonstrated in several specific conditions, such as developing brains and several neurodegenerative disorders, including Menkes kinky hair disease, familial spinocerebellar ataxia, acute encephalopathy linked to familial hemiplegic migraine, and Huntington's disease; however, no MSA cases have been reported with sprouting from the soma of Purkinje cells. Axonal damage caused by oligodendroglial dysfunction could be crucial in the development of Purkinje cell loss in MSA. Moreover, no apparent α-synuclein accumulation has been described in the Purkinje cells of MSA. We propose that MSA is another degenerative disorder associated with somatic sprouts of Purkinje cells.

Case Study: Somatic Sprouts and Halo-Like Amorphous Materials of the Purkinje Cells in Huntington's Disease.

We described a 63-year-old Japanese female with genetically confirmed Huntington's disease who showed unusual pathological findings in the cerebellum. This case exhibited typical neuropathological features as Huntington's disease, including severe degeneration of the neostriatum and widespread occurrence of ubiquitin and expanded polyglutamine-positive neuronal intranuclear and intracytoplasmic inclusions. The cerebellum was macroscopically unremarkable; however, somatic sprouts and halo-like amorphous materials of Purkinje cell with a large amount of torpedoes were noteworthy. Furthermore, the Purkinje cells were found to have granular cytoplasmic inclusions. Somatic sprouting is a form of degenerated Purkinje cell exhibited in several specific conditions. Although this finding usually appeared in developmental brains, several neurodegenerative disorders, including Menkes kinky hair disease, familial spinocerebellar ataxia, acute encephalopathy linked to familial hemiplegic migraine, and several other conditions, have been reported showing sprouting from the soma of Purkinje cell. We propose that Huntington's disease is another degenerative condition associated with these distinct neuropathological findings of Purkinje cell. Abnormally accumulated huntingtin protein in the cytoplasm could be related to the development of these structures.

Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT†R406W mutation presenting with a broad distribution of abundant senile plaques.

We report the autopsy results of a patient with familial dementia who was diagnosed as having frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with an R406W mutation in the microtubule-associated protein tau (MAPT) gene. This patient showed Alzheimer's disease (AD)-like clinical manifestations from the age of 59, with reduced ß-amyloid1-42 (Aß42 ) and elevated total and phosphorylated tau levels in the cerebrospinal fluid. He did not present with any apparent parkinsonism throughout the disease course. His autopsy at age 73 showed atrophy and neurodegeneration in many brain regions, particularly in the antero-medial temporal cortex and hippocampus, followed by the frontal lobes, with abundant neurofibrillary tangles. In addition, a diffuse distribution of Aß-positive senile plaques, including many neuritic plaques, was observed and classified as stage C according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. These results suggest that analyzing of the MAPT gene is essential for diagnosing familial dementia, even if amyloid markers such as Aß42 in the cerebrospinal fluid and amyloid imaging are positive, or if neuropathological findings indicate a diagnosis of AD.

Clinical features in association with neurodegenerative diseases and malignancies.

OBJECTIVE: To examine whether there are clinical features in Japanese patients with both neurodegenerative diseases and cancers. METHODS: We analyzed the clinical characteristics of consecutive Japanese patients with neurodegenerative diseases during the past 5 years, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), dementia with Lewy bodies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). RESULTS: Out of 292 patients, 39 patients had cancers, including a past history, as follows: ALS, n = 16; PD, n = 8; PSP, n = 7; CBD, n = 1, and MSA, n = 7. About 10% of patients with neurodegenerative diseases developed cancer after onset of the disease; about 30% of patients with ALS, PD, or PSP occurring with cancers died of cancer. Gastric cancer was most common before the onset of ALS (62.5%) but did not develop after the onset of ALS. Conversely, PD patients frequently developed gastric cancers after the onset of neurological signs (60.0%) in spite of no cancer before the onset of PD. The proportion of breast cancer in MSA (45.5%) was significantly higher than in other neurodegenerative diseases. CONCLUSION: ALS, PD, or MSA patients with cancer showed clinical characteristics unique to each neurodegenerative disease in Japan compared to other countries.

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.

An autopsy case of an aged patient with spinocerebellar ataxia type 2.

We report the case of a woman who developed limb clumsiness in her fifties and gait disturbance in her sixties. She was bedridden after bone fractures at age 75 and showed disorientation, slow eye movement, gaze palsy, ataxic speech, muscle atrophy and weakness, and areflexia with pathological reflex. She died of respiratory failure at age 85. This patient was diagnosed genetically as having spinocerebellar ataxia type 2 (SCA2), and the number of expanded CAG repeats was 41. At autopsy, the brain weighed 965 g, and the brainstem, cerebellum, frontal convexity and spinal cord were atrophic. Neuronal loss and gliosis were severe in the pontine nucleus, inferior olivary nucleus, cerebellar cortex, gracile and cuneate nuclei and moderate in the substantia nigra, cerebellar dentate nucleus, anterior horns of the spinal cord and dorsal root ganglia. Axonal loss was observed in the middle and inferior cerebellar peduncles, pyramidal tract and posterior column of the spinal cord. Senile plaques and neurofibrillary tangles (NFTs) were diffusely found in the cerebrum (plaque stage C; NFT stage IV). Expanded polyglutamine-immunoreactive inclusions in the neuronal cytoplasm were widely distributed in the CNS, and neuronal intranuclear inclusions were observed in the pontine nucleus and cerebral cortex. This patient in this autopsy case is a late-onset and aged patient with SCA2, and this is the first report of SCA2 combined with Alzheimer's disease (AD) pathology. Neuropathological findings in this patient, except for AD pathology, were consistent with those of reported SCA2 cases. However, the olivo-ponto-cerebellar system of this patient was relatively preserved and the cerebellar dentate nucleus was more involved as compared with previously reported cases. These results suggest that age at onset or the number of CAG repeat expansions could correlate with the distribution pattern of SCA2 neurodegeneration.

Effectiveness of Levodopa in Patients with Multiple System Atrophy and Associated Clinicopathological Features.

Objective To determine the clinicopathological features of levodopa or dopamine agonist (DA) responders with multiple system atrophy (MSA), an autopsy-confirmed diagnosis is vital due to concomitant cases of MSA and Parkinson's disease (PD). We therefore aimed to investigate the effectiveness of levodopa and DA in autopsy cases of MSA without PD and thereby clarify the clinical course, magnetic resonance imaging (MRI) findings, and pathological features of levodopa-responsive MSA cases. Methods The medical records (clinical data, MRI findings, and pathological findings) of 12 patients with MSA were obtained, and the patients were pathologically confirmed to not have PD. The clinical diagnoses of the patients were MSA with predominant parkinsonism (MSA-P) (n=7), MSA with predominant cerebellar ataxia (MSA-C) (n=4), and progressive supranuclear palsy (PSP) with a concomitant pathology of MSA (n=1). Results Nine patients received a maximum dose of 300-900 mg of levodopa as treatment, which was effective in two MSA-P patients and mildly effective in another two MSA-P patients. DA was mildly effective in one MSA-C patient. The levodopa responders showed marked autonomic dysfunction relatively late and became bedridden after 10 years. Additionally, they exhibited bilateral hyperintense putaminal rims in MRIs after six and nine years, respectively, after disease onset. One levodopa responder and one DA mild responder showed relatively mild neurodegeneration of the putamen. Conclusion Levodopa responders, despite having MSA-P, may show a relatively slow progression in putaminal neurodegeneration, and might maintain prolonged daily life activities in cases without an early occurrence of autonomic dysfunction.

Difference in the Care of Patients with Amyotrophic Lateral Sclerosis With and Without Intervention from the Palliative Care Team: Observations from a Center in Japan.

Background: Despite the significant palliative care needs for people living with amyotrophic lateral sclerosis (ALS), palliative medicine in Japan is mainly focused on oncologic disease. Objective: To compare the care provided to patients with ALS with and without intervention from the palliative care team (PCT and non-PCT groups, respectively). Design: This is a retrospective case-control study. Setting: One ALS center in Japan. Participants: Sixty patients with clinically definite ALS treated until death from January 2012 to December 2019. Measurements: We compared the two groups based on the presence of advance directives, patient age, use of noninvasive and invasive ventilation, maximum opioid dosage, and use of nonopioid palliative medications such as antidepressants and anxiolytics. We also compared the prescribing practices of the attending physicians. Results: There was no difference in the rate of advance directive completion between the PCT and non-PCT groups. Although all but one patient in the PCT group used opioids, only half of the patients in the non-PCT group used opioids (p < 0.001). The mean maximum opioid dosage was higher in the PCT group than in the non-PCT group (p = 0.003). Moreover, 79.2% and 41.7% of the PCT and non-PCT groups, respectively, received antidepressants or antianxiety agents (p = 0.004). Maximum opioid dosages were not different on the basis of attending physician's experience level. Conclusions: Opioid and nonopioid medications intended for symptom management were more likely to be prescribed to patients with ALS who received intervention from a PCT.

Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).

BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. TRIAL REGISTRATION: JMACTR, JMA-IIA00156.

A neuropathological study of autosomal-dominant chorea-acanthocytosis with a mutation of VPS13A.

We report the first autopsy case of genetically confirmed, autosomal-dominant chorea-acanthocytosis (AD-ChAc), showing a heterozygous mutation (G-A) at nucleotide position 8,295 in exon 57 of VPS13A. The patient was a 36-year-old Japanese man and the duration of his illness was 11 years. Neuropathologically, the patient showed marked atrophy and neuronal loss, particularly small and medium-sized neurons, with astrocytic gliosis in the caudate nucleus, putamen and globus pallidus. These findings were similar to previous autopsy reports of autosomal-recessive ChAc (AR-ChAc) with mutations of VPS13A. The broad distribution of atrophic neurons and astrocytosis throughout the whole brain was unique in our AD-ChAc patient and has not been described in AR-ChAc. The neuronal density of the dorsal caudate nucleus was lower than that of the ventral side in this patient as well as in three Huntington's disease (HD) patients. The neuronal densities in both the rostral and caudal sides were lower than that in the middle region at the anterior commissure level, while in the three HD patients, the neuronal densities of the caudate nucleus were more decreased in the caudal side. This ChAc patient showed faint immunoreactivity in the caudate nucleus and globus pallidus with antibodies against the striatal neurotransmitters, methionine-enkephalin, leucine-enkephalin and substance P. The difference in patterns of neuronal vulnerability could reflect those in the mechanisms of neurodegeneration between ChAc and HD.

Prevalence of spinocerebellar degenerations in the Hokuriku district in Japan.

BACKGROUND: The prevalence of disease subtypes of spinocerebellar degenerations (SCDs) varies between countries, and even between areas within a country. We report unprecedented epidemiologic data on SCDs in the Hokuriku district, which is located in the central, western part of Japan. METHODS: Clinical and genetic data on SCD patients were obtained via questionnaires distributed to all the departments of neurology, psychiatry and internal medicine in the Hokuriku district (n = 418). RESULTS: Among the SCD patients, autosomal dominant cerebellar ataxias (ADCAs) were noted in 40.4%, multiple system atrophy in 24.7%, cortical cerebellar atrophy in 13.3% and autosomal recessive cerebellar ataxia in 0.3%. Genetically confirmed ADCA patients included those with Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3; 63.3%), SCA6 (20.0%), ADCA linked to chromosome 16q22.1 (10.0%), dentatorubral pallidoluysian atrophy (4.4%), SCA1 (1.1%) and SCA2 (1.1%). MJD/SCA3 was highly prevalent in the Toyama prefecture of the Hokuriku district, accounting for 90% of genetically confirmed ADCAs by birthplace; MJD/SCA3 patients were concentrated in the Gosei area, the western part of the Toyama prefecture, giving an estimated prevalence of 19.1 per 100,000 inhabitants. CONCLUSIONS: The Hokuriku district, especially the Gosei area of Toyama, had a surprisingly high relative frequency and prevalence of MJD/SCA3, which is comparable to that in the Azores, Portugal.

A clinical phenotype of distal hereditary motor neuronopathy type II with a novel HSPB1 mutation.

We report a Japanese family with distal hereditary motor neuronopathy type II (distal HMN II) due to a novel K141Q mutation in heat-shock 27-kDa protein 1 gene (HSPB1/HSP27). A 47-year-old man (proband) with diabetes mellitus (DM) developed distal wasting and weakness of the legs and severe autonomic dysfunctions in his early forties, while his father and grandfather, without DM, demonstrated slowly progressive muscular wasting and weakness in all limbs still later in life. This mutation appears linked with the late-onset clinical phenotype as distal HMN II. Severe autonomic disturbances in the proband were probably due to uncontrolled DM, but may have been related to HSPB1 mutation.

Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus.

BACKGROUND: Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. OBJECTIVE: To elucidate a nationwide epidemiology of FAP in Japan. DESIGN, SETTING, AND PATIENTS: (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003-2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. RESULTS: (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87-1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11-15.5), followed by Kumamoto (10.1-10.3), and then Ishikawa (3.5-4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. CONCLUSIONS: Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.