Proposed Guidelines for Newly Defined Alzheimer's Disorders

Press release

Tuesday, April 30, 2019

Recommendations for scientists and the public emerge from an NIH funded workshop.

A newly recognized brain disorder that mimics the clinical features of Alzheimer's disease has been defined for the first time with recommended diagnostic criteria and other guidelines to advance and catalyze future research. Scientists from several institutions funded by National Institutes of Health, in collaboration with international peers, have described the new pathway of dementia, predominantly limbic, age-related TDP-43 encephalopathy, in a published report on April 30, 2019, in the newspaper Brain.

"We have certainly made progress in research on Alzheimer's disease, including new biomarkers and new genetic discoveries, but we still sometimes ask," When is Alzheimer's disease not Alzheimer's disease in the elderly? Said Richard J. Hodes, MD, director of the National Institute on Aging (NIA), a member of NIH. "The guidance provided in this report, including the definition of" LATE ", is a critical step in increasing awareness and advancing research on this disease and on Alzheimer's disease."

Alzheimer's disease is the most common form of dementia, namely the loss of cognitive functions – thinking, remembering and reasoning – and daily behavioral skills. In the past, Alzheimer's disease and dementia were often considered identical. It is now understandable more and more that a variety of diseases and pathological processes contribute to dementia. Each of these diseases appears differently when a brain sample is examined at autopsy. However, it became increasingly clear that in old age, a large number of people had dementia symptoms with no telltale signs in their brain at autopsy. Recent research suggests that the TDP-43 protein – although not an isolated explanation – contributes to this phenomenon.

What is TDP-43?

TDP-43 (43 kDa transactively-responsive DNA binding protein) is a protein that normally helps regulate the expression of genes in the brain and other tissues. Previous studies have shown that exceptionally misfolded TDP-43 has a causal role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these diseases are relatively rare. A recent important development observed in recent research is that the misfolded TDP-43 protein is very common in the elderly. About 25% of people over age 85 have enough misfolded TDP-43 protein to affect their memory and / or thinking abilities.

The pathology of TDP-43 is also frequently associated with sclerosis of the hippocampus, with severe narrowing of the region of the hippocampus of the brain – the part of the brain that deals with the learning and the memory. The sclerosis of the hippocampus and its clinical symptoms of cognitive impairment may be very similar to the effects of Alzheimer's.

"Recent research and clinical trials of Alzheimer's disease have taught us two things: first, not all people who do not have Alzheimer's disease have it; Secondly, it is very important to understand the other contributors to dementia, "said Nina Silverberg, Ph.D., director of the program centers for Alzheimer's disease at ANI. In the past, many people who participated in clinical trials were probably not seropositive for amyloid. Noting the trend in research involving the TDP-43 as a possible mimic of Alzheimer's disease, a panel of experts organized a workshop to provide a starting point for further research that will help to better understand another factor contributing to late brain changes, "explained Silverberg. In addition to American scientists, experts from Australia, Austria, Sweden, Japan and the United Kingdom, specialize in clinical diagnosis, neuropathology, genetics, neuropsychology and clinical practice. brain imaging.

Supported by the NIA, the workshop was held on October 17 and 18, 2018 in Atlanta and was co-chaired by Dr. Silverberg and Peter Nelson, MD, Ph.D., of the University of Toronto. Kentucky, Lexington, the main author of the paper. As published in the report, the results included the classification guidelines for the diagnosis and staging of TARD as well as recommendations for future research directions.

Late: a new research priority

The authors wrote that TARD is an under-recognized condition with a very significant impact on public health. They pointed out that the "oldest people" were the most at risk and felt that the impact of LAT on public health was at least equal to that of Alzheimer's in this group.

The clinical and neurocognitive features of LATE affect many areas of cognition, ultimately affecting activities of daily living. Moreover, based on existing research, the authors suggested that TARDI progressed more progressively than Alzheimer's. However, LATE associated with Alzheimer's disease – which is common to these two widespread brain diseases – seems to be causing a faster decline than either.

"It's important to note that the disease itself is not new. LATE has always been there, but we hope that this report will allow for faster progress in research to help us better understand the causes and create new treatment opportunities, "said Dr. Silverberg.

LATE and TDP-43 were also featured as emerging scientific topics at the recent Alzheimer Disease Dementia Summit 2019, during which presenters announced the research priorities discussed in the report. Brain report.

Laying the groundwork for the end

A key recommendation concerned the routine evaluation of autopsy and the classification of LATE. The researchers suggest that the autopsy diagnosis be done in three stages, depending on where TDP-43 is detected in the brain:

• Step 1: Amygdala only
• Step 2: amygdala and hippocampus
• Step 3: amygdala, hippocampus and frontal frontal gyrus

Other recommendations include the urgent need to develop biomarkers, to pursue pathological studies and to create new animal models. Suggestions were provided on possible strategies to guide future therapeutic interventions, including the importance of removing late subjects from other clinical trials, which could significantly improve the chances of successful breakthroughs in Alzheimer's disease. Researchers also discussed the importance of more epidemiological, clinical, neuroimaging and genetic studies to better characterize LATE, as well as the need for research in diverse populations.

"It can not be overemphasized that this research would not have been so advanced – and can not go further – without those who are willing to donate brain tissue after death," said Dr. Hodes. "We are grateful to organ donors and their families, as well as to all clinical trial participants, who play a critical role in advancing discoveries that could lead to treatments and therapies." cures. "

For more information on participating in clinical research on Alzheimer's Disease and related dementias, visit www.nia.nih.gov/health/participating-alzheimers-disease-research.

The funding includes grants from the NIH: U01AG016976, P01AG003949, R01AG03749, P50AG016574, R01AG054449, P30AG028303, P30AG012300, P30AG049638, P30AG010124, P30AG010161, P50AG047366, P50AG025688, P50AG005131, R37AG011378, R01AG041851, R01AG042210, R01AG017917, R01AG034374, UF1AG053983 and UF1AG057707.

About the National Institute of Aging (ANI)NIA leads the federal government's efforts to lead and support research on aging, the health and well-being of seniors. The NIA provides information on age-related cognitive changes and neurodegenerative diseases, particularly in its Alzheimer's Disease Education and Referral Center (ADEAR) at www. nia.nih.gov/Alzheimers. To learn more about health and aging in general, visit www.nia.nih.gov. To sign up for e-mail alerts about new discoveries or publications, please visit the website.

About the National Institutes of Health (NIH):
The NIH, the country's medical research agency, has 27 institutes and centers and is part of the US Department of Health and Human Services. NIH is the lead federal agency that leads and supports basic, clinical and translational medical research. She studies causes, treatments and cures for common and rare diseases. For more information on NIH and its programs, visit www.nih.gov.

NIH … transforming discovery into health^®

###