May 6, 2019Neurology
Alzheimer's disease (AD) is the most common form of dementia, which is the loss of cognitive functions - thinking, remembering, and reasoning - and every-day behavioral abilities. According to an article published in the journal Brain (30 April 2019), a recently recognized brain disorder, Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, mimics clinical features of AD. LATE has for the first time been defined with recommended diagnostic criteria and other guidelines for advancing and catalyzing future research.
In the past, AD and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 contributes to that phenomenon.
TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25% of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities. TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain - the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of AD.
The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than AD. However, LATE combined with AD, which is common for these two highly prevalent brain diseases, appears to cause a more rapid decline than either would alone.
LATE and TDP-43 also were featured as emerging scientific topics at the recent Alzheimer's Disease-Related Dementias Summit 2019, at which presenters foreshadowed research priorities covered in the Brain report. A key recommendation was for routine autopsy evaluation and classification of LATE. The authors suggested the autopsy diagnosis be in three stages, according to where in the brain TDP-43 is detected:
-- Stage 1: amygdala only
-- Stage 2: amygdala and hippocampus
-- Stage 3: amygdala, hippocampus and middle frontal gyrus
Additional recommendations include highlighting the great need for the development of biomarkers, further pathological studies, and the generation of new animal models. Suggestions were provided for possible strategies to help guide future therapeutic interventions, including the importance of removing subjects with LATE from other clinical trials, which could significantly improve the chances of successful Alzheimer's breakthroughs. The researchers also discussed the importance of more epidemiological, clinical, neuroimaging and genetic studies to better characterize LATE, and the need for research in diverse populations.
The following link provides more information about participating in Alzheimer's disease and related dementias clinical research.