Limbic-predominant age-related TDP-43 encephalopathy, or LATE, is a recently recognized form of dementia that affects memory, thinking, and social skills. It mimics (and sometimes coexists with) Alzheimer’s disease or AD, but LATE is a different condition, with its own risks and causes.
In a new study, published December 15, 2022, in the journal Alzheimer’s and dementiaUC San Diego School of Medicine researchers, along with colleagues elsewhere, provide new insights into the pathology of LATE, which could help lead to the development of diagnostics for a disease that is currently poorly understood and very difficult to identify in living patients.
Specifically, the researchers, led by the study’s senior author, Robert Rissman, PhD, professor of neurosciences at UC San Diego School of Medicine, reported significantly elevated plasma levels of TDP-43, a DNA-binding protein previously It has been associated with other neurodegenerative diseases. such as frontotemporal lobe degeneration, amyotrophic lateral sclerosis, and AD, although the latter condition is much more commonly characterized by the accumulation of two other proteins: amyloid-beta and tau.
The study looked at the levels of TDP-43 extracted from exosomes secreted into the bloodstream by various cell types, including neurons and glial cells. Exosomes are extracellular vesicles or sacs that transport DNA, RNA, and proteins into the cell until released. The researchers analyzed the brains of 64 postmortem patients, 22 with autopsy-confirmed LATE and 42 patients who died without an indication of LATE.
The effect was detected only in astrocyte-derived exosomes, not neuronal or microglial. Astrocytes are a subtype of glial cells that perform many essential functions in the central nervous system, from regulating blood flow to providing the building blocks of neurotransmitters. They outnumber neurons by more than five times.
The effective treatment of all neurological diseases depends to a large extent on early diagnosis. However, at the moment, LATE can only be diagnosed after death and is often confused with the fact that living patients can have both LATE and AD. The findings that increased plasma TDP-43 concentrations could be a telltale indicator of LATE are encouraging, Rissman said.
“Research is accelerating into the utility of blood biomarkers, which may offer earlier diagnoses of these difficult conditions without resorting to time-consuming, costly, and invasive methods,” he said.
“Increased plasma concentrations of TDP-43 have been observed in other neurological conditions, but its correlation with cognitive dysfunction and disease progression is not well established. Much more research is needed.”
Rissman added that taking advantage of the findings could lead not only to earlier diagnoses of dementia, but also to greater accuracy. “I think some of the problems with the failed AD trials so far is that LATE patients are entering them. Of course, they wouldn’t respond to treatment because they don’t have AD.”
People with LATE have memory problems, but they often occur at a slower rate of clinical change than people with AD. They may start out with difficulty remembering facts and conversations, become increasingly forgetful, and eventually have trouble with daily activities, such as getting dressed, cooking, or paying bills.
LATE generally affects older people, particularly those over the age of 80, although dementia is not part of the typical aging process. Heredity is thought to play a role, with at least five genes associated with the risk of LATE. These genes may also be involved with other forms of dementia.
Currently, there is no definitive treatment or cure for LATE. Therapy often involves lifestyle improvements, such as maintaining a healthy diet and regular exercise, reducing alcohol consumption, avoiding smoking, and treating comorbid chronic conditions, such as hypertension, obesity, and diabetes.
Coauthors include: Charisse N. Winston, Sonal Suckreet, and Hailey Lynch, all at UC San Diego; John Q. Trojanowski and Virginia Lee, University of Pennsylvania; and Peter T. Nelson, University of Kentucky.