New subtype of dementia mimicking Alzheimer's disease

The predominant age-related TDP-43 encephalopathy in limbic (LATE) is a specific type of dementia that mimics Alzheimer's disease (AD) but is caused by TDP-43 protein deposits in the brain rather only by accumulation of beta-amyloid and mainly affects the elderly. 80 years old, says a consensus working group convened by the US National Institute on Aging.

LATE has "an increasing but under-recognized impact on public health", as the "oldest people" – a rapidly growing demographic group – are the most exposed, according to the authors.

Autopsy data indicate that about one in four people over 85 years of age presented with a neuropathological change LAT (LATE) to a degree sufficient to be associated with perceptible cognitive impairment, they say.

The findings of the task force were published online on April 30 in the journal Brain.

Important step forward

The need to accurately define the LATE subtype of dementia has grown.

"People from around the world have witnessed the existence of a neurodegenerative disease that was not Alzheimer's disease but that was confused with Alzheimer's disease because the Cognitive symptoms overlapped a lot, "wrote first author, Peter Nelson, MD, PhD, of Sanders-Brown. Center on Aging, University of Kentucky, Lexington, said Medscape Medical News.

"We brought together a large group of international multidisciplinary experts to discuss the subject and arrived at a new nomenclature and new methods of classifying the disease." This is a step forward. important, because it will provide a much better basis for the study of diseases at the root of the disease, dementia syndrome, "Nelson said.

The recommendations of the working group include guidelines for the diagnosis and staging of LATE-NC. For routine autopsy examinations of LATE-NC, the group proposes a preliminary anatomical staging system that reflects a hierarchical pattern of brain damage:

• Step 1: Amygdala only

• Step 2: amygdala and hippocampus

• Step 3: amygdala, hippocampus and frontal frontal gyrus

LATE-NC seems to affect the structures of the medial temporal lobe preferentially, but other areas are also affected, says the group. Neuroimaging studies demonstrate that, in patients with TAGN, there is also atrophy of the medial temporal lobes, frontal cortex, and other brain regions.

Genetic studies have so far indicated five genes with alleles at risk for LATE-NC: GRN TMEM106B, ABCC9, KCNMB2, and APOE. "The discovery of these genetic risk variants indicates that LATE shares the pathogenic mechanisms with frontotemporal lobar degeneration and Alzheimer's disease, but also suggests underlying mechanisms specific to the disease," the group said.

One of the main objectives of the working group is to catalyze future research on LATE. The authors described "major gaps in our understanding of LATE" and "an urgent need for research focused on LATE".

In particular, the identification of specific biomarkers for LATE "should be a high scientific priority," they said. Until there are biomarkers for LATE, clinical trials should be able to feed protein protein TDP-43, they suggest. They note that the coexistence of LATE neuropathology and neuropathology AD could mask the effects of a potential disease modifying agent.

"In the short term, it is important for everyone to know that there is more of a disease that causes dementia.It is unfortunate in the sense that many diseases can affect the brain." it also offers good opportunities to start developing treatments, one disease at a time, "said Nelson Medscape Medical News.

The summit of the iceberg?

Commenting on the report in a statement, Maria Carrillo, PhD, scientific lead at the Alzheimer's Association, said that this "reinforces the fact that Alzheimer's disease and associated dementias are extremely complex diseases. Learn more about each of the contributing causes of dementia in order to understand how these changes begin and interact and co-occur, as well as the best way to diagnose, treat and prevent them.

"This is an important area of ​​research, but it is not likely to affect clinical practice until this research is completed.We need to learn more about the cause, progression and risk factors of TARD and be able to measure them in living individuals (ie, a biomarker) in order to be able to fully understand their contribution – alone and when it appears with Alzheimer's disease, "said Carrillo.

Howard Fillit, MD, founding executive director and chief scientist at the Alzheimer's Foundation's Drug Discovery New York, said Medscape Medical News that this work "builds on much of the knowledge we have had for a number of years now and integrates that knowledge into this new entity.

"In medicine, we have slicers and desiccators," he added, "and from a scientific point of view, it is useful to define these subtypes of groups of clinical and pathological pathologies of people. I think this is just the tip of the iceberg and makes TDP-43 one of the misfolded proteins that could be a target for therapeutic trials.

"But it is very likely that none of these misfolded proteins are pure, and most people will suffer from multicomorbid pathology." Try to eliminate a misfolded protein in the aging brain, such as beta-amyloid. amyloid, probably will not work, "Fillit said.

The National Institute on Aging has provided significant support to the working group. Authors Carrillo and Fillit did not disclose relevant financial relationships.

Brain. Posted online 30 April 2019. Full text

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