COPENHAGEN—TDP-43, a protein that has been associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis, also could be contributing to brain shrinkage in Alzheimer’s disease, thus adding another potential biomarker and treatment target for the disease, according to research presented at the 2014 Alzheimer’s Association International Conference.
Jennifer L. Whitwell, PhD
The study of brain scans for 133 patients with Alzheimer’s disease who were diagnosed at autopsy revealed that the TAR DNA binding protein of 43 kDa, or TDP-43, was associated with faster rates of hippocampal and cortical atrophy. The protein also was associated with memory loss and clinical features linked to the disease, said Jennifer L. Whitwell, PhD, Associate Professor of Radiology at the Mayo Clinic in Rochester, Minnesota.
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, Keith Josephs, MD, and colleagues recently showed that the protein was present in almost 60% of 342 brains with Alzheimer’s disease that they studied using the Mayo Clinic neuropathologic database.
The researchers 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 stages IV and V than in 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. They looked for 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 determine whether the shrinkage was caused by TDP-43, tau, or both.
The average age at death was 82, and death occurred equally often in males and females. The results showed that TDP-43 was significantly associated with volume loss at the hippocampus, while tau had no such association.
In the cortex, TDP-43 and tau were associated with the rate of volume change, although tau had a stronger association with this outcome. Also, the rate of cortical atrophy was strongly associated with age at death, while the rate of hippocampus shrinkage was not. The investigators adjusted their models for other features found in the brains of 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, PhD, Chair of the Alzheimer’s Association Medical and Scientific Advisory Council. “This might be one of the missing factors that we’ve been looking for for quite some time, and it may be a hopeful prospect for a new biomarker.”
—Naseem S. Miller