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.

Dystextia and dystypia due to phonological errors after ischemic stroke: a case report in a Japanese patient.

A 69-year-old Japanese male presented with acute dystextia and dystypia, defined as texting and typing impairments, respectively. His text input speed decreased due to a phonologically incorrect kana flick input on his smartphone. Additionally, dystypia occurred due to phonemic paragraphia of Romaji. Brain MRI revealed a new left lenticulostriate infarction sparing the cerebral cortex. SPECT showed reduced cerebral blood flow in the left inferior precentral frontal gyrus as well as in the infarction area. It was concluded that his abnormal phonological processes resulted from hypoperfusion in the left inferior precentral gyrus that is assumed to be an endpoint of the arcuate fasciculus.

Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson's disease.

The pathological hallmarks of Parkinson's disease (PD) are α-synuclein (αSYN)-positive inclusions referred to as Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology (LRP). LRP is thought to propagate in an ascending manner throughout the brain as the disease progresses. LRP is visible with histologic methods and is thought to represent a later stage of the disease process, while αSYN oligomers, which are not visible with routine histologic methods, are considered earlier. There is increasing evidence to suggest that αSYN oligomers may be more toxic than visible LRP. Detecting αSYN oligomers requires special techniques, and their distribution and association with clinical features are important research objectives. In this report, we describe the distribution of αSYN oligomers in multiple cortical and subcortical regions of PD using a proximity ligation assay (PLA). We observe widespread distribution of αSYN oligomers with PLA and more restricted distribution of LRP with αSYN immunohistochemistry. The distribution of αSYN oligomers differed from LRP in that αSYN oligomer burden was significantly greater in the neocortex, while LRP was greater in vulnerable subcortical regions, including the brainstem. We also found that cognitive impairment was associated with αSYN oligomers in the hippocampus. These results suggest that αSYN oligomers may be widely distributed in PD early in the disease process and that they may contribute to cognitive impairment in PD.

[COVID-19-associated Guillain-Barré syndrome in infectious period: a case report].

A 75-year-old man with a history of hypertension developed weakness and sensory disturbance in the extremities 1 week after upper respiratory tract infection and faced difficulty walking. Screening at the time of hospital admission revealed an incidental positive SARS-CoV-2 PCR test, and COVID-19 was diagnosed. Neurological findings showed dysarthria, dysphagia, absence of deep tendon reflexes in the extremities, distal-dominant muscle weakness, sensory disturbance, urinary retention and constipation. Nerve conduction studies showed prolonged distal latency, decreased conduction velocity, and poor F-wave response, leading to a diagnosis of COVID-19-associated Guillain-Barré syndrome (GBS). The patient was treated with intravenous immunoglobulin, and his neurological symptoms improved without the need of a ventilator. Anti-ganglioside autoantibodies were negative. The patient developed GBS during the infectious period of SARS-CoV-2 and was treated in the isolation ward by clinical staff with personal protective equipment. Because COVID-19-associated GBS can develop during the infectious period of SARS-CoV-2, it is important for neurologists to consider GBS and other neurological disorders as being potentially COVID-19-related, and to treat patients with COVID-19 accordingly.

Impact of tracheostomy invasive ventilation on survival in Japanese patients with multiple system atrophy.

INTRODUCTION: Tracheostomy invasive ventilation (TIV) is therapeutic intervention to prolong survival. However, few reports have addressed TIV in multiple system atrophy (MSA). This study sought to evaluate the impact of TIV on survival in MSA patients. METHODS: This retrospective cohort study examined medical records of probable or definite MSA for patients in Hyogo-Chuo National Hospital from January 2000 to September 2021 to investigate overall survival and cause of death in those with tracheostomy and TIV. RESULTS: The study enrolled 12 definite and 127 probable MSA patients. Mean age at onset was 61.3 ± 9.8 years, and median survival time was 9.0 years. Tracheostomy was performed in 53 patients, 21 of whom were ventilated. Mean time from onset to tracheostomy and TIV was 7.0 ± 3.0 and 8.4 ± 4.4 years, respectively. After propensity score matching, tracheostomy showed a significant prolongation of median survival compared with no tracheostomy (10.1 vs. 7.5 years, p = 0.001) and TIV significantly prolonged survival compared with tracheostomy alone (17.8 vs. 9.2 years, p = 0.023). On Cox regression analysis, the hazard ratio for tracheostomy was 0.35 (95% confidence interval [CI] 0.17-0.68, p = 0.002) and TIV was 0.22 (95% CI 0.07-0.89, p = 0.032). In MSA with TIV, sudden death was significantly lower compared with tracheostomy alone, and infection was the most common cause of death. CONCLUSION: Results showed that TIV prolonged survival and reduced sudden death compared with tracheostomy alone in MSA, although sudden death can never be completely prevented.

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.

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.

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.

Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease.

OBJECTIVE: Vanishing white matter disease (VWM) is a chronic, progressive leukoencephalopathy associated with episodes of rapid deterioration following minor stress events such as head traumas or infectious disorders. The white matter of the patients with VWM exhibits characteristic radiological findings. METHOD: The genes encoding all five subunits of eukaryotic translation initiation factor 2B (EIF2B) were analyzed in patients, who were tentatively diagnosed with VWM, by Sanger sequencing. RESULTS: Seven mutations were identified in the genes encoding the subunits 1, 2, 4, and 5 of EIF2B. Among them, one mutation (p.V83E) in the subunit 2 (EIF2B2) was recurrently identified in three alleles, indicating the most common mutation in Japanese patients with VWM. Two patients were homozygous, and the other four patients were compound heterozygous. CONCLUSION: All patients showed white matter abnormalities with various degrees. One patient showed manifestations of end-stage VWM disease. Some patients showed late onset and slow progression associated with brain magnetic resonance imaging displaying T2 high intensity only in the deep white matter. There was clinical heterogeneity among patients with VWM.

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.