Limbic-predominant age-related TDP-43 encephalopathy
LATE is a term that describes a prevalent medical condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome.
“Limbic” is related to the brain areas first involved, “age-related” and the name “LATE” itself refer to the onset of disease usually in persons aged 80 or older.
For reasons that are presently unknown, the disease process of LATE-NC preferentially affects medial temporal lobe structures of the brain, particularly the amygdala and hippocampus.
[2] In a significant proportion of persons with LATE-NC, there is atrophy, cell loss and astrogliosis in the hippocampus, diagnosable at autopsy (and somewhat less specifically via MRI during life) as hippocampal sclerosis.
[8][18][15] With or without co-existing Alzheimer's disease pathology or other brain changes, persons with LATE-NC generally lack the clinical features of frontotemporal dementia (FTD).
[1] This impairment is often severe enough to interfere with daily functioning and usually remains the chief neurologic deficit, unlike other types of dementia in which non-memory cognitive domains and behavioral changes might be noted earlier or more prominently.
There is indication from broader dementia research that higher educational attainment and engaging in mentally stimulating activities might delay the onset of clinical symptoms in neurodegenerative diseases.
[33] Lifestyle factors that influence susceptibility to dementia include diet, physical activity, social and intellectual stimulation, cardiovascular health, and exposure to toxins.
The exact triggers of TDP-43 aggregation are not fully understood but are believed to involve both genetic predispositions and acquired factors that may include mechanical or toxin-related stress.
[5][8][9] The diagnosis of LATE in live individuals is challenging because its symptoms overlap with those of other types of dementia, especially Alzheimer's disease, and there are no specific molecular biomarkers (as of November 2024), to predict the presence of the pathology.
The current approach to diagnosing LATE in living patients involves a combination of clinical evaluation, neuroimaging, and biomarker analysis, as detailed below.
These tests help differentiate LATE from other neurodegenerative diseases based on the presence of primarily amnestic versus multi-domain cognitive impairments.
In LATE, MRI may reveal severe atrophy in the medial temporal lobe, particularly in the hippocampus and amygdala, which are key areas affected by TDP-43 pathology, and may indicate hippocampal sclerosis.
The absence of these signals may support the diagnosis of LATE by ruling out significant amyloid or tau misfolded proteins in the brain (which would in turn indicate the presence of Alzheimer's disease).
[67] These include potential CSF markers or blood-based biomarkers derived from advanced protein assays, which could specifically indicate the presence of abnormal TDP-43.
[71] Understanding the progression, expected outcomes, and influencing factors is crucial for managing LATE effectively and providing appropriate support to affected individuals and their families.
Several high-quality autopsy cohorts evaluating the "oldest-old" (>90yrs at death) have found that the correlative impact of LATE-NC on dementia rivals or exceeds that of Alzheimer's pathology in that age group.
[5][78] The recognition and reporting of LATE may vary depending on the local healthcare system's capacity to diagnose and record cases of dementia, particularly in settings where detailed neuropathological examinations are less common.
Understanding the true epidemiological impact of LATE is essential for planning of research, healthcare, and resource allocation, especially as populations age.
The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues,[79][3] and this clinical-pathologic entity was subsequently confirmed by many others.
[1] TDP-43 proteinopathy itself (a disease-associated phenomenon discovered by Dr. Manuela Neumann and colleagues at UPENN in the Drs John Trojanowski/Virginia Lee CNDR Lab[82]) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases.
[1] This report formally recognized LATE as a distinct disease entity, described its neuropathological criteria, and provided a consensus description of clinical relevance.
Thus, LATE was distinguished from other memory disorders of aging, and from other TDP-43 proteinopathies, and provided a universal terminology as required to facilitate communication (and raise awareness) among clinicians and researchers.
