1/194. Tau pathology in a family with dementia and a P301L mutation in tau.Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.- - - - - - - - - - ranking = 1keywords = parkinsonism (Clic here for more details about this article) |
2/194. Reversible dementia in idiopathic normal pressure hydrocephalus. A case report.OBJECTIVE: To present a woman with idiopathic normal pressure hydrocephalus (NPH) showing marked improvement in mental function after shunt operation. DESIGN: Case report. SETTING: primary health care. PATIENT: The clinical symptoms of gait disturbance, occasional urine incontinence and severely impaired mental function typical of NPH were all present. Although dementia predominated in the clinical picture, the diagnosis was confirmed by computer tomography (CT) and cerebrospinal fluid infusion test and cisternography. MAIN OUTCOME MEASURES: A marked improvement of mental functions was observed after shunt operation. RESULTS: Mini Mental State Examination score before shunt operation was 9 compared with 20 one year after operation. Also ventricle size was reduced as evaluated by CT scan. CONCLUSION: This reported case contrasts previous reports concluding that shunt responsive patients have only slight mental disturbances without significant improvement of mental status after shunt operation.- - - - - - - - - - ranking = 0.001719028232298keywords = idiopathic (Clic here for more details about this article) |
3/194. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative rna splicing regulatory elements.frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17) is caused by mutations in the tau gene, and the signature lesions of FTDP-17 are filamentous tau inclusions. Tau mutations may be pathogenic either by altering protein function or gene regulation. Here we show that missense, silent, and intronic tau mutations can increase or decrease splicing of tau exon 10 (E10) by acting on 3 different cis-acting regulatory elements. These elements include an exon splicing enhancer that can either be strengthened (mutation N279(K)) or destroyed (mutation Delta280(K)), resulting in either constitutive E10 inclusion or the exclusion of E10 from tau transcripts. E10 contains a second regulatory element that is an exon splicing silencer, the function of which is abolished by a silent FTDP-17 mutation (L284(L)), resulting in excess E10 inclusion. A third element inhibiting E10 splicing is contained in the intronic sequences directly flanking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inclusion. Thus, tau mutations cause FTDP-17 by multiple pathological mechanisms, which may explain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described here with tau pathology as well as amyloid and neuritic plaques.- - - - - - - - - - ranking = 5keywords = parkinsonism (Clic here for more details about this article) |
4/194. Clinical genetics of familial progressive supranuclear palsy.Recent studies have shown that progressive supranuclear palsy (PSP) could be inherited, but the pattern of inheritance and the spectrum of the clinical findings in relatives are unknown. We here report 12 pedigrees, confirmed by pathology in four probands, with familial PSP. Pathological diagnosis was confirmed according to recently reported internationally agreed criteria. The spectrum of the clinical phenotypes in these families was variable including 34 typical cases of PSP (12 probands plus 22 secondary cases), three patients with postural tremor, three with dementia, one with parkinsonism, two with tremor, dystonia, gaze palsy and tics, and one with gait disturbance. The presence of affected members in at least two generations in eight of the families and the absence of consanguinity suggests autosomal dominant transmission with incomplete penetrance. We conclude that hereditary PSP is more frequent than previously thought and that the scarcity of familial cases may be related to a lack of recognition of the variable phenotypic expression of the disease.- - - - - - - - - - ranking = 1keywords = parkinsonism (Clic here for more details about this article) |
5/194. A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy.Recently intronic and exonic mutations in the Tau gene have been found to be associated with familial neurodegenerative syndromes characterized not only by a predominantly frontotemporal dementia but also by the presence of neurological signs consistent with the dysfunction of multiple subcortical neuronal circuitries. Among families, the symptomatology appears to vary in quality and severity in relation to the specific Tau gene mutation and often may include parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We carried out molecular genetic and neuropathological studies on two patients from a French family presenting, early in their fifth decade, a cognitive impairment and supranuclear palsy followed by an akinetic rigid syndrome and dementia. The proband died severely demented 7 years after the onset of the symptoms; currently, his brother is still alive although his disease is progressing. In both patients, we found a Tau gene mutation in exon 10 at codon 279, resulting in an asparagine to lysine substitution (N279K). Neuropathologically, widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem nuclei as well as in the white matter were the hallmark of the disease. These deposits were shown by immunohistochemistry and immunoelectron microscopy, using a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes present in multiple tau regions. In the neocortex, tau-immunopositive glial cells were more numerous than immunopositive neurons; the deeper cortical layers as well as the white matter adjacent to the cortex contained the largest amount of immunolabeled glial cells. In contrast, some brain stem nuclei contained more neurons with tau deposits than immunolabeled glial cells. The correlation of clinical, neuropathological and molecular genetic findings emphasize the phenotypic heterogeneity of diseases caused by Tau gene mutations. Furthermore, to test the effect of the N279K mutation and compare it with the effect of the P301L exon 10 mutation on alternative splicing of Tau exon 10, we used an exon amplification assay. Our results suggest that the N279K mutation affects splicing similar to the intronic mutations, allowing exon 10 to be incorporated more frequently in the Tau transcript.- - - - - - - - - - ranking = 1keywords = parkinsonism (Clic here for more details about this article) |
6/194. Intracranial dural arteriovenous fistula (DAVF) presenting progressive dementia and parkinsonism.We studied three patients with dural arteriovenous fistula (DAVF). Major symptoms were progressive dementia and parkinsonism, both of which progressed in step-wise fashion. Two of the three patients showed diffuse cerebral white matter lesions on brain CT and MRI. Progressive dementia and parkinsonism in our patients could be caused by diffuse cerebral parenchymal disturbance: impaired cerebral circulation due to severe venous hypertension. DAVF is important for the differential diagnosis in patients with progressive dementia and parkinsonism.- - - - - - - - - - ranking = 7keywords = parkinsonism (Clic here for more details about this article) |
7/194. Familial dementia with lewy bodies (DLB).We report a rare familial case of dementia with lewy bodies (DLB). The patient was a man who died at the age of 51. His parents were first cousins. Among three siblings, two were diagnosed as probable cases of DLB, and one was a possible case, according to the clinical diagnostic criteria of the consortium on DLB. Following the patient's autopsy, he was found to have had DLB without neurofibrillary tangles or senile plaques (pure form of diffuse lewy body disease). His other siblings have been followed for more than ten years. Although these patients with familial DLB displayed clinical variability, all three siblings showed progressive dementia of early onset and progressive language disorder with paraphasia and difficulty in finding words. Psychotic features were also seen in the three siblings. The patient's sister showed compulsive behavior, and the other two siblings showed symptoms of parkinsonism. Neuropathologically, in addition to the usual neuropathology of DLB, the autopsy findings showed numerous small spheroids in the stratum pyramidale from the subiculum to CA1 of the hippocampus. Significant neuronal loss in CA2-3 of the hippocampus was detected. Axonal flow disturbance may be involved in the hippocampal formations of this incidence of familial DLB.- - - - - - - - - - ranking = 1.0021476255088keywords = parkinsonism, body (Clic here for more details about this article) |
8/194. FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation.Recently, mutations in the tau gene on chromosome 17 were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP-17). We describe a family carrying a missense mutation at nucleotide 1137 C --> T, resulting in the amino acid substitution P301S. methods of investigations include clinical, electrophysiological, and imaging techniques. This kindred presents with a novel phenotype characterized by an early onset of rapidly progressive frontotemporal dementia and parkinsonism in combination with epileptic seizures. We define the dopaminergic deficits as being predominantly presynaptic by the use of single-photon emission computed tomography with a dopamine transporter ligand. The association of this early-onset phenotype with P301S mutation is not entirely consistent with current criteria for the diagnosis of frontotemporal dementias and may encourage the search for tau mutations in diseases similar but not identical to FTDP-17. Also, the change from proline to serine suggests that this mutation might contribute to tau hyperphosphorylation.- - - - - - - - - - ranking = 6keywords = parkinsonism (Clic here for more details about this article) |
9/194. Electrophysiological observations in hereditary parkinsonism-dementia with Lewy body pathology.We studied the only two living affected individuals who are part of a previously reported kindred that expresses a hereditary parkinsonism-dementia syndrome with Lewy body pathology. The electrophysiological characteristics of the hyperkinetic movement disorders in these patients were examined to provide physiological insights into the clinical phenotype of this syndrome. Evaluation of both patients showed 7-9 Hz electromyographic discharges in upper extremity muscles during postural activation, and one patient showed a 4-5 Hz discharge pattern correlating to a rest tremor. Brief (<50 ms) myoclonic electromyographic discharges were seen in both patients, and a time-locked relationship to a focal cortical premovement electroencephalographic potential was elicited in one patient. Somatosensory evoked potentials were not enlarged and long latency reflexes were not enhanced. electroencephalography was normal in one patient but showed pathologic slow frequencies in the other. The electrophysiological findings show evolution which correlates with an apparent characteristic evolution of hyperkinetic movement disorders that accompanies the severe progression of parkinsonism-dementia in this kindred. These results have implications for the future study of this and similar syndromes.- - - - - - - - - - ranking = 6.0107381275442keywords = parkinsonism, body (Clic here for more details about this article) |
10/194. Parkinsonism, dementia and vertical gaze palsy in a Guamanian with atypical neuroglial degeneration.A 58-year-old Chamorro female patient, who died in 1993, was examined clinicopathologically. At the age of 51, she suffered from hemiparkinsonism, then bradykinesia, rigidity without tremor, and dementia. Extrapyramidal symptoms developed, and at the age of 57, vertical gaze palsy was noted. The clinical diagnosis was parkinsonism-dementia complex (PDC) with vertical gaze palsy. The brain showed atrophy in the frontal and temporal lobes, and the atrophy was accentuated in the dentate gyrus, Ammon's horn and parahippocampal gyrus. The basal ganglia, thalamus and midbrain were moderately atrophic. The substantia nigra and locus ceruleus were completely depigmented. Numerous neurofibrillary tangles (NFTs) were seen in the subiculum and amygdaloid nucleus. Many NFTs were evident in the parahippocampal gyrus, lateral occipitotemporal gyrus, insula, Sommer sector, basal nucleus of meynert, lateral nucleus of the thalamus, subthalamic nucleus and brain stem, and several were observed in the globus pallidus and hypothalamus. The Sommer sector, substantia nigra, locus ceruleus and basal nucleus of meynert showed severe loss of neurons, and a moderate loss of neurons was exhibited by the globus pallidus. These findings were apparently consistent with those associated with PDC. However, in this patient, severe neuronal loss was seen in the subthalamic nucleus and lateral nucleus of the thalamus, and grumose degeneration, which has not previously been reported in PDC, was seen in the dentate nucleus. In addition, many tufted astrocytes, which have been reported to occur in progressive supranuclear palsy (PSP) and postencephalitic parkinsonism, but scarcely observed in PDC, were present. Furthermore, astrocytic plaques, which have been considered as a specific finding of corticobasal degeneration (CBD), were observed in the cerebral cortex. On the other hand, granular hazy astrocytic inclusions, previously reported to occur in PDC, were not seen. Chromatolytic neurons were not observed. The question thus arises as to whether it is appropriate to consider this patient as having suffered from a combination of PDC, PSP and CBD. From the view points of absence of granular hazy astrocytic inclusions and chromatolytic neurons, and of tufted astrocytes in the neostriatum, it is conceivable that this patient is a case of a new disease entity.- - - - - - - - - - ranking = 3keywords = parkinsonism (Clic here for more details about this article) |
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