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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

As therapies for hereditary neuromuscular diseases are developed, the need for presymptomatic genetic testing and genetic counseling for early treatment is expected to increase. In Japan, there is no uniformly recommended protocol for presymptomatic genetic testing. In order to provide basic data for the establishment of a presymptomatic genetic testing system, we surveyed medical genetics departments in Japan about their current status (response rate: 67.4%). The questionnaire survey revealed that approximately 60% of facilities had established their own procedures for presymptomatic genetic testing, but the approaches used varied from facility to facility. The interview survey enabled us to identify the essential factors for the establishment of a presymptomatic genetic testing system for each case, each facility, and at the overall level. In the future, there is a need to develop a standardized protocol to help establish a presymptomatic genetic testing system.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) refers to a multi-system neurodegenerative disorder, with middle-age onset, which mainly presents with progressive imbalance. Imbalance is attributable to isolated or combined impairment of the cerebellar, proprioceptive, and vestibular systems. Chronic spasmodic cough, which usually precedes neurological symptoms, serves as a useful diagnostic clue to CANVAS. Diagnostic criteria have been proposed for CANVAS in 2016, based on 3 cardinal features. In 2019, a biallelic intronic AAGGG repeat expansion (AAGGG)

Idiopathic sporadic ataxia (ISA) is the clinical term for nonfamilial ataxia with adult-onset and a slowly progressive course. However, immune-mediated cerebellar ataxia cannot be completely excluded from ISA. The current study investigated the neuropil antibodies against cell-surface antigens and clarified the clinical features and neuroimaging findings of patients with these antibodies. Using tissue-based immunofluorescence assays (TBAs), we examined antibodies against the cerebellum in serum samples from 67 patients who met the ISA diagnostic criteria, including 30 patients with multiple system atrophy with predominant cerebellar features (MSA-C) and 20 patients with hereditary ataxia (HA), and 18 healthy control subjects. According to the TBA results, we divided subjects into three groups: subjects positive for neuropil antibodies, subjects positive for intracellular antibodies only, and subjects negative for antibodies. We compared clinical features and neuroimaging findings in ISA patients among these three groups. The prevalence of neuropil antibodies in ISA (17.9%) was significantly higher than that in MSA-C (3.3%), HA (0%), or healthy subjects (0%). The neuropil antibody-positive ISA patients showed pure cerebellar ataxia more frequently than the other ISA patients. Two neuropil antibody-positive patients showed significant improvement of cerebellar ataxia after immunotherapy. We detected neuropil antibodies in 17.9% of ISA patients. Characteristic clinical features of neuropil antibody-positive ISA patients were pure cerebellar ataxia. Some cases of neuropil antibody-positive ISA responded to immunotherapy.

Background: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disease progressively affecting cognitive and motor functions, most often caused by mutations in the colony-stimulating factor 1 receptor gene (CSF1R). / Aim: To elucidate the mechanism of disease progression, changes in white matter lesions and cortical cerebral blood flow (CBF) were evaluated in cases during various stages of the disease. ...

Background: Recently, robot-assisted gait training (RAGT) has been applied widely to individuals with stroke to regain and improve walking ability. We have developed a non-exoskeleton rehabilitation robot, “curara®,” and examined its immediate effect in patients with spinocerebellar degeneration and stroke, but its rehabilitative effect has not been clarified. The purpose of this study was to examine the effect of curara® on gait training in stroke patients.Methods: Forty stroke patients were enrolled in this study. The participants were divided randomly into two groups (groups A and B). The subjects in group A were assigned RAGT with curara® type 4, whereas those in group B received conventional therapist-assisted gait training. The clinical trial period was 15 days. The 10-m walking time (10mWT), 6-min walking distance (6mWD), timed up and go test, and gait parameters (stride duration and length, standard deviation of stride duration and length, cadence, ratio of the stance/swing phases, minimum/maximum knee joint angle, and minimum/maximum hip joint angle) were measured using a RehaGait® analyzer. The Berg Balance Scale was evaluated on days 0 and 14. Gait training was performed for 30 ± 5 min per day through days 2–6 and days 8–13 (total, 12 days) in both groups. The improvement rate was calculated as the difference of values between days 14 and 0 divided by the value on day 0. The improvement rates of the 10mWT and 6mWD were set as the main outcomes.Results: The data of 35 participants were analyzed. There was no significant difference in the main outcomes between both groups. As for intragroup changes, gait speed, stride length, stride duration, and cadence were improved significantly between days 0 and 14 in each group. There was no significant difference between the measured joint angle and the left-right angle ratio of symmetry within or between the groups. When assessing the interaction effect between the day of measurement and group, stride duration and cadence were more significantly improved in group A than in group B.Conclusions: The wearable curara® robot has the potential to improve gait function during stroke rehabilitation.Trial registration: Japan Registry of Clinical Trials (jRCTs032180163). Registered on February 22, 2019; https://jrct.niph.go.jp/en-latest-detail/jRCTs032180163UMIN Clinical Trials Registry (UMIN000034237). Registered on September 22, 2018; https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000038939

Background Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband’s mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

A 64-year-old woman visited our hospital with early-onset dementia and progressive gait disturbance. She had demonstrated a mild communication disorder at the age of ~40 years; however, her psychiatric symptoms at that time were mild and were not accompanied by social problems. At the age of 59, she presented with memory loss, visual hallucinations, and delusions. Over the following five years she developed gait difficulties that gradually deteriorated and suffered frequent falls. On admission, neurological examinations revealed severe pyramidal and extrapyramidal signs of akinetic mutism. MRI of the brain showed cerebral atrophy, enlarged lateral ventricles, thinning of the corpus callosum, and leukoencephalopathy in the frontal-parietal lobes. Additionally, CT revealed a small spotty calcification in the frontal subcortical white matter. Genetic analysis revealed a single-base substitution (c.2330G>A/p.R777Q) in exon 18 of the colony stimulating factor 1 receptor (CSF1R) gene, encoding the CSF1R protein. She was diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS is included in the differential diagnosis of early-onset dementia and should be considered in patients with mild personality change and abnormal behavior in the early course of the illness.

Background Ataxic gait is one of the most common and disabling symptoms in people with degenerative cerebellar ataxia. Intensive and well-coordinated inpatient rehabilitation improves ataxic gait. In addition to therapist-assisted gait training, robot-assisted gait training has been used for several neurological disorders; however, only a small number of trials have been conducted for degenerative cerebellar ataxia. We aimed to validate the rehabilitative effects of a wearable “curara®” robot developed in a single-arm study of people with degenerative cerebellar ataxia. Methods Twenty participants with spinocerebellar ataxia or multiple system atrophy with predominant cerebellar ataxia were enrolled. The clinical trial duration was 15 days. We used a curara® type 4 wearable robot for gait training. We measured the following items at days 0, 7, and 14: Scale for the Assessment and Rating of Ataxia, 10-m walking time (10 mWT), 6-min walking distance (6 mWD), and timed up and go test. Gait parameters (i.e., stride duration and length, standard deviation of stride duration and length, cadence, ratio of the stance and swing phases, minimum and maximum knee joint angles, and minimum and maximum hip joint angles) were obtained using a RehaGait®. On days 1–6 and 8–13, the participants were instructed to conduct gait training for 30 ± 5 min with curara®. We calculated the improvement rate as the difference of values between days 14 and 0 divided by the value on day 0. Differences in the gait parameters were analyzed using a generalized linear mixed model with Bonferroni’s correction. Results Data from 18 participants were analyzed. The mean improvement rate of the 10 mWT and 6 mWD was 19.0% and 29.0%, respectively. All gait parameters, except the standard deviation of stride duration and length, improved on day 14. Conclusions Two-week RAGT with curara® has rehabilitative effects on gait function comparable to those of therapist-assisted training. Although the long-term effects after a month of RAGT with curara® are unclear, curara® is an effective tool for gait training of people with degenerative ataxia. Trial registration jRCT, jRCTs032180164. Registered: 27 February 2019; retrospectively registered. https://jrct.niph.go.jp/en-latest-detail/jRCTs032180164.

Background and purpose The purpose was to identify statistically factors that correlate with the presence of a colony-stimulating factor 1 receptor (CSF1R) mutation and to reevaluate the accuracy of the current diagnostic criteria for CSF1R-related leukoencephalopathy. Methods CSF1R testing was conducted on 145 consecutive leukoencephalopathy cases who were clinically suspected of having adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. From these, 135 cases whose detailed clinical information was available were enrolled. Forward logistic stepwise regression was performed to generate a probability model to predict a positive CSF1R mutation result. The current diagnostic criteria were also applied to our cohort and their sensitivity and specificity were calculated. Results Twenty-eight CSF1R-mutation-positive cases and 107 CSF1R-mutation-negative cases were identified. Our probability model suggested that factors raising the probability of a CSF1R-mutation-positive result were younger onset, parkinsonism, thinning of the corpus callosum and diffusion-restricted lesions. It also showed that involuntary movements and brainstem or cerebellar atrophy were negative predictors of a CSF1R-mutation-positive result. In our cohort, the sensitivity and specificity for 'probable' or 'possible' CSF1R-related leukoencephalopathy were 81% and 14%, respectively. Conclusions Clinical and brain imaging features predictive of the presence of a CSF1R mutation are proposed. Consideration of these factors will help prioritize patients for CSF1R testing.

Background Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. Methods Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. Results Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. Conclusions Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.

Marie et al. (1922) first proposed a disease entity "late cortical cerebellar atrophy (LCCA)", which is characterized neuropathologically by pure cerebello-olivary degeneration. LCCA was originally described as sporadic, late-onset, pure cerebellar ataxia of unknown etiology; however, it has occasionally been used to denote familial or secondary ataxias, particularly alcoholic cerebellar degeneration. Sporadic ataxia is classified mainly into LCCA or CCA and olivo-ponto-cerebellar atrophy (OPCA) in Japan. OPCA, now multiple system atrophy with predominant cerebellar ataxia, has characteristic brain imaging features and is clearly diagnosed based on the consensus criteria. On the other hand, there is no specific biomarker for LCCA/CCA, and neuropathological examination is required for a definitive diagnosis. Therefore, the clinical diagnosis of LCCA/CCA depends on the exclusion of other diseases manifesting as cerebellar ataxia. However the differential diagnosis for LCCA/CCA is not necessarily made carefully. As a result, the LCCA/CCA category in Japan is a "waste basket," including OPCA, hereditary ataxias, and secondary ataxias, which are unidentified yet. To refine the LCCA/CCA category, we proposed the clinically-defined term "idiopathic cerebellar ataxia (IDCA)" and established its diagnostic criteria. By nationwide screening, we have identified 51 patients with probable IDCA according to the criteria so far. Here we review the clinical characteristics of IDCA patients.

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.

We have been developing the robotic wear curara as both a welfare device and rehabilitation robot that assists the elderly and disabled. curara is aimed at user friendliness. We have, thus, chosen a non-exoskeleton structure made of a plastic so that the robot is as light in weight as possible and to minimize the restraining stress against natural human movement. We verified the assistance effect of curara on 15 hemiplegic patients with stroke by comparing gait parameters (i.e., velocity, step length, cadence, and symmetry of joint angles) among three conditions. The conditions were "without assistance" (i.e., a control mode that cancels frictional resistances in actuators), Condition A (where joint angles are enlarged but there is no change in gait cycle), and Condition B (where there is no change in joint angles but the gait cycle is shortened). curara improved the walking velocity by 19% and 27% under Conditions A and B, respectively. Improvements in step length and cadence were, respectively, 11% and 7% under Condition A and 14% and 11% under Condition B. Moreover, the two assistance conditions reduced the difference in joint angles between unaffected and paralyzed legs. We consider that curara will facilitate the rehabilitation of stroke patients.

A 72-year-old Japanese woman suffered from mild pancytopenia 3 years before her initial hospitalization. On admission, the levels of trace elements, particularly copper, and ceruloplasmin were significantly decreased in her blood serum. Abdominal lymphadenopathy and bone marrow dysplasia were detected. Hemosiderin deposition was observed in her lymph nodes and bone marrow, and magnetic resonance imaging suggested its deposition in various organs. A novel missense pathogenic variant (c.T1670G) was detected in the ceruloplasmin gene, resulting in an amino acid change (p.M557R). When copper deficiency is accompanied by cytopenia and dysplasia in a patient, it is worthwhile to consider a differential diagnosis of aceruloplasminemia.

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient’s expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.

Objectives We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia. Methods Five patients with SCA with cortical atrophy (ages 60‐69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET. Results Postsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%). Interpretation Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello‐thalamo‐cortical network.

Background and purpose To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

Background It is quite difficult to evaluate ataxic gait quantitatively in clinical practice. The aim of this study was to analyze the characteristics of ataxic gait using a triaxial accelerometer and to develop a novel biomarker of integrated gate parameters for ataxic gait. Methods Sixty-one patients with spinocerebellar ataxia (SCA) or multiple system atrophy with predominant cerebellar ataxia (MSA-C) and 57 healthy control subjects were enrolled. The subjects were instructed to walk 10 m for a total of 12 times on a flat floor at their usual walking speed with a triaxial accelerometer attached to their back. Gait velocity, cadence, step length, step regularity, step symmetry, and degree of body sway were evaluated. Principal component analysis (PCA) was used to analyze the multivariate gait parameters. The Scale for the Assessment and Rating of Ataxia (SARA) was evaluated on the same day of the 10-m walk trial. Results PCA divided the gait parameters into four principal components in the controls and into two principal components in the patients. The four principal components in the controls were similar to those found in earlier studies. The second principal component in the patients had relevant factor loading values for gait velocity, step length, regularity, and symmetry in addition to the degree of body sway in the medio-lateral direction. The second principal component score (PCS) in the patients was significantly correlated with disease duration and the SARA score of gait (ρ = −0.363, p = 0.004; ρ = −0.574, p

The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.

This article was retracted by author’s request.

Background Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and “focal lesions” of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017). Methods Seven autopsied brains of ALSP and five controls were neuropathologically examined. Results Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the “focal lesions” were identical with those of centrum semiovale. Conclusion Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, “focal lesions” were formed in connection with the lesions in centrum semiovale., Highlights • Preferential thinning and “focal lesions” of corpus callosum in ALSP. • Seven autopsied brains of ALSP and five controls were neuropathologically examined. • Larger spheroids and more microglial alteration in corpus callosum than centrum semiovale. • “Focal lesions” were formed in connection with the lesions in the centrum semiovale. • Peculiar morphological change of microglia leads to the preferential thinning of corpus callosum.

Background and purpose The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. Methods Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

Heat-shock proteins (HSPs) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to examine whether the serum levels of HSPs (HSP27, HSP70, and HSP90) are altered in patients with ALS. We included 58 patients diagnosed with ALS and 85 control individuals. Serum HSP levels of patients and controls were determined using enzyme-linked immunosorbent assay. The serum levels of HSP70 and HSP90 were significantly higher in patients than in controls. In contrast, serum levels of HSP27 did not differ significantly between the patient and control groups. Moreover, serum levels of HSP70 and HSP90 in patients remained high throughout the duration of the disease. Taken together, our findings suggest that HSPs might have a role in ALS progression throughout the course of the disease. Further studies are needed to clarify the role of HSPs in the pathogenesis of ALS.

We report lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in the patients with familial amyotrophic lateral sclerosis having L106V mutation in the SOD1 gene. Ten of 20 patients showed lower urinary tract dysfunction and 5 patients developed within 1 year after the onset of weakness. In 8 patients with an artificial respirator, 6 patients showed lower urinary tract dysfunction. Lower urinary tract dysfunction and respiratory failure requiring an artificial respirator occurred simultaneously in 3 patients. Neuronal loss and gliosis were observed in the neural circuits controlling micturition, such as frontal lobe, thalamus, hypothalamus, striatum, periaqueductal gray, ascending spinal tract, lateral corticospinal tract, intermediolateral nucleus and Onufrowicz' nucleus. Lower urinary tract dysfunction, especially storage symptoms, developed about 1 year after the onset of weakness, and the dysfunction occurred simultaneously with artificial respirator use in the patients.

Colony stimulating factor-1 receptor (CSF1R) plays important roles in the differentiation and proliferation of macrophage and microglia in systemic organs and the brain. A genetic defect in CSF1R causes hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS mainly affects the cerebral white matter and shows pre-senile cognitive decline, motor disturbance, and epilepsy. However, systemic manifestations outside the brain have not yet been described in patients with HDLS. Here, we report the case of a 41-year-old man with HDLS carrying the p. K793T mutation in CSF1R, who unexpectedly died of sepsis and hemophagocytic syndrome shortly after the onset of HDLS. The fetal sequence of sepsis and hemophagocytic syndrome was triggered by enterocolitis. An autopsy revealed that focal inflammation in the intestine had almost resolved. Most strikingly, massive infiltration of cluster of differentiation (CD) 68- and CD163-immunopositive macrophages with hemophagocytosis was observed in the bone marrow, spleen, and liver. Less abundant infiltration of CD68- and CD204-immunopositive macrophages without hemophagocytosis was also seen in the lung and intestine. At present, the pathogenetic link between CSF1R mutation and hemophagocytic syndrome in this patient is unclear. Our case, however, clearly shows that even in patients with HDLS, aberrant activation of functional macrophages can be induced under certain conditions in visceral organs.

Background Spinocerebellar degeneration (SCD) mainly manifests a cerebellar ataxic gait, leading to marked postural sway and the risk of falling down. Gait support using a wearable robot is expected to be an effective solution to maintaining the status quo and/or delaying symptom progression. The aim of this study was to evaluate the effects of gait support in patients with SCD by using a wearable robotic system called curara ®; while undergoing walking tests. Methods The curara system assists both the hip and knee joints and supports the wearer’s rhythmic gait using a synchronization control based on a central pattern generator. The system reflects the wearer’s intended motion in response to the gait support by detecting an interactive force that is generated from slight movements of the wearer. The degree of coordinated motion between the robot and the wearer can be adjusted by modifying the synchronization gain. In this study, we provided gait support using three high-gain conditions (A, B, C) to more easily follow the wearer’s movement in each joint. The synchronization gains for both the hip and knee joints (i.e., C h and C k ) were set at 0.5 for condition A and at 0.4 for condition B. Condition C had different gains for the hip and knee joints (i.e., C h =0.4 and C k =0.5). With the walking test, we assessed the effects of the gait support provided by the curara system on walking smoothness (measured using the harmonic ratio: HR) and spatiotemporal parameters (gait speed, stride length, cadence) in SCD patients (n=12). We compared the performance between the three high-gain conditions and without assistance from the robot. Results Under condition C, the HRs in the anteroposterior, mediolateral, and vertical directions (HR-AP, HR-ML, and HR-V) were especially high compared with those under conditions A and B. The results of the statistical analyses using repeated measures analysis of variance followed by Tukey’s test showed that gait support with condition C results in a statistically significant increase in the HR-AP (2.04 ±0.52; p=0.025) and HR-V (2.06 ±0.37; p=0.032) when compared with walking without assistance from the system. In contrast, the gait speed, stride length, and cadence under condition C were no major changes in most patients, compared with the patient’s walking without assistance. Conclusions The significantly increased HR indicates that gait support under condition C achieved smoother walking than when not wearing the power unit of the system. Consequently, we suggest that gait support using the curara system has the potential to improve walking smoothness in patients with SCD.

Spinocerebellar ataxia type 21 (SCA21) is a rare subtype of autosomal dominant cerebellar ataxias, which was first identified in a French family and has been reported almost exclusively in French ancestry so far. We here report the first Japanese family with SCA21, in which all affected members examined carried a heterozygous c.509C > T:p.Pro170Leu variant in TMEM240. Their clinical features were summarized as a slowly progressive ataxia of young-adult onset (5–48 years) associated with various degree of psychomotor retardation or cognitive impairment. The MR images revealed atrophy in the cerebellum, but not in the cerebrum or brainstem. These clinical findings were consistent with those in the original French families with SCA21. Neuropathological findings in one autopsied patient showed a prominent decrease of cerebellar Purkinje cells, but no specific abnormalities outside the cerebellum.

A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs*3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.

A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs*3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.

This paper aimed to verify the effectiveness of the wearable robotic system "curara" for patients with spinocerebellar degeneration (SCD) by evaluating walking smoothness. The curara system supports the wearer's gait using a synchronization control method that uses a neural oscillator based on a central pattern generator network. The system reflects the motional intention by adjusting the synchronization gains. This modifies the degree of interactive coordinated motion between the curara and the wearer. As a feasibility study, we evaluated the waking smoothness of 10 patients with SCD using three gain condition settings. Harmonic ratio (HR), which has been used extensively to quantify the smoothness during walking, was used to assess their walking. The results show that most HRs in the medio-lateral, anterior-posterior, and vertical directions using the three gain conditions were higher than those for patients not wearing the system. In particular, the increasing rates of the HR in all directions during the gait support were 11.1%, 23.4%, and 23.2% compared with unassisted walking, when the gain condition settings of hip and knee joints are set at 0.4 and 0.5, respectively. Consequently, these results verified the effectiveness of the curara system for patients with SCD.

Cortical cerebellar atrophy (CCA) and multiple system atrophy with predominant cerebellar ataxia (MSA-C) are the two major forms of adult-onset sporadic ataxia. Contrary to MSA-C, there are neither diagnostic criteria nor neuroimaging features pathognomonic for CCA. Therefore, it is assumed that the category of CCA in the Japanese national registry include heterogeneous cerebellar ataxic disorders. To refine this category in more detail, we here used a clinical-based term, "idiopathic cerebellar ataxia (IDCA)", and proposed its diagnostic criteria. We collected 346 consecutive patients with the core features of the criteria (sporadic, insidious-onset and slowly progressive cerebellar ataxia in adults, and cerebellar atrophy on brain imaging). Of these, 212 (61.3%) were diagnosed with probable or possible MSA, and 30, who did not meet the diagnostic criteria for MSA at examination, were also excluded because of MRI findings suggestive of MSA. Twenty two were proven to have hereditary spinocerebellar ataxias by genetic testing, and 19 had secondary ataxias. Finally, the remaining 63 (18.2%) were diagnosed with IDCA. The mean (standard deviation) age at onset was 57.2 (10.8) years. Of these, 25 (39.7%) showed pure cerebellar ataxia, and the remaining 38 (60.3%) had some of extracerebellar features including abnormal tendon reflexes (46.0%), positive Babinski sign (9.5%), sensory disturbance (12.7%), cognitive impairment (9.5%), and involuntary movements (7.9%). Our results show that IDCA refined by the diagnostic criteria still includes clinically and genetically heterogeneous ataxic disorders. More extensive genetic analyses will be of significance for further clarification of this group.

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin-G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.