Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report an autopsy case of progressive supranuclear palsy (PSP) with a five-year clinical course. A 67-year-old man was suffering from a gait disturbance and mental deterioration. Neurological examination at the age of 71 revealed pseudobulbar palsy, horizontal ophthalmoplegia, and truncal dystonia, and a diagnosis of PSP was made. Mental deterioration including forgetfulness and character change was also noted, and the patient sometimes exhibited intermittent stuporous states. Cranial computed tomography and magnetic resonance images revealed moderate brain atrophy, predominantly in the frontal lobes. The patient died of bronchopneumonia at the age of 71. Neuropathological examination confirmed typical pathological changes of PSP, such as neuronal loss, neurofibrillary tangles, and fibrillary gliosis in the subcortical nuclei. Gallyas-Braak silver impregnation revealed neurofibrillary tangles, silver-positive glia and thread-like structures in degenerating subcortical nuclei. In addition to these classical lesions, the argentophilic structures were detected in the cerebral cortex, cortical white matter and cerebellar white matter. In the cerebral cortex, they were abundant mostly in the precentral gyrus and subcortical white matter. Immunohistochemical studies revealed that most silver-positive structures were also tau 2 antibody-positive. Thus, these argentophilic structures seemed to be closely related to abnormal tau protein. Their distribution in this case implies that lesions related to abnormal tau protein may occur more extensively in the brains of PSP than expected.
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PMID:[Widespread argentophilic structures in progressive supranuclear palsy--an autopsy case report]. 806 Jun 88

Alzheimer's disease (AD) is the most common form of dementia, and is characterized by a degeneration of neurones and their synapses, and a higher number of senile plaques (SP) and neurofibrillary tangles (NFT) compared with that found in non-demented individuals of the same age. NFT are composed of a hyperphosphorylated and ubiquitinated form of tau protein. Previous studies have found that in the cerebrospinal fluid (CSF) both tau and ubiquitin are increased in AD. We examined CSF-tau and CSF-ubiquitin in a population based sample of 85-year-olds, 26 demented (11 with probable Alzheimer's disease (AD), 13 with probable vascular dementia (VAD) and 2 with mixed (AD/VAD) type of dementia) and 35 non-demented individuals. CSF-tau was significantly higher both in the probable AD group (254 +/- 113 pg/mL; P < 0.01), and in the probable VAD group (247 +/- 75 pg/mL; P < 0.005), than in the non-demented group (171 +/- 78 pg/mL), but did not significantly differ between the probable AD and probable VAD groups. In contrast, CSF-ubiquitin did not significantly differ between the probable AD (100 +/- 24 ng/mL), probable VAD (102 +/- 16 ng/mL), and non-demented (97 +/- 27 ng/mL) groups. CSF-tau increased with increasing severity of dementia (P < 0.001), though no such relation was found for CSF-ubiquitin. Neither CSF-tau nor CSF-ubiquitin differed between patients with or without the apolipoprotein E E4 isoform. Higher CSF-tau and CSF-ubiquitin levels were also associated with increasing degree of cortical and central brain atrophy as measured by computerized tomography. The relationships between CSF-tau and severity of dementia and to brain atrophy suggest that CSF-tau may be used as a measure of neuronal/axonal degeneration in patients with dementia. We have previously shown a marked increase in both CSF-tau and CSF-ubiquitin in younger patients with AD and VAD. The less pronounced increase in CSF-tau and the lack of difference in CSF-ubiquitin in older patients suggest that the severity of the degenerative process is less in older than in younger demented patients.
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PMID:A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds: relation to severity of dementia and cerebral atrophy, but not to the apolipoprotein E4 allele. 884 37

We examined a 65-year-old patient with clinicopathological features that met the criteria of frontotemporal dementia (FTD), particularly frontal lobe degeneration (FLD). He came from a family with concentrated occurrence of dementia symptoms in the presenium. Neuropathological examination disclosed brain atrophy locally pronounced on the frontotemporal lobes with characteristic neuronal loss, microvacuolation and astrocytic gliosis. There were no pathological hallmarks such as senile plaques, Pick bodies (PBs), achromatic cells and neurofibrillary tangles. Precise separation of FTD from Pick disease (PD) and motor neuron disease with dementia (MNDD) has not yet been established, and they are included in one spectrum. Antibodies against paired helical filament tau protein demonstrated immunopositive cytoskeletal structures within the neurons as well as the glial cells in the brain of the present case. They were selectively stained with tau 199/202 but not tau 396, which were provided newly to recognize phosphorylation at Ser 199/202 or Ser 396 in tau, respectively. We investigated tau pathology in the present case in comparison to 8 cases with PD that were clinicopathologically confirmed. Neither tau 199/202 nor tau 396 stained the CNS structures in PD cases with few PBs, while both stained evidently those as well as PBs in PD cases associated with many PBs; so that the present case could be distinguished from PD on the basis of the immunoreactivity to site-specific phosphorylated tau. Our result suggests that FTD, especially familial FLD type might involve unique tau pathology, no matter whether FLD is a distinct entity from PD, or a variant form in the wide FTD spectrum including PD and MNDD and other related disorders.
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PMID:Selective expression of Ser 199/202 phosphorylated tau in a case of frontotemporal dementia. 952 99

The unequivocal diagnosis of Alzheimer's disease (AD) rests on histopathological evidence at brain autopsy or biopsy. The morphology of AD includes cerebral atrophy, deposition of beta A4 amyloid (A beta) (senile plaques and amyloid angiopathy), neuritic changes (neuritic plaques, neurofibrillary tangles (NFT) and neuropil threads) with formation of paired helical filaments (PHF) containing polymerized hyperphosphorylated tau protein triplet, causing disruption of the neuronal cytoskeleton with loss of synapses and neurons, with altered cortico-cortical connectivity, leading to disconnection of the cerebral cortex. Defining criteria for the morphologic diagnosis of AD is difficult due to the phenotypic heterogeneity of the disease, the absence of specific markers, and overlap of AD morphology with that observed in non-demented elderly individuals. This gray zone between normal to pathologic aging and full-fledged AD represents an important diagnostic problem and should be overcome by better standardized criteria that will allow to minimize interrater and interlaboratory variability in the diagnosis of AD. Current criteria for the morphologic diagnosis of AD are based on (semi)quantitative assessment of diffuse and neuritic plaques (NIA), exclusively neuritic plaques (CERAD), plaques and NFT in neocortex and hippocampus (Tierney et al., 1988), and staging of hierarchic spreading of neuritic AD changes (Braak and Braak, 1991); all of them have weaknesses and need to be revalidated. Multivariant analysis of an autopsy series of elderly subjects revealed significant correlations between psychostatus and both the CERAD criteria and Braak staging. Recent recommendations of the NIA-Reagan Institute for the morphologic diagnosis of AD are presented. Although the role of plaques and NFT in the pathogenesis of AD remains undetermined, clinicopathological correlative studies have shown that both lesions, if present in sufficient numbers, particularly in the neocortex, are considered the best morphological signposts for AD. Recent studies on neuron death in AD that, at least in part, appears different from classical apoptosis and may precede the symptomatic stage of AD, have shown varying results indicating only indirect relationship between DNA fragmentation and both A beta deposition and NFTs. Both these AD-typical markers appear to increase the risk of cells to degenerate, but are not the sole responsibles of the degenerative process in AD, the basic mechanisms of which remain to be elucidated.
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PMID:Neuropathology of Alzheimer's disease: a critical update. 985 Sep 17

The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 +/- 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy-both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.
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PMID:A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24. 1521 18

Alzheimer's disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL-CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.
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PMID:Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component. 1526 64

Constitutive genomics are probably determinant for the onset of dementia in conjunction with cerebrovascular and environmental factors. Furthermore, pharmacogenomic studies predict that the therapeutic response in Alzheimer's disease (AD) is genotype-specific, and that the expression of genes involved in the regulation of drug metabolism can influence efficacy and safety issues in pharmacotherapy. AD and dementia with a vascular component (DVC = VD + MXD) are the most prevalent forms of dementia. These clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folic acid and vitamin B(12) levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: (a) anthropometric values, (b) cardiovascular function, (c) blood pressure, (d) lipid metabolism, (e) uric acid levels, (f) peripheral calcium levels, (g) liver function (GOT, GPT, GGT), (h) alkaline phosphatase, (i) lactate dehydrogenase, (j) red and white blood cells, (k) regional brain atrophy (left temporal region, inter-hippocampal distance) and (l) brain blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30 to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0 to 5%. The relative polymorphic variation in genetic clusters integrated by 2, 3 or 4 genes associated with AD ranges from 1 to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are essential for the expression of dementia symptoms that might be accelerated or induced by environmental and/or cerebrovascular factors.
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PMID:Genomics and phenotypic profiles in dementia: implications for pharmacological treatment. 1534 38

More than 180 genes distributed across the human genome are potentially involved in the pathogenesis of Alzheimer's disease (AD). The AD population shows a higher genetic variation rate than the control population. Significant differences in allelic distribution and frequency exist when AD-related polygenic clusters are compared with other forms of dementia, indicating that the genetic component in neurodegenerative dementia differs from that of other CNS disorders. The characterization of AD genotype-related phenotypic profiles reveals substantial differences in biological markers among AD clusters associated with different genes and/or allelic combinations. AD and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in their major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometric values, cardiovascular function, blood pressure, lipid metabolism, uric acid metabolism, peripheral calcium homeostasis, liver function, alkaline phosphatase, lactate dehydrogenase, red and white blood cells, regional brain atrophy, and brain blood flow velocity. Functional genomic studies incorporating apolipoprotein E (APOE)-related changes in biological markers extended the difference between AD and DVC by up to 57%. Structural genomic studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS, and PRNP, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate in the range of 30-80%, depending upon genes and genetic clusters. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1 to 3%. The main phenotypic differences in AD are genotype dependent, indicating a powerful influence of polygenic factors on the AD phenotypic profile. All these genotypic and phenotypic variations bring about important consequences for the pharmacogenomics of AD.
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PMID:Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia. 1558 76

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a group of hereditary, adult-onset, progressive neurodegenerative syndromes, which lead to the accumulation of intracellular deposits of hyperphosphorylated tau protein. Since the original definition of FTDP-17 in the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 80 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 35 different mutations outside and on exon 10 of tau gene. The symptomatic onset of FTDP-17 is usually insidious. The clinical phenotypes are characterized by behavioral, cognitive and motor disturbances that may occur in various combinations and in varying degrees of severity. Affected individuals develop a constellation of signs, including at least two of the three cardinal manifestations of FTDP-17. It should be noted that there is significant clinical phenotypic heterogeneity in individuals with different mutations. In addition, interfamilial and intrafamilial variability of clinical phenotype is often seen among individuals carrying the same mutation. Macroscopically, the degree of brain atrophy observed varies with a brain weight ranging from approximately 825 to 1,290 grams. In the advanced stages, the degree of atrophy varies and may be present in the frontal and temporal lobes, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus and ventral hypothalamus. Microscopically, the neuropathologic hallmark is the presence of tau protein deposits in neurons or in both neurons and glia. The cellular pathology of the neuron may resemble that of Alzheimer disease (AD) or Pick disease for the presence of neurofibrillary tangles or Pick bodies. The cellular pathology of glial cells may resemble that of progressive supranuclear palsy or corticobasal degeneration for the presence of coiled bodies in oligodendroglial cells, tufted astrocytes or astrocytic plaques. Mutations in exons 1, 10 and intron following exon 10 are associated with neuronal and glial tau deposition. Mutations in exons 9, 11, 12 and 13 lead to deposits of tau filaments predominantly in neurons.
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PMID:[Clinical, genetic and pathological aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)]. 1565 19

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the MAPT gene which encodes the microtubule-associated protein tau. This hereditary tauopathy is a rare clinical syndrome, affecting approximately two hundred kindreds and about six hundred individuals bearing thirty nine known MAPT mutations. The disorder is thought to be related to the altered proportion of tau protein isoforms or the ability of tau to bind to microtubules and to promote microtubule assembly and organization. The clinical presentation of FTDP-17 includes behavioral, cognitive and motor abnormalities. This disorder has both a variable course and phenotype. Gross neuropathological examination reveals brain atrophy, especially of the frontal and temporal lobes, and selective atrophy of the basal ganglia and brainstem nuclei. The major microscopic features of FTDP-17 demonstrate the presence of neurofibrillary tangles, neuropil threads and glial inclusions composed of insoluble tau protein. Distribution and amount of tau deposits vary, depending on the type of MAPT mutation. The definitive diagnosis of FTDP-17 requires a set of clinical and pathological features combined with a molecular genetic analysis. Currently, there is no known effective treatment for FTDP-17.
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PMID:Frontotemporal dementia and parkinsonism linked to chromosome 17. 1641 90


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