0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 1

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario

brightcove.createExperiences();