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1/10. Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations.

    Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices. Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia. Two affected family members presented with symptoms of dementia and later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls. The mutation is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.
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2/10. Progressive supranuclear palsy on guam.

    This is the first report demonstrating that progressive supranuclear palsy (PSP) exists on guam. This 75-year-old Guamanian Chamorro patient with slight dementia and rigidity with restriction of ocular up gaze was diagnosed as parkinsonism-dementia complex (PDC) of guam clinically. However, neurofibrillary tangles (NFTs) were scarcely seen in the cerebral cortices and hippocampus, but many NFTs, composed of 15-17 nm straight tubules, were detected in the subthalamic nucleus and brain stem. A large number of tuft-shaped astrocytes were observed in the putamen and motor cortex, and numerous argyrophilic grains were seen in the CA1 and subiculum. These pathological findings are different from those of PDC and consistent with PSP. The present case indicates that PSP and PDC clinically resemble each other, and that precise neuropathological examination is indispensable for the final diagnosis of the patient with parkinsonism, dementia and disturbance of vertical external ocular movement.
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3/10. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype.

    MAPT, the gene encoding tau, was screened for mutations in 96 progressive supranuclear palsy subjects. A point mutation (R5L) was identified in a single progressive supranuclear palsy subject that was not in the other progressive supranuclear palsy subjects or in 96 controls. Functionally, this mutation alters the ability of tau to promote microtubule assembly. Analysis of soluble tau from different brain regions indicates that the mutation does not affect the ratio of tau isoforms synthesized. Aggregated insoluble tau from subcortical regions was predominantly four-repeat tau with no or one amino terminal insert (0N4R and 1N4R). Insoluble tau from cortical regions also contained 1N3R tau. Thus, the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain-of-function mechanism.
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4/10. A case of dementia parkinsonism resembling progressive supranuclear palsy due to mutation in the tau protein gene.

    BACKGROUND: Few cases of frontotemporal dementia parkinsonism (FTDP-17) have been described in the literature. To our knowledge, this is the first Italian case. OBJECTIVE: To report a case of FTDP linked to chromosome 17, exhibiting progressive supranuclear palsy on initial examination. PATIENT: A 50-year-old woman had a 4-year history of behavior changes associated with slowly progressive mental decay and parkinsonism, with poor balance, supranuclear vertical gaze palsy, and bradykinesia. The symptoms were not responsive to dopaminergic therapy. Her father had died at age 46 years after a 7-year history of parkinsonism, and her brother, diagnosed as having progressive supranuclear palsy, died at age 45 years. RESULTS: magnetic resonance imaging showed mild midbrain atrophy, results of an electroencephalogram were normal, and cognitive evaluation showed moderate cognitive impairment, especially evident in the executive and attentional functions. genetic testing revealed a tau gene mutation at codon 279 (AAT-->AAG) of exon 10. CONCLUSION: Exon 10 mutations (including the N279K mutation) that result in overproduction of the tau isoform with 4 microtubule binding motifs seem to be associated with a mainly parkinsonian phenotype at disease onset.
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5/10. Progressive supranuclear palsy-like syndrome in two siblings of a consanguineous marriage.

    Two siblings of a consanguineous marriage showed identical clinical features consisting of supranuclear vertical ophthalmoplegia, bradykinesia, rigidity, stooped posture, pseudobulbar palsy, and dementia, all beginning in the sixth decade. There was no history of encephalitis or of exposure to known chemicals. L-Dopa therapy was only partially and temporarily effective. autopsy of one patient revealed extensive neurofibrillary degeneration with prominent involvement of the limbic system. There were no senile plaques or lewy bodies. Under electron microscopy, there were paired helical filaments as well as 15-nm-wide straight tubules. The diffuse appearance of neurofibrillary tangles, predominant in the limbic system, and familial occurrence are unusual in progressive supranuclear palsy; these cases may, therefore, constitute a different, distinctive clinicopathologic disease.
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6/10. Occurrence of 15-nm-wide straight tubules in neocortical neurons in progressive supranuclear palsy.

    Ultrastructural investigations were carried out on the cerebral neocortex in two cases of progressive supranuclear palsy. In both cases, characteristic 15-nm-wide straight tubules were observed in the neurons. The numbers of cells containing the straight tubules and of tubules in individual cells were small. However, the occurrence of the tubules strongly suggests that the cerebral neocortex is also exposed to the disease process in progressive supranuclear palsy.
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7/10. Progressive supranuclear palsy with limbic system involvement: report of a case with ultrastructural investigation of neurofibrillary tangles in various locations.

    An autopsied case of a 65-year-old woman with progressive supranuclear palsy (PSP) characterized by dementia, hallucination and delirium is described. On neuropathologic examination, widespread neurofibrillary tangles (NFTs) associated with neuronal cell loss and gliosis were observed in the basal ganglia, subthalamic nucleus and various brain stem nuclei, corresponding to the well-established pathology of PSP. In addition, a large number of NFTs with neuronal cell loss were shown in the hippocampus, parahippocampal gyrus, amygdaloid nucleus, subcallosal area, anterior perforated substance, cingulate gyrus and anterior olfactory nucleus. Ultrastructurally, NFTs observed in the periaqueductal central grey, locus ceruleus and hippocampus were composed almost exclusively of straight tubules. On the other hand, those in the amygdaloid and anterior olfactory nuclei were composed mainly of twisted tubules of Alzheimer type. NFTs composed of twisted tubules alone were not observed. The present case was considered as a rare peculiar type of PSP which showed massive systemic appearance of NFTs in the so-called limbic system.
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8/10. Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy.

    The neuropathological findings, including immunohistochemistry and electron microscopy, of two patients with clinical findings consistent with corticobasal degeneration (CBD) are reported. Both patients showed degeneration of the precentral cortex, the substantia nigra, the pallidum, and the thalamus. Many ballooned neurons were seen in the cerebral cortex, and argentophilic, skein-like inclusions suggesting neurofibrillary tangles (NFTs) were found in the brain stem and precentral cortex in patient 1. In contrast, patient 2 clearly showed NFTs in the brain stem and dentate nucleus which were indistinguishable from those seen in progressive supranuclear palsy (PSP), while only a few ballooned neurons were found in the cerebral cortex. Gallyas silver stain showed many argentophilic inclusions suggesting NFTs in the brain stem, subcortical nuclei, and cerebral cortex in both patients. immunohistochemistry for tau showed tau-positive neurons in the cerebral cortex, brain stem, subcortical nuclei and spinal cord, and tau-positive glial cells were seen in the cerebral cortex, white matter and subcortical nuclei, and thread-like structures were seen in the cerebral cortex and white matter. Electron microscopy of the brain stem showed NFTs consisting of paired helical filaments in patient 1, and paired helical filaments and straight tubules in patient 2. Immunoelectron microscopy revealed parallel tau-positive filaments in the cerebral cortex in patient 1. From the two patients, the wide-spread appearance of abnormal tau and NFTs is one of the essential pathological features in CBD, and it also appears that CBD and PSP have some common underlying pathological processes. Patient 2 is closer to PSP than patient 1 and suggests CBD would link to PSP.
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9/10. Corticobasal degeneration: etiopathological significance of the cytoskeletal alterations.

    We have studied brain tissues from three patients with corticobasal degeneration (CBD) histologically, ultrastructurally and immunohistochemically. Ballooned neurons in the cerebral cortex and severe degeneration of the substantia nigra were observed in them all and weakly basophilic neurofibrillary tangles (NFTs) were distributed widely in the basal ganglia and brain stem. Ultrastructural examination demonstrated that the NFTs comprised characteristic 15-nm-wide straight tubules, which showed positive immunohistochemical staining with an antibody against tau, but not ubiquitin. Tau-immunoreactive neuronal cell bodies without NFTs also were found in the cerebral cortex and subcortical nuclei, predominantly in the brain stem, and the greatest number of tau-positive glial inclusions occurred in the cerebral gray and white matter of the pre- and post-central gyri. These inclusions comprised tubular structures with diameters of about 15 nm and were localized in the oligodendroglial cellular cytoplasm and processes. These findings indicate that there is a close cytoskeletal pathological relationship between CBD and progressive supranuclear palsy.
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10/10. Corticobasal degeneration: widespread argentophilic threads and glia in addition to neurofibrillary tangles. Similarities of cytoskeletal abnormalities in corticobasal degeneration and progressive supranuclear palsy.

    A 57-year-old man had exhibited cortical sensory disturbance, rigidity, spasticity, dementia, alien hand, grasp reflex, supranuclear ophthalmoplegia, pseudobulbar palsy, and neck dystonia for 4 years. Histological examination of autopsied specimens revealed neuronal loss in the cerebral cortex, with ballooned neurons, subthalamic nucleus, substantia nigra, basal ganglia, midbrain tegmentum, and the thalamus. There were neurofibrillary tangles in the subthalamic nucleus and the substantia nigra. Gallyas-Braak silver impregnation demonstrated numerous argentophilic tangles, threads, and a few argentophilic glia in the cerebral cortex, subcortical white matter, particularly in the precentral gyrus, subcortical nuclei, and the brainstem. These argentophilic structures were largely positive for tau, and negative for ubiquitin, paired helical filaments, and phosphorylated neurofilament. Ultrastructurally, 15-nm-wide straight tubules were observed in the neurons of the substantia nigra, globus pallidus, and the precentral cortex, coexisting with a few twisted tubules periodically constricted at 160- to 230-nm intervals. It was conclusively shown that Gallyas- and tau-positive cytoskeletal abnormalities occurred widely in brain of corticobasal degeneration. Both distribution and morphology of abnormal phosphorylated tau protein in corticobasal degeneration appear to resemble these features in progressive supranuclear palsy. These findings suggest a common cytoskeletal etiopathological significance in corticobasal degeneration and progressive supranuclear palsy.
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