An autopsy case of progressive supranuclear palsy treated with monoclonal antibody against tau.

We report an autopsy case of progressive supranuclear palsy (PSP-Richardson syndrome). The individual had been enrolled in a phase 2 trial and received a monoclonal tau antibody (tilavonemab, ABBV-8E12); he died of intrahepatic cholangiocarcinoma and gastrointestinal bleeding during the clinical trial. Neuropathological examination demonstrated neuronal loss, gliosis, and widespread deposits of phosphorylated tau in the neurofibrillary tangles, tufted astrocytes, coiled bodies, and threads, which mainly occurred in the inferior olive nucleus, dentate nucleus of the cerebellum, substantia nigra, midbrain tegmentum, subthalamic nuclei, globus pallidus, putamen, and precentral gyrus, confirming typical PSP pathology. Phosphorylated tau was also found to accumulate in Betz cells, Purkinje cells, and pencil fibers in the basal ganglia. In conclusion, no additional changes or pathological modifications, which were expected from immunotherapy targeting tau, were visible in the present case.

Neuropathology of spinocerebellar ataxia type 8: Common features and unique tauopathy.

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative condition that presents with several neurological symptoms, such as cerebellar ataxia, parkinsonism, and cognitive impairment. It is caused by a CTA/CTG repeat expansion on chromosome 13q21 (ataxin 8 opposite strand [ATXN8OS]). However, the pathological significance of this expansion remains unclear. Moreover, abnormal CTA/CTG repeat expansions in ATXN8OS have also been reported in other neurodegenerative diseases, including progressive supranuclear palsy. In this study, we analyzed all available autopsy cases in Japan to investigate common pathological features and profiles of tau pathology in each case. Severe neuronal loss in the substantia nigra and prominent loss of Purkinje cells, atrophy of the molecular layer, and proliferation of Bergmann glia in the cerebellum were common features. Regarding tauopathy, one case presented with progressive supranuclear palsy-like 4-repeat tauopathy in addition to mild Alzheimer-type 3- and 4-repeat tauopathy. Another case showed 3- and 4-repeat tauopathy accentuated in the brainstem. The other two cases lacked tauopathy after extensive immunohistochemical studies. The present study confirmed common pathological features of SCA8 as degeneration of the substantia nigra in addition to the cerebellum. Our study also confirmed unique tauopathy in two of four cases, indicating the necessity to further collect autopsy cases.

TDP-43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease.

Accumulation of abnormal transactivation response DNA-binding protein of 43 kDa (TDP-43) independently induces dopaminergic neuronal loss in the substantia nigra without Lewy pathology, and results in typical Parkinson's disease-like motor symptoms.

An autopsy case of Alzheimer's disease with amygdala-predominant Lewy pathology presenting with frontotemporal dementia-like psychiatric symptoms.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases associated with several cognitive and behavioral symptoms. It is sometimes difficult to distinguish AD from FTD in a patient because both of them can exhibit clinical overlap. In the present study, we report a case of a patient who showed sychiatric symptoms mimicking the behavioral variant of FTD (bvFTD) and combined AD amygdala-predominant Lewy pathologies on autopsy. The patient was a Japanese man who developed personality changes in his late 50s, presenting with obsessive-compulsive stereotypical behavior, stereotypy of speech, behavioral disinhibition, inertia, loss of empathy or sympathy, change in eating habits, and stimulus-bound behavior. He also frequently left during medical examinations. Eventually, he was clinically diagnosed as having possible bvFTD, according to the International Consensus Criteria for bvFTD. The patient died of systemic metastasis of gastric cancer at 69 years of age. Postmortem neuropathological examination revealed severe AD pathology (Braak Amyloid stage C, Consortium to Establish a Registry for Alzheimer's Disease [CERAD] stage C, Thal phase 5, and Braak AT8 stage IV) along with Lewy pathology and argyrophilic grains, predominantly in the amygdala. Furthermore, no transactivation response DNA-binding protein of 43 kDa (TDP-43) pathology was observed. Our results suggest that a combination of these pathologies causes bvFTD-like cognitive and behavioral symptoms. This case is very insightful when considering the lesions responsible for the psychiatric symptoms characteristic of bvFTD.

Amyotrophic lateral sclerosis with speech apraxia, predominant upper motor neuron signs, and prominent iron accumulation in the frontal operculum and precentral gyrus.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease; transactivation response DNA-binding protein of 43 kDa (TDP-43) and iron accumulation are supposed to play a crucial role in the pathomechanism of the disease. Here, we report an unusual case of a patient with ALS who presented with speech apraxia as an initial symptom and upper motor neuron deficiencies. In the early clinical stages, single-photon emission computed tomography visualized focal hypoperfusion of the right frontal operculum, and magnetic resonance imaging identified a hypointense area along the frontal lobe on T2-weighted images. Neuropathological examination revealed that neuronophagia of Betz cells, gliosis, appearance of phosphorylated TDP-43 (p-TDP-43)-positive glial and neuronal inclusions, and prominent iron accumulation were frequently visible in the precentral gyrus. TDP-43 pathology and focal iron accumulation were also visible in the frontal operculum, but only a mild neuronal loss and a few p-TDP-43-positive neuronal and glial inclusions were found in the hypoglossal nucleus of the medulla oblongata and anterior horn of the spinal cord. Immunoblot analysis revealed an atypical band pattern for ALS. In our case, abnormal TDP-43 and iron accumulation might possibly have caused neurodegeneration of the frontal operculum, in tandem or independently; it might then have spread into the primary motor area. Our results suggest a causative association between TDP-43 and iron accumulation in the pathomechanisms of ALS presenting with upper motor neuron signs.

A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy.

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3' splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.

TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis.

OBJECTIVES: The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis. METHODS: We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing. RESULTS: A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 in the family. DISCUSSION: The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with TNNI2 variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a TNNI1 nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of TNNI1 in the disease.

[A case study of a patient with myotonic dystrophy type 1 whose gait disturbance was improved by gait training with hybrid assistive limbs].

A Japanese woman first noticed dysarthria at the age of 23. She visited a hospital at the age of 32 and was diagnosed as having myotonic dystrophy clinically. She was diagnosed genetically as having myotonic dystrophy type 1 at 47 years old with 160-270 CTG repeats on the DMPK gene. At the age of 48, she needed non-invasive positive pressure ventilation because of hypoxia at night. Her gait function also deteriorated. She could not stand up from the supine position by herself. However, when she stood, she could walk without a cane for a short distance. She was admitted to our hospital to receive rehabilitation against progressive gait disturbance at the age of 53. She received gait training with hybrid assistive limb® (HAL®). We evaluated some parameters such as walking distance of 2-minute walk test (2MWT), gait speed /cadence/stride length of 10-meter walk test (10MWT), before and just after the course. The first course was performed in September 2017 and the second was done in May 2018 so the interval was about six months. After two courses of HAL® gait training, the distance on the 2-minute walk test increased from 111 m to 154 m, the average speed and the cadence of 10MWT improved from 2.01 m/s to 2.78 m/s and from 2.21 steps/s to 3.05 steps/s respectively. The score of the muscular disability quality of life (QOL) rating scale was also improved. The factors including "defecation," "breathing," and "ADL" suggest that the patient's physical abilities improved and she could move easily. Other factors such as "hope", "activity" and "human relationship" suggest that patient's mood improved after the HAL® training.It was suggested that HAL® gait training could improve QOL as well as gait function in patients with progressive neuromuscular disorder.

[A case of meningoencephalitis associated with pembrolizumab treated for squamous cell lung cancer].

A 61-year-old man with squamous cell lung cancer was admitted to our hospital because of consciousness disturbance after treated with pembrolizumab. Cerebrospinal fluid examination revealed increased protein level (209.2 mg/dl) and lymphocytic pleocytosis(79/µl). He was diagnosed as a meningoencephalitis probably caused by an immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), and was successfully treated with 1,000 mg methylprednisolone intravenously for 3 days twice and the consequent oral 1 mg/kg prednisolone. As ICIs, which activate the immune systems, are becoming important choices of the treatments against malignancies, we should keep the possibility of irAE in mind and, when needed, start the treatment as soon as possible.