Natsumi Furuta

Anti-MuSK Antibody-positive Myasthenia Gravis Mimicking Amyotrophic Lateral Sclerosis.

We herein investigated the clinical features of three patients with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG), which was initially difficult to distinguish from amyotrophic lateral sclerosis (ALS). The patients exhibited dropped head syndrome or dysphagia as initial symptoms. Although their clinical findings were compatible with the revised El Escorial Criteria for ALS, their progression appeared to be more rapid than that of ALS. Both the edrophonium and repetitive nerve stimulation tests yielded negative results, and diurnal fluctuation was not confirmed. The patients were ultimately diagnosed with anti-MuSK antibody-positive MG. We therefore recommend the measurement of anti-MuSK antibodies when encountering such cases.

Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer’s disease with PS1 mutations

Abstract We studied seven cases of Alzheimer’s disease (AD). Six of the patients had presenilin 1 (PS1) mutations (PS1AD). Three novel PS1 mutations (T99A, H131R and L219R) and three other missense mutations (M233L, H163R and V272A) were found in the PS1AD group. We measured the levels of phosphorylated tau (ptau-181, ptau-199) and Aβ (Aβ1-42, Aβ1-40 and Aβ1-38) in the cerebrospinal fluid (CSF) of PS1AD patients, early-onset sporadic AD (EOSAD), late-onset sporadic AD (LOSAD) and non-demented subjects (ND). The CSF levels of Aβ1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Aβ1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Aβ1-40 and Aβ1-38 levels in the CSF of the PS1AD group were significantly lower than those of the three other groups (p < 0.0001, respectively). The levels of Aβ1-40, Aβ1-38 and Aβ1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Aβ1-42, but also Aβ1-40 and Aβ1-38 decreased in the advanced stages of PS1AD.

Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift FUS Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment.

A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed.

Encephalopathy with amyloid angiopathy and numerous amyloid plaques with low levels of CSF Aβ1–40/Aβ1–42

A middle-aged male suffering from encephalopathy with cerebral amyloid angiopathy (CAA) with amyloid beta (Aβ) presented with initial symptoms of transient consciousness disturbance and left visual field photophobia. Lesions with aberrantly high signal on T2-weighted magnetic resonance imaging (MRI) of the brain appeared in the right temporal lobe posterior to the occipital lobe and spread to other areas. Brain biopsy revealed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. Based on MRI findings, Initial corticosteroid therapy with beta methasone effectively improved the neurological symptoms of consciousness disturbance and motor deficits. After corticosteroid therapy was stopped at 4 weeks, recurrence occurred. Additional corticosteroids did not improve clinical symptoms and the patient progressed to a bed-ridden state with a severe consciousness disturbance. Notably, CSF Aβ1–42 and CSF Aβ1–40 decreased while the recurrent encephalopathy worsened. After intense deterioration, the patient became stable. CSF Aβ1–42 increased but remained at a very low level. This case of CAA encephalopathy with apolipoprotein E ϵ4/ϵ4 homozygosity showed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. The clinical course suggests that reduction of CSF Aβ1–42 and Aβ1–40 might be related to clinical deterioration in cases of encephalopathy.

Anti-Hu Antibody-associated Paraneoplastic Neurological Syndrome Showing Peripheral Neuropathy and Atypical Multifocal Brain Lesions

A 64-year-old Japanese woman presented with a three-month history of progressive numbness and weakness of the lower extremities. A neurological examination and nerve conduction study indicated sensorimotor polyneuropathy. Since the serum anti-Hu antibody titer was remarkably elevated, paraneoplastic neurological syndrome was highly suspected. A thoracoscopic biopsy of the hilar lymph nodes, in which (18)F-fluorodeoxyglucose uptake was obviously increased, revealed pathological findings for small-cell lung cancer (SCLC). Subsequently, the patient presented with generalized tonic-clonic seizures, and cerebral MRI showed reversible multifocal brain lesions, considered to reflect paraneoplastic encephalopathy. After two courses of chemotherapy for SCLC, the brain lesions totally disappeared.

Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis

Overexpression of BTBD10 (BTB/POZ domain‐containing protein 10) suppresses G93A‐superoxide dismutase 1 (SOD1)‐induced motor neuron death in a cell‐based amyotrophic lateral sclerosis (ALS) model. In the present study, paraffin sections of spinal cords from 13 patients with sporadic ALS and 10 with non‐ALS disorders were immunostained using a polyclonal anti‐BTBD10 antibody. Reduced BTBD10 expression in the anterior horn cells was more frequent in spinal cords from ALS patients than in cords from patients with non‐ALS disorders. We further investigated the relationship between the level of BTBD10 immunoreactivity and the morphology of the Golgi apparatus (GA) and the presence of phosphorylated TAR‐DNA‐binding protein 43 (pTDP‐43). Mirror sections of spinal cords from five sporadic ALS cases were immunostained with antibodies against BTBD10 and trans‐Golgi‐network (TGN)‐46 or pTDP‐43. Whereas 89.7–96.5% of the neurons with normal BTBD10 immunoreactivity showed normal GA morphology and no pTDP‐43 cytoplasmic aggregates, 86.2–94.3% of the neurons with reduced BTBD10 expression showed GA fragmentation and abnormal pTDP‐43 aggregates. These findings suggest that reduced BTBD10 expression is closely linked to the pathogenesis of sporadic ALS.

An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis

A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO2) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement.

Charcot-Marie-Tooth disease showing transient central nervous system lesions after a large amount of alcohol intake: A case report

A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to GJB1 mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of GJB1 was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.

Tumoral ectopic calcinosis causing cervical spinal cord compression in a patient with systemic sclerosis

A 54 year-old woman complained of neck pain, weakness and dysesthesia of the upper limbs. She had had a medical history of systemic sclerosis diagnosed at 52 years old. Neurological examination revealed bilateral biceps reflexes are normal, however, bilateral triceps, patellar, and Achilles’ tendon reflexes were hyperactive. Cervical spinal MRI showed a tumoral lesion located in the posterior part of the spinal canal at the levels of C3-5 (Figs. 1a and 1b), and its internal portion was not clearly enhanced with gadolinium (Fig. 1c). This lesion entirely showed high density on CT (Fig. 1d), and was considered to be generated from an ectopic calcinosis due to systemic sclerosis. Macroscopic findings during surgery identified the ectopic calcinosis existed in the epidural space with intact dura mater. Pathological evaluation after the total resection (Fig. 1e) revealed it was actually a soft calcified tissue. After the surgical resection, her clinical symptoms were remarkably improved. It should be noticed that a tumoral ectopic calcinosis occurred in the spinal canal can rarely cause myelopathy or myeloradiculopathy in a patient with systemic sclerosis.1 This article is protected by copyright. All rights reserved.

MICROBLEEDS IN CLINICAL SUBTYPES OF ALZHEIMER'S DISEASE ON CSF AND NEUROIMAGING MARKERS

(BMI) is associated with reduced risk for future development of Alzheimer’s Diseases (AD), particularly in older subjects (Emmerzaal et al., 2015). Therefore, we sought to investigate how BMI in late middle aged and elderly subjects relates to regional cerebral metabolic rate of glucose (rCMRgl) and whether this relationship is influenced by the status of APOEε4 allele, a genetic risk for AD, or age. Methods: 197 cognitively healthy, non-diabetic subjects (59M/138F; age 61.066.3y; BMI 27.364.9kg*m), including homozygous (n1⁄440) and heterozygous (n1⁄458) carriers of the APOEε4 allele, underwent quantification of rCMRgl using 2-[F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography. Voxelwise multiple regression analyses across the whole brain and within specific regions of interest (ROI) including precuneus, posterior cingulate, parietal, temporal, prefrontal, and occipital brain regions were employed to investigate associations of BMI with rCMRgl and potential interactions with APOEε4 carrier status, age and gender. Furthermore, we applied the hypometabolic convergence index (HCI; Chen et al., 2011) in order to explore the relationship between BMI and AD typical hypometabolic patterns. Results:We found extensive and exclusively positive associations of BMI with rCMRgl in regions known to be affected by AD such as occipital, parietal, temporal (including the bilateral hippocampal region), and other brain regions (i.e. cerebellum, frontoinsular and subcortical regions). Confirmatory results were found for specific ROIs. A significant BMI by gender interaction was observed with stronger associations within the right temporal and the right orbitofrontal cortex in males. However, no significant BMI by APOEε4 carrier status interaction or BMI by age group interaction was detected. Additionally, BMI was negatively correlated with HCI, indicating less convergence to AD typical hypometabolic patterns in subjects with high BMI measures. Conclusions: BMI is positively associated with rCMRgl in healthy late middle aged and elderly subjects, including brain regions that are typically affected by AD, thus providing a potential explanation for the proposed beneficial effects of higher BMI with respect to AD development. These associations seem to be modified by gender, possibly as the result of differences in body composition, but not by APOEε4 genotype or age.