Original Investigation |

TDP-43 Pathology, Cognitive Decline, and Dementia in Old Age

Robert S. Wilson, PhD1; Lei Yu, PhD1; John Q. Trojanowski, MD, PhD2; Er-Yun Chen, MD1; Patricia A. Boyle, PhD1; David A. Bennett, MD1; Julie A. Schneider, MD1
[+] Author Affiliations
1Department of Neurological Sciences, Behavioral Sciences, and Pathology, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
2Department of Pathology and Laboratory Medicine, Institute on Aging Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia
JAMA Neurol. 2013;70(11):1418-1424. doi:10.1001/jamaneurol.2013.3961.
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Importance  Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood.

Objective  To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late-life cognitive decline.

Design, Setting, and Participants  Longitudinal clinical-pathologic cohort study involving more than 40 Catholic groups across the United States. A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified.

Main Outcomes and Measures  Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death.

Results  Transactive response DNA-binding protein 43 pathology, ranging from sparse to severe, was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. Transactive response DNA-binding protein 43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment.

Conclusion and Relevance  The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.

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Figure 1.
Transactive Response DNA-Binding Protein 43 Immunoreactive Inclusions in the Entorhinal Cortex

Transactive response DNA-binding protein 43 immunoreactive cellular inclusions (brown) and hematoxylin counter stain in the entorhinal cortex from 3 cases: case 1 with sparse (A and B), case 2 with moderate (C and D), and case 3 with frequent (E and F) inclusions. Scale bar = 100 μm in A, C, and E; and 50 μm in B, D, and F.

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Figure 2.
Relation of Transactive Response DNA-Binding Protein 43 (TDP-43) Pathologic Burden to Rate of Cognitive Decline

The top panel shows the individual rates of global cognitive decline, adjusted for age at death, plotted by level of TDP-43 pathology, and fitted with a locally reweighted linear smooth function. The bottom panel shows the 10-year paths of global cognitive decline in typical participants with no TDP-43 pathology (solid line) and with low (long dashes, 10th percentile), moderate (short dashes, 50th percentile), or high (dotted line, 90th percentile) levels of TDP-43 pathology, adjusted for age at death, amyloid, tangles, and hippocampal sclerosis.

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