Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Neurology (Impact Factor: 8.29). 06/2008; 70(19 Pt 2):1850-7. DOI: 10.1212/01.wnl.0000304041.09418.b1
Source: PubMed


TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity.
Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls.
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity.
The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.

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Available from: Clifford R Jack, Jun 17, 2014
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    • "For each increase in dementia severity rating (none, minimal, mild, moderate, severe), those with hippocampal or entorhinal TDP-43 pathology were twice as likely to be rated in a more severe category. This finding is consistent with a clinic-based study, which found that TDP-43 pathology was associated with a more severe presentation of dementia [8]. Our results therefore suggest that the significance of TDP- 43 in terms of clinical dementia is not confined to rare early-onset FTDs, but rather it has a broader significance which includes a role in late onset dementia including the oldest old. "
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    • "TDP-43 inclusions in our case were sparse and confined to the limbic system [50]. TDP-43 immunoreactivity may modify clinical features in AD and other types of dementia [51] and is closely associated with hippocampal sclerosis [51,52]. The cause and mechanism of TDP-43 inclusions in tauopathies remain elusive but it is postulated that tau aggregates may promote aggregation of TDP-43 pathology through cross-seeding [28,38]. "
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    02/2014; 2(1):24. DOI:10.1186/2051-5960-2-24
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    • "Another important limitation of the study was that while we had a measure of Aβ, we did not have a measure of tau in these CN participants, so it is impossible to determine whether participants with evidence of fibrillar brain amyloid also have evidence of substantial tau pathology. Other proteins are also often present in the brains of AD participants that could influence the patterns of atrophy, such as TDP-43 (Josephs et al., 2008b). "
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