COPENHAGEN – TDP-43, a protein that has been associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis, could also be contributing to brain shrinkage in Alzheimer’s disease, adding another potential biomarker and treatment target for the disease, according to researchers at the Mayo Clinic.
The study of brain scans for 133 patients with Alzheimer’s disease diagnosed at autopsy revealed that TAR DNA binding protein of 43 kDa, or TDP-43, was associated with faster rates of hippocampal and cortical atrophy. The protein was also associated with memory loss and clinical features associated with the disease, said Jennifer L. Whitwell, Ph.D., of the Mayo Clinic, Rochester, Minn., who presented the study at the annual Alzheimer’s Association International Conference.
Michele Sullivan/Frontline Medical News
Dr. Jennifer L. Whitwell
The results suggest that TDP-43 could be a target for treatment and should be considered in future studies and clinical trials, Dr. Whitwell said. "Can we target TDP-43 and try to slow down the disease processes?" she asked. "If we can remove it or prevent it from accumulating, perhaps we could slow down the rate of hippocampal loss."
Dr. Whitwell is part of Dr. Keith Josephs’s team at the Mayo Clinic. The group recently showed that the protein was present in almost 60% of 342 Alzheimer’s disease brains they studied using the Mayo Clinic neuropathological database (Acta Neuropathol. 2014;127:811-24).
They found that TDP-43–positive subjects were 10 times more likely to be cognitively impaired at death, compared with TDP-43–negative individuals. (Some patients had normal cognition at death.) Resilient cognition seemed to be almost nonexistent in the presence of TDP-43, Dr. Whitwell said. Also, the protein seemed to have a greater effect in Braak stage IV and V than with stage VI.
In a longitudinal analysis of the same 342 subjects, the team analyzed the data for 133 individuals who had two MRIs before death, separated by a mean interval of 3.4 years. There was a mean of 3.7 years between the repeat scan at the time of death. They looked for presence of TDP-43 and tau neurofibrillary tangle burden in the hippocampus and the lateral temporal cortex, an area affected in Alzheimer’s disease. They then measured the rates of hippocampal and cortical atrophy and tried to decide if the shrinkage was driven by TDP-43, tau, or both.
The average age of death was 82 years, and the population was split almost evenly by sex.
The results showed that the presence of TDP-43 was significantly associated with volume loss at the hippocampus, while tau showed no such association.
In the cortex, both TDP-43 and tau were associated with the rate of volume change, although tau showed a stronger association (P less than .0001 for tau vs. P = .01 for TDP-43). Also, the rate of cortical atrophy was strongly associated with age of death, while the rate of hippocampus shrinkage wasn’t. The investigators adjusted their models for other features found in the brains patients with Alzheimer’s disease, such as the presence of amyloid-beta plaques and Lewy bodies, Dr. Whitwell said.
The findings "would suggest that [TDP-43] might be a new target," said Ralph Nixon, Ph.D., chair of the Alzheimer’s Association Medical and Scientific Advisory Council, in a comment on the association’s website. "This might be one of the missing factors that we’ve been looking for, for quite some time, any it maybe a hopeful prospect for a new biomarker."
The study was funded by the National Institute on Aging. Dr. Whitwell and Dr. Nixon had no financial disclosures.
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