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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.

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.

Hyaluronic acid in the basilar artery of 10 patients with sporadic amyotrophic lateral sclerosis (ALS) and 7 age-matched control subjects was examined histochemically and densitometrically. The intensity of staining with alcian blue was significantly increased (P=0.0007) in the media in ALS patients compared with that in control subjects. The staining was virtually eliminated by Streptomyces hyaluronidase. These results clearly indicate an increase of hyaluronic acid in the media of the basilar artery in ALS patients.

We performed a quantitative investigation of arginine-vasopressin (AVP) immunopositive neurons in the suprachiasmatic nucleus (SCN), which is the endogenous clock of the brain of a patient with multiple system atrophy (MSA) who exhibited nocturnal polyuria associated with decreased urinary specific gravity and depression of nocturnal AVP secretion. Eleven age- and sex-matched subjects were used as controls. Although, the number of AVP-positive neurons was decreased in neither the supraoptic nucleus nor the paraventricular nucleus, the number of AVP-positive neurons in the SCN was decreased and gliosis was present in the SCN. The cytoplasmic area of AVP-immunopositive neurons in the SCN was smaller in the patient than in the control subjects. These findings raise the possibility that SCN is involved in MSA and the neurodegeneration in the SCN results in altered circadian rhythm of AVP secretion and nocturnal polyuria.

We report a biopsy-proven and genetically determined case with leukoencephalopathy showing autosomal dominant inheritance and pre-senile dementia. A 51-year old woman gradually developed a decline in cognitive functions with aphasia and epileptic seizures. Four of her family members were diagnosed as having dementia in their forties to sixties. Five years later she became apathetic and bed-ridden. Brain MRI initially showed fronto-temporal dominant cerebral atrophy with multiple small lacunar-like lesions in the deep white matter, but these white matter lesions became diffuse at an advanced stage. Such possibilities as hereditary vascular or fronto-temporal dementia were clinically suspected, but her family members requested a definitive diagnosis. Brain biopsy showed severe loss of myelin and axons in the white matter with relatively preserved cortical structure. The remaining axons disclosed irregular shapes with the formation of many spheroids, and these findings were consistent with a histopathological diagnosis of neuroaxonal dystrophy. DNA analysis disclosed a novel heterozygous c.2345G>A (p.782Arg>His) mutation in exon 18 of the colony stimulating factor 1 receptor gene (CSF1R). Hereditary diffuse leukoencephalopathy with axonal spheroids should be included in the differential diagnosis of familial occurrence of pre-senile dementia.

Midkine (MK) is a heparin-binding growth factor that occurs as a product of the retinoic acid-inducible gene. Alteration of MK expression in ischemic brain lesions was examined in humans immunohistochemically in nine patients and in two control subjects without neurological disorders. Some neurons were MK-immunopositive, but no evident MK-immunoreactivity was observed in astrocytes in brains of control subjects. In the ischemic lesions, significant elevation of MK-immunoreactivity in the astrocytes and depletion of the reactivity in neurons were seen, especially in the early period, where edema and eosinophilic neurons were prominent. On the other hand, MK-immunoreactivity was not observed in hypertrophic and fibrillary astrocytes in the later period. These findings suggest that the MK in astrocytes play some role in the repair process in the early period of the ischemic brain lesions in humans.

We report a 57-year-old woman with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement of 11 years duration. The patient had been on a respirator for more than 5 years before death. In addition to the well established pathology of this form of familial ALS, there were obvious degenerative changes in the brainstem tegmentum, including the reticular formation, cerebellar cortex, dentate and red nuclei, thalamus and mammillary body. Of great interest in this case was intracytoplasmic accumulation of neurofilaments in the remaining neurons in these areas, some of which, for instance, those in the oculomotor and abducens nuclei, still showed only minimal loss. This patient had survived considerably beyond the point of respiratory failure, which is the final stage in the natural history of the disease. We considered that in this patient the underlying degenerative process of the disease had become manifested in wider areas than recognized previously during the prolonged clinical course due to respiratory support. However, whether or not such widespread degeneration would occur in all patients with this disease who survive longer with the help of respiratory support awaits further studies.

In an autopsy case of galactosialidosis, G M3 , G M2 , G M1 , and G D1a were accumulated in sympathetic and spinal ganglia and grey matter of the spinal cord. Especially, the accumulations of G M3 and G M2 amounted to 41- and 86-fold increases in sympathetic ganglia, respectively, as compared to normal controls. In addition LacCer, GA 2 and GA 1 were accumulated in sympathetic and spinal ganglia. The accumulations of G M3 and G D1a are considered to be the result of defective lysosomal sialidase activity and the accumulation of G M1 , LacCer and GA 1 is also considered to be due to decreased β-galactosidase activity in this disorder. To better understand the possible mechanism of G M2 accumulation, we determined the activity of G M2 synthesizing enzyme (G M3 : UDP-GalNAc transferase), as well as hexosaminidase activity, in sympathetic ganglia, but they did not change. Abnormal ganglioside and neutral glycosphingolipid metabolism, as well as sialyloligosaccharide and sialylglycoprotein metabolism, may be involved in the pathogenesis of this disorder.