Guidelines developed for newly-recognised TDP-43 (LATE) dementia

Neurodegenerative disorders

By Michael Woodhead

3 May 2019

Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, as seen by microscope and MRI. Images courtesy of Nelson et. al. and Brain.

The first diagnostic criteria and guidance have been developed for a newly recognised form of non-Alzheimer dementia known as limbic-predominant age-related TDP-43 encephalopathy (LATE).

Published in Brain, the consensus-based recommendations on LATE describe it as a dementia syndrome typically affecting older patients with neuropathological change defined by a stereotypical TDP-43 proteinopathy, with or without coexisting hippocampal sclerosis pathology.

An international expert consensus group, led by Professor Peter Nelson of the University of Kentucky, say that emerging research seems to indicate that TDP-43 (transactive response DNA binding protein of 43 kDa) is associated with a high proportion of non-Alzheimer dementia.

The article notes that about 25% of brains from autopsy cohorts of older adults have sufficient burden of LATE pathology to be associated with discernible cognitive impairment.

Previous research has shown that TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

“LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy,” says the report co-authored by Professor Glenda Halliday of the Brain and Mind Institute at Sydney University.

“Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognised impact on public health,” the authors say.

The report says LATE-NC appears to affect the medial temporal lobe structures preferentially, and people with the condition also have atrophy in the medial temporal lobes, frontal cortex, and other brain regions.

A key recommendation is for routine autopsy evaluation and classification of LATE. The researchers suggest 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

The report authors say that the clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. They add that it appears to progress more gradually than Alzheimer’s. However, LATE often co-exists with Alzheimer’s  and this appears to cause a more rapid decline than either would alone.

“It is important to note that the disease itself is not new. LATE has been there all along, but we hope this report will enable more rapid advancement in research to help us better understand the causes and open new opportunities for treatment,” says report co-author Dr Nina Silverberg, PhD., director of the Alzheimer’s Disease Centers Program at the US National Institute on Aging.

Additional recommendations include 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.

Professor Nelson said the guidance showed it was time to stop thinking of dementia as a “one-size-fits-all” disease.

“LATE probably responds to different treatments than Alzheimer’s which might help explain why so many past Alzheimer’s drugs have failed in clinical trials,” he said.

“Now that the scientific community is on the same page about LATE, further research into the ‘how’ and ‘why’ can help us develop disease-specific drugs that target the right patients.”

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