Diagnostic guidelines released for limbic-predominant age-related TDP-43 encephalopathy

New guidelines will help doctors identify patients with a common memory loss syndrome that is often misdiagnosed as Alzheimer’s disease in older adults. The diagnostic criteria for limbic predominant age-related TDP-43 encephalopathy (LATE) were published this month in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association from an international team led by researchers from Penn Medicine. These guidelines are an important first step in advancing clinical research and treatments for this lesser-known but common type of memory loss disorder.

Clear guidelines for diagnosing various diseases not only help inform patients and their families about their prognosis, but also aid in making decisions about which treatments to pursue. As therapies become available that clear the amyloid associated with Alzheimer’s disease, we should be able to determine whether a patient actually has these proteins in their brain and will benefit from treatment. And if they don’t, we have to determine what disease they do have, and that could be LATE.”

David Wolk, MD, co-director of the Penn Memory Center and first author of the study

A common, but not widely known condition

LATE is a newly characterized form of dementia that causes memory loss in individuals generally over the age of 80. Because the main symptom of LATE is memory loss, it is often incorrectly diagnosed with AD. However, LATE has a different underlying cause than AD; While AD is characterized by a buildup of proteins in the brain called beta-amyloid and tau, LATE is caused by a buildup of another protein called TDP-43, which was discovered at Penn Medicine by Breakthrough Prize-winning researchers, Virginia Lee and colleagues. .

Autopsy analysis has shown that LATE is quite common in adults over 80 years of age; TDP-43 buildup associated with LATE was present in 40 percent of adults in that age group. Autopsies of individuals with AD showed that 55 percent also had LATE. Compared to people with AD alone, those with LATE alone have different cognitive symptoms. LATE mainly affects memory, while people with Alzheimer’s disease experience impairments in broader cognitive functions, such as executive functioning, planning, language and visuospatial function. Individuals with LATE also tend to have a slower progression of symptoms than AD, but when individuals have both LATE and AD, symptoms tend to progress more quickly. Research shows that patients with LATE alone have a more stable course and live longer than patients with AD alone, or patients with both LATE and AD.

Unlike beta-amyloid and tau, there is no test for TDP-43, and its presence in the brain can only be confirmed by brain autopsy after death. In the new report, researchers describe criteria for diagnosing LATE on its own or when it co-occurs with AD, using cognitive assessments, MRI scans looking for atrophy in the hippocampus, and testing for the presence of beta-amyloid and tau in cerebrospinal fluid and in PET scans of the brain.

These diagnostic criteria also help distinguish LATE from other forms of dementia, such as frontotemporal lobar degeneration (FTLD), which also involves TDP-43 accumulation, or dementia with Lewy bodies, in which proteins misfold and accumulate in the brain . In FTLD, individuals experience loss of executive functions and language rather than memory loss, which can be noted by cognitive evaluation. Furthermore, these individuals will not show atrophy of the hippocampus or medial temporal lobe. In dementia with Lewy bodies, individuals experience impaired motor function, among other cognitive impairments.

“Being able to accurately diagnose LATE in both forms sets the stage for further, important research,” Wolk said. “Not only can we use this diagnosis to develop clinical trials for TDP-43 drugs, but we can also investigate the efficacy of existing therapies in individuals with both LATE and AD, and potentially develop and test new therapies that target both diseases These criteria provide a first step in this direction.”

This research was supported by the National Institutes of Health (P30AG072979, R01 AG064233, P01 AG066597, R01AG034374, R01AG080667, K23AG062750, P30 AG066509).