Limbic-predominant age-related TDP-43 encephalopathy

LATE neuropathologic changes (LATE-NC). A normal centenarian brain, cut in the coronal plane (top left) is compared to a brain with LATE-NC (top right). The hippocampi on both sides are atrophic (shrunken) in the brain with LATE-NC. The bottom 3 panels show photomicrographs of a hippocampus with LATE-NC, stained for phosphorylated TDP-43 protein (TDP-43). Insets show TDP-43 positive neuronal cytoplasmic inclusions (Inset A--in dentate granule cells) and wispy non-tapering cellular processes stained for TDP-43 protein (Inset B--in CA1).

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a term that describes a prevalent condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome.^[1] In LATE, there is a buildup of misfolded TDP-43 protein in the brain, especially in the amygdala and hippocampus, and the disease typically affects persons older than 75 years of age (with some exceptions; please see below).

As of December 2021, LATE can only be diagnosed with certainty at autopsy. The terminology used to refer to the brain changes identified in autopsy-confirmed LATE is: LATE neuropathologic change (LATE-NC).

LATE is a very common condition, with autopsy studies around the world indicating that LATE-NC is present in the brains of about a quarter of people over 85.^[1] LATE-NC is often comorbid with (i.e., occurs in the same brain as) other pathologic changes that are associated with dementia, such as Alzheimer's disease and cerebrovascular disease(s).

LATE has a large impact on public health. Clinical-pathologic correlation studies have established that the presence of LATE-NC in the brain is associated with impairments in memory and thinking.^[1] In older persons whose brains lack Alzheimer's disease-type amyloid plaques and neurofibrillary tangles, the presence of LATE-NC at autopsy is associated with a relatively slow cognitive decline (in comparison with Alzheimer's disease), mostly affecting the memory domain.^[2] However, most people (~75%) beyond age 85 have some Alzheimer's disease-type pathology and in this common scenario the impact of LATE-NC is very important.^[3] Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC.^[4][5][6] In these persons, the presence of LATE-NC is associated with a swifter disease course and with more severe clinical (memory and thinking) impairment than when only Alzheimer's disease pathology is present.^[7][8][9][2] A common combination of brain pathologies—with Alzheimer's disease pathology, Lewy body pathology, and LATE-NC in the same brain—tends to affect younger individuals (often <75 yrs of age) and, on average, is associated with more aggressive (faster) cognitive deterioration.^[10][11] 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).^[12][13]

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.^[14] 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.^[15] Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone.^[16] The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues,^[17][15] and this clinical-pathologic entity was subsequently confirmed by many others.^{[18][19][20][21][22]} However, brain changes diagnosable as "hippocampal sclerosis" is/are also seen in other diseases (such as epilepsy), and many LATE-NC brains lack full-blown hippocampal sclerosis, so, hippocampal sclerosis is neither a sensitive nor specific feature of LATE-NC.^[1]

The major known risk factors for LATE-NC are genetic: variations in the TMEM106B, GRN, APOE, ABCC9, KCNMB2, and WWOX genes have been linked to altered risk for LATE-NC (and/or hippocampal sclerosis dementia).^{[1][23][24][25][26][27][28][29]}

There currently is no known cure or preventative strategy for LATE-NC.

The deleterious impact(s) of TDP-43 proteinopathy may influence the brain via a number of different mechanisms. In normal brains and other tissues, the TDP-43 protein helps to ensure proper functioning of genes in the cell; the misfolded TDP-43 may thus impair normal gene expression regulation (so in LATE-NC, there is a loss-of-normal-function), and, the aberrant TDP-43 protein in LATE-NC may induce toxic gains of function also.^[30][31]

TDP-43 proteinopathy (a disease-associated phenomenon discovered by Dr. Manuela Neumann and colleagues at UPENN in the Drs John Trojanowski/Virginia Lee CNDR Lab^[32]) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases.^[33][34][32]

References[]

Further reading[]

• "Guidelines proposed for newly defined Alzheimer's-like brain disorder". National Institute on Aging. National Institute of Health. Retrieved 30 April 2019.