A novel mouse model for investigating α-synuclein aggregates in oligodendrocytes: implications for the glial cytoplasmic inclusions in multiple system atrophy.

The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.

Favorable Outcome with Intravenous Immunoglobulin Therapy in Late-Onset Anti-mGluR1 Encephalitis: A Case Report and Literature Review.

Anti-metabotropic glutamate receptor 1 (mGluR1) encephalitis is a rare autoimmune disorder manifesting with cerebellar syndrome. Patients with mGluR1 encephalitis have been treated with immunomodulatory therapies; however, little is known about the efficacy of this therapy. A 58-year-old Japanese woman presented with dizziness when walking and standing up. Symptoms persisted and the patient gradually deteriorated. The neurological examination revealed a broad-based gait, horizontal and slightly gaze-evoked nystagmus, noticeable head titubation, and truncal ataxia without limb ataxia. Magnetic resonance imaging was normal. The 123I-isopropyl-iodoamphetamine single-photon emission-computed tomography scans showed normal cerebellar perfusion. Based on a positive antibody test for anti-mGluR1, the patient was diagnosed with anti-mGluR1 encephalitis. She was treated with intravenous methylprednisolone and intravenous immunoglobulin (IVIg). Symptoms gradually improved over 1 month and almost disappeared after additional IVIg therapy. Anti-mGluR1 encephalitis is a rare disease, and effective treatment is unclear. In this case, a favorable outcome was obtained with immunomodulatory therapy, even though the neurological disability of the disease course is worse. We emphasize the importance of early diagnosis and therapeutic intervention, suspecting the disease on the basis of its characteristic symptoms.

Two Lambert-Eaton Myasthenic Syndrome Patients with Ameliorated Activities of Daily Living Due to Cholinesterase Inhibitors.

We herein report two P/Q-type voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS) patients who responded dramatically to cholinesterase inhibitors. Patient 1, a 76-year-old man, had small-cell lung cancer and developed LEMS during chemotherapy. When symptomatic treatment was started with pyridostigmine, gait disturbance was ameliorated, and his modified Rankin scale decreased from 4 points to 3 points. Patient 2, a 68-year-old man, had cancer-free LEMS. Distigmine bromide was very effective and ameliorated not only his gait disturbance but also autonomic symptoms, and his modified Rankin scale decreased from 2 points to 1 point. Cholinesterase inhibitors alone may be effective in a small portion of LEMS patients.

Count of Fasciculation in Ultrasound Can Predict the Prognosis of Amyotrophic Lateral Sclerosis.

BACKGROUND: Although muscle ultrasound (MUS) is known to facilitate the diagnosis and evaluation of the severity of amyotrophic lateral sclerosis (ALS), the number of fasciculation has been scarcely examined as a predictive marker of the prognosis in ALS. OBJECTIVE: The objective of this study was to examine the predictive value of fasciculation number for the prognosis of ALS. MATERIALS AND METHODS: We examined fasciculation count (FasC), defined as the number of fasciculation per unit of time and area in MUS, of 11 patients with clinically probable or definite ALS. Thereafter, they were observed for maximally 2 years, unless they reached the endpoint of decease or receiving tracheostomy. RESULTS: Six patients, who thereafter reached the endpoint within 2 years, had significantly higher FasC (223 [49.3] vs. 34 [13], P = 0.0043) and shorter disease duration (7 [2.3] vs. 33 [17], P = 0.0022) at MUS than the remaining five patients without reaching the endpoint. DISCUSSION AND CONCLUSION: Our study suggested that high FasC in MUS can predict rapid progression in ALS. Due to the limitations such as small sample size, suboptimal length of the observational period, and confounding factor of disease duration, further investigations are required.

Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson's disease. In contrast to previous studies, AS-PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.

Injection of Onabotulinum Toxin A into the Bilateral External Oblique Muscle Attenuated Camptocormia: A Prospective Open-Label Study in Six Patients with Parkinson's Disease.

INTRODUCTION: Camptocormia (severe bending of the spine) is a debilitating complication of Parkinson's disease (PD) without established treatment. Botulinum toxin (BT) may be beneficial, but data is scarce regarding the efficacy of administration of BT into the bilateral external oblique (EO) muscle for treatment of camptocormia in PD. METHODS: Six patients with PD and camptocormia, with flexion of the thoracic spine, were enrolled in the study. BT (75 or 90 units, onabotulinum toxin A) were injected into each EO bilaterally under sonographic guidance. Camptocormia angle (CA) was defined as the angle between the acromion-greater trochanter line and a vertical line. CA and disabling symptoms were evaluated during the treatment course. RESULTS: Two weeks after the injection of BT, the mean CA showed significant attenuation [median (interquartile range); 38° (23.5°) vs. 18° (21°), p = 0.028]. Subjective relief was present in cases 1-3 and 6, and absent in cases 4 and 5. Cases 1-3 received repeated injections to maintain the amelioration; in cases 1 and 2, this was for 1 year or longer, while falls of case 3 limited the amelioration. CONCLUSION: Botulinum therapy into bilateral EO attenuated the angle of thoracic-level camptocormia in six patients with PD over the observation period of 2 weeks. The reproducibility of the results, long-term efficacy, and subjective relief of symptoms require further examination.

The characteristics of camptocormia in patients with Parkinson's disease: A large cross-sectional multicenter study in Japan.

PURPOSE: The goal of the present study was to clarify the clinical characteristics and laboratory results of parkinsonian symptoms among patients with and without camptocormia. METHODS: Seventy-eight Parkinson's disease (PD) patients with camptocormia and 78 PD patients without camptocormia underwent a neurological examination, a blood test, and spinal magnetic resonance imaging (MRI). PD with camptocormia group and PD with non-camptocormia group were matched on age, age at PD onset, and sex. PRINCIPAL RESULTS: Camptocormia group had significantly higher prevalence of compression fractures, more severe parkinsonian symptoms, and a greater incidence of dementia than those without camptocormia. Serum creatine kinase levels in camptocormia group significantly elevated compared with non-camptocormia group. There were higher prevalence of abnormal findings in spine MRI including compression fractures and paravertebral muscle changes in camptocormia group compared with non-camptocormia group. MAJOR CONCLUSIONS: Camptocormia is associated with a greater prevalence of compression fractures and associated with greater UPDRS part II, part III score, axial score, and lower MMSE in this cross-sectional study. Thus, it can be concluded that camptocormia in PD is predominantly myopathic.

A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation.

Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin depositions in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy.

Somatic instability of CTG repeats in the cerebellum of myotonic dystrophy type 1.

INTRODUCTION: We statistically analyzed somatic instability of the CTG expansion in the central nervous system and visceral organs in 7 patients with myotonic dystrophy type 1 and also report intracerebellar instability in 2 patients. METHODS: CTG repeat expansion was estimated in the samples from autopsied brains and visceral organs by Southern blot analysis. Pathological study was performed. Samples were taken from several sites in the cerebellum to examine intracerebellar instability. RESULTS: The CTG repeat expansion was shortest in the cerebellar cortex among all tissues examined. With regard to the intracerebellar difference, the shortest expansion was seen in the cortices of the hemisphere and vermis, whereas it was moderate in the dentate nucleus and longest in the white matter of the hemisphere and middle cerebellar peduncle. CONCLUSIONS: The shortest expansion might be attributable to packed granule cells in the cerebellar cortex. Further analysis of cell-specific methylation states might elucidate the enigma of somatic instability.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1.

Myotonic dystrophy (DM1) is known to be an adult-onset muscular dystrophy caused by the expansion of CTG repeats within the 3' untranslated region of the dystrophin myotonin protein kinase (DMPK) gene. The clinical features of DM1 include CNS symptoms, such as cognitive impairment and personality changes, the pathogenesis of which remains to be elucidated. We hypothesized that the distribution of neuropathological changes might be correlated with the extent of the length of the CTG repeats in the DMPK genes in DM1 patients. We studied the neuropathological changes in the brains of subjects with DM1 and investigated the extent of somatic instability in terms of CTG repeat expansion in the different brain regions of the same individuals by Southern blot analysis. The neuropathological changes included état criblé in the cerebral deep white matter and neurofibrillary tangles immunoreactive for phosphorylated tau in the hippocampus and entorhinal cortex, both of which were compatible with the subcortical dementia in DM1 patients. However, the length of the CTG repeats did not correlate with the regional differences in the extent of neuropathological changes. Our data suggested that pathomechanisms of dementia in DM1 might be more multifactorial rather than a toxic gain-of-function due to mutant RNA.

Depression in patients with subacute myelo-optico-neuropathy (SMON).

OBJECTIVE: We investigated the psychiatric disorders in subacute myelo-optico-neuropathy (SMON) patients by structured interview. The prevalence of major depressive disorder in SMON patients was estimated by structured interview and using Beck's depression inventory (BDI) questionnaires. MATERIALS AND METHODS: Psychiatric conditions were evaluated in 26 SMON patients (9 males, 17 females, mean age 70.7 years) living in Kyoto prefecture through a structured interview given by psychiatrists. BDI questionnaires and clinical symptoms of SMON were investigated in 106 patients, ranging from 51 to 91 years in age (mean, 73.5) with SMON patients living in Kinki area. BDI questionnaires were obtained from 92 age-matched aged healthy people, ranging from 57 to 91 years in age (mean, 75.8), living in Kyoto city. RESULTS: Among the psychiatric disorders in SMON patients, the prevalence of major depressive disorder and suicidal ideation significantly increased during the period of clioquinol intake and four patients (15.4%) out of 26 SMON patients still suffer from major depressive disorder. The prevalence of major depressive disorder in SMON patients was estimated at 15.1% (16/106) and this percentage was about seven times as frequent as in the age-matched aged healthy people (2.2%; 2/92). In female SMON patients, the degree of the depressive states was significantly correlated with the severe degree of dysesthesia of the lower extremities, and it was inversely correlated with the duration of SMON disease and the total scores of the Barthel index. CONCLUSION: This is the first report that shows the prevalence of major depressive disorder in SMON patients at present, which was seven times more frequent than age-matched aged healthy persons.

[Four siblings with becker muscular dystrophy (BMD) manifesting severe mental retardation].

A 33-year-old man with BMD manifesting severe mental retardation is reported. This patient has mild pseudohypertrophy in his calf muscles and showed an elevation of creatine kinase (CK) level in the serum (2215 IU/L). He was diagnosed as autistic at the age of three. His intellectual level was estimated to be two years old in social intelligence and four months old in speech ability at the age of 33. However his muscle strength remains within the normal range. All of his three siblings have similar symptoms, such as severe mental retardation and elevated CK level in the serum (1735-3641 IU/L) and lack apparent muscular weakness. Gene analyses by multiplex PCR and Southern blotting showed all of the siblings had the deletion of exon 4 in the dystrophin gene. Pathological findings of a muscle biopsy specimen showed a mild irregular dystrophin stain of the muscle surface membrane. This is a rare familial case of Becker muscular dystrophy manifesting severe mental retardation with scarce muscular weakness.

[Posterior spinal cord infarction presenting Brown-Séquard syndrome].

We report a 56 year-old-woman with spinal cord infarction. She experienced left-sided girdle pain without precipitating symptoms and she developed monoparesis of her left leg and urinary retention. She also presented the segmental loss of total sensations in the Th10-11 area of the left trunk, the disturbance of position and vibration senses in the left leg and the disturbance of pain and temperature senses in the right leg. T2-weighted MR imagings showed high signal intensity lesion in the left half of the spinal posterior column at Th9-10 vertebral levels. Somatosensory evoked potentials confirmed that the loss of position and vibration senses was unilateral. Though she became able to walk with canes two months later, her sensory disturbance showed no improvement. This is a rare case of unilateral posterior spinal cord infarction presenting Brown-Séquard syndrome.

[Transient left ventricular apical ballooning, "Takotsubo" cardiomyopathy, in an amyotrophic lateral sclerosis patient on long-term respiratory support].

A 52-year-old woman developed dysarthria and dysphagia in April 1997, then experienced progressive weakness in her arms and legs several months later, which led to a diagnosis of amyotrophic lateral sclerosis (ALS). In October 1998, the patient was placed on respiratory support and thereafter in a bedridden state. On December 6, 2004, the patient suddenly fell into cardiogenic shock. An echocardiographic examination demonstrated extensive akinesis of the left ventricle together with the hyperkinetic constraction of the cardiac base. The left ventricular akinesis completely returned to normal by December 13. Based on our these results and her clinical course, we made a diagnosis of "Takotsubo" cardiomyopathy. This is the first case reported to have developed this condition in an ALS patient on long-term respiratory support. Physicians should be aware of the potential risk of developing "Takotsubo" cardiomyopathy in respirator-dependent ALS patients.

Autopsy case of pure akinesia showing pallidonigro-luysian atrophy.

A 60-year-old man developed levodopa-resistant pure akinesia. The patient gradually became more akinetic without accompanying gaze palsies, nuchal dystonia, or other parkinsonian features such as rigidity or tremor. At the age of 71, he died of bronchopneumonia. Neuropathologically, bilateral marked neuronal loss and gliosis were restrictedly observed in the globus pallidus, substantia nigra and corpus luysii, whereas mild gliosis without neuronal loss was found in the brain stem. With Gallyas-Braak silver stain, numerous argyrophilic fibrous structures partly surrounding glial nuclei were observed in the three major affected regions. With Bodian stain, however, they were rarely recognized. The structures were partly positive for tau protein. Rare neurofibrillary tangles were found in the three areas and brain stem. They were relatively more numerous but still sparse in the hippocampus and the parahippocampus. The present case was diagnosed as having pallidonigro-luysian atrophy based on two characteristic findings: (i) the distribution of lesions showing neuronal loss with gliosis; and (ii) significant presence of tau-positive argyrophilic fibrous structures related to glia but with the absence of neurofibrillary tangles in the major affected regions and the brain stem. As our present case uniquely showed pure akinesia for the whole clinical course, it is noteworthy to report it here with a full neuropathological evaluation. In addition, a moderate number of diffuse plaques positive for beta-amyloid were distributed in the thalamus.

[A case of esophageal achalasia followed by Parkinson's disease].

In 1992, a 63 year-old woman complained of dysphagia and chest pain, and was diagnosed with esophageal achalasia. Three years later, she developed resting tremor, cog-wheel rigidity, and retro-pulsion, and was diagnosed with Parkinson's disease and given appropriate medication. Several years later, intractable vomitting and aspiration pneumonia developed, and the lower esophageal sphincter was dilated using a pneumatic balloon dilator under gastroscopic guidance in 2004. That procedure improved her symptoms and the esophageal dilation was visualized on chest CT images. Herein, we report this rare case of esophageal achalasia followed by Parkinson's disease and discuss the relationship between the two diseases.

[Tactile hallucinations induced by trihexyphenidyl in a patient with Parkinson's disease].

We report a 71-year-old woman with tactile hallucinations induced by trihexyphenidyl. Six and a half months after starting trihexyphenidyl, this patient with Parkinson's disease complained of tactile hallucinations, mainly on her feet, at night while in bed. Four days after stopping the medication, the sensations disappeared. Although tactile hallucinations induced by trihexyphenidyl are rare, it should be noted that the condition can be induced by anti-Parkinson's disease drugs.

[Allergic skin rashes by methylprednisolone in a case with multiple sclerosis].

We reported a 34-year-old woman with multiple sclerosis showing an allergic reaction to methylprednisolone sodium succinate. She was admitted to our hospital with a complaint of hypesthesia in the right side of the face and body. MRI showed several high signal intensity lesions in her brain with Gd-DTPA enhancement effect. She was diagnosed as having an acute relapse of MS from previous episodes and clinical findings. We started a methylprednisolone pulse therapy. After the injection on the first day, skin rashes appeared on her trunk and thigh. On the second day, the skin rashes spread over her whole body. Patch test for methylprednisolone sodium succinate (MP) was positive. The steroid administration was substituted by intravenous injections of betamethasone 100mg/day for three days. Her neurological and radiological findings were successfully disappeared without any side effects. This case indicates the efficacy of substitution therapy of betamethasone for MP.