Dataset Information

The MAPT H1 haplotype is associated with tangle-predominant dementia.

ABSTRACT: Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (A?)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble A? in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated A? is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein ? (sAPP?) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3' untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3' UTR underlies an A?-independent mechanism for neurodegeneration in TPD.

SUBMITTER: Santa-Maria I

PROVIDER: S-EPMC3608475 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The MAPT H1 haplotype is associated with tangle-predominant dementia.

Santa-Maria Ismael I Haggiagi Aya A Liu Xinmin X Wasserscheid Jessica J Nelson Peter T PT Dewar Ken K Clark Lorraine N LN Crary John F JF

Acta neuropathologica 20120717 5

Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identif ...[more]

PMID: 22802095

Similar Datasets

Project description:BACKGROUND: Tangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD. RESULTS: We investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms. CONCLUSIONS: To our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural circuits. In all but one TPD cases used in this study, delusion was a consistent clinical feature. Whether the Acb tau accumulation is related to the psychiatric symptoms in TPD may be an issue for further investigation.

Project description:Alzheimer's disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.

Dataset Information

The MAPT H1 haplotype is associated with tangle-predominant dementia.

Publications

The MAPT H1 haplotype is associated with tangle-predominant dementia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets