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The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.SIGNIFICANCEA neurodegenerative disease of unknown cause on the island of Guam and the Kii peninsula of Japan has been widely studied, because patients can suffer from the combined symptoms of motor neuron disease, parkinsonism and dementia. Abnormal filamentous inclusions made of tau protein characterise this amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) and their formation closely correlates with neurodegeneration. Here we have used electron cryo-microscopy (cryo-EM) to show that tau filaments from ALS/PDC are identical to those from chronic traumatic encephalopathy (CTE), a disease caused by repetitive head impacts or blast waves. CTE tau filaments are also found in subacute sclerosing panencephalitis, which is a rare consequence of measles infection. ALS/PDC may therefore also be caused by environmental factors.

The presence of polyglutamine-immunoreactive deposits in neurons of the neostriatum has been reported in dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and Huntington disease (HD). However, among these diseases, precise quantitative investigations on neurons have been performed only for HD. Changes in the number of neurons and the immunohistological features of polyglutamine deposits in the caudate head and putamen were examined in six patients with DRPLA, three with MJD, and four with HD. In the neostriatum in DRPLA, the numbers of large and small neurons were reduced to 33-38% and 48-68% relative to controls, respectively, whereas the corresponding figures in MJD were 19-26% and 65-76%, respectively, and those in HD were 34-35% and 12-16%, respectively. In DRPLA, 2-55% of neurons remaining in the neostriatum showed diffuse nuclear accumulation of polyglutamine, in contrast to 3-20% in MJD and a few percent in HD. These findings indicate that, in the neostriatum, a decrease in the number of small neurons is predominant in HD, whereas a decrease in the number of large neurons is predominant in DRPLA and MJD. Thus, it is suggested that disease processs differ among polyglutamine diseases.

A 57-year-old man with no family history of amyotrophic lateral sclerosis (ALS) or diabetes was diagnosed with ALS, and placed in long-term care where an artificial respirator with tracheotomy was used. He was fed through a gastric fistula tube. He gradually lost the ability to communicate, and computed tomography revealed advanced atrophy of the frontotemporal lobe. He was abruptly suffered from polyuria 11 years after the onset of ALS, and was diagnosed with hyperosmolar hyperglycemic state (HHS). It recurred six years later with severe ascites and worsening of pleural effusion. He passed away 18 years after the onset of ALS. Pathological examination revealed a reduced numbers of Betz cells in the motor cortex, anterior horn cells in the spinal cord, and hypoglossal neurons. The remaining lower motor neurons and cells in the hippocampal dentate gyrus were positive for phosphorylated TDP-43. These corresponded to Type B on harmonized classification system for frontotemporal lobar degeneration (FTLD)-TDP pathology (Mackenzie, et al. 2011). Furthermore, the lateral, anterior, and anterolateral funiculi of the spinal cord, globus pallidus, thalamus, and brainstem tegmentum showed atrophy. The findings were compatible with ALS pathology in totally locked-in state (TLS). Hyalinized islets of Langerhans were observed scattered throughout the pancreas. The patient's muscles were nearly completely replaced by white, firm fat tissue. We considered that the patient's diabetic conditions contributed to the accumulation of excess fat in internal and external fat tissue as a result of the long-term dependence on enteral nutrition. Moreover, a disturbance in glucose metabolism in skeletal muscles that resulted from severe atrophy could have been another cause.

A Japanese man in the present study experienced acute weakness in his right leg as a two year old. The strength in his leg gradually recovered and developed, and he could play golf and climb mountains up to around the age of 50. From approximately 55 years of age, he became unable to stand up from a stooped position. Muscle weakness and atrophy spread to his right arm, and an electromyography revealed a neurogenic pattern in his lower and upper extremities. The patient was diagnosed as having post-poliomyelitis syndrome (PPS). Numbness in both the legs and pain in the buttocks occurred after 60 years of age. Computed tomography and magnetic resonance imaging at that time revealed spondylosis and protrusion of an osteophye in lower thoracic vertebrae compressing the second lumbar segment of the spinal cord. He died of malignant lymphoma and acute interstitial pneumonia at 80 years of age. Pathological examination revealed transverse myelopathy at the second lumbar segment of the spinal cord and total necrosis. The anterior horn and the intermediate zone of the third and fourth lumbar segments of the spinal cord on the right side were atrophic and diffusely gliotic. An oval-shaped plaque-like lesion was observed in the right anterior horn at the third and fourth lumbar segments of the spinal cord. Neurons and synaptophysin immunoreactivity had completely disappeared in the plaque-like lesion. A striking spread of vimentin-immunoreactive cells was found corresponding to the lesion, while glial fibrillary acidic protein-immunoreactive astrocytes existed evenly in the anterior horn and intermediate zone on both sides of the third and fourth lumber segments of the spinal cord. Virological examination using the autopsied materials was negative for poliovirus. Neither transactivation response DNA-binding protein of 43 kDa-immunoreactive inclusion nor Bunina body was seen in the spinal cord. The present paper demonstrates new findings of a noteworthy response of the vimentin-immunoreactive cells within the peculiar "plaque-like lesion" in the PPS.

Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear. At the neuropathological level, Kii ALS/PDC is characterized by neuronal loss and tau-dominant polyproteinopathy. Here, we report the accumulation of several proteins involved in protein homeostasis pathways, that is, the ubiquitin-proteasome system and the autophagy-lysosome pathway, in postmortem brain tissue from a number of Kii ALS/PDC cases (n = 4). Of particular interest is the presence of a mutant ubiquitin protein (UBB+1), which is indicative of disrupted ubiquitin homeostasis. The findings suggest that abnormal protein aggregation is linked to impaired protein homeostasis pathways in Kii ALS/PDC.

Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles composed of hyperphosphorylated tau, marked deposition of transactive response DNA-binding protein 43 kDa (TDP-43), and neuronal loss. The mechanisms that underlie neurodegeneration in G-PD are poorly understood. Here, we report that the unfolded protein response (UPR) is activated in G-PD brains. Specifically, we show that the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa and phosphorylated (activated) ER stress sensor protein kinase RNA-like ER kinase accumulate in G-PD brains. Furthermore, proteinaceous aggregates in G-PD brains are found to contain several proteins related to the ubiquitin-proteasome system (UPS) and the autophagy pathway, two major mechanisms for intracellular protein degradation. In particular, a mutant ubiquitin (UBB+1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBB+1 is a potent modifier of TDP-43 aggregation and cytotoxicity in vitro. Overall, these data suggest that UPR activation and intracellular proteolytic pathways are intimately connected with the accumulation of aggregated proteins in G-PD.

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5-positive diffuse large B-cell lymphoma (DLBCL) who presented with Guillain-Barre syndrome (GBS)-like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS-like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, "CD5-positive" DLBCL may tend to develop neurolymphomatosis. If a patient with "CD5-positive" DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5-positive DLBCL with neurolymphomatosis who presented with GBS-like neuropathy.

The patient was an 81-year-old woman diagnosed with atypical motor neuron disease who died after a long clinical course (7.5 years without mechanical assistance of ventilation) characterized by lower motor neuron signs and symptoms. Upper motor neuron signs and cognitive impairment were not apparent. Autopsy demonstrated severe neuronal loss in the anterior horn of the spinal cord, and some of the remaining neurons showed enlargement of Nissl substance and apparent thickening of the nuclear envelopes. No Bunina bodies, skein-like inclusions, or structures immunoreactive for phosphorylated transactivation response DNA-binding protein 43 were found. Immunoreactivity for superoxide dismutase-1 was focally seen in the enlarged Nissl substance. Ultrastructural examination demonstrated an increase of rough-surfaced endoplasmic reticulum (rough ER) and free ribosomes, disaggregation of polyribosomes, and dispersion of free ribosomes. Cisterns of rough ER were slightly dilated, and some of them were closely attached to the nuclear envelopes. Enlargement of Nissl substance may be related to "ER stress", and the abnormal findings of rough ER and free ribosomes may represent a degenerative process. However, another possibility, that they represent a compensatory hyperplastic change, cannot be excluded. The close attachment of cisterns of rough ER to the nuclear envelopes may be a mechanism to support or compensate for the abnormally-fragile nuclear envelopes. .

Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a “totally locked-in” state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved. Neurons in the anterior horn and Clarke's column were markedly lost, and many Bunina bodies and a few skein-like inclusions were found. Some remaining anterior horn cells had round and densely eosinophilic or amphophilic intracytoplasmic inclusions. They were immunoreactive for ubiquitin, p-TDP43, cystatin C and transferrin. On confocal laser microscopy, cystatin C was found to consistently surround p-TDP43 within the inclusions. The inclusions ultrastructurally consisted of granule-associated fibrils and, in the central portion, dense aggregates of fibrils were associated with masses of electron-dense, coarsely granular or amorphous material. Although their pathogenesis remains unknown, these unique inclusions may have been formed under a specific condition whereby p-TDP43 and cystatin C interacted with each other.

The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.

We herein report the clinical and autopsy findings of a 48-year-old right-handed man with athetoid cerebral palsy who suffered from cervical myelopathy due to abnormal neck movement, and who died of respiratory failure. Pathologically, the external appearance of the ventral surface of the cervical spinal cord revealed a linear indentation running obliquely at the level between the C4 and C5 segments. In the most severely compressed lesion, the gray matter was predominantly affected and severely atrophic. Microscopically, clusters of oligodendrocytes associated with thinly myelinated axons were also observed in the lateral funiculus. The latter findings are unique, and could be interpreted as regenerative and/or restorative phenomena of the central nervous system following chronic repetitive spinal cord compression.

Background Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. Case presentation A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. Conclusions The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

Background Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and “focal lesions” of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017). Methods Seven autopsied brains of ALSP and five controls were neuropathologically examined. Results Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the “focal lesions” were identical with those of centrum semiovale. Conclusion Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, “focal lesions” were formed in connection with the lesions in centrum semiovale., Highlights • Preferential thinning and “focal lesions” of corpus callosum in ALSP. • Seven autopsied brains of ALSP and five controls were neuropathologically examined. • Larger spheroids and more microglial alteration in corpus callosum than centrum semiovale. • “Focal lesions” were formed in connection with the lesions in the centrum semiovale. • Peculiar morphological change of microglia leads to the preferential thinning of corpus callosum.

We report lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in the patients with familial amyotrophic lateral sclerosis having L106V mutation in the SOD1 gene. Ten of 20 patients showed lower urinary tract dysfunction and 5 patients developed within 1 year after the onset of weakness. In 8 patients with an artificial respirator, 6 patients showed lower urinary tract dysfunction. Lower urinary tract dysfunction and respiratory failure requiring an artificial respirator occurred simultaneously in 3 patients. Neuronal loss and gliosis were observed in the neural circuits controlling micturition, such as frontal lobe, thalamus, hypothalamus, striatum, periaqueductal gray, ascending spinal tract, lateral corticospinal tract, intermediolateral nucleus and Onufrowicz' nucleus. Lower urinary tract dysfunction, especially storage symptoms, developed about 1 year after the onset of weakness, and the dysfunction occurred simultaneously with artificial respirator use in the patients.

Materials and methods The present paper examines the brains and spinal cords in 7 patients with amyotrophic lateral sclerosis (ALS) receiving artificial respirator support in a totally locked-in state (TLS) neuropathologically in order to clarify whether any anatomical structures in the central nervous system are preserved. Results and conclusion We found that the visual and olfactory pathways, hypothalamus, nucleus basalis of Meynert, and commissura anterior were remarkably well preserved, whereas the somatosensory, auditory, and gustatory pathways in the brain stem and/or spinal cord showed severe deterioration.

Predictors of communication impairment in patients with amyotrophic lateral sclerosis (ALS) using tracheostomy-invasive ventilation (TIV) were investigated. Seventy-six ALS patients using TIV were enrolled and classified into three subgroups of communication ability: patients who could communicate with communication devices (Stage I), patients who had difficulty with communication (Stage II, III, or IV), and patients who could not communicate by any means (Stage V). Predictors of communication impairment were analysed by the Cox proportional hazard model. Results demonstrated that there were no significant differences in disease duration between subgroups. Within 24 months after disease onset, patients who needed TIV and tube feeding, developed oculomotor impairment or became totally quadriplegic and progressed from Stage I to II and V significantly earlier. Multivariate analyses revealed that within 24 months from onset, the need for TIV and progression to total quadriplegia were significant events in patients who progressed to Stage II, whereas the development of oculomotor limitation was significant in patients who progressed to Stage V. In conclusion, TIV, impaired oculomotor movement and total quadriplegia are predictors of severe communication impairment. Rapid disease progression might indicate future communication impairment after the use of TIV. We highly recommend early detection of impaired communication and identification of the best methods of communication.

The cornu ammonis 1 (CA1) area in the hippocampus of the parkinsonism-dementia complex (PDC) of Guam was examined quantitatively with special references to the number of neurons, intraneuronal (i) and extracellular (e) neurofibirillary tangles (NFTs), and TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein)-immunopositive structures, in 24 Chamorro patients with PDC of Guam and seven control Chamorro Guamanians (both groups having no ischemic or anoxic complications). The results were that: (i) in the patients with mildly involved PDC, total numbers of neurons, iNFTs and eNFTs were almost the same as those of neurons of controls; (ii) in patients severely involved, total numbers of neurons, iNFTs and eNFTs decreased markedly; (iii) the decrease of the number of pyramidal neurons in CA1 with positive nuclear TDP-43 was intimately correlated with the decrease in total neuron numbers; (iv) whereas the numbers of neurons and TDP-43-immunopositive intracytoplasmic aggregation in the CA1 area were inversely correlated; and (v) depression of nuclear TDP-43 immuonostainability was not affected by the presence or absence of NFTs. In conclusion, hippocampal sclerosis exists in PDC; there is a possibility of elimination of eNFTs which appeared in the CA1 in patients with PDC and loss of the neurons correlates with disappearance of nuclear TDP-43, but not with appearance of intraneurocytoplasmic TDP-43 aggregation or iNFTs.

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons.

Previously we found that, after temporary cerebral ischemia, microvasculogenic secondary focal cerebral cortical ischemia occurred, caused by microvascular obstruction due to compression by swollen astrocytic end‐feet, resulting in focal infarction. Herein, we examined whether mannitol infusion immediately after restoration of blood flow could protect the cerebral cortex against the development of such an infarction. If so, the infusion of mannitol might improve the results of vascular reperfusion therapy. We selected stroke‐positive animals during the first 10 min after left carotid occlusion performed twice with a 5‐h interval, and allocated them into four groups: sham‐operated control, no‐treatment, mannitol‐infusion, and saline‐infusion groups. Light‐ and electron‐microscopic studies were performed on cerebral cortices of coronal sections prepared at the chiasmatic level, where the focal infarction develops abruptly in the area where disseminated selective neuronal necrosis is maturing. Measurements were performed to determine the following: (A) infarct size in HE‐stained specimens from all groups at 72 and 120 h after return of blood flow; (B) number of carbon‐black‐suspension‐perfused microvessels in the control and at 0.5, 3, 5, 8, 12 and 24 h in the no‐treatment and mannitol‐infusion groups; (C) area of astrocytic end‐feet; and (D) number of mitochondria in the astrocytic end‐feet in electron microscopic pictures taken at 5 h. The average decimal fraction area ratio of infarct size in the mannitol group was significantly reduced at 72 and 120 h, associated with an increased decimal fraction number ratio of carbon‐black‐suspension‐perfused microvessels at 3, 5 and 8 h, and a marked reduction in the size of the end‐feet at 5 h. Mannitol infusion performed immediately after restitution of blood flow following temporary cerebral ischemia remarkably reduced the size of the cerebral cortical focal infarction by decreasing the swelling of the end‐feet, thus preventing the microvascular compression and stasis and thereby microvasculogenic secondary focal cerebral ischemia., Article, NEUROPATHOLOGY.34(4):360-369(2014)

We report here a case of a 37-year-old man with human immunodeficiency virus (HIV) infection followed by JC virus (JCV) infection and primary central nervous system lymphoma (PCNSL). The patient had been infected with HIV type 1 due to blood products for hemophilia A during infancy. He had progression of nervous symptoms and was diagnosed with progressive multifocal leukoencephalopathy (PML) clinically at the age of 36, when his CD4-positive lymphocyte counts ranged between 350 and 450/μl. Oral mefloquine, intravenous methylprednisolone pulse therapy, and intravenous immunoglobulin were not effective for the PML, and the patient entered a vegetative state. Brain biopsy revealed JCV infection without pathological findings of PML. Eight months after the clinical diagnosis of PML, he developed respiratory failure and brain magnetic resonance imaging revealed a mass lesion in the brain stem. The patient died 19 months after the diagnosis of PML. Autopsy findings were compatible with PCNSL. EBV-encoded small RNA-1-positive cells were not detected. We present a case of JCV-positive PCNSL with HIV infection complicated with clinical PML.

Gliomatosis cerebri is a rare diffuse glioma that is neither mass-forming nor necrotic, and does not disrupt existing structures. Gliomatosis occurring in the cerebellum is known as gliomatosis cerebelli, and only three such cases examined by biopsy have been reported. Here we describe the first autopsy findings of a patient who was diagnosed as having gliomatosis in the cerebellum. Neuropathological examination identified the tumor cells as being positive for glial fibrillary acidic protein, vimentin and nestin, with atypical nuclei that were cashew-nut- or dishcloth-gourd-shaped. These tumor cells were dense in the right cerebellum, but also spread broadly throughout the brain including the left cerebrum and optic nerve. Mitotic figures were frequently seen in the cerebellum, brain stem and cerebrum. Scherer's secondary structures were evident not only in the cerebellum but also the cerebrum. No necrosis, microvascular proliferation or destruction of anatomical structures was detected in the whole brain. Differences in the origin of the tumors of the gliomatoses cerbri and cerebelli suggests these tumors are different types of brain tumors. Thus the findings support that the gliomatosis cerebelli is a novel type of brain tumor classification. Furthermore, by the similarities of the histological features among the tumors, it appears appropriate to establish a novel category of "gliomatosis encephali" which includes both gliomatosis cerebri and gliomatosis cerebelli.

Object Several materials, such as polyethylene glycol (PEG) hydrogel and fibrin glue, have been used to seal dural incisions after brain and spinal surgeries. Although the use of PEG sealant is gaining popularity, it can be associated with postoperative cerebrospinal fluid leakage and infection. However, the reasons for this association are currently unknown. The present study aimed to investigate the effects of PEG sealant and fibrin glue on wound healing and brain damage in vivo. Methods Oval-shaped bone defects and dural defects were created bilaterally over the parietal lobes of 22 Japanese white rabbits. The dural defects were covered with 0.5 ml of fibrin glue on one side and 0.5 ml of PEG sealant on the other side. Dural regeneration and brain damage were investigated in each harvested brain and dura mater using light microscopy. Results Dural regeneration was more effective in the presence of fibrin glue than it was with PEG sealant (p = 0.014). Of the 22 rabbits, 11 showed thick (Grades ++ and +++) dural regeneration by 28 days postsurgery in the hemisphere where fibrin glue was used, whereas Grade +++ dural regeneration was not observed in the PEG hydrogel hemisphere, and only 4 rabbits showed Grade ++ regeneration. Abscess and granulation formation also tended to be more severe when PEG hydrogel sealant was used. No Grade ++ granulation/abscess formation was observed with fibrin glue, and Grade + was only observed in 13 of 22 rabbits. Conversely, with PEG hydrogel sealant, only 2 rabbits did not show granulation/abscess formation, and Grade +, ++, and +++ granulation/abscess formation was observed in 8, 7, and 5 rabbits, respectively. The extent of cortical damage was significantly greater in rabbits with abscesses and granulations, compared with rabbits without these lesions (p = 0.007). Conclusions Dural regeneration tended to occur more rapidly with fibrin glue, whereas granulation was more likely with PEG hydrogel sealant, which led to postoperative complications. Histological analysis indicated that PEG hydrogel sealant inhibited the normal tissue healing process and that outcomes were improved by the use of fibrin glue.

We investigated the pathological features of frontotemporal lobar degeneration (FTLD) with fused in sarcoma protein (FUS) accumulation (FTLD-FUS) in the Japanese population. Only one out of nine FTLD-FUS cases showed pathology that corresponds to atypical FTLD with ubiquitin-positive inclusions (aFTLD-U). Five were basophilic inclusion body disease (BIBD) and two were neuronal intermediate filament inclusion disease. The last case was unclassifiable and was associated with dystrophic neurites (DNs) as the predominant FUS pathology. The results of this study indicate an ethnic difference from western countries. In Japan, BIBD is the most common subtype of FTLD-FUS and aFTLD-U is rare, a finding which contrasts with aFTLD-U being the most common form in western countries. Immunohistochemical analyses of these FTLD-FUS cases reveal that FUS abnormally accumulated in neuronal cytoplasmic inclusions (NCIs) and DNs has an immunohistochemical profile distinct from that of normal, nuclear FUS. NCIs and DNs are more readily stained than the nuclei by antibodies to the middle portion of FUS. Antibodies to the carboxyl terminal portion, on the other hand, stain the nuclei more readily than NCIs and DNs. Such an immunohistochemical profile of NCIs and DNs was similar to that of cytoplasmic granular FUS staining which we previously reported to be associated with dendrites and synapses. Redistribution of FUS from the nucleus to the cytoplasm could be associated with the formation of abnormal FUS aggregates in FTLD-FUS.

We evaluated the clinicopathological features of familial amyotrophic lateral sclerosis (ALS) with the fused in sarcoma (FUS) P525L mutation. Two sisters and their mother had a similar clinical course, which was characterized by the development of limb weakness at a young age with rapid disease progression. An elder sister, patient 1, progressed into a totally locked-in state requiring mechanical ventilation and died 26 years after the onset of the disease. In contrast, the younger sister, patient 2, died in the early stages of the disease. The patients had neuropathological findings that indicated a very active degeneration of motor neurons and multiple system degeneration, which led to marked brain and spinal cord atrophy in the long term clinical outcome. The multiple system degeneration included the frontal lobe, the basal ganglia and substantia nigra, cerebellum and related area. Compared with previously reported ALS cases, the severe degeneration of the frontal lobe and the striatum were the characteristic features in the patient 1 in this case study. The degeneration spread over multiple systems might be caused not only by the appearance of the FUS immunoreactive neuronal cytoplasmic inclusions but also by the degeneration of neuronal connections from the primary motor cortex and related areas.

In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI. The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients. Regardless of accumulated protein, all the patients showed common lesions in the pallido-nigro-luysian system, brainstem reticular formation, and cerebellar efferent system, in addition to motor neurons. In patients with pTDP-43-ir NCI, patients with NCI in the hippocampal dentate granule neurons (DG) showed a neuronal loss in the cerebral cortex, and patients without NCI in DG showed a preserved cerebral cortex. By contrast, in patients with FUS-ir NCI, patients with NCI in DG showed a preserved cerebral cortex and patients without NCI in DG showed marked cerebral degeneration. The cerebral cortex of patients with SOD1-ir NCI was preserved. Together, these findings suggest that lesions of the cerebrum are probably not necessary for progression to Stage V. In conclusion, patients with ALS that had progressed to result in communication Stage V showed rapidly-progressed symptoms, and their common lesions could cause the manifestations of communication Stage V., Article, ACTA NEUROPATHOLOGICA COMMUNICATIONS.4:107(2016)

An 84-year-old man presented with acute bilateral visual impairment 2 weeks after an upper respiratory tract infection. A few days later, he developed left hemiparesis, followed by paraplegia. The brain magnetic resonance imaging (MRI) showed high-intensity lesions in the right cerebellum, pons, left and right corona radiata, and right putamen. The diffusion weighted image also showed these high-intensity lesions. The spinal MRI showed an edematous, longitudinally extensive, cord lesion at the C5-Th6 level of the spine. Intravenous corticosteroid therapy was initiated, but the patient showed mild improvement. Although methylprednisolone pulse therapy was administered 5 times, he continued to present with clinical relapse and died on day 50. Anti-aquaporin-4 (AQP4) antibodies were detected in the patient's serum. Autopsy findings showed necrotic lesions at the spinal cord, brain, and optic chiasma and nerves. An immunohistopathological study showed the loss of AQP4- and glial fibrillary acidic protein (GFAP)-positive cells, with relatively preserved myelin basic protein (MBP)-positive myelin in the necrotic lesions. We diagnosed the patient as having neuromyelitis optica (NMO) because of the seropositivity for anti-AQP4 antibodies and on the basis of above-mentioned other immunohistochemical findings. It is difficult to distinguish NMO from ADEM clinically, when the patient has a preceding infection. NMO should be considered in patients with multifocal lesions in the central nervous system who have prominent myelitis and optic neuritis, irrespective of the postinfectious onset of the lesions and the sex and age of the patient.

We examined the mechanisms underlying the abrupt onset of the focal infarction in disseminated selective neuronal necrosis (DSNN) after temporary ischemia. Stroke-positive animals were selected according to their stroke-index score during the first 10 minutes after left carotid occlusion performed twice at a 5-hour interval. The animals were euthanized at various times after the second ischemia. Light- and electron-microscopical studies were performed chronologically on the coronal-cut surface of the cerebral cortex at the chiasmatic level, where focal infarction evolved in the maturing DSNN. We counted the number of neurons, astrocytes, and astrocytic processes (APs); measured the areas of end-feet and astrocytes; and counted the numbers of obstructed microvessels and carbon-black-suspension-perfused microvessels (CBSPm). Between 0.5 and 5 hours after ischemia, DSNN matured, with the numbers of degenerated and dead neurons increasing, and those of APs cut-ends decreasing; whereas the area of the end-feet and the numbers of obstructed microvessels increased and those of CBSPm decreased. At 12 and 24 hours after ischemia, the infarction evolved, with the area of end-feet and astrocytic number decreased; whereas the numbers of obstructed microvessels decreased and the CBSPm number increased. The focal infarction evolved by temporary microvascular obstruction because of compression by swollen end-feet.

Background and Purpose— Astrocytes support neuronal functions by regulating the extracellular ion-homeostasis and levels of neurotransmitters, and by providing fuel such as lactate to the neurons via their astrocytic processes (APs). Whether injured APs are associated with neuronal survival/death is still an unanswered question. We investigated APs in the neuropil, especially those around astrocytes and normal-appearing, degenerating, and dead neurons in cerebral cortical regions peripheral to the cortical infarction (RPI). Methods— Stroke-positive gerbils were euthanized at various times after the ischemic insult. Ultrathin sections were obtained from the RPI sectioned coronally at the infundibular level. We counted the number of normal-appearing, degenerated, and dead neurons and astrocytes in paraffin sections, the number of cut-ends and mitochondria in APs in the neuropil on electron-microscopic photographs, and determined the percent-volume of APs by Weibel point-counting method. We compared the number of cut-ends and mitochondria and percent-volume of APs around astrocytes at 5 hours and 48 hours, and around normal-appearing, degenerated, and dead neurons at 12 hours. Results— Although the number of astrocytes did not change (average of 12.3±0.20%) during 0 to 48 hours, that of the dead neurons increased from 9.71±1.34 to 44.39±1.40% during 5 to 48 hours postischemia. The number of normal-appearing APs and mitochondria in APs decreased respectively from 13.49±0.65 to 1.61±0.14/28.20 μm 2 and from 1.86±0.18 to 0.61±0.07/28.20 μm 2 in the neuropil during 0 to 48 hours. The number of normal-appearing APs around astrocytes decreased from 12.3±0.19 to 1.7±0.05/38.33 μm 2 with an increase in percent-volume of degenerated APs from 1.17±0.04 to 11.45±0.23%, from 5 to 48 hours postischemia. The number of normal-appearing APs decreased from 4.36±0.52 to1.56±0.17/38.33 μm 2 with an increase in percent-volume of degenerated APs, from 2.41±0.52 to 12.55±1.0%, from around the normal-appearing to dead neurons, at 12 hours. Conclusions— In the RPI, heterogeneous degeneration of APs was closely associated with disseminated selective neuronal necrosis and the maturation phenomenon seen in ischemic neuronal injury.

Respiratory muscle paralysis is inevitable in the clinical course of amyotrophic lateral sclerosis (ALS). Our objective was to electrophysiologically assess the function of the phrenic nerve and diaphragm motor cortex in ALS. Phrenic nerve M waves, diaphragm motor evoked potentials (MEPs) induced by transcranial magnetic stimulation, and their clinical correlations were analyzed in 29 ALS patients. The M wave amplitude was significantly lower in patients than in healthy control subjects (p

Niemann-Pick disease type C (NPC) is characterized by an accumulation of unesterified cholesterol in the endosomal/lysosomal (E/L) system, resulting in progressive neurodegeneration and death during early childhood. To investigate the cellular pathomechanism of nervous system involvement in NPC, continuous neural cell lines are desirable. In this study, we obtained neuronal and Schwann cell cultures and established spontaneously immortalized Schwann cell lines from dorsal root ganglia and peripheral nerves of NPC model mouse (spm/spm). One of the cell lines, designated SPMS9, had distinct Schwann cell phenotypes and was maintained over 10 months without phenotypic alterations. The level of Npc1 mRNA was markedly decreased, and NPC1 protein was not detectable in SPMS9 cells. These cells contained intracytoplasmic granules positive for filipin cholesterol staining and immunoreactive for GM2 ganglioside. Electron-microscopically, intracytoplasmic polymorphous membranous inclusions and vacuoles were demonstrated in SPMS9 cells. The treatment with an inhibitor of ceramide-specific glucosyltransferase, N-butyldeoxynojirimysin (NB-DNJ) markedly reduced the intracytoplasmic granular immunofluorescence for GM2 ganglioside in SPMS9 cells, whereas the amount of filipin-positive granules remained unchanged. The SPMS9 cells retained vesicular fluorescence of cationic dye acriflavine 16-24 hours after loading, indicating the defect of transmembrane efflux pump activity of NPC1 in the E/L compartment in these cells. These immortalized Schwann cells can be useful in studies on the nervous system lesions in NPC.

We describe a 52-year-old man with body weight loss and bulbar palsy, who exhibited muscle atrophy and weakness with fasciculation especially in the respiratory muscles 4 years prior to death, necessitating respiratory support for 4 years, but who was able to walk until the end-stage. He had no significant family history. Neuropathological examination revealed severe loss of motor neurons in the spinal cord and brainstem, and ubiquitin-positive skein-like inclusions and Bunina bodies in the remaining neurons. In addition, prominent degeneration of the anterolateral funiculus and severe loss of neurons in the intermediate zone of the spinal cord were evident, without marked alteration of the corticospinal tracts. Degeneration of the subthalamic nucleus, increased iron deposition in the substantia nigra, and axonal swelling, residual nodules and acidophilic granules in the spinal ganglia were found. The patient's condition was considered to have been a forme fruste or incipient form of widespread-type amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) with pallido-nigro-luysian atrophy (PNLA). The neuropathological features of the present case appear to be important for understanding the nature of widespread-type ALS and MND with PNLA.

We describe a 39-year-old Japanese woman with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Gly93-->Ser) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been available. The disease duration was 16 years, and she died of respiratory failure. The initial sign was weakness of the lower limbs. She had no clear upper motor neuron involvement. Respiratory muscle weakness had developed 1 year before her death. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke's nucleus, the spinocerebellar tract, the posterior column, the dentatorubral system, and anterolateral columns of the spinal cord. However, the patient has no Lewy body-like hyaline inclusions (LBHIs), which are characteristic features of mutant SOD1-related FALS with posterior column involvement. Based on clinical, genetic and pathological findings with a review of the literature, we suggest that degeneration of the dentatorubral system and the absence of LBHIs in our case are pathological features in FALS with the Gly93Ser mutation.

A study was conducted to clarify the effects of magnesium (Mg) administration in a rat Parkinson disease (PD) model involving culture of ventral mesencephalic-striatal cells with 1-methyl-4-phenylpyridinium (MPP+), based on recent evidence for significant loss of dopaminergic neurons exclusively in the substantia nigra of 1-year-old rats after exposure to low Mg intake over generations [Oyanagi, K., Kawakami, E., Kikuchi-Horie, K., Ohara, K., Ogata, K., Takahama, S., Wada, M., Kihira, T., Yasui, M., 2006. Magnesium deficiency over generations in rats with special references to the pathogenesis of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Neuropathology 26, 115-128.]. The results indicated that Mg might protect dopaminergic neurons in the substantia nigra from degeneration. The concentration of Mg in the culture medium varied from 0.8 mM, corresponding to the control condition, to 4.0 mM. Effects were estimated by counting the number of surviving dopaminergic neurons immunopositive for tyrosine hydroxylase and measuring the length of dopaminergic neurites. An increase in the concentration of Mg to 1.2 mM significantly inhibited the toxicity of MPP+, and a concentration of 4.0 mM completely prevented any decrease in the number of dopaminergic neurons. The length of dopaminergic neurites was significantly preserved in the presence of Mg at 1.2 and 4.0 mM. An increase in the concentration of Mg to 1.2 and 4.0 mM led to a significant amelioration in the length of dopaminergic neurites after MPP+ toxicity. This is the first report to document a significant and striking effect of Mg for prevention of neurite and neuron pathology, and also amelioration of neurite pathology in a PD model.

Motoneuron number and expression of cytoplasmic RNA and ribosomal RNA (rRNA) gene transcription activity in the facial nucleus were examined quantitatively and chronologically for up to 4 weeks in rats after facial nerve axotomy and avulsion in order to elucidate interrelationships in axonal changes. The right facial nerves of adult Fischer rats were avulsed at a portion of the outlet or axotomized at a portion of the foramen stylomastoideus. The number of large motoneurons in the facial nucleus was reduced by 40% 2 weeks after avulsion and by 70% 4 weeks after avulsion but displayed a 19% loss even 4 weeks after axotomy. The amount of cytoplasmic RNA decreased significantly and progressively from 1 day after avulsion. rRNA gene transcription activity in the large motoneurons of the facial nucleus decreased significantly beginning 30 min after both axotomy and avulsion, but the severity of the decrease was far more marked in the avulsion group, showing a 59% loss from the control value 4 weeks after avulsion. These findings indicate that rRNA gene transcription activity, expression of cytoplasmic RNA, and the number of motoneurons that survive are interrelated and that the decrease in rRNA gene transcription activity is a very early event in the phenomena observed in the axonal reactions of motoneurons.

While both neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD) show frontotemporal lobar degeneration and/or motor neuron disease, it remains unclear whether, and how, these diseases differ from each other. Here, we compared the clinicopathological characteristics of four BIBD and two NIFID cases. Atypical initial symptoms included weakness, dysarthria, and memory impairment in BIBD, and dysarthria in NIFID. Dementia developed more than 1 year after the onset in some BIBD and NIFID cases. Upper and lower motor neuron signs, parkinsonism, and parietal symptoms were noted in both diseases, and involuntary movements in BIBD. Pathologically, severe caudate atrophy was consistently found in both diseases. Cerebral atrophy was distributed in the convexity of the fronto-parietal region in NIFID cases. In both BIBD and NIFID, the frontotemporal cortex including the precentral gyrus, caudate nucleus, putamen, globus pallidus, thalamus, amygdala, hippocampus including the dentate gyrus, substantia nigra, and pyramidal tract were severely affected, whereas lower motor neuron degeneration was minimal. While alpha-internexin-positive inclusions without cores were found in both NIFID cases, one NIFID case also had alpha-internexin- and neurofilament-negative, but p62-positive, cytoplasmic spherical inclusions with eosinophilic p62-negative cores. These two types of inclusions frequently coexisted in the same neuron. In three BIBD cases, inclusions were tau-, alpha-synuclein-, alpha-internexin-, and neurofilament-negative, but occasionally p62-positive. These findings suggest that: (1) the clinical features and distribution of neuronal loss are similar in BIBD and NIFID, and (2) an unknown protein besides alpha-internexin and neurofilament may play a pivotal pathogenetic role in at least some NIFID cases.

Background and Purpose— Because the mechanism for scavenging acidophilic electron-dense dead neurons disseminated among the neuritic networks of surviving neurons in the ischemic penumbra of the cerebral cortex is still obscure, we investigated the fate of them up to 24 weeks after the ischemic insult. Methods— Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with a 5-hour interval. The animals were killed at various times after the second ischemic insult. Ultrathin sections including the second through fourth cortical layers were obtained from the neocortex coronally sectioned at the infundibular level in which the penumbra appeared and was observed by electron microscopy. We determined the percentages of resting, activated, and phagocytic microglia and astrocytes in the specimens obtained at various times postischemia. Results— The electron-dense neurons had been fragmented into granular pieces by invading astrocytic processes from the periphery of the dead neurons and only the central portion remained. These granular pieces were dispersed along the extracellular spaces in the neuropil. By 8 to 24 weeks, the central core portion became a tiny vesicular particle (3.5 to 5.5 μm in diameter) with a central dot. Microglia and astrocytes phagocytized these dispersed granular pieces. Conclusions— We found a novel scavenger mechanism in the ischemic penumbra, one by which dead neurons were fragmented by invading small astrocytic processes and only a thinned-out core portion remained, which finally became a tiny vesicular particle. The dispersed fragmented pieces were phagocytized by the microglia and astrocytes late, at 8 to 24 weeks postischemia.

Hereditary diffuse leukoenchephalopathy with axonal spheroids (HDLS) is a disease showing progressive dementia and convulsion in humans at the age around 40's. HDLS usually shows autosomal dominant inheritance, but frequently has de novo occurrence. The causative gene is reported to be a gene encoding the colony stimulating factor 1 receptor (CSF1R). Neuropathological examination reveals severe loss of axons with axonal spheroids in the cerebral white matter. Microglia and astrocytes are upregulated in the lesions.

Background and Purpose— Because the recovery process of axon terminals, synapses, and spine-dendrites in the ischemic penumbra of the cerebral cortex is obscure, we studied the temporal profile of these structures up to 12 weeks after the ischemic insult, using a gerbil model. Methods— Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with 5-hour interval. The animals were euthanized at various times after the second ischemic insult. Ultra-thin sections including the 2nd to 4th cortical layers were obtained from the neocortex coronally sectioned at the infundibular level, in which the penumbra appeared. We counted the number of synapses, spines and multiple synapse boutons, measured neurite thickness, and determined the percent volume of the axon terminals and spines by Weibel point counting method. Results— The number of synapses, synaptic vesicles and spines and the total percent volume of the axon terminals and spines decreased until the 4th day. From 1 to 12 weeks after the ischemic insult, these values increased to or exceeded the control ones, and neuritic thickening and increase in number of multiple synapse boutons occurred. Conclusions— In the ischemic penumbra, the above structures degenerated, with a reduction in their number and size, until 4 days and then recovered from 1 to 12 weeks after the ischemic insult.