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. In other words, the symptoms of LATE are similar to those of Alzheimer's disease.

The acronym LATE stands for L imbic-predominant A ge-related T DP-43 E ncephalopathy: “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,  “TDP-43” indicates the aberrant mis-folded protein (or proteinopathy) deposits in the brain that characterize LATE, and “encephalopathy” means illness of brain.

At present 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). The diagnosis of LATE-NC at autopsy requires detection of pathologic TDP-43 protein deposits in the brain, especially in the amygdala and hippocampus.

LATE is a very common condition: autopsy studies around the world indicate that LATE is present in the brains of about one-third of people over 85. LATE typically affects persons older than 75 years of age (with some exceptions; please see below) and becomes increasingly prevalent every year in advanced old age. This is in contrast to Alzheimer's disease pathology, which tends to level off and perhaps decrease in prevalence among persons beyond age 85 years. LATE 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 is associated with impairments in memory and thinking. 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. 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. Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC. 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. 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. 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).

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. 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. Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone. The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues, and this clinical-pathologic entity was subsequently confirmed by many others. 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.

Cognitive symptoms
The hallmark symptom of LATE is a progressive memory loss that predominantly affects short-term and episodic memory. 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. The amnestic syndrome in LATE tends to worsen gradually, leading to significant memory deficits over time. Thus, the cognitive decline in LATE, when it is the chief pathology present, is typically relatively slow.

The term dementia refers to a clinical syndrome, rather than a particular disease process – it can be caused by many different subtypes of brain disease, which often occur in combination with each other. Thus, many different diseases including LATE contribute to dementia. The implications of the term dementia are that there is cognitive impairment severe enough to impair activities of daily living such as feeding oneself. Approximately half of dementia in advanced age includes both Alzheimer's disease and LATE pathologies, and these individuals are at risk for more swift and severe disease course.[2]

Causes
The exact causes of LATE are not fully understood, but a combination of factors, particularly genetic risk factors, are believed to contribute to its development. Here we explore these factors based on current research and theories.

Risk factors[edit]

The strongest known risk factor for LATE is advanced age. The prevalence of LATE increases significantly in individuals over 80 years old  and the average patient with LATE is ten years older than the average patient with Alzheimer's disease, suggesting that aging-related biological processes—yet to be comprehensively identified (but which include TMEM106B c-terminal fragments), -- play roles in the development of LATE. Although brain trauma (either single or multiple/chronic traumatic impacts) can produce brain changes that are qualitatively different from LATE-NC there may be interactions between brain trauma and LATE-NC mechanistically. Further, those with brain damage from trauma or other sources may have worse outcomes with a given burden of LATE-NC in the brain. 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. Whether this directly affects the risk of developing LATE or just modifies its presentation is still under investigation. While specific lifestyle factors directly causing LATE have not been definitively identified, general factors that affect brain health appear to influence risk of a given amount of pathology being correlated with cognitive impairment. Lifestyle factors include diet, physical activity, social and intellectual stimulation, cardiovascular health, and exposure to toxins. Chronic inflammation in the brain is a known factor in many neurodegenerative diseases and may also play a role in LATE. Inflammatory processes could contribute to or exacerbate TDP-43 pathology. Disruptions in protein homeostasis, which include protein synthesis, folding, trafficking, and degradation, are likely involved in LATE. An imbalance in these processes could lead to the accumulation of misfolded TDP-43, contributing to disease progression.

Genetic factors[edit]

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).

Pathophysiology[edit]
TDP-43 (Transactive response DNA-binding protein) is a nuclear protein involved in regulating gene expression by modifying RNA. It plays critical roles in RNA processing, including splicing, stability, and transport. In healthy cells, TDP-43 is predominantly found in the nucleus. In LATE, TDP-43 protein abnormally accumulates in the cytoplasm of neurons and glial cells, forming aggregates. This cellular mislocalization disrupts its normal nuclear functions and contributes to cellular dysfunction and neuronal death. The exact triggers of TDP-43 aggregation are not fully understood but are believed to involve both genetic predispositions and acquired factors.

LATE neuropathology is typically graded based on the extent and distribution of TDP-43 inclusions within the brain. Early stages may involve localized TDP-43 pathology in the amygdala, while more advanced stages involve the hippocampus and other medial temporal lobe structures, whereas in more advanced disease the TDP-43 pathology is far more extensive. For more details on the pathological stages of LATE-NC, see “Pathologic Examination”, below.

Advanced LATE is often associated with hippocampal sclerosis, characterized by severe neuron loss and gliosis in the hippocampus. This feature significantly contributes to the memory deficits observed in LATE. LATE often coexists with a small blood vessel pathology affecting cerebral arterioles, which is termed arteriolosclerosis. LATE is more common in cases with comorbid tauopathy, including ADNC, primary age-related tauopathy (PART), and age-related tau astrogliopathy.

Certain genetic factors, such as mutations or polymorphisms in genes related to TDP-43 processing and function, may predispose individuals to develop LATE. These genetic elements can affect the stability, aggregation propensity, or cellular trafficking of TDP-43. For example, the APOE e4 allele that confers increased risk for ADNC also increases risk of LATE-NC; further, FTLD risk genes TMEM106B and GRN/progranulin are also implicated in risk of LATE-NC.

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.

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 ) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases.