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OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. MSA patients show various phenotypes during the course of their illness including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. MSA is classified into the parkinsonian (MSA-P) or cerebellar (MSA-C) variant depending on the clinical motor phenotype at presentation. MSA-P and MSA-C are predominant in Western countries and Japan, respectively. The mean age at onset is 55 to 60 years. Prognosis ranges from 6 to 10 years, but some cases survive for more than 15 years. Early and severe autonomic failure is a poor prognostic factor. MSA patients sometimes present with isolated autonomic failure or motor symptoms/signs, and the median duration from onset to the concomitant appearance of motor and autonomic symptoms was approximately 2 years in our previous study. As the presence of the combination of motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. We experienced MSA patients who died before presentation of the motor symptoms/signs diagnostic for MSA (i.e., premotor MSA). Detection of the nature of autonomic failure consistent with MSA and identification of the dysfunctional anatomical sites may increase the probability of a diagnosis of premotor MSA. Dementia is another problem in MSA. Although dementia had been thought to be rare in MSA, frontal lobe dysfunction is observed frequently during the early course of the illness. Magnetic resonance imaging can show progressive cerebral atrophy in longstanding cases. More recently, MSA patients presenting with frontotemporal dementia preceding the presence of motor and autonomic manifestations diagnostic of MSA have been reported. Novel diagnostic criteria based on an expanding concept of the clinical conditions and symptoms of MSA will be needed for the development of disease-modifying therapies and better management.

The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (<50 vs. 60-69 years: p = 0.029, <50 vs. ≥70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS.

We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients.

Speech and voice disorders are one of the most common adverse effects in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). However, the pathophysiology of voice and laryngeal dysfunction after STN-DBS remains unclear. We assessed 47 PD patients (22 treated with bilateral STN-DBS (PD-DBS) and 25 treated medically (PD-Med); all patients in both groups matched by age, sex, disease duration, and motor and cognitive function) using the objective and subjective voice assessment batteries (GRBAS scale and Voice Handicap Index), and laryngoscopy. Laryngoscopic examinations revealed that PD-DBS patients showed a significantly higher incidence of incomplete glottal closure (77 vs 48 %; p = 0.039), hyperadduction of the false vocal folds (73 vs 44 %; p = 0.047), anteroposterior hypercompression (50 vs 20 %; p = 0.030) and asymmetrical glottal movement (50 vs 16 %; p = 0.002) than PD-Med patients. On- and off-stimulation assessment revealed that STN-DBS could induce or aggravate incomplete glottal closure, hyperadduction of the false vocal folds, anteroposterior hypercompression, and asymmetrical glottal movement. Incomplete glottal closure and hyperadduction of the false vocal folds significantly correlated with breathiness and strained voice, respectively (r = 0.590 and 0.539). We should adjust patients' DBS settings in consideration of voice and laryngeal functions as well as motor function.

OBJECTIVES: To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. RESULTS: Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. CONCLUSIONS: Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects.

BACKGROUND AND PURPOSE: Most patients with multiple system atrophy (MSA) develop autonomic dysfunction; however, orthostatic hypotension is not always present. Failure of the vasoconstrictor response is thought to be responsible for orthostatic hypotension, but the degree of impairment of this response in patients with MSA is unclear. We assessed autonomic function in patients with MSA by evaluating the vasoconstrictive response during a head-up tilt test and determining its relationship to orthostatic hypotension. As an additional examination, the efficacy of norepinephrine in treating orthostatic hypotension was also assessed. METHODS: The study included 82 patients with MSA and 28 controls. Measures of total peripheral resistance were obtained during a head-up tilt test. Norepinephrine was administered to the patients lacking a vasoconstrictive response to evaluate its ability to treat orthostatic hypotension. RESULTS: At a 60° tilt, orthostatic hypotension occurred in 47.6% of the patients and 0% of controls. Reduction in total peripheral resistance from baseline at a 60° tilt was observed in 69.5% of the patients and 0% of controls. In patients with MSA, changes in systolic blood pressure from the baseline at a 60° tilt correlated positively with changes in the total peripheral resistance (r = 0.69, p < 0.0001). Norepinephrine prevented the reduction of total peripheral resistance and development of orthostatic hypotension. CONCLUSIONS: A large number of patients with MSA with and without orthostatic hypotension have an impaired peripheral vasoconstrictive response, suggesting a high frequency of cardiovascular dysautonomia with an associated risk of developing orthostatic hypotension. A norepinephrine infusion was effective for treating orthostatic hypotension.

Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

Voice and speech disorders are one of the most important issues after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease patients; however, their characteristics remain unclear. We performed a comprehensive voice evaluation including the multi-dimensional voice program for acoustic analysis, the GRBAS scale for perceptual analysis, and the evaluation of the voice handicap index (VHI) for psychosocial analysis. In total, 68 patients who had undergone STN-DBS (37 assessed in the on- and off-stimulation conditions) and 40 who had been treated with medical therapy alone were evaluated. Further, we performed laryngoscopic examinations in 13 STN-DBS and 19 medical-therapy-alone patients. The STN-DBS group, especially females, showed widespread impairment of voice parameters and significantly poorer VHI scores than the medical-therapy-alone group. The degree of voiceless (DUV) and strained voice were the most impaired factors in the STN-DBS group; and DUV significantly improved after stopping stimulation. Furthermore strained voice, breathiness, and asthenia improved after stopping stimulation. Laryngoscopic examination showed that abnormal laryngeal muscle contraction and incomplete glottal closure were more prominent in the STN-DBS group than in the medical-therapy-alone group. We demonstrated that (1) more widespread voice impairment in females, (2) poorer voice-related QOL, (3) worse DUV and strained voice, and (4) abnormal laryngeal muscle contraction were the characteristic voice and laryngeal findings in the STN-DBS group compared with those in the medical-therapy-alone group.

OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Although chronic myopathy has been reported to affect skeletal muscle in sarcoidosis, its clinicopathological features have not been fully elucidated. We characterized the clinical, histopathological, and prognostic features of eleven patients with sarcoidosis manifesting with chronically progressive, generalized myopathy that was confirmed with muscle biopsy. Generalized muscle weakness extending to the four extremities and trunk was the cardinal feature of these cases. Muscle atrophy was evident in nine patients, particularly in the lower limbs, whereas myalgia was reported in only two patients. Myopathy was the first manifestation of sarcoidosis in five patients. Only six patients showed elevated plasma creatine kinase levels. Using skeletal muscle computed tomography, the distribution of muscle atrophy was predominant in the hip adductors, knee flexors and ankle plantarflexors. Radiological assessments, including magnetic resonance imaging, gallium scintigraphy, and fluorodeoxyglucose positron emission tomography-computed tomography imaging, revealed findings suggestive of skeletal muscle inflammation in only half of the patients examined. However, in all patients, muscle biopsy specimens revealed an active inflammatory process, as observed by focal non-caseating epithelioid granuloma with predominant CD4-positive lymphocytic infiltration. Sarcolemmas were diffusely stained with HLA-ABC, HLA-DR and intercellular adhesion molecule-1 antibodies, suggesting diffuse and active antigen presentation. Functional improvement after immunomodulatory treatment was significantly better in patients with short disease durations (p < 0.05). The therapeutic response was poor in patients with long disease durations; thus, early diagnosis and early initiation of treatment are important.

BACKGROUND: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression. METHODS: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits. RESULTS: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 ± 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease. CONCLUSIONS: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 ± 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

OBJECTIVE: Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases. DESIGN: Retrospective, observational. SETTING: Autopsied patients. PARTICIPANTS: We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included. PRIMARY OUTCOME MEASURES: Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles. RESULTS: Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology. CONCLUSIONS: PMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological profile. The remaining patterns have LMN degeneration with TDP-43 pathology without UMN degeneration, or a combination of UMN and LMN degeneration with FUS-positive basophilic inclusion body disease.

OBJECTIVES: We assessed the usefulness of differential diagnosis of parkinsonism by evaluating lesions of the decussation of the superior cerebellar peduncle (SCP) in patients with progressive supranuclear palsy (PSP) using a new MRI procedure known as readout segmentation of long variable echo-trains (RESOLVE). METHODS: We evaluated 100 cases, consisting of 20 with PSP, 24 with Parkinson's disease (PD), 13 with multiple system atrophy with predominant parkinsonism (MSA-P), 18 with multiple system atrophy with predominant cerebellar ataxia (MSA-C), and 24 controls. All patients were scored on the Unified Parkinson's Disease Rating Scale Part III and the Scale for the Assessment and Rating Scale of Ataxia, and MRI using RESOLVE was conducted. RESULTS: Images acquired by this MRI procedure clearly showed high intensity areas corresponding to the decussation of the SCP in all controls, PD, and MSA patients. In contrast, ten of the 20 PSP patients exhibited abnormal iso intensities of the decussation of the SCP, while the other 10 showed high intensity signals. Among the PSP patients, there were no differences in clinical features between those with and those without visualization of the decussation of the SCP. Iso intensity signals had a sensitivity of 50% and a specificity of 100% for differentiating PSP from PD, MSA, and controls. CONCLUSION: This MRI procedure (RESOLVE) shows a potential for detecting the involvement of the decussation of the SCP in PSP, and can be used for discriminating PSP from PD and MSA-P.

Development and growth of hematopoietic tissue outside of the bone marrow is termed extramedullary hematopoiesis (EMH). It occurs in patients with hematological diseases such as myelofibrosis and thalassemia. Liver and spleen are the usual sites of EMH. However, spinal cord compression caused by EMH is a rare complication. A 65-year-old man with myelofibrosis was admitted to our hospital with progressive paraparesis. Thoracic spine MRI revealed epidural masses causing cord compression. Histological examination of the epidural mass showed evidence of EMH consisting of megakaryocytic and erythroid hyperplasia. After surgical decompression and radiotherapy, lower limb weakness and sensory disturbance were significantly improved. MRI showed disappearance of the spinal cord compression. With this therapy, he had no recurrence until he died of myelofibrosis. Spinal EMH should be considered as a differential diagnosis in patients with hematological diseases presenting with paraparesis. Surgical decompression and radiotherapy are effective approaches for the treatment of paraparesis due to EMH.

OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients. METHODS: We conducted a multicentre-based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS. RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors. CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS.

OBJECTIVE: To elucidate the effect of liver transplantation (LT) on brain dysfunctions in cirrhotic patients who had no clinical evidence of hepatic encephalopathy (HE), we performed a prospective study of voxel-based diffusion tensor imaging (DTI) and detailed cognitive examination. METHODS: We assessed 12 consecutive patients as transplant candidates by DTI, with neurological and cognitive examinations just before and at 6 months after LT. RESULTS: After LT, cirrhotic patients showed significant improvement in visual reproduction, digit symbol, digit span, Stroop test, and Trail-making test scores, suggesting recovery of frontal-temporal function. As for voxel-based DTI, increased mean diffusivity (MD) and reduced fractional anisotropy (FA) values were found before LT in the frontal and temporal lobes of cirrhotic patients. After LT, the unusual FA and MD values observed in the frontal and temporal lobes preoperatively were significantly reduced. CONCLUSION: End-stage cirrhotic patients without clinical evidence of HE showed increased MD and decreased FA values in both frontal and temporal lobes. These parameters improved after LT, in line with cognitive function. MD and FA values might be of value as a biomarker in end-stage cirrhotic patients for investigating brain tissue dysfunctions and evaluating the efficacy of LT.

BACKGROUND: The aim of this study was to investigate the cortical and subcortical brain structures in Parkinson's disease (PD) with visual hallucination (VH), and to elucidate the association between the proposed hypothesis of VH in PD and regional brain volume changes. METHODS: We used 3T magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to investigate the brain structures of PD patients with VH (PD-VH; n = 13) and PD patients without VH (PD-C; n = 13). RESULTS: The PD-VH patients showed significant cortical atrophy compared to the PD-C patients in the bilateral dorsolateral prefrontal cortex, left rostral region of the prefrontal cortex, left ventral section of the cingulate cortex, bilateral primary visual cortex, and secondary visual cortex including the left inferior occipital gyrus, right lingual cortex, right supramarginal gyrus, and left fusiform gyrus. Significant subcortical atrophic changes were observed in the white matter of the right parahippocampal gyrus, the bilateral posterior part of the cingulate gyrus, the left lingual gyrus, and the right middle occipital gyrus. CONCLUSIONS: VH in PD can occur due to distinctive neuroanatomical involvement.

RATIONALE AND OBJECTIVES: There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MATERIALS AND METHODS: MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. RESULTS: Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. CONCLUSION: Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.

We report a 61-year-old Parkinson's disease patient presenting with severe repetitive speech phenomena after deep brain stimulation. On admission, he showed impaired loudness, rough hoarseness, monoloudness and monopitch. It had been difficult for him to converse because of voice repetitive speech phenomena since 57 years of age. Medical control, regulation of contact location and voltage amplitude did not improve these symptoms. Lee Silverman Voice Treatment(®) improved loudness and voice quality, but did not improve repetitive speech phenomena. After speech treatment with a pacing board, his repetitive speech phenomena improved more than before. Treatment with a pacing board may be effective for repetitive speech phenomena in Parkinson's disease after deep brain stimulation.

We present a case of a patient with reversible cerebral vasoconstriction syndrome (RCVS) triggered by nicotine patches. A-50-year-old woman had no medical history and no regular medication. She smoked 20 cigarettes a day for 30 years. Six days after using nicotine patches, she had recurrent severe headaches of sudden onset (thunderclap headaches). On examination, the blood pressure was 142/88 mmHg. Her neurological and general examination, laboratory serum investigations, and cerebrospinal fluid examination were normal. Magnetic resonance imaging (MRI) including magnetic resonance angiography (MRA) on admission, day 10 after the first episode showed severe multifocal segmental narrowing of the bilateral posterior cerebral artery (PCA). Cessation of nicotine patches and administration of calcium-channel antagonist amlodipine 5 mg daily ameliorated her headache. Follow-up MRA, 37 days after the first episode, showed improvement of PCA stenosis. We diagnosed her as reversible cerebral vasoconstriction syndrome (RCVS) due to nicotine patches. It is important to recognize nicotine patches as a trigger of RCVS.

We report the case of a 33-year-old man with diplopia, sleepiness, and paresthesia of the left upper limb that were slowly progressive. On admission, he presented with restriction in the vertical movement of the eyes and abduction of the right eye, and horizontal and convergence nystagmus. Slight weakness of the left upper limb, bilateral Babinski sign, and truncal ataxia were also noted. Cerebral magnetic resonance imaging was performed, and gadolinium-enhanced T1-weighted imaging revealed a mass lesion that involved the diencephalon and the corpus callosum, which was invariably enhanced. Specimens obtained using a brain biopsy showed epithelioid granuloma with the presence of foreign body giant cells and lymphocytic infiltration. Prednisolone was administrated because we suspected neurosarcoidosis, but the clinical symptoms worsened with the enlargement of the lesion. A re-evaluation of the biopsy specimens using immunohistochemistry revealed tumor cells of germinoma that were scattered among the lymphocytes and positive for periodic acid-Schiff staining, placental alkaline phosphatase, and c-kit. A combination of chemotherapy and radiation resulted in clinical improvement and marked reduction of the mass lesion in size. We concluded that the possibility of germinoma should be considered in case granulomatous inflammation is observed in brain biopsy specimens.

This symposium discusses the utility of the different MR techniques in the diagnosis and management of spinocerebellar degeneration (SCD). Conventional MRI is widely used and can show characteristic signal abnormalities such as putaminal hyperintensity, hyperintense putaminal rim, putaminal hypointensity, hot cross bun sign in the pontine base, and hyperintensity in the middle cerebellar peduncles strengthening a diagnosis of multiple system atrophy (MSA). However, the diagnostic utility of these signal abnormalities in early MSA remains restricted. In addition, it should be considered that different magnetic field strengths and sequences could be influenced on the findings resulting false negative. On the other hand, proton magnetic resonance spectroscopy, diffusion weighted imaging (DWI), diffusion tensor imaging (DTI) and voxel based morphometry (VBM) in the pontine base, cerebellum, and putamen will be informative in the early diagnosis of MSA and other SCD prior to conventional MRI changes and even before any clinical manifestation of symptoms. Particularly, DWI, DTI, and VBM are expected to have potential as surrogate markers of disease progression. Further prospective and large studies including earlier disease stages will be needed to clarify whether these novel MR techniques will aid in the future sets of diagnostic criteria and therapeutic trials.

We investigated the magnetic resonance imaging (MRI) findings of 32 multiple sclerosis (MS) patients using voxel-based morphometry (VBM) and voxel-based analysis of white matter fluid-attenuated inversion recovery image (FLAIR) high-intensity lesions and diffusion tensor imaging (DTI). Compared with 18 healthy controls, MS patients showed gray matter volume reduction in the thalamus, hypothalamus, caudate, limbic lobe, and frontal lobe. A marked volume reduction of white matter was evident along the ventriculus lateralis and corpus callosum. FLAIR high-intensity lesions were observed beside the ventriculus lateralis. DTI revealed reduced fractional anisotropy areas similar to those of the FLAIR high-intensity lesions. Changes in the volume of increased mean diffusivity (MD) were the most widespread and extended to normal-appearing white matter (p<0.001). Multiple regression analysis revealed that MD values were significantly correlated with both disease duration (r=0.381, p=0.032) and expanded disability status scale scores (EDSS) (r=0.393, p=0.026). This study demonstrated that combined voxel-based analysis for volumetry, FLAIR high-intensity lesions, and DTI could reveal widespread brain abnormalities in MS patients. Furthermore, DTI, especially MD, showed far more widespread brain degeneration than other MRI parameters, and was significantly correlated with both severity and disease duration.

OBJECTIVE: To investigate short- and long-term effects of intensive rehabilitation on ataxia, gait, and activities of daily living (ADLs) in patients with degenerative cerebellar disease. METHODS: A total of 42 patients with pure cerebellar degeneration were randomly assigned to the immediate group or the delayed-entry control group. The immediate group received 2 hours of inpatient physical and occupational therapy, focusing on coordination, balance, and ADLs, on weekdays and 1 hour on weekends for 4 weeks. The control group received the same intervention after a 4-week delay. Short-term outcome was compared between the immediate and control groups. Long-term evaluation was done in both groups at 4, 12, and 24 weeks after the intervention. Outcome measures included the assessment and rating of ataxia, Functional Independence Measure, gait speed, cadence, functional ambulation category, and number of falls. RESULTS: The immediate group showed significantly greater functional gains in ataxia, gait speed, and ADLs than the control group. Improvement of truncal ataxia was more prominent than limb ataxia. The gains in ataxia and gait were sustained at 12 weeks and 24 weeks, respectively. At least 1 measure was better than at baseline at 24 weeks in 22 patients. CONCLUSIONS: Short-term benefit of intensive rehabilitation was evident in patients with degenerative cerebellar diseases. Although functional status tended to decline to the baseline level within 24 weeks, gains were maintained in more than half of the participants.

A 53-year-old woman visited us for a neurological consultation before her liver transplantation. She had a history of primary biliary cirrhosis that began at 37 years of age. She showed falling episodes and met with a traffic accident at 52 years old. Since then, her symptoms had worsened. The neurological examination showed masked face, rigidity on bilateral arms and legs, and lack of balance. Her Mini-Mental State Examination Score was 28/30, but she suffered from loss of memory and had trouble with executive function in detailed examinations. Her T(1) weighted image showed hyperintensity in bilateral globus pallidus, putamen, dentate nucleus and cerebral peduncle. There was a significant improvement in intellectual function and neurological signs 6 months after her orthotopic liver transplantation. In addition, post-liver transplantation images showed a decrease in the area of hyperintensities. This case suggests that even in a patient with severe liver cirrhosis a complete cure of neurological manifestations can be obtained after the liver transplantation.

To investigate the longitudinal course of Japanese patients with Amyotrophic Lateral Sclerosis (ALS), we constructed a multicenter registration and follow-up system called Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS). Genomic DNA samples of ALS patients were stored and linked to the clinical information. We designed a telephone survey system using a clinical research coordinator (CRC) to check the score of the ALS Functional Rating Scale-R (ALSFRS-R) and the prognosis every 3 months. In January 2006, we began registering ALS patients, and, at present, 22 neurology facilities are participating in the JaCALS. Currently, 571 Japanese ALS patients are registered. From the longitudinal data of the 279 patients who were registered before September 2009, the older age at onset was a significant risk factor for not only earlier death or introduction of mechanical ventilation, but also earlier loss of speech, loss of swallowing function and loss of upper limb function. In collaboration with the RIKEN Center for Genomic Medicine, genome-wide association studies (GWAS) using 1,305 ALS samples from the JaCALS and BioBank Japan were conducted, which showed that ZNF512B gene was associated with susceptibility to ALS. The JaCALS has established an efficient registration and follow-up system with genomic DNA resources of ALS patients, and will contribute to identify ALS-associated genes and to promote clinical researches.

To investigate the various clinical courses of patients with amyotrophic lateral sclerosis (ALS), we developed a telephone survey system for determining the activities of daily living (ADL) status of patients with ALS. In this system, every 3 months, clinical research coordinators (CRCs) conducted a telephone survey using the flow charts of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R; Japanese version). To confirm the reliability of the results of the telephone survey, we compared the scores of 37 ALS patients obtained in the telephone surveys (telephone scores) to the scores obtained during clinical examinations by neurologists (neurologists' scores). The mean (SD) age of the included patients was 62.6 (11.8) years. Eighteen patients answered the surveys themselves, whereas the primary caregivers of 19 patients answered the surveys for the patients. Before the study, we informed the CRCs of the study plan, general knowledge of ALS, procedures of the telephone survey, ethical issues relevant to the study, and requisite considerations for ALS patients and caregivers. The intraclass correlation coefficient (ICC) between the telephone scores and the neurologists' scores in the 37 ALS patients was 0.97 (95% confidence interval [CI], 0.94-0.98). The kappa statistics of 12 questions of the ALSFRS-R between the telephone scores and the neurologists' scores ranged from 0.58 to 0.85. The ICC of the scores of the 18 cases in which the patients answered the telephone questions themselves was 0.96 (95% CI, 0.89-0.98). The ICC of the scores of the 19 cases in which the caregivers answered the telephone questions was 0.97 (95% CI, 0.92-0.99). These results showed a good reliability of the telephone survey, regardless of whether the patients themselves or the caregivers answered telephone questions. In 2006, a longitudinal multicenter study of Japanese ALS patients was initiated called the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS). In the JaCALS, prospective clinical information was obtained using this telephone survey system. Of the 284 ALS patients who were registered at JaCALS over a year ago, 93% were followed up and provided ALSFRS-R scores and information relevant to prognosis. We have established an efficient and reliable telephone survey system for studying the longitudinal clinical courses of patients with ALS.

We report a 53-year-old woman with an unusual presentation characterized by acute onset of generalized sensory symptoms associated with anhidrosis, anosmia, ageusia, and elevated titers of anti-GalNAc-GD1a antibodies. After intravenous immunoglobulin therapy, a remarkable improvement in the pain and temperature sensation was noted in her face, trunk, and extremities. The impaired pain and temperature sensation remained distributed along cranial and spinal dermatomes in a non-length-dependent manner, suggesting that the ganglionopathy affected small neurons.

BACKGROUND: Oxidative stress is causally associated with the pathogenesis of Parkinson's disease (PD). Oxygen generates a large amount of reactive oxygen species (ROS). ROS including hydroxyl radicals and H(2)O(2) react with guanine residues in DNA and produce 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG serves as a biomarker for oxidative stress in various diseases. METHOD: We investigated urinary 8-OHdG levels in 61 PD patients and 28 normal subjects to evaluate the correlation with various clinical features. We quantified disease severity using the Unified Parkinson's Disease Rating Scale for motor symptoms (UPDRS part 3), the Mini-Mental State Examination (MMSE) for mental function, and the Tottori University Hallucination Rating Scale (TUHARS) for quantifying hallucinations. RESULTS: There were significant correlations between 8-OHdG and all the examined parameters, but the partial correlation coefficients excluding contributions of all the other parameters showed that only TUHARS and UPDRS part 3 are significantly related to 8-OHdG. In particular, TUHARS correlates best with urinary 8-OHdG levels. CONCLUSION: The significant correlation between urinary 8-OHdG levels and hallucinations but not with dementia suggests that hallucinations are likely to have unique but unidentified mechanisms that lead to excessive production of 8-OHdG.

We investigated 17 patients with sporadic amyotrophic lateral sclerosis (ALS) using voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) at baseline and after a six-month follow-up. Compared with 17 healthy controls, ALS patients at baseline showed only minimal white matter volume decreases in the inferior frontal gyrus but marked decreases in the gray matter of several regions, especially in the bilateral paracentral lobule of the premotor cortex. DTI revealed reduced fractional anisotropy in the bilateral corticospinal tracts, insula, ventrolateral premotor cortex, and parietal cortex. Increased mean diffusivity was noted bilaterally in the motor cortex, ventrolateral premotor cortex, insula, hippocampal formation, and temporal gyrus. At the six-month follow-up, ALS patients showed widespread volume decreases in gray matter, and DTI abnormalities extended mainly into the bilateral frontal lobes, while volume changes in the white matter remained minimal but more distinct. Our combined VBM and DTI techniques revealed extra-corticospinal tract neuronal degeneration mainly in the frontotemporal lobe of ALS patients. In particular, follow-up examinations in these patients showed that whole-brain DTI changes occurred predominantly in the regions of brain atrophy. These objective analyses can be used to assess the disease condition of the ALS brain.

We delineated the effects of magnetic field strength on signal intensities to facilitate the specific findings of multiple system atrophy (MSA). Fifteen patients with probable MSA were imaged by 0.35T fast spin-echo (FSE), 1.5T FSE, and 3.0T FSE using a consistent protocol, testing all field strengths on the same day. Sixty patients with probable Parkinson's disease (PD) also underwent imaging. Moderate or marked hyperintensity at the dorsolateral outer putaminal margin, hyperintensity of the putaminal body, hypointensity relative to the globus pallidus at the dorsolateral putaminal margin, and infratentorial signal changes were evaluated as specific findings for MSA. As the field strength increased, the occurrence of hyperintensity both at the dorsolateral outer putaminal margin and of the putaminal body decreased, while the occurrence of hypointensity at the dorsolateral putaminal margin increased in MSA. The occurrence of uniform mild hyperintensity of the outer putaminal margin was evident in 7% at 0.35T, 40% at 1.5T, and 47% at 3.0T in MSA and in 5% at 0.35T, 60% at 1.5T, and 75% at 3.0T in PD. However, no PD patients showed hyperintensity at the dorsolateral outer putaminal margin and that of the putaminal body. Putaminal magnetic resonance imaging (MRI) findings in MSA were altered considerably by magnetic field strength. The severity and distribution of signal changes are important for assessing putaminal MRI findings in MSA.

A 21-year-old man had sudden-onset right hemiplegia and aphasia with respiratory infection. A chest X-ray disclosed consolidation in both lungs and magnetic resonance imaging showed an embolism in the left middle cerebral artery. A pelvic computed tomography scan revealed deep venous thrombus in both femoral veins. Patent foramen ovale was detected by transesophageal echocardiogram. Antibodies to M. pneumoniae were highly elevated, and hypercoagulability was subsequently detected. This case suggests that the possible pathogenic mechanism for M. pneumoniae infection-related stroke might be paradoxical brain embolism with deep venous thrombus as a consequence of the hypercoagulability related to this infection.

BACKGROUND: The International Cooperative Ataxia Rating Scale (ICARS) is widely used as a scale for the assessment of the severity of cerebellar ataxia. However, this scale comprises several items; thus, making the application of this scale is not sufficiently practical to perform daily assessment of ataxic patients. A new rating scale--Scale for the Assessment and Rating of Ataxia (SARA)--was shown to provide highly reliable assessments; further, the scores on SARA correlated with the ICARS score and the Barthel index. After obtaining the permission, original SARA was translated into Japanese. OBJECTIVE AND METHODS: To examine the reliability and internal consistency of the Japanese version of the SARA for the assessment of cerebellar ataxia in 66 patients with spinocerebellar degeneration. RESULTS: Intraclass coefficients (ICC) were observed to be greater than 0.8 except in the case of the inter-rater "finger chase" and "fast alternating hand movement" tests. CONCLUSIONS: The Japanese version of SARA is highly reliable and very useful for the assessment of cerebellar ataxia on a daily basis.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA. METHODS: Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474). RESULTS: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem. INTERPRETATION: These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.

PURPOSE: To profile the detailed clinical features of sporadic amyotrophic lateral sclerosis (ALS) on large-scale samples in Japan. METHODS: We assessed the clinical features of sporadic ALS patients in Japan, based on the nationwide registration system of the Ministry of Health, Labor and Welfare of Japan. We described 3,428 new cases registered cases between 2003 and 2006 to analyze initial symptoms and related clinical features, 4,202 cases registered in the single year of 2005 to describe the cross-sectional overview of the ALS patients, and a total of 2,128 cases with tracheostomy positive pressure ventilation (TPPV) from all of the registration data from 2003 to 2006 to describe the features of ALS patients with TPPV. RESULTS: The patients with an older age at onset progressed more rapidly to the TPPV stage than those with a younger age at onset. The subpopulation of patients with long-standing TPPV showed ophthalmoplegia, while its appearance rate was less in the patients with an older age at onset than in those with a younger age at onset. Furthermore, age at onset strongly influenced the frequency of initial symptoms: dysarthria, dysphagia, neck weakness and respiratory disturbance were more frequent in patients with an older age at onset, while upper or lower limb weakness was observed more frequently in patients with a younger age at onset. In addition, those initial symptoms were still the most prominent at the follow-up stage, suggesting that the initial symptoms determine the major clinical features even in advanced illness. CONCLUSIONS: Our present study demonstrated that symptomatic features of ALS are strongly influenced by the age at onset by the large scale of samples.

OBJECTIVE: Pathological studies have shown remarkable pyramidal tract involvement in multiple system atrophy (MSA), while clinical pyramidal signs are relatively rare. We investigated the fractional anisotropy (FA) values to assess the degree of pyramidal tract involvement in MSA, in comparison with amyotrophic lateral sclerosis (ALS) and controls. Furthermore, we compared FA values between MSA patients with or without clinical pyramidal signs and controls, and between MSA patients with or without positive conventional MRI findings and controls. METHODS: We evaluated FA values in the internal capsule, corona radiate and whole pyramidal tract using visualized tractography of 65 subjects (20 probable MSA patients, 28 age-matched ALS patients, and 17 age-matched healthy controls) using a 3.0T magnetic resonance system. RESULTS: The FA values in the internal capsule, corona radiate, and whole pyramidal tract were significantly lower in MSA patients than in controls and were at a level similar to those of ALS patients. In addition, low FA values were prominent in MSA patients, even in those with short duration of illness, lacking precentral gyrus hyperintensity in FLAIR images, and without pyramidal signs. CONCLUSION: FA values could identify pyramidal tract degeneration even in patients with early phase MSA and those without clinical pyramidal signs or abnormal MRI findings. More extensive degeneration of the pyramidal tract occurs in MSA than so far believed.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. Because the progression of SBMA is slow, it is plausible to identify biomarkers that monitor disease course for therapeutic development. To verify whether the 6-min walk test (6MWT) is a biomarker of SBMA, we performed the 6MWT in 35 genetically confirmed patients and in 29 age-matched healthy controls. The walk distance covered within 6 min (6MWD) was significantly less in SBMA than it was in controls (323.3 +/- 143.9 m and 637.6 +/- 94.2 m, respectively; P < 0.001). In test-retest analysis, the intraclass correlation coefficient for the 6MWD was high in SBMA patients (r = 0.982). In a 1-year follow-up the 6MWD significantly decreased at a rate of 11.3% per year. Our observations suggest that the 6MWT is a biomarker that can be used to monitor progression of motor impairment in SBMA.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, lower motor neuron disease caused by an aberrant elongation of a CAG repeat in the androgen receptor (AR) gene. The main symptoms are weakness and atrophy of bulbar, facial and limb muscles, but sensory disturbances are frequently found in SBMA patients. Motor symptoms have been attributed to the accumulation of mutant AR in the nucleus of lower motor neurons, which is more profound in patients with a longer CAG repeat. We examined nerve conduction properties including F-waves in a total of 106 patients with genetically confirmed SBMA (mean age at data collection = 53.8 years; range = 31-75 years) and 85 control subjects. Motor conduction velocities (MCV), compound muscle action potentials (CMAP), sensory conduction velocities (SCV) and sensory nerve action potentials (SNAP) were significantly decreased in all nerves examined in the SBMA patients compared with that in the normal controls, indicating that axonal degeneration is the primary process in both motor and sensory nerves. More profound abnormalities were observed in the nerves of the upper limbs than in those of the lower limbs. F-waves in the median nerve were absent in 30 of 106 cases (28.3%), but no cases of absent F-waves were observed in the tibial nerve. From an analysis of the relationship between CMAPs and SNAPs, patients were identified with different electrophysiological phenotypes: motor-dominant, sensory-dominant and non-dominant phenotypes. The CAG repeat size and the age at onset were significantly different among the patients with motor- and sensory-dominant phenotypes, indicating that a longer CAG repeat is more closely linked to the motor-dominant phenotype and a shorter CAG repeat is more closely linked to the sensory-dominant phenotype. Furthermore, when we classified the patients by CAG repeat size, CMAP values showed a tendency to be decreased in patients with a longer CAG repeat (> or =47), while SNAPs were significantly decreased in patients with a shorter CAG repeat (<47). In addition, we found that the frequency of aggregation in the sensory neuron cytoplasm tended to inversely correlate with the CAG repeat size in the autopsy study, supporting the view that the CAG repeat size differentially correlates with motor- and sensory-dominant phenotypes. In conclusion, our results suggest that there are unequivocal electrophysiological phenotypes influenced by CAG repeat size in SBMA.

OBJECTIVE: To determine whether apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values can detect early pathological involvement in multiple system atrophy (MSA), and be used to differentiate MSA-P (multiple system atrophy if parkinsonian features predominate) from Parkinson's disease (PD). METHODS: We compared ADC and FA values in the pons, cerebellum and putamen of 61 subjects (20 probable MSA patients, 21 age matched PD patients and 20 age matched healthy controls) using a 3.0 T magnetic resonance system. RESULTS: ADC values in the pons, cerebellum and putamen were significantly higher, and FA values lower in MSA than in PD or controls. These differences were prominent in MSA lacking dorsolateral putaminal hyperintensity (DPH) or hot cross bun (HCB) sign. In differentiating MSA-P from PD using FA and ADC values, we obtained equal sensitivity (70%) and higher specificity (100%) in the pons than in the putamen and cerebellum. In addition, all patients that had both significant low FA and high ADC values in each of these three areas were MSA-P cases, and those that had both normal FA and ADC values in the pons were all PD cases. Our diagnostic algorithm based on these results accurately diagnosed 90% of patients with MSA-P. CONCLUSION: FA and ADC values detected early pathological involvement prior to magnetic resonance signal changes in MSA. In particular, low FA values in the pons showed high specificity in discriminating MSA-P from PD. In addition, combined analysis of both FA and ADC values in all three areas was more useful than only one.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.

We investigated the usefulness of quetiapine and olanzapine for delusion in nine patients with Parkinson's disease (PD). Two of five patients initially treated with quetiapine showed resolution of delusion on low dose (25 mg and 50 mg/day), whereas three patients had no improvement in spite of increasing the dose to 300 mg/day. Quetiapine non-responders had a tendency to more severe delusion and dementia compared with responders. Not only all four patients initially treated but also two of three quetiapine non-responders showed a remarkable resolution of delusion on olanzapine. In particular, three of seven patients responded to an extremely low dose of 0.625 mg/day. However, severe motor debilitation was observed in one patient treated with 1.25 mg/day. Olanzapine might be useful for delusion of PD in patients not responded to quetiapine, although it should be started at a very low dosage to ameliorate worsening parkinsonism.