An autopsied case of unclassifiable sporadic four-repeat tauopathy presenting with parkinsonism and speech disturbances.

A 48-year-old Japanese woman experienced slow-onset parkinsonism and speech disturbances. Neurological examinations revealed rigidity in the trunk and extremities, bradykinesia and postural instability, although cognitive impairments and psychiatric symptoms were not apparent in the early disease stage. Neuroimaging revealed progressive bilateral frontotemporal lobe atrophy with cerebral blood flow hypoperfusion. No apparent signs of lower motor neuron involvement were observed, such as fasciculation or electromyogram findings. She eventually reached the akinetic mutism state, and gastrostomy and tracheotomy were performed at 4 years after onset. A clinical diagnosis of progressive supranuclear palsy was made prior to her death, which occurred 6 years after onset. Post mortem examinations revealed that the brain weighed 1200 g and showed atrophy of the frontotemporal lobe and brainstem. Severe neuron loss and gliosis were observed in the frontotemporal lobe. The superior and middle frontal gyri were the most severely affected and showed spongiform changes in the superficial layer. The globus pallidus, subthalamic nucleus, cerebellar dentate nucleus, substantia nigra and inferior olivary nucleus also showed neuronal loss with gliosis. Using hyperphosphorylated tau (AT-8) immunostaining, pretangle-like neurons, numerous short threads and glial tau pathology were extensively observed. Using Gallyas-Braak silver staining, thin and short threads were also extensively observed, but considerably fewer than those observed by AT-8 immunostaining. Neither astrocytic plaques nor tuft-shaped astrocytes were observed. Examination by immunoelectron microscopy showed straight fibrils approximately 15 nm in diameter in the neuronal cytoplasmic inclusions in the cerebral cortex and in the fibrillary structures in the cerebral white matter. Western blot analysis of sarkosyl-insoluble tau revealed predominantly four-repeat tau and a banding pattern similar to that seen in progressive supranuclear palsy. No pathogenic mutations were found during the gene analysis of microtubule-associated protein tau. After completing our comprehensive investigation, we diagnosed this patient with unclassifiable four-repeat tauopathy.

Gerstmann-Straeussler-Scheinker disease with P102L prion protein gene mutation presenting with rapidly progressive clinical course.

We describe an autopsied case of a Japanese woman with Gerstmann-Straeussler-Scheinker disease (GSS) presenting with a rapidly progressive clinical course. Disease onset occurred at the age of 54 with dementia and gait disturbance. Her clinical course progressively deteriorated until she reached a bedridden state with myoclonus 9 months after onset. Two months later, she reached the akinetic mutism state. Nasal tube feeding was introduced at this point and continued for several years. Electroencephalograms showed diffuse slowing without periodic sharp-wave complexes. Diffusion-weighted magnetic resonance imaging (MRI) showed widespread cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed a Pro to Leu point mutation at codon 102 with methionine homozygosity at codon 129. The patient died of respiratory failure after a total disease duration of 62 months. Neuropathologic examination revealed widespread spongiform change with numerous eosinophilic amyloid plaques (Kuru plaques) in the cerebral and cerebellar cortices by H & E staining. Diffuse myelin pallor with axon loss of the cerebral white matter, suggestive of panencephalopathic-type pathology was observed. Numerous PrP immunopositive plaques and diffuse synaptic-type PrP deposition were extensively observed, particularly in the cerebral and cerebellar cortices. Western blot analysis of proteinase Kresistant PrP showed a characteristic band pattern with a small molecular band of 6 kDa. The reason for the similarity in clinicopathologic findings between the present case and Creutzfeldt-Jakob disease is uncertain; however, the existence of an unknown disease-modifying factor is suspected.

Immunohistochemical localization of spatacsin in α-synucleinopathies.

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP-TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α-synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti-spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin-positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α-synuclein-containing inclusions suggests that spatacsin may be involved in the pathogenesis of α-synucleinopathies.

An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement.

A Japanese male patient presented with gait disturbance at the age of 69 years. His principal symptom was cerebellar ataxia for several years. He was initially diagnosed as having olivopontocerebellar atrophy because dysarthria and ataxia gradually developed, and head CT scan showed apparent atrophy of the cerebellum and brainstem and dilatation of the fourth ventricle. Later, he showed vertical gaze palsy, dysphagia, retrocollis, parkinsonism, axial dominant rigidity and grasp reflex, and therefore, the diagnosis was modified to progressive supranuclear palsy (PSP). Progressive atrophy of the frontotemporal lobe, cerebellum and brainstem, and dilatation of the lateral, third and fourth ventricles were evident on MRI. Gastrostomy and tracheotomy were performed 9 and 10 years after onset, respectively, and the patient died after 11 years disease duration. At autopsy the brain weighed 1000 g and showed atrophy of the frontotemporal lobe, cerebellum and brainstem. Neurofibrillary tangles, mainly globose-type revealed by Gallyas-Braak silver staining, were extensively observed in the cerebral cortex and subcortical grey matter. Numerous glial fibrillary tangles, including tuft-shaped astrocytes and coiled bodies, and extensive argyrophilic threads were also recognized, particularly in the frontal lobe, basal ganglia, cerebellar white matter, brainstem and spinal cord. The Purkinje cell layer showed severe neuron loss with Bergmann's gliosis, and the dentate nucleus showed severe neuron loss with grumose degeneration. Tau-positive/Gallyas-positive inclusions in the Purkinje cells and the glial cells of the Purkinje cell layer were observed. Pathological findings of the present patient were consistent with the diagnosis of PSP, but the olivopontocerebellar involvement, particularly in the cerebellum, was generally more severe, and the quantity of tau-positive/Gallyas-positive structures were more abundant than in typical PSP cases. The existence of a distinct, rare PSP subtype with severe olivopontocerebellar involvement, "PSP-C", which tends to be clinically misdiagnosed as spinocerebellar degeneration in the early disease stage, is noteworthy. The present case corresponded to this rare subtype of PSP.

An autopsied case of Creutzfeldt-Jakob disease with mutation in the prion protein gene codon 232 and type 1+2 prion protein.

A 68-year-old Japanese man gradually showed abnormal behavior and gait disturbance with bradykinesia. Slowly progressive dementia, including memory disturbance and disorientation, was also observed. Cerebral cortical hyperintensity on diffusion-weighted MRI was observed 6 months after onset. The patient progressed to an akinetic mutism state with mild myoclonus, and atypical periodic sharp-wave complexes were observed by electroencephalogram 13 months after onset. He was clinically suspected of having atypical CJD and died after 19 months total disease duration. The brain weighed 1160 g and showed mild atrophy of the cerebrum and cerebellum with ventricular dilatation. Spongiform changes with varying vacuole size and gliosis was extensive in the cerebral cortex and basal ganglia. Neuron loss in the cerebral cortex, basal ganglia and thalamus was relatively mild. The cerebellum showed mild spongiform changes of the molecular layer and mild neuron loss in the Purkinje cell layer. PrP immunostaining showed mainly coarse-type combined with diffuse synaptic-type PrP deposition in the cerebral gray matter. Some perivacuolar-type PrP deposition was also present. Numerous plaque-type PrP depositions were observed in the molecular layer of the cerebellum. Analysis of the PrP gene revealed a methionine-to-arginine (Met-to-Arg) substitution at codon 232 (M232R) with Met homozygosity at codon 129. Western blot analysis of protease-resistant PrP indicated type 2 dominant PrP combined with type 1. Genetic CJD with M232R substitution in the PrP gene has only been reported in Japan. Although two clinical phenotypes (rapid-type and slow-type) were suggested in the M232R CJD cases (despite the presence of the same PrP genotype), the pathological and molecular backgrounds have not been well understood because there have only been a few autopsied case reports. This is the first case report of M232R CJD presenting with 1 + 2 PrP.

Senile onset frontotemporal lobar degeneration with TAR-DNA binding protein 43 proteinopathy primarily presenting with wasteful habits.

We present an autopsied case of a senile Japanese woman with sporadic frontotemporal lobar degeneration (FTLD) presenting as frontotemporal dementia. Disease onset was at the age of 70 and presented as a behaviour disorder, particularly involving wasteful habits. The patient had repeated incidents of making expensive purchases and then had difficulty making payments. Following these symptoms, she showed other changes of character such as lethargy and apathy. She gradually showed signs of parkinsonism including rigidity and bradykinesia, and in the terminal stage, an akinetic mutism state with quadriplegia in flexion was observed. Head magnetic resonance imaging revealed severe frontotemporal lobe atrophy with severe lateral ventricular dilatation and frontal white matter degeneration. At autopsy, the brain weighed 930 g and the frontotemporal cerebral cortex showed neuron loss with gliosis, tissue rarefaction and spongiform change, particularly in the superficial layers. Pathologic degeneration was more severe in the anterior portion of the frontal lobe with extensive white matter degeneration. Immunostaining for phosphorylated TAR-DNA binding protein 43 (TDP-43) revealed numerous neuronal cytoplasmic inclusions and extensive short dystrophic neuritis, particularly in the frontotemporal cortex. Many TDP-43-positive cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. The patient was pathologically diagnosed with FTLD with TDP-43-positive inclusions (FTLD-TDP) without motor neuron disease. The immunohistochemical findings corresponded to type A of the FTLD-TDP pathology classification system.

An Autopsy Confirmed Neuromyelitis Optica Spectrum Disorder with Extensive Brain White Matter Lesion and Optic Neuritis but Intact Spinal Cord, Clinically Mimicking a Secondary Progressive Multiple Sclerosis-like Course.

A 57-year-old woman presented with optic neuritis with repeated clinical symptoms of focal demyelination of the cerebral white matter and brain stem for 14 years. At the end of the patient's course, the clinical signs mimicked secondary progressive multiple sclerosis, but whether it was caused by interferon administration or neuromyelitis optica spectrum disorders (NMOSD) - or a combination of both or others - was unclear. Histopathological findings indicated the etiology to be NMOSD, with no apparent plaque in spinal cord specimens. This case suggests that an accurate clinical diagnosis requires serum anti-aquaporin 4 antibody measurements as well as an autopsy examination.

A Case of Anti-CRMP5 Paraneoplastic Neurological Syndrome Induced by Atezolizumab for Small Cell Lung Cancer.

We herein report a 76-year-old man who developed irritability and forgetfulness 5 months after the introduction of atezolizumab for the treatment of small cell lung cancer (SCLC). Brain magnetic resonance imaging showed lesions of the striatum, and an investigation of the serum revealed a high titer of anti-CRMP5 antibody. After stopping atezolizumab and starting steroid pulse therapy, these clinical features improved. Given these findings, it is considered that CRMP5-assciated striatal encephalitis was induced by atezolizumab in this case with SCLC.

Direct comparison of histology of microbleeds with postmortem MR images: a case report.

BACKGROUND: Although the clinical significance of so-called microbleeds (MBs) in gradient-echo MR images (GRE-MRI) has been extensively researched, the histopathological evaluation is notably insufficient. METHODS: Postmortem GRE-MRI was obtained of water-immersed formalin-fixed tissue blocks from a 97-year-old hypertensive woman with 9 antemortem MBs. Histologic slides were compared with those of MRI. RESULTS: Microscopic examination revealed clusters of hemosiderin-laden macrophages in 8 MBs and arteriolar pseudocalcification in 1 MB in the left pallidum. Hypertensive microangiopathies were found in 5 lesions. The sizes of the lesions with hemosiderin deposits were roughly comparable with the MBs of GRE-MRI. CONCLUSIONS: All of the MBs but for 1 exception were proved to be hemosiderin deposits and frequently associated with hypertensive microangiopathy.

Amyotrophic Lateral Sclerosis after Receiving the Human Papilloma Virus Vaccine: A Case Report of a 15-year-old Girl.

We herein report a 15-year-old girl who developed rapid progressive muscle weakness soon after the third injection of a bivalent human papilloma virus (HPV) vaccine. Although immunotherapies were performed for possible vaccine-related disorders, she died of respiratory failure 14 months after the onset of the disease. A genetic analysis identified a heterozygous p.P525L mutation of the fused in sarcoma (FUS) gene, and a histopathological analysis was also consistent with FUS-associated amyotrophic lateral sclerosis (ALS) without any evidence of neuroinflammation. We concluded the diagnosis to be FUS-ALS, although we cannot completely rule out the possibility that the vaccination worked as a trigger.

[Myorhythmia emerging on day 15 in a case of an infarction in the midbrain-pontine tegmentum].

A 72-year-old woman was admitted to our hospital because of dysarthria, dysstasia, and diplopia. Examination demonstrated wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome, dysarthria, truncal ataxia, and dysmetria of the four limbs. Cranial MR images demonstrated an acute infarct in the paramedian, lower midbrain-pontine tegmentum. Peduncular hallucinosis was observed during the first several days of hospitalization. Myorhythmia (skeletal myoclonus) appeared as early as day 15 and has persisted to date, with a frequency of approximately 1.5 Hz on the head and chin, and 3.5 Hz on the left upper extremity. Cranial MR images 5 months after onset demonstrated bilateral inferior olivary hypertrophy, while palatal tremor appeared later. Only a limited number of case reports are available in which myorhythmia emerged as early as in our case after the onset of a brain infarct.

Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT.

Comparison of the clinical course of Japanese MM1-type sporadic Creutzfeldt-Jakob disease between subacute spongiform encephalopathy and panencephalopathic-type.

BACKGROUND: Approximately half of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases show panencephalopathic-type (PE-type) pathology, which is a rare subtype in North Americans and Europeans. Until now, the differences in the clinical course between subacute spongiform encephalopathy (SSE) cases and PE-type cases have been unclear. METHODS: To investigate the clinical course of both subtypes, clinical findings from 42 Japanese MM1-type sCJD cases (20 SSE cases and 22 PE-type cases) were retrospectively evaluated by statistical analysis. RESULTS: No significant differences could be found regarding age at disease onset, the period between disease onset and first observation of myoclonus, the period between disease onset and the first observation of periodic sharp-wave complexes on electroencephalogram, or the period between disease onset and progression to the akinetic mutism state - whereas total disease duration and the period between the akinetic mutism state and death were significantly longer in PE-type cases. The prolonged disease duration was induced by the extended survival period in the akinetic mutism state. There was a statistically significant difference between the two series regarding performance of tube-feeding, but no statistically significant difference regarding performance of tracheotomy or gastrostomy. None of the cases received mechanical ventilation. CONCLUSION: We speculate that the most crucial factor of the prolonged survival period of Japanese sCJD cases, particularly in the PE-type, is that the introduction of tube-feeding in the akinetic mutism state leads to the stabilization of the patient's general condition.

Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy.

Pretangles are defined under the light microscope as diffuse and granular tau immunoreactivity in neurons in tissue from patients with Alzheimer disease (AD) or corticobasal degeneration (CBD) and are considered to be a premature stage before neurofibrillary tangle formation. However, the ultrastructure of pretangles remains to be described. To clarify the similarities and differences between pretangles from patients with AD and CBD (AD-pretangles and CBD-pretangles, respectively), we examined cortical pretangles in tissue from patients with each of diseases. For direct light and electron microscopic (LM/EM) correlation of the pretangles, we used quantum dot nanocrystals (QDs) with dual fluorescent and electron-dense properties. We first identified tau-labeled pretangles on fluorescence LM and subsequently examined the same neurons on EM. Energy dispersive X-ray spectrometry (EDX) color mapping identified selenium (Se) and cadmium (Cd) as elementary components of QDs and highlighted each QD particle clearly against gray-scale EM images. With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level. Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage. In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.

Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology.

In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

Argyrophilic grains are reliable disease-specific features of corticobasal degeneration.

Argyrophilic grains are discrete punctate structures that bind to silver stains; they can be observed within the neuropil of the limbic system, particularly in the elderly. It has been reported that argyrophilic grains are more frequent in patients with corticobasal degeneration (CBD) compared with the elderly population in general. To determine the frequency and significance of argyrophilic grains in CBD, we examined the temporal lobes from 35 patients with autopsy-proven CBD (mean age, 69.1 years) and 28 patients with argyrophilic grain disease (mean age, 95.7 years). Grain distributions and densities were evaluated semiquantitatively using Gallyas-Braak stains and immunohistochemistry with AT8 and RD4 antibodies. Argyrophilic grains were observed in all CBD cases (100%) despite a lower average age at death in this population. We also observed the following features that were specific to argyrophilic grains in CBD: 1) grains were likely to be widespread throughout the temporal lobe, 2) grains were consistently found with abundant argyrophilic threads, and 3) the ultrastructure of grains contained paired helical filaments with a periodicity of 120 to 130 nm. In conclusion, we confirm that argyrophilic grains in CBD are specifically related to the 4-repeat tau pathology of CBD and are not simply a result of aging.

Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis.

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.