CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

Hypertrophy of the inferior olivary nucleus in corticobasal degeneration: A neuropathological study.

AIMS: Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The status of the inferior olivary nucleus (ION) in CBD has been inadequately investigated. In this study, we conducted a pathological investigation of the ION in CBD. MATERIALS AND METHODS: We reviewed the data of Japanese patients with pathologically confirmed CBD who underwent consecutive autopsies between 1985 and 2020 at our institute. We retrospectively examined clinical data from medical records and clinicopathological conferences and semi-quantitatively assessed the ION, central tegmental tract, superior cerebellar peduncle, and dentate nucleus. RESULTS: Of the 32 patients included, 14 (43.8%) had hypertrophy of the ION (HION), of whom 6 showed laterality. In the 14 HION cases, with or without laterality, except in 1 unevaluable case, atrophy/myelin pallor of the central tegmental tract was observed on the same side as the hypertrophy. Ten patients with HION, with or without laterality, had atrophy/myelin pallor of the superior cerebellar peduncle on the contralateral side to the hypertrophy. CONCLUSION: The ION presents with hypertrophic changes in CBD. The lesion is a primary degeneration in CBD and is related to the degeneration of the Guillain-Mollaret triangle. This finding contributes to the elucidation of the specific pathological characteristics of CBD.

Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration.

TDP-43 is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in cases of amyotrophic lateral sclerosis. TDP-43 pathology has also been found in brain tissues under non-amyotrophic lateral sclerosis conditions, suggesting mechanistic links between TDP-43-related amyotrophic lateral sclerosis and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (n = 26), corticobasal degeneration (n = 12), globular glial tauopathy (n = 5), Alzheimer's disease (n = 21) or Pick's disease (n = 6) and neurologically healthy controls (n = 36). Ten of the progressive supranuclear palsy cases (38%) and seven of the corticobasal degeneration cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43 aggregates were found to be skein-like, round-shaped, granular or dot-like and contained insoluble C-terminal fragments showing blotting pattern of amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in haematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and four-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the Alzheimer's disease, Pick's disease, globular glial tauopathy and control groups. Next, we assessed SFPQ expression in spinal cord motor neurons; SFPQ is a recently identified regulator of amyotrophic lateral sclerosis/frontotemporal lobar degeneration pathogenesis, and it is also reported that interaction between SFPQ and FUS regulates splicing of MAPT exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis-TDP cases but not in Alzheimer's disease, Pick's disease and globular glial tauopathy cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of progressive supranuclear palsy and corticobasal degeneration cases. Our results indicate that progressive supranuclear palsy and corticobasal degeneration may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with amyotrophic lateral sclerosis-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.

Clinicopathological features of progressive supranuclear palsy with asymmetrical atrophy of the superior cerebellar peduncle.

Progressive supranuclear palsy (PSP) can be diagnosed despite the presence of asymmetrical parkinsonism depending on the clinical diagnostic criteria. Some studies have reported that atrophy of the superior cerebellar peduncle (SCP) is more frequent in PSP than in Parkinson's disease. There have also been reports of PSP cases with an asymmetrically atrophic SCP. Therefore, we analyzed 48 specimens from consecutive autopsy cases that were neuropathologically diagnosed as PSP to investigate the laterality of brain lesions, including the SCP. We measured the width of the SCP and evaluated the laterality of atrophy. We semi-quantitatively evaluated neuronal loss, atrophy/myelin pallor, and tau pathology in three steps. Asymmetrical atrophy of the SCP was present in seven (14.6%) of 48 cases. The atrophic side of the SCP corresponded to the dominant side of the tau pathology in the cerebellar dentate nucleus. It was opposite to the dominant side of the myelin pallor and tau pathology in the red nucleus and of the tau pathology in the central tegmental tract and inferior olivary nucleus, coinciding with the neurologically systematic anatomy of the Guillain-Mollaret triangle. Neurodegeneration of PSP can progress asymmetrically from one side to the initially intact side in PSP with an initial predominance of Richardson's syndrome, progressive gait freezing, ocular motor dysfunction, parkinsonism, or corticobasal syndrome. To our knowledge, no previous study has reported asymmetrical PSP neuropathology; this is the first study to report the presence of PSP cases with asymmetrical SCP atrophy and systematically asymmetrical degeneration of the Guillain-Mollaret triangle.

Neurogenic intermittent claudication caused by vasculitis in the cauda equina: an autopsy case report.

PURPOSE: Intermittent claudication (IC) refers to leg pain that is induced by walking and relieved by rest. Neurogenic IC is usually associated with lumbar canal stenosis (LCS). We present rare findings from an autopsied patient who had neurogenic IC caused by vasculitis in the cauda equina. METHODS: We performed antemortem neurological and electrophysiological assessments, sural nerve biopsy, and post-mortem examination of the spinal cord and brain. RESULTS: A 61-year-old man noted sudden-onset leg pain that was not associated with any traumatic trigger. His leg pain consistently appeared when the patient walked and quickly faded on stopping. Spine surgery and cardiovascular departments both made a diagnosis of IC. However, magnetic resonance imaging (MRI) did not show LCS, and all ankle-brachial pressure indices were normal. He subsequently developed diffuse muscle weakness of the legs a month after disease onset. Myeloperoxidase antineutrophil cytoplasmic autoantibody was seropositive (140 IU/mL), and a sural nerve biopsy revealed axonal injury and angiitis. MRI showed multiple cerebral infarctions. He was diagnosed with microscopic polyangiitis (MPA) and underwent corticosteroid therapy. He died from complications two months after the onset. A post-mortem study revealed vasculitis in the subarachnoid space of the cauda equina, spinal cord, and brain parenchyma. The cauda equina showed a combined loss of small and large axonal fibres. The lumbar cord displayed central chromatolysis of the lower motor neurons. CONCLUSION: MPA is a rare cause of neurogenic IC when the symptom is acute and multimodal. Small-vessel vasculitis affecting the cauda equina may underlie MPA-associated IC.

Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis.

The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.

Pathological observations of a long spinal cord lesion in a patient with multiple sclerosis.

We report an autopsy case of multiple sclerosis (MS) manifesting as a long spinal cord lesion. The patient was a Japanese woman. At the age of 59 years, she presented with a one-month history of progressive paraplegia, dysesthesia in the lower extremities, and urinary retention. Magnetic resonance imaging revealed a long, hyperintense lesion on T2-weighted images that extended from the inferior portion of the medulla oblongata to the cervical segments of the spinal cord and an isolated lesion at the T6 level. Cerebrospinal fluid (CSF) examination revealed the presence of oligoclonal bands and increased myelin basic protein levels (999 pg/mL). Serum antibody against aquaporin 4 (AQP4) was undetectable in this patient. She was diagnosed as having atypical MS and experienced symptom improvement following immunotherapy with corticosteroids and plasma exchange. She died of pneumonia and renal failure at the age of 62 years. Postmortem examination revealed a long demyelinating lesion that extended from the inferior portion of the medulla oblongata to the sacral segments of the spinal cord. The lesion was comprised of numerous demyelinating plaques with inflammatory cell infiltration. A long spinal cord lesion is usually indicative of neuromyelitis optica spectrum disorder (NMOSD), and there are limited reports of postmortem observations of long spinal cord lesions among patients with anti-AQP4 antibody-seronegative MS. Our findings suggest that the pathomechanisms of such long spinal cord lesion formation differ between anti-AQP4 antibody-seronegative MS and NMOSD.

Macroscopic diagnostic clue for parkinsonism.

The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.

Neurolymphomatosis in follicular lymphoma: an autopsy case report.

Neurolymphomatosis is a neurological manifestation of lymphoma that involves the cranial or spinal peripheral nerves, nerve roots, and plexus with direct invasion of neoplastic cells. Neurolymphomatosis is rare among patients with low-grade lymphoma. We report an autopsied case of neurolymphomatosis that arose from follicular lymphoma. A 49-year-old woman who presented with pain of her neck and shoulder and numbness of her chin. Computed tomography revealed enlarged lymph nodes in her whole body, and biopsy from the axillary lymph node revealed grade 2 follicular lymphoma. Although the patient underwent chemotherapy, she gradually developed muscle weakness in the upper limbs and sensory disturbances of the trunk and limbs. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed increased tracer uptake of the cervical nerve roots. Repeated FDG-PET after additional therapy revealed progression of disease within the nerve roots and brachial plexus, whereas gadolinium-contrast magnetic resonance imaging (MRI) showed weak enhancement of the cervical nerve roots without formation of mass lesions. She died after a total disease duration of 12 months. Postmortem observations revealed invasion of lymphoma cells into the cervical nerve roots, dorsal root ganglia, and subarachnoid spaces of the spinal cord. Neurolymphomatosis was prominent at the segments of C6-Th2. Combined loss of axons and myelin sheaths was observed in the cervical nerve roots and posterior columns. Lymphoma cells also invaded the cranial nerves. The subarachnoid and perivascular spaces of the brain demonstrated focal invasion of the lymphoma. Mass lesions were not observed in the central nervous system. The lymphoma cells did not show histological transformation to higher grades, and the density of the centroblasts remained at grade 2. Our report clarifies that low-grade follicular lymphoma can manifest as neurolymphomatosis and central nervous system invasion in the absence of transformation toward higher histological grades. FDG-PET may be more sensitive to non-mass-forming lesions, including neurolymphomatosis, than gadolinium-contrast MRI.

Neuropathological investigation of patients with prolonged anorexia nervosa.

OBJECTIVES: Recent neuroimaging studies have indicated that the mesolimbic pathway, known to work as reward neuronal circuitry, regulates cognitive-behavioral flexibility in prolonged anorexia nervosa (AN). Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues. METHODS: The neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum. RESULTS: Histologically, neuronal deformation with cytoplasmic shrinkage was seen in reward-related brain regions, such as the orbitofrontal cortex/anterior cingulate cortex. The NAcc showed massive GFAP-positive astrocytes and dot-like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP-positive astrocytes in the NAcc (P = 0.0079) and VTA (P = 0.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18 to 25 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway. CONCLUSION: Our findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward-related network might induce neuropsychiatric symptoms associated with AN.

TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?

Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset of patients with tauopathies, and vice versa. The concomitant pathology often spreads in a disease-specific manner and has morphological characteristics in each primary disorder. The findings from translational studies have suggested that comorbid TDP-43 or tau pathology has clinical impacts and that the comorbid pathology is not a bystander, but a part of the disease process. Shared genetic risk factors or molecular abnormalities between TDP-43 proteinopathies and tauopathies, and direct interactions between TDP-43 and tau aggregates, have been reported. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.

Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases.

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

Unexpected postmortem diagnoses in cases of clinically diagnosed amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that is clinically and pathologically characterized by impairment of the upper and lower motor neurons. The clinical diagnosis of ALS is not always straightforward because of the lack of specific biomarkers and clinical heterogeneity. This review presents the clinical and pathological findings of four autopsied cases that had been diagnosed with ALS before death. These cases had demonstrated definite and progressive motor neuron signs and symptoms, whereas postmortem assessment revealed miscellaneous disorders, including fungal infection, paraneoplastic syndrome, and amyloidosis. Importantly, nonmotor neuron signs and symptoms, including seizures, extra-pyramidal signs, ocular movement disorders, sensory disturbance, and dysautonomia, had also been documented during the disease course of the cases in the present study. The ALS-unlike symptoms were indicative of the "true" diagnosis in each case when those symptoms were isolated from motor neuron signs/symptoms.

The hot cross bun sign in corticobasal degeneration.

The hot cross bun (HCB) sign encompasses a cross-shaped hyperintensity area in the pons on axial T2-weighted magnetic resonance imaging (MRI). The HCB sign is characteristic of multiple system atrophy (MSA) and has occasionally been observed in other neurological disorders. Here, we report an autopsied case of corticobasal degeneration (CBD) that showed the HCB sign. A female patient presented with progressive gait disturbance and cognitive impairment at the age of 60 years. A neurological examination revealed dysarthria, muscle rigidity of the limbs, akinesia, truncal ataxia, urinary incontinence, and dementia. The HCB sign was observed on a brain MRI at the age of 65 years, and a clinical diagnosis of possible MSA was made. She died of pneumonia at the age of 67 years. A postmortem observation, provided neuropathological findings characteristic of CBD, including the presence of astrocytic plaques, pretangles, neuropil threads, and ballooned neurons in association with four-repeat-tau aggregation. Interestingly, the pons displayed severe neuronal loss and astrogliosis that were prominent in the pontine and raphe nuclei. Myelin sheath depletion was prominent in the transverse fibers of the pontine base and the myelinated fibers of the pontine tegmentum in contrast to relative sparing of the pontine corticospinal tract and medial lemniscus. The cerebellar dentate nucleus exhibited neuronal loss and grumose degeneration. Western blot analysis of sarkosyl-insoluble fractions from brain tissue lysates using an anti-phosphorylated tau antibody identified immunoreactive signal bands in approximately 37-40, 43, 64, and 68 kDa, consistent with CBD. Genetic analysis did not reveal any known pathogenic mutations in the microtubule-associated protein tau gene (MAPT). Our case was characterized by the HCB sign and concordant neuropathological changes in the pons. CBD should be considered an underlying pathology of the HCB sign, even though the pontocerebellar changes would be unusual in CBD cases.

Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations.

Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Neuronal inclusion of transactivation response DNA-binding protein 43 kDa (TDP-43) is known to be a pathologic hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43, which is physiologically a nuclear protein, is mislocalized from the nucleus and aggregated within the cytoplasm of affected neurons in ALS and FTLD patients. Neuropathologic or experimental studies have addressed mechanisms underlying spreading of TDP-43 inclusions in the central nervous system of ALS and FTLD patients. On the basis of postmortem observations, it is hypothesized that TDP-43 inclusions spread along the neural projections. A centrifugal gradient of TDP-43 pathology in certain anatomical systems and axonal or synaptic aggregation of TDP-43 may support the hypothesis. Experimental studies have revealed cell-to-cell propagation of aggregated or truncated TDP-43, which indicates a direct transmission of TDP-43 inclusions to contiguous cells. However, discrepancies remain between the cell-to-cell propagation suggested in the experimental models and the anatomical spreading of TDP-43 aggregations based on postmortem observations. Trans-synaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of trans-synaptic transmission of aggregated proteins remain to be elucidated. Moreover, the spreading of TDP-43 inclusions varies among patients and genetic backgrounds, which indicates host-dependent factors for spreading of TDP-43 aggregations. Perturbation of cellular TDP-43 clearance may be a possible factor modifying the aggregation and spreading. This review discusses postmortem and experimental evidence that address mechanisms of spreading of TDP-43 pathology in the central nervous system of ALS and FTLD patients.

Identification of intracerebral hemorrhage in the early-phase of MM1+2C-type sporadic Creutzfeldt-Jakob disease: A case report.

We report a case of early-phase sporadic Creutzfeldt-Jakob disease (sCJD) complicated by intracerebral hemorrhage (ICH), classified as MM1 + 2C-type based on autopsy. A 61-year-old Japanese man presented to our hospital with speaking difficulties including repeated usage of the same words. He was hospitalized on the seventh day after symptom onset, and diffusion-weighted images on magnetic resonance imaging showed hyperintense regions in the frontal cortex and caudate nucleus. On the 11th day after symptom onset, head computed tomography revealed ICH in the right occipital and parietal lobes. Routine laboratory evaluations and angiography revealed no cause of ICH. Myoclonus of the extremities and drowsiness were observed on the 15th day after symptom onset. He reached the state of akinetic mutism approximately two months after symptom onset. The cerebrospinal fluid test revealed positive real-time quaking-induced conversion and 14-3-3 protein. Electroencephalography revealed periodic sharp wave complexes. A clinical diagnosis of probable Creutzfeldt-Jakob disease was made according to the diagnostic criteria. After a relapse of pneumonia, he passed away on the 103rd day after symptom onset. Postmortem examination revealed ICH in the right posterior cingulate gyrus. No pathological change that might have caused ICH was obtained. Although the effect of sCJD on the onset of ICH is undeniable, the cause of ICH was unknown. Prion protein immunohistochemistry revealed the following results: (1) weak synaptic-type deposits in the tissue rarefacted by ICH; (2) synaptic-type deposits in the cerebral cortex, which showed fine vacuoles; and (3) perivacuolar-type deposits in the inferior temporal gyrus and lingual gyrus, which showed frequent large confluent vacuoles. Although it could be considered MM1-type sCJD clinically, this case was neuropathologically diagnosed as having MM1 + 2C-type sCJD. It was shown that ICH may occur in early-phase sCJD. To improve sCJD prognosis, treatment of complications and careful follow up are important. Furthermore, pathological diagnosis is indispensable for sCJD type diagnosis.

Increased prevalence of granulovacuolar degeneration in C9orf72 mutation.

Granulovacuolar degeneration (GVD) is usually found in Alzheimer's disease (AD) cases or in elderly individuals. Its severity correlates positively with the density of neurofibrillary tangles (NFTs). Mechanisms underlying GVD formation are unknown. We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). Consecutively autopsied cases with FTLD/ALS-TDP and C9orf72 mutations (FTLD/ALS-C9; N = 29), cases with FTLD/ALS-TDP without C9orf72 mutations (FTLD/ALS-nonC9; N = 46), and age-matched healthy controls (N = 40) were studied. The prevalence of GVD was significantly higher in the FTLD/ALS-C9 cases (26/29 cases) than in the FTLD/ALS-nonC9 cases (15/46 cases; Fisher exact test; p < 2×10-6) or in the control group (12/40 individuals; p < 1×10-6). Average Braak stages and ages of death were not significantly different among the groups. The CA2 sector was most frequently affected in the FTLD/ALS-C9 group, whereas the CA1/subiculum was the most vulnerable area in the other groups. Extension of GVD correlated with the clinical duration of the disease in the FTLD/ALS-C9 cases but not in the FTLD/ALS-nonC9 cases. The GVD-containing neurons frequently had dipeptide repeat (DPR) protein inclusions. GVD granules labeled with antibodies directed against charged multivesicular body protein 2B or casein kinase 1δ were attached to DPR inclusions within GVD. Our results suggest that development of GVD and DPR inclusions is related to common pathogenic mechanisms and that GVD is not only associated with NFTs seen in AD cases or aging individuals.

Autopsy case of MV2K-type sporadic Creutzfeldt-Jakob disease with spongiform changes of the cerebral cortex.

Comprehensive analysis is required for the accurate diagnosis of MV2-type sporadic Creutzfeldt-Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy-confirmed MV2K-type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion-weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole-type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic-type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal-type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque-type PrP with synaptic-type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic-type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrPSc (scrapie type) and intermediate-type PrPSc .

Structural MRI correlates of amyotrophic lateral sclerosis progression.

PURPOSE: Amyotrophic lateral sclerosis (ALS) presents with varying degrees of brain degeneration that can extend beyond the corticospinal tract (CST). Furthermore, the clinical course and progression of ALS varies widely. Brain degeneration detected using structural MRI could reflect disease progression. SUBJECTS AND METHODS: On study registration, 3-Tesla volumetric MRI and diffusion tensor imaging scans were obtained at baseline in 38 healthy controls and 67 patients with sporadic ALS. Patients had Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of ≥36 and did not have the chromosome 9, open reading frame 72 repeat expansion. Six months later, changes in ALSFRS-R (ΔALSFRS-R) scores were calculated and patients were grouped into three categories, namely, patients with slow progression with ΔALSFRS-R scores ≤3 (n=19), intermediate progression with ΔALSFRS-R scores =4, 5 and 6 (n=36) and rapid progression with ΔALSFRS-R scores ≥7 (n=12). We analysed voxel-based morphometry and tract-based spatial statistics among these subgroups and controls. RESULTS: In comparison with controls, patients with ALS showed grey matter atrophy and decreased fractional anisotropy beyond the motor cortex and CST, especially in the frontotemporal lobes and basal ganglia. Moreover, the degree of change was highly proportional to ΔALSFRS-R at the 6-month assessment. CONCLUSION: A more rapid disease progression and poorer functional decline were associated with greater involvement of the extra-motor cortex and basal ganglia, suggesting that the spatial extent of brain involvement can be an indicator of the progression in ALS.