By Will Boggs MD
NEW YORK—Limbic-predominant age-related TDP-43 encephalopathy (LATE), a recently recognized dementia, clinically resembles Alzheimer's disease but has different pathology, according to a consensus working group report.
"It's increasingly clear that Alzheimer's disease (AD) is only a subset of the diseases that contribute to the dementia clinical syndrome," Dr. Peter T. Nelson of the University of Kentucky, in Lexington, told Reuters Health by email. "LATE is probably the most impactful (factoring in both prevalence and impact to an individual) subtype of Alzheimer's-mimicking disorder. It is estimated that over a million people in America suffer from dementia due partly or wholly to LATE."
Transactive response DNA binding protein of 43kDa (TDP-43) proteinopathy is often seen in the limbic brain structures of people over 80 and has been linked with cognitive impairment that mimicked Alzheimer disease.
Dr. Nelson and colleagues propose LATE as a new terminology, suggest guidelines for the autopsy evaluation and staging of LATE neuropathological change (LATE-NC) and review the medical literature pertaining to the condition in their report, online April 30 in Brain.
The authors propose three stages of LATE-NC based on the anatomical distribution of TDP-43 proteinopathy at autopsy: stage 1, amygdala only; stage 2, hippocampus as well; and stage 3, middle frontal gyrus as well.
The neuropathological features of LATE-NC may be present in up to 50% of individuals past age 80 years, according to large community-based autopsy series.
The lack of longitudinal biomarker data and the limitations of current animal models make it challenging to study disease mechanisms, and further investigations are clearly needed.
The LATE amnestic cognitive syndrome can evolve to incorporate multiple cognitive domains and to impair activities of daily living, and the cognitive impairment is greater than can be accounted for by Alzheimer disease neuropathological changes (ADNC) or other pathologies.
Individuals with relatively pure LATE-NC seem to experience a more gradual clinical decline, compared with those with pure ADNC, while those with comorbid LATE-NC and ADNC show faster decline and more severe cognitive impairment than those with either ADNC or LATE-NC alone.
TDP-43 proteinopathy has been documented in some cognitively unimpaired subjects, but this likely represents preclinical disease in individuals dying before onset of clinical symptoms.
"Additional epidemiological, clinical, neuroimaging, and genetic studies will be important to better characterize the public health impact and clinical phenotypes for LATE," the researchers note. "Animal models and basic science research into LATE are imperative, with the caveat that the aged human brain is challenging to model accurately."
"Ultimately," they conclude, "it is hoped that these collective research efforts will one day result in successful preventative and therapeutic strategies."
"There's no known cure or preventive measure for LATE but knowing about LATE seems like an important precondition to developing cures for both - cases of LATE must be excluded from AD clinical trials, and there should be clinical trials for LATE also," Dr. Nelson said. "A quick consideration of these goals leads one to the important priority - developing a clinical biomarker for LATE."
"Clinicians need to be ready for a time, hopefully in the near future, when some subsets of neurodegenerative disease(s) are treatable," he said. "When this happens, there will be an enormous shift in clinical practice and a commensurately strong drive - in both the clinician and layperson domains - for optimizing diagnostic and therapeutic strategies."
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