Background: We evaluated whether the Walkaide® device could effectively improve walking ability and lower extremity function in post-stroke patients with foot drop. Patients aged 20–85 years with an initial stroke within ≤6 months and a functional ambulation classification score of 3 or 4 were eligible. Materials and Methods: Patients were randomly allocated to the functional electrical stimulation (FES) or control group at a 1:1 ratio. A 40 min training program using Walkaide was additionally performed by the FES group five times per week for 8 weeks. The control group received the 40 min training program without FES. Results: A total of 203 patients were allocated to the FES (n = 102) or control (n = 101) groups. Patients who did not receive the intervention or whose data were unavailable were excluded. Finally, the primary outcome data of 184 patients (n = 92 in each group) were analyzed. The mean change in the maximum distance during the 6-MWT (primary outcome) was 68.37 ± 62.42 m and 57.50 ± 68.17 m in the FES and control groups (difference: 10.86 m; 95% confidence interval: −8.26 to 29.98, p = 0.26), respectively. Conclusions: In Japanese post-stroke patients with foot drop, FES did not significantly improve the 6 min walk distance during the convalescent phase. The trial was registered at UMIN000020604.

Spinocerebellar ataxia (SCA) type 17-digenic TBP/STUB1 disease (SCA17-DI) has been recently segregated from SCA17, caused by digenic inheritance of two gene mutations – intermediate polyglutamine-encoding CAG/CAA repeat expansions (polyQ) in TBP ( TBP 41 − 49 ) and STUB1 heterozygosity – the former being associated with SCA17, and the latter with SCA48 and SCAR16 (autosomal recessive). In SCA17, most patients carry intermediate TBP 41 − 49 alleles but show incomplete penetrance, and the missing heritability can be explained by a new entity whereby TBP 41 − 49 requires the STUB1 variant to be symptomatic. The STUB1 gene encodes the chaperone-associated E3 ubiquitin ligase (CHIP) involved in ubiquitin-mediated proteasomal control of protein homeostasis. However, reports of the neuropathology are limited and role of STUB1 mutations in SCA17-DI remain unknown. Here we report the clinicopathologic features of identical twin siblings, one of whom was autopsied and was found to carry an intermediate allele (41 and 38 CAG/CAA repeats) in TBP and a heterozygous missense mutation in STUB1 (p.P243L). These patients developed autosomal recessive Huntington’s disease-like symptoms. Brain MRI showed diffuse atrophy of the cerebellum and T2WI revealed hyperintense lesions in the basal ganglia and periventricular deep white matter. The brain histopathology of the patient shared features characteristic of SCA17, such as degeneration of the cerebellar cortex and caudate nucleus, and presence of 1C2-positive neurons. Here we show that mutant CHIP fails to generate the polyubiquitin chain due to disrupted folding of the entire U box domain, thereby affecting the E3 activity of CHIP. When encountering patients with cerebellar ataxia, especially those with Huntington’s disease-like symptoms, genetic testing for STUB1 as well as TBP should be conducted for diagnosis of SCA17-DI, even in cases of sporadic or autosomal recessive inheritance.

A 47-year-old right-handed man was admitted to our hospital for rehabilitation after right basal ganglion hematoma. On day 57, he noticed a supernumerary motor phantom limb (SPL) involving his right arm, originating at the level of the elbow. The most notable finding of his SPL was the motor characteristic. When the subject had the intention to move the upper paralyzed limb simultaneously with the trainer’s facilitating action, he said “there is another arm.” The intention to move the paralyzed arm alone or passive movement of the paralyzed arm did not induce the SPL. He showed a severe left sensorimotor impairment and mild hemineglect, but no neglect syndromes of the body (e.g., asomatognosia, somatoparaphrenia, personification and misoplegia, or anosognosia) were observed. Brain MRI demonstrated a hematoma in the right temporal lobe subcortex, subfrontal cortex, putamen, internal capsule, and thalamus. Single-photon emission computed tomography images showed more widespread hypoperfusion in the right hemisphere in comparison to the lesions on MRI. However, the premotor cortex was preserved. Our case is different from Staub’s case in that SPL was not induced by the intention to move the paralyzed limb alone; rather, it was induced when the patient intended to move the paralyzed limb with a trainer’s simultaneous facilitating action. The SPL may reflect that an abnormal closed-loop function of the thalamocortical system underlies the phantom phenomenon. However, despite the severe motor and sensory impairment, the afferent pathway from the periphery to the premotor cortex may have been partially preserved, and this may have been related to the induction of SPL.

Cardiac 123I-MIBG scintigraphy (cMIBG) and an olfactory function test using the Odor Stick Identification Test for Japanese (OSIT-J) were performed for 46 patients with idiopathic REM behavior disorder (iRBD). The H/M ratio on cMIBG of iRBD patients was classified according to the Hoehn-Yahr's (H-Y) stages of Parkinson's disease (PD) as follows: early images, normal range, 11(23.9%); H-YI, 3 (6.5%); H-YII, 5 (10.9%); ≥ H-YIII, 27 (58.7%); and delayed images, normal range, 9 (19.6%); H-YI, 3 (6.5%); H-YII, 1 (2.2%); ≥ H-YIII, 33 (71.7%). The OSIT-J scores decreased in 76.2% of iRBD patients, and 20.5% of Normal subjects. The OSIT-J scores in iRBD patients were strongly correlated with the H/M ratio on early and delayed cMIBG images (p<0.001, Pearson correlation coefficient). PD progresses from H-Y stage I to V, with the H/M ratio on cMIBG decreasing as the H-Y stage progresses.The H/M ratio in iRBD patients decreased to PD H-Y III/IV or dementia with Lewy bodies (DLB) levels in 71.7% of patients.Thus, in many cases, iRBDs is a precursor of DLBs but not of PDs. Although olfactory dysfunction has no disease specificity, it is a simple and useful screening test that can be applied before cMIBG for patients with iRBD.

The purpose of this study was to investigate the diagnostic availability of cMIBG in differentiating Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) from related Neurodegenerative Diseases (NDDs) and to clarify the utility of cMIBG as a predicative biomarker for the conversion from Idiopathic REM Sleep Abnormal Behavior Disorder (iRBD) to α-synucleinopathies.

Background and Purpose— Our aim was to study the efficacy of robotic therapy as an adjuvant to standard therapy during poststroke rehabilitation. Methods— Prospective, open, blinded end point, randomized, multicenter exploratory clinical trial in Japan of 60 individuals with mild to moderate hemiplegia 4 to 8 weeks post stroke randomized to receive standard therapy plus 40 minutes of either robotic or self-guided therapy for 6 weeks (7 days/week). Upper extremity impairment before and after intervention was measured using the Fugl–Meyer assessment, Wolf Motor Function Test, and Motor Activity Log. Results— Robotic therapy significantly improved Fugl–Meyer assessment flexor synergy (2.1±2.7 versus −0.1±2.4; P<0.01) and proximal upper extremity (4.8±5.0 versus 1.9±5.5; P<0.05) compared with self-guided therapy. No significant changes in Wolf Motor Function Test or Motor Activity Log were observed. Robotic therapy also significantly improved Fugl–Meyer assessment proximal upper extremity among low-functioning patients (baseline Fugl–Meyer assessment score <30) and among patients with Wolf Motor Function Test ≥120 at baseline compared with self-guided therapy (P<0.05 for both). Conclusions— Robotic therapy as an adjuvant to standard rehabilitation may improve upper extremity recovery in moderately impaired poststroke patients. Results of this exploratory study should be interpreted with caution. Clinical Trial Registration— URL: http://www.umin.ac.jp/. Unique identifier: UMIN000001619.

RBD is often observed as a preclinical symptom of DLB/PD. The aim of this study was to investigate whether DLB/PD and RBD had similar findings on 123-I-metaiodobenzylguanidine (MIBG) scintigraphy and differed from other neurodegenerative diseases. A total 731 patients were recruited from the medical records and were enrolled in this study. These include 530 with DLB/PD (DLB, n=88; Hoehn & Yahr stage 1 [ PD1 ], n=58; stage 2 [ PD2 ], n= 106; stage 3 [ PD3 ], n= 230; and stage 4 [ PD4 ], n= 48), 42 with Alzheimer’s disease, 19 with corticobasal syndrome, 33 with multiple system atrophy, 41 with progressive supranuclear palsy, 24 with normal pressure hydrocephalus, 18 with essential tremor, 13 with vascular parkinsonism and dementia, and 12 subjects with RBD. MIBG scintigraphy was obtained at 30min (early image) and 4 hour (delayed image) post-injection, and the H/M ratio, and washout rate were evaluated. The H/M ratios in DLB/PD and RBD were significantly lower than those in other diseases (p<0.05). The upper confidence limit of 95% was 2.17 in the early image, and 2.03 in the delayed image. A significantly lower delayed H/M ratio in comparison to the early H/M ratio was observed in DLB/PD (p<0.05) and RBD (p<0.05), but not in the other diseases, meaning that the washout rate was higher in DLB/PD and RBD patients. Among DLB/PD and RBD, the H/M ratio decreased in the following order: PD1, PD2, PD3, DLB, RBD, and PD4. The mean H/M ratios of DLB and RBD was 1.64±0.27 (mean±SD) and 1.64±0.19 respectively, in the early, and 1.33±0.25 and 1.29±0.21 in the delayed image. In 8 RBD examined by DaT scan, 3 subjects revealed a decreased uptake. The MIBG scintigraphy clearly differentiated DLB/PD from the other neurodegenerative disorders. It is a striking finding that the H/M ratio in RBD decreased to the same level as in DLB before showing the clinical signs of DLB/PD, suggesting that RBD could be a preclinical sign of DLB.

Mild Cognitive Impairment (MCI) has been proposed as a transitional stage between the cognitive changes of normal aging and dementia. 10 to 15% of MCI patients progress to Alzheimer's disease (AD) within one year. The aim of this study was to investigate whether perfusion brain SPECT imaging at the initial hospital visit could predict progression from MCI to AD. The SPECT device used in this study was Infina Hawkeye 4, General Electronics, with rotating two-headed gamma camera with a fan beam collimator (64x64). The data were acquired for 20 minutes, beginning 20 minutes after the intravenous administration of 123I- IMP (111MBq). The easy Z-score Imaging System (eZIS) and Voxel Based Stereotactic Extraction Estimation (vbSEE) were used in this study for the quantitative assessment of brain SPECT images. More than 20% decrease in the extent % comparison to the control subjects was used to assess the hypoperfusion in the vbSEE analysis. To determine the frequent hypoperfusion regions in the vbSEE analysis, 80 hemispheres of 40 patients with probable AD (29 female, 11 male, age range 52-82) were analyzed. Nine regions were selected as the frequent hypoperfusion regions including angular gyrus, supramarginal gyrus, inferior parietal lobule, precuneus, middle temporal gyrus, superior parietal lobule, superior temporal gyrus, cingulated gyrus. Among 82 MCI patients (male 21, female 61), 36 patients showed abnormal SPECT (A group) and 46 patients showed normal SPECT (N group). The age and MMSE were not significantly different between the groups. Progression from MCI to AD was observed for the period of 1-5 years. Among 61 patients observed for one year, 17 patients progressed from MCI to AD, including 6 patients in N group (35.3%) and 11 patients in A group (64.7%). The Logrank test demonstrated a significant difference in survival curve between the group A and N (P value=0.00842; p<0.01). The eZIS and vbSEE analysis of SPECT imaging at the initial hospital visit in MCI patients is a useful tool for predicting the progression to AD in the near future.

The aim of this study was to probe the brain activity in subjects with mild cognitive impairment (MCI) while they performed various tests. Fifteen MCI subjects of 78.9±9.8 years of age, with a mean MMSE score of 27.3±1.4, and 17 control subjects of 72.3±7.3 years of age, with a mean MMSE score of 29.3±0.9, were investigated using NIRS. All of the subjects took three types of tests. 1) The Kana pick-up test (Kana are Japanese letters). The subjects were instructed to select 5 specified letters from randomly arranged Kana letters (Task 1); and old Japanese fairy tales written entirely in Kana letters (Task 2). The test consists of 10 s of rest followed by 60 s to perform Task 1, then 20 s of rest and 60 s to perform Task 2. Each of these tasks was repeated twice. 2) A modified Stroop test. The subjects were asked to name the color of ink (Task 1) and the color of Chinese letters (Task 2). The test consists of 10 s of rest followed by 30 s to perform each task; the test was repeated three times. 3) The phonological verbal fluency task. The subjects were instructed to generate words beginning with a specified letter. The test consists of 10 s of task followed by 5 s of rest; the test was repeated 10 times. We used a 16-probe, 46-channeled NIRS device (OMM 3000, Shimazu Corporation, Japan). The task achievement levels in the MCI subjects were lower than those of the control subjects in the following tasks: Kana pick-up Task 1 (P<0.01), Kana pick-up Task 2 (P<0.001), modified Stroop test Task 2 (P<0.05) by Cochran-cox analysis. With the exception of Kana pick-up Task 1, the oxyHb concentrations were significantly decreased in the MCI subjects in comparison to the controls in all of the tests. The results in this study indicate that the frontal brain function was impaired in the stage of “MCI due to Alzheimer’s disease”. The measurement of oxyHb using NIRS is useful in the diagnosis of MCI.

Bunina bodies (BBs) are small eosinophilic neuronal cytoplasmic inclusions (NCIs) found in the remaining lower motor neurons (LMNs) of patients with sporadic amyotrophic lateral sclerosis (SALS), being a specific feature of the cellular pathology. We examined a case of SALS, unassociated with TDP‐43 or C9ORF72 mutation, of 12 years duration in a 75‐year‐old man, who had received artificial respiratory support for 9 years, and showed widespread multisystem degeneration with TDP‐43 pathology. Interestingly, in this patient, many NCIs reminiscent of BBs were observed in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus. As BBs in the cerebellar dentate nucleus have not been previously described, we performed ultrastructural and immunohistochemical studies of these NCIs to gain further insight into the nature of BBs. In each region, the ultrastructural features of these NCIs were shown to be identical to those of BBs previously described in LMNs. These three regions and the relatively well preserved sacral anterior horns (S1 and S2) and facial motor nucleus were immunostained with antibodies against cystatin C (CC) and TDP‐43. Importantly, it was revealed that BBs exhibiting immunoreactivity for CC were a feature of LMNs, but not of non‐motor neurons, and that in the cerebellar dentate nucleus, the ratio of neurons with BBs and TDP‐43 inclusions/neurons with BBs was significantly lower than in other regions. These findings suggest that the occurrence of BBs with CC immunoreactivity is intrinsically associated with the particular cellular properties of LMNs, and that the mechanism responsible for the formation of BBs is distinct from that for TDP‐43 inclusions.

脳梗塞後に, 拮抗性失行および口頭命令に対する左上肢の運動の困難さを認めた 61 歳の右利き女性例について報告した。拮抗性失行は強制把握を伴わず突発的に出現し, 行為の開始時あるいは行為の途中に多く認められ, 左手が右手の行為に対して反対目的の動作をとるという異常行為が主体であった。また, 左手の観念運動性失行を認めた。さらに, 口頭命令において左手の運動開始が困難あるいは開始までに時間を要す特徴的な症状を認めた。頭部CT では左前頭葉皮質下と脳梁膝部から膨大部にかけて低吸収域を認め, 脳血流シンチでは左に強く右により軽度の, 前部帯状回および下・中前頭回を中心とする広範な前頭葉の血流低下を認めた。本例の左手に見られた異常行動は間欠性運動開始困難と位置づけ, 超皮質性運動失語に伴う発話の発動性の低下および右前頭前野の機能低下による左手の動作の発動性の低下がより強調されて現れているものと解釈された。

A 66-year-old, right-handed male, was admitted to our hospital with difficulty in recognizing faces and colors. He had suffered a stroke in the right occipital region three years earlier that had induced left homonymous hemianopsia, but not prosopagnosia. A neurological examination revealed prosopagnosia, color agnosia, constructional apraxia, and topographical disorientation, but not either hemineglect or dressing apraxia. The patient was unable to distinguish faces of familiar persons such as his family and friends, as well as those of unfamiliar persons such as doctors and nurses. Brain MRI demonstrated an old infarction in the right medial occipital lobe and a new hemorrhagic infarction in the left medial occipital lobe, including the fusiform and lingual gyrus. It is unclear whether a purely right medial occipital lesion can be responsible for prosopagnosia, or whether bilateral medial occipital lesions are necessary for this occurrence. The current case indicated that bilateral medial occipital lesions play an important role in inducing porsopagnosia.

The origin of patchy white matter hyperintensities commonly seen in the elderly on magnetic resonance (MR) images with long repetition time (TR) is still controversial. We describe MR findings in older patients in whom white matter hyperintensities were attenuated by compression of the cerebral hemisphere from a chronic subdural hematoma. These sequential MR findings substantiate the hypothesis that leukoaraiosis may arise when drainage of the bulk flow of brain interstitial fluid is disturbed.

Creutzfeldt-Jakob disease (CJD) is a subacute spongiform encephalopathy characterized clinically by progressive dementia with myoclonus and extrapyramidal symptoms. If no characteristic EEG findings are found, clinical diagnosis is difficult. CT is of little use. MRI has been reported both to be of little value' and to be helpful in the diagnosis of CJD.Y-4 A few CJD patients with a point mutation at codon 232 of prion protein gene have been reported."-' We describe MRI changes in the cerebral cortex of a patient with a mutation at codon 232. Case report. A 64-year-old woman who had about a year's history of difficulty in dressing was admitted to our hospital. At that time, she had developed abnormalities in her cortical functions (dressing apraxia, constructional apraxia, limb-kinetic apraxia, idiomotor apraxia, ideational apraxia, and apraxic agraphia). She showed no disturbance of recent or remote memory. Her past medical and family histories were unremarkable, and she was taking no medication. No myoclonic jerks, muscle weakness, rigidity, or ataxia were observed. CSF evaluation showed only a slight increase in protein content. An EEG done 1 month after admission showed periodic sharp discharges (PSD) when there were no myoclonic jerks. A serial CT showed no atrophy, calcification, or other brain abnormalities. Serial MRI (0.5T, Hitachi, Japan) was performed. MRI done 8 months after the onset of illness showed increased signal intensity on the T2-weighted images in the parietal and parietotemporal borders of the cerebral cortex bilaterally (figure, A). On admission, increased signal intensity areas were seen bilaterally in the temporal cortex (figure, B). One year and 3 months after onset, when dementia was present, increased signal intensity areas were spread throughout the cerebral cortex (figure, C). One and a half years after onset, she developed akinetic mutism and severe muscular rigidity. MRI showed increased signal intensity in the basal ganglia (caudate nucleus and putamen bilaterally) (figure, D), and atrophy of the frontal, parietal, and temporal lobes had progressed. Thereafter, there was no enhancement after gadopentetate dimeglumine was administered. For the prion protein genetic analysis, we prepared high-molecular-weight DNA from her peripheral blood lymphocytes. The presence of a mutation a t codon 232 was shown by polymerase chain reaction amplification (PCR), the RFLP method, and by direct sequencing analysis. A point mutation at codon 232 (Met to Arg) was confirmed. Discussion. This patient had atypical clinical CJD features: signs and symptoms of abnormal cortical functions, particularly of the parietal cortex at the onset of illness, and the absence of dementia for more than 1 year after onset. PSDs on the EEG, not specific in themselves, were important aids for the diagnosis of CJD. CT was of little use, showing only atrophy of the brain in the advanced stage. Several reports on the value of MRI in diagnosing CJD have found increased signal intensity in the basal ganglia on T2-weighted images2-' and to a lesser extent in the cerebral cort e ~ . ~ In our patient, MRI showed increased signal intensity in the parietal cortex during the initial stage of the disease, which spread as the disease progressed throughout the cerebral cortex and finally to the striatum. Changes in her clinical signs and symptoms, the dressing and constructional apraxia at onset, together with the subsequent development of dementia, as well as akinetic mutism and muscular rigidity in the advanced stage, correlated well with the MRI findings, and this may reflect gliosis and nerve cell loss during the progress of the disease. In this atypical case, the MRI changes, although not specific in themselves, precisely showed the spread of the disease and therefore were valuable in making the differentiating CJD from other diseases with accompanying dementia. At present, five cases in which there is a codon 232 mutation have been reported, but only from Kitamoto et aL5 reported that no mutation at codon 232 was present in the DNA from 100 control individuals. Detection of the mutation at codon 232 in our patient strongly supports the diagnosis of CJD.