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)

An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
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PMID:Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22. 939 79

In order to treat frontotemporal dementia (FTD) we must first evaluate the patient's medical condition, as well as his or her social setting (caregiver, financial resources, home characteristics). Primary health-care team must receive information about the patient's disease, and the family should be informed about the disease itself and the social resources they can ask for. It is advisable to formulate a therapeutic scheme including some counsels to improve the suitability of environment, social help measures, behaviour therapy, cognitive stimulation and pharmacological treatment. Atypical antipsychotics have improved "positive symptoms" as logorrhoea, wandering, agitation and aggression, without impairing cognitive function. Selective serotonin reuptake inhibitors improve depressive symptoms, compulsions, food craving and disinhibition. A few reports suggest that idazoxan (alpha 2-noradrenergic antagonist) can improve attention, verbal fluency and planning efficiency. In some cases with "FTD and parkinsonism linked to chromosome 17" it could be justified to perform a genetic analysis to the offspring, in order to know if genetic counseling is necessary. An inflammatory reaction has been observed in brain damaged areas, and therefore antiinflammatory treatment efficacy should be investigated. It would also be interesting to look for neuroprotective agents that lessen the tau protein abnormality. All types of receptors which are involved in FTD should be identified, and then their selective agonists or antagonists could be administered in synergic combinations. We hope that all genetic alterations producing or facilitating FTD are eventually known, and harmless curative means are developed.
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PMID:[Frontotemporal dementia: therapeutic possibilities]. 1072 74

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.
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PMID:Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. 1122 Jul 33

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with frontotemporal dementia (FTD). FTD most often presents with either a change in personality or behavior, such as social withdrawal, increased gregariousness, disinhibition, or obsessive behaviors; or with impairment of language function. Memory difficulties are common, but usually are less prominent than these other symptoms in the early stages of the disease. Frequently, psychiatric diagnoses are initially the primary consideration. Cases may be either familial or sporadic. In this familial case, an autopsy was ultimately performed and revealed findings characteristic of FTD, with grossly evident focal brain degeneration in the frontal and temporal regions, microscopic signs of gliosis, and cellular abnormalities of the intracellular microtubule-associated protein tau.
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PMID:Frontotemporal dementia. 1284 24

Quantitative neuropsychiatry has provided increasingly precise descriptions of behavioral phenotypes associated with neurodegenerative disorders. Degenerative diseases of the brain are disturbances of protein metabolism, with failure of protein degredation by the ubiquitin-proteosome system, production of neurotoxic peptide oligomers, and accumulation of intracellular protein deposits. Abnormalities of amyloid beta peptide, alpha-synuclein protein, and hyperphosphorylated tau protein account for more than 90% of degenerative dementias. Functionally related neuroanatomical systems have shared metabolic characteristics and common vulnerabilities to protein dysmetabolism, providing the basis for phenotypes that reflect the underlying proteotype. Patients with alpha-synuclein disorders are particularly prone to hallucinations, delusions, and rapid eye movement sleep behavior disorder. Patients with tauopathies manifest disproportionate disinhibition and apathy, and may exhibit compulsions. Alzheimer's disease is a triple proteinopathy with abnormalities of A-beta, tau, and alpha-synculein leading to a complex behavioral phenotype. This molecular approach to neuropsychiatry may assist in understanding the mechanisms of degenerative diseases, provide insight into the pathophysiology of neuropsychiatric symptoms, and contribute to monitoring disease-modifying therapies.
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PMID:Toward a molecular neuropsychiatry of neurodegenerative diseases. 1289 66

The neuropathological hallmark shared between Alzheimer's disease (AD) and familial frontotemporal dementia (FTDP-17) are neurofibrillary tangles (NFT) which are composed of filamentous aggregates of the microtubule-associated protein tau. Their formation has been reproduced in transgenic mice, which express the FTDP-17-associated mutation P301L of tau. In these mice, tau aggregates are found in many brain areas including the hippocampus and the amygdala, both of which are characterized by NFT formation in AD. Previous studies using an amygdala-specific test battery revealed an increase in exploratory behavior and an accelerated extinction of conditioned taste aversion in these mice. Here, we assessed P301L mice in behavioral tests known to depend on an intact hippocampus. Morris water maze and Y-maze revealed intact spatial working memory but impairment in spatial reference memory at 6 and 11 months of age. In addition, a modest disinhibition of exploratory behavior at 6 months of age was confirmed in the open field and the elevated O-maze and was more pronounced during aging.
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PMID:Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. 1687 31

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.
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PMID:Clinical and molecular aspects of frontotemporal dementia. 1690 93

The management of frontotemporal dementia (FTD), a disorder characterized by varied behavioral symptoms, primarily involves the use of psychoactive medications. Although there are no approved treatments for the disorder, selective serontonin receptor inhibitors, such as sertraline, paroxetine, or fluoxetine, can decrease disinhibition-impulsivity, repetitive behaviors, and eating disorders in FTD. Low doses of trazodone or an atypical antipsychotic such as aripriprazole can also help manage significantly disturbed or agitated behavior. The acetylcholinesterase inhibitors used for patients with Alzheimer's disease have not had significant efficacy for patients with FTD, but memantine, another dementia medication, is under investigation for the treatment of this disorder. In addition to drug therapy, the nonpharmacological management of patients with FTD focuses on education, behavioral interventions, and care of the caregivers. Most recently, investigators have initiated steps toward rational drug therapy with the development of outcome measures for clinical drug trials in FTD and the characterization of treatment targets such tau protein or the TAR DNA-binding protein 43. This approach holds great promise for an eventual treatment for this devastating early-onset dementia.
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PMID:Frontotemporal dementia: therapeutic interventions. 1918 75

We describe a 46-year-old woman who presented with a 2-year history of aprosodic speech together with apathy and disinhibition. Brain magnetic resonance imaging showed subcortical hyperintensities over both insular regions that later extended to both frontal and temporal cortices. The post-mortem exam showed a massive tau protein deposition throughout the brain. No mutation in the gene MAPT was detected. This case illustrates an atypical clinical-radiological presentation of a frontotemporal dementia with an unusual speech and abnormal signal of both insulae. Furthermore, it reinforces the crucial role of the insula in the development of symptoms in frontotemporal dementia.
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PMID:Aprosodic speech with insular hyperintensities and 4R Tau pathology on autopsy. 2299 54

Frontotemporal dementia (FTD) encompasses several clinical syndromes that involve a progressive change in behavior and/or language; it is more common than Alzheimer's disease in early-onset dementia under the age of 60 years. In the behavioral variant of FTD (bvFTD) patients have social and emotional changes with prominent disinhibition, apathy, lack of empathy, changes in diet, and repetitive behaviors. Motor neuron disease or parkinsonism are seen in association with bvFTD. Frontal and/or temporal atrophy are often seen on structural brain imaging. Several pathological entities can cause bvFTD, and they are defined by the presence of specific abnormal protein accumulations. Most cases are characterized by accumulation of the proteins tau, TAR-DNA-binding protein-43 (TDP-43), and fused in sarcoma (FUS). Though most cases are sporadic, a variety of genes have been identified that cause autosomal dominant forms of FTD. The most common mutations occur in C9ORF72, MAPT, and GRN. No disease-modifying treatments have been currently identified, but limited evidence supports the use of antidepressants or neuroleptics in symptomatic management, and education regarding nonpharmacologic methods may be helpful to caregivers.
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PMID:Frontotemporal dementia. 2423 54


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