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).

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

The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: “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.[1][2][3] 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.[1] 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.[1] 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).[4][5][6]

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.[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.[7] 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.[8] Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC.[9][10][11] 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.[12][13][14][7] 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.[5][15][12] 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).[16][17]

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.[18] 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.[19] Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone.[20]

Signs and symptoms

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Cognitive symptoms

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The hallmark symptom of LATE is a progressive memory loss that predominantly affects short-term and episodic memory.[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.[1] The amnestic syndrome in LATE tends to worsen gradually, leading to significant memory deficits and functional disabiltiy over time.[21][22][23]  Thus, the cognitive decline in LATE, when it is the chief pathology present, is typically relatively slow.[24]

Combinations of brain pathology, and their correlation with cognitive impairment over time. Note that the combination of AD+LATE is the most common and most severe.

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.[25] 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][26][27]

Causes

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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

The strongest known risk factor for LATE is advanced age. The prevalence of LATE increases significantly in individuals over 80 years old [1] 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[28][29])—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[30] 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.[31] Lifestyle factors that influence susceptibility to dementia include diet, physical activity, social and intellectual stimulation, cardiovascular health, and exposure to toxins. These may impair cognition in reciprocal relation to cognitive reserve.[32] 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.[33] Disruptions in protein homeostasis, which include protein synthesis, post-translational modification, folding, trafficking, and degradation, are likely involved in promoting TDP-43 pathology in LATE.[34] An imbalance in these processes could lead to the accumulation of misfolded TDP-43, contributing to disease progression.[35]

Genetic factors

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][36][37][38][39][40][41][42] These genetic elements are associated with biochemical changes that 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; it is also remarkable that FTLD risk genes TMEM106B and GRN/progranulin are also implicated in risk of LATE-NC.

Pathophysiology

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TDP-43 (Transactive response DNA-binding protein) is a nuclear protein involved in regulating gene expression by modifying RNA.[43] More specifically, TDP-43plays 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 mis-localization 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.[44] 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.[45][46][35]

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,[47][19] characterized by severe neuron loss and gliosis in the hippocampus.[48][49][50][51] This feature significantly contributes to the memory deficits observed in LATE.[52] LATE often coexists with a small blood vessel pathology affecting cerebral arterioles, which is termed arteriolosclerosis.[53] LATE is more common in cases with comorbid tauopathy, including Alzheimer's-type plaques and tangles, primary age-related tauopathy (PART), and age-related tau astrogliopathy.[2][5][6]

Diagnosis

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The diagnosis of LATE is challenging because its symptoms overlap with those of other types of dementia, especially Alzheimer's disease, and there are no specific biomarkers to predict the presence of the pathology.[54] Thus, at present LATE is primarily diagnosed at autopsy, i.e., through neuropathological examination. However, ongoing research aims to refine the antemortem diagnostic criteria and methods. The current approach to diagnosing LATE in living patients involves a combination of clinical evaluation, neuroimaging, and biomarker analysis, as detailed below.

Clinical evaluation

Detailed patient history focusing on age at onset and nature and rate of decline of cognitive functions, particularly memory loss, is critical.[55] Clinicians also assess other cognitive domains and inquire about any changes in behavior or personality that might indicate broader neurological impact. Neuropsychologic examinations include testing to assess memory, executive function, language abilities, and other cognitive functions. These tests help differentiate LATE from other neurodegenerative diseases based on the presence of primarily amnestic versus multi-domain cognitive impairments.

MRI of subject with eventual autopsy-proven LATE

MRI scans are used to observe structural changes in the brain. 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.[56][54] Other MRI abnormalities have recently been also observed in association with LATE.[57] While PET scans are commonly used to detect amyloid and tau pathologies in Alzheimer's disease, the absence of marked aberration in these may support the diagnosis of LATE by ruling out significant amyloid or tau burdens indicative of Alzheimer's disease.[55] FDG-PET scans may also be used to predict the presence of an underlying LATE-NC pathology.[58][59]

Biomarkers for neuronal damage such as tau protein and neurofilaments can be measured in the cerebrospinal fluid and blood. A lack of amyloid-beta and tau relative to the degree of cognitive impairment may suggest LATE, if typical Alzheimer's pathology is not present.[55] Vigorous efforts are ongoing to identify specific biomarkers for TDP-43 pathology.[60] These include potential CSF markers or blood-based biomarkers derived from advanced protein assays, which could specifically indicate the presence of abnormal TDP-43.

Pathological examination[edit]

Definitive diagnosis of LATE currently relies on post-mortem examination, in which brain tissues are examined for a specific pattern of TDP-43 proteinopathy. The distribution and severity of TDP-43 inclusions, especially in the amygdala and hippocampus (but with none or modest density of pathology in the frontal cortex), confirm the presence of LATE. The specific severity/extent of LATE-NC follows on the basic staging scheme based on a stereotypic expansion of TDP-43 pathology in the aged brain.[1] This pattern was originally identified Keith Josephs and colleagues,[61] and was later corroborated by Dr. Julie Schneider and colleagues at Rush University Medical Center.[62]  For routine LATE-NC diagnosis, the pathology is staged along a 0-3 staging scheme: when TDP-43 pathology is only seen in the amygdala, that is LATE-NC Stage 1; when TDP-43 pathology is in the amygdala and hippocampus, that is LATE-NC Stage 2; and, when TDP-43 pathology is in amygdala, hippocampus, and middle frontal gyrus, that is LATE-NC Stage 3.[1][63]

Prognosis

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The prognosis of LATE varies significantly depending on several factors including the age at onset, stage of the disease at diagnosis, the presence and degree of cerebrovascular disease and of other comorbidities, and individual patient factors.[64] Understanding the progression, expected outcomes, and influencing factors is crucial for managing LATE effectively and providing appropriate care and support to affected individuals and their families.[55]

LATE typically manifests as a slow, progressive decline in memory and other cognitive functions, which distinguishes it from more rapidly progressing forms of dementia.[64][55] The rate of progression can vary widely among individuals. Early stages may involve subtle memory impairments that gradually worsen. As LATE progresses, patients may experience more significant memory loss and eventually exhibit symptoms affecting other cognitive domains, although the primary impairment usually remains in memory.[64] Progression to severe dementia is common, and as with many forms of dementia, individuals with LATE gradually require more assistance with daily activities, leading to significant dependency on caregivers.

Epidemiology

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LATE is an increasingly recognized neurodegenerative condition and LATE neuropathological changes are present in >30% of individuals older than 85 years,[2] making it one of the more common dementia-associated conditions in the elderly. LATE often coexists with other common brain pathologies of aging, such as Alzheimer's disease and/or cerebrovascular disorder.[64] The risk of developing LATE increases with age,[65] being unusual in individuals under 65 and increasingly common in those over 80. Studies have not shown consistent differences between males and females in the prevalence of LATE. 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.[66][67] Limited data are available on the prevalence of LATE across different ethnic and racial groups. Initial studies have not indicated significant differences in prevalence based on race or ethnicity.[68][69][70] However, LATE has been identified in all the populations for which it has been evaluated, in studies around the world.[2][71] However, differences in study designs, diagnostic criteria, and awareness of the disease may affect reported rates from different countries. The recognition and reporting of LATE may also vary significantly 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.

History

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The pathological signatures of the disorder now known as LATE have been observed at least since the mid-1990s, but attention on the TDP-43 protein that is part of its mechanism have been relatively recent.

The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues,[72][19] and this clinical-pathologic entity was subsequently confirmed by many others.[73][74][49][50][51] 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] 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[75]) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases.[76][77][75]

It was not until the late 2000s and early 2010s that researchers began to recognize a pattern of TDP-43 pathology that was distinct from ALS and FTLD in elderly individuals, often co-existing with but distinct from Alzheimer's disease pathology.[78] A milestone in the history of LATE was the publication of a consensus report in 2019 by an international group of experts.[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.  There has been some debate and discussion as to optimal nomenclature for this condition.[79][80]

References

[edit]
  1. ^ a b c d e f g h i j k l m Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, et al. (June 2019). "Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report". Brain. 142 (6): 1503–1527. doi:10.1093/brain/awz099. PMC 6536849. PMID 31039256.
  2. ^ a b c d Nelson PT, Brayne C, Flanagan ME, Abner EL, Agrawal S, Attems J, et al. (July 2022). "Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts". Acta Neuropathologica. 144 (1): 27–44. doi:10.1007/s00401-022-02444-1. PMC 9552938. PMID 35697880. S2CID 249628141.
  3. ^ Nichols E, Merrick R, Hay SI, Himali D, Himali JJ, Hunter S, et al. (March 2023). "The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia". The Lancet. Healthy Longevity. 4 (3): e115–e125. doi:10.1016/S2666-7568(23)00019-3. PMC 9977689. PMID 36870337.
  4. ^ Harrison WT, Lusk JB, Liu B, Ervin JF, Johnson KG, Green CL, et al. (November 2021). "Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old". Acta Neuropathologica. 142 (5): 917–919. doi:10.1007/s00401-021-02360-w. PMC 8816525. PMID 34415381.
  5. ^ a b c Wang SJ, Guo Y, Ervin JF, Lusk JB, Luo S (July 2022). "Neuropathological associations of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) differ between the oldest-old and younger-old". Acta Neuropathologica. 144 (1): 45–57. doi:10.1007/s00401-022-02432-5. PMC 9997084. PMID 35551470. S2CID 248701133.
  6. ^ a b Tomé SO, Gawor K, Thal DR (July 2024). "LATE-NC in Alzheimer's disease: Molecular aspects and synergies". Brain Pathology. 34 (4): e13213. doi:10.1111/bpa.13213. PMC 11189776. PMID 37793659.
  7. ^ a b Nag S, Yu L, Wilson RS, Chen EY, Bennett DA, Schneider JA (February 2017). "TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD". Neurology. 88 (7): 653–660. doi:10.1212/WNL.0000000000003610. PMC 5317379. PMID 28087828.
  8. ^ Braak H, Thal DR, Ghebremedhin E, Del Tredici K (November 2011). "Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years". Journal of Neuropathology and Experimental Neurology. 70 (11): 960–969. doi:10.1097/NEN.0b013e318232a379. PMID 22002422. S2CID 739734.
  9. ^ Buciuc M, Wennberg AM, Weigand SD, Murray ME, Senjem ML, Spychalla AJ, et al. (2020). "Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer's Disease Neuropathological Changes". Journal of Alzheimer's Disease. 73 (4): 1511–1523. doi:10.3233/JAD-191040. PMC 7081101. PMID 31929165.
  10. ^ Nag S, Barnes LL, Yu L, Wilson RS, Bennett DA, Schneider JA (October 2020). "Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents". Neurology. 95 (15): e2056–e2064. doi:10.1212/WNL.0000000000010602. PMC 7713750. PMID 32759188.
  11. ^ Hunter S, Hokkanen SR, Keage HA, Fleming J, Minett T, Polvikoski T, et al. (2020). "TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort". Journal of Alzheimer's Disease. 75 (1): 337–350. doi:10.3233/JAD-191093. PMID 32280087. S2CID 215748586.
  12. ^ a b Karanth S, Nelson PT, Katsumata Y, Kryscio RJ, Schmitt FA, Fardo DW, et al. (October 2020). "Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults". JAMA Neurology. 77 (10): 1299–1307. doi:10.1001/jamaneurol.2020.1741. PMC 7309572. PMID 32568358.
  13. ^ Josephs KA, Whitwell JL, Tosakulwong N, Weigand SD, Murray ME, Liesinger AM, et al. (November 2015). "TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features". Annals of Neurology. 78 (5): 697–709. doi:10.1002/ana.24493. PMC 4623932. PMID 26224156.
  14. ^ Josephs KA, Dickson DW, Tosakulwong N, Weigand SD, Murray ME, Petrucelli L, et al. (November 2017). "Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study". The Lancet. Neurology. 16 (11): 917–924. doi:10.1016/S1474-4422(17)30284-3. PMC 5646369. PMID 28919059.
  15. ^ Katsumata Y, Abner EL, Karanth S, Teylan MA, Mock CN, Cykowski MD, et al. (November 2020). "Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy". Acta Neuropathologica. 140 (5): 659–674. doi:10.1007/s00401-020-02211-0. PMC 7572241. PMID 32797255.
  16. ^ Nelson PT (August 2021). "LATE Neuropathologic Changes with Little or No Alzheimer Disease is Common and is Associated with Cognitive Impairment but Not Frontotemporal Dementia". Journal of Neuropathology and Experimental Neurology. 80 (7): 649–651. doi:10.1093/jnen/nlab050. PMC 8357339. PMID 34270750.
  17. ^ Amador-Ortiz C, Ahmed Z, Zehr C, Dickson DW (March 2007). "Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration". Acta Neuropathologica. 113 (3): 245–252. doi:10.1007/s00401-006-0183-4. PMC 1794627. PMID 17195931.
  18. ^ Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, et al. (April 2016). "Updated TDP-43 in Alzheimer's disease staging scheme". Acta Neuropathologica. 131 (4): 571–585. doi:10.1007/s00401-016-1537-1. PMC 5946692. PMID 26810071.
  19. ^ a b c Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, et al. (May 2007). "TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease". Annals of Neurology. 61 (5): 435–445. doi:10.1002/ana.21154. PMC 2677204. PMID 17469117.
  20. ^ Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, et al. (January 2010). "Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons". Brain Pathology. 20 (1): 66–79. doi:10.1111/j.1750-3639.2008.00244.x. PMC 2864342. PMID 19021630.
  21. ^ Buciuc M, Tosakulwong N, Machulda MM, Whitwell JL, Weigand SD, Murray ME, et al. (2021). "TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death". Journal of Alzheimer's Disease. 80 (2): 683–693. doi:10.3233/JAD-201166. PMC 8020877. PMID 33579840.
  22. ^ Farfel JM, Capuano AW, Buchman AS, Schneider JA, Bennett DA (May 2024). "Association of Alzheimer's Disease and Other Neuropathologies with Functional Disability in Persons With and Without Dementia". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences: glae118. doi:10.1093/gerona/glae118. PMID 38757945.
  23. ^ Leiby AC, Scambray KA, Nguyen HL, Basith F, Fakhraee S, Melikyan ZA, et al. (2023). "Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series". Journal of Alzheimer's Disease. 96 (1): 113–124. doi:10.3233/JAD-230238. PMC 10615772. PMID 37742640.
  24. ^ Kapasi A, Yu L, Boyle PA, Barnes LL, Bennett DA, Schneider JA (October 2020). "Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging". Neurology. 95 (14): e1951–e1962. doi:10.1212/WNL.0000000000010454. PMC 7682843. PMID 32753441.
  25. ^ Mesulam MM (May 1985). "Dementia: its definition, differential diagnosis, and subtypes". JAMA. 253 (17): 2559–2561. doi:10.1001/jama.1985.03350410125033. PMID 3981786.
  26. ^ Hamilton CA, Matthews FE, Attems J, Donaghy PC, Erskine D, Taylor JP, et al. (June 2024). "Associations between multimorbidity and neuropathology in dementia: consideration of functional cognitive disorders, psychiatric illness and dementia mimics". The British Journal of Psychiatry. 224 (6): 237–244. doi:10.1192/bjp.2024.25. PMC 7615979. PMID 38584319.
  27. ^ Hiya S, Maldonado-Díaz C, Walker JM, Richardson TE (December 2023). "Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease". Journal of Neuropathology and Experimental Neurology. 83 (1): 2–10. doi:10.1093/jnen/nlad098. PMC 10746699. PMID 37966908.
  28. ^ Neumann M, Perneel J, Cheung S, Van den Broeck M, Nygaard H, Hsiung GR, et al. (July 2023). "Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology". Acta Neuropathologica. 146 (1): 163–166. doi:10.1007/s00401-023-02580-2. PMID 37171635.
  29. ^ Riordan R, Saxton A, McMillan PJ, Kow RL, Liachko NF, Kraemer BC (June 2024). "TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy". bioRxiv: 2024.06.11.598478. doi:10.1101/2024.06.11.598478. PMC 11195232. PMID 38915598.
  30. ^ Nicks R, Clement NF, Alvarez VE, Tripodis Y, Baucom ZH, Huber BR, et al. (April 2023). "Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis". Acta Neuropathologica. 145 (4): 395–408. doi:10.1007/s00401-023-02539-3. PMID 36681782.
  31. ^ "2023 Alzheimer's disease facts and figures". Alzheimer's & Dementia. 19 (4): 1598–1695. April 2023. doi:10.1002/alz.13016. PMID 36918389.
  32. ^ Pinto JO, Peixoto B, Dores AR, Barbosa F (January 2024). "Measures of cognitive reserve: An umbrella review". The Clinical Neuropsychologist. 38 (1): 42–115. doi:10.1080/13854046.2023.2200978. PMID 37073431.
  33. ^ Kapasi A, Yu L, Leurgans SE, Agrawal S, Boyle PA, Bennett DA, et al. (May 2024). "Association between hippocampal microglia, AD and LATE-NC, and cognitive decline in older adults". Alzheimer's & Dementia. 20 (5): 3193–3202. doi:10.1002/alz.13780. PMC 11095444. PMID 38494787.
  34. ^ Keating SS, San Gil R, Swanson ME, Scotter EL, Walker AK (April 2022). "TDP-43 pathology: From noxious assembly to therapeutic removal". Progress in Neurobiology. 211: 102229. doi:10.1016/j.pneurobio.2022.102229. PMID 35101542.
  35. ^ a b Cheng F, Chapman T, Zhang S, Morsch M, Chung R, Lee A, et al. (April 2024). "Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease". Ageing Research Reviews. 96: 102246. doi:10.1016/j.arr.2024.102246. PMID 38401571.
  36. ^ Dickson DW, Baker M, Rademakers R (2010). "Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly". Neuro-Degenerative Diseases. 7 (1–3): 170–174. doi:10.1159/000289231. PMC 2859236. PMID 20197700.
  37. ^ Murray ME, Cannon A, Graff-Radford NR, Liesinger AM, Rutherford NJ, Ross OA, et al. (September 2014). "Differential clinicopathologic and genetic features of late-onset amnestic dementias". Acta Neuropathologica. 128 (3): 411–421. doi:10.1007/s00401-014-1302-2. PMC 4412022. PMID 24899141.
  38. ^ Nelson PT, Estus S, Abner EL, Parikh I, Malik M, Neltner JH, et al. (2014). "ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology". Acta Neuropathologica. 127 (6): 825–843. doi:10.1007/s00401-014-1282-2. PMC 4113197. PMID 24770881.
  39. ^ Dugan AJ, Nelson PT, Katsumata Y, Shade LM, Boehme KL, Teylan MA, et al. (September 2021). "Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study". Acta Neuropathologica Communications. 9 (1): 152. doi:10.1186/s40478-021-01250-2. PMC 8442328. PMID 34526147.
  40. ^ Yang HS, Yu L, White CC, Chibnik LB, Chhatwal JP, Sperling RA, et al. (September 2018). "Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study". The Lancet. Neurology. 17 (9): 773–781. doi:10.1016/S1474-4422(18)30251-5. PMC 6154505. PMID 30093249.
  41. ^ Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, et al. (September 2014). "Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias". PLOS Genetics. 10 (9): e1004606. doi:10.1371/journal.pgen.1004606. PMC 4154667. PMID 25188341.
  42. ^ Dugan AJ, Nelson PT, Katsumata Y, Shade LM, Teylan MA, Boehme KL, et al. (March 2022). "Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes". Neurobiology of Aging. 111: 95–106. doi:10.1016/j.neurobiolaging.2021.10.011. PMC 8761217. PMID 34852950. S2CID 240120472.
  43. ^ Cheng F, Chapman T, Zhang S, Morsch M, Chung R, Lee A, et al. (April 2024). "Understanding age-related pathologic changes in TDP-43 functions and the consequence on RNA splicing and signalling in health and disease". Ageing Research Reviews. 96: 102246. doi:10.1016/j.arr.2024.102246. PMID 38401571.
  44. ^ Nilaver BI, Urbanski HF (2023). "Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated Mini-Review". Frontiers in Aging Neuroscience. 15: 1142617. doi:10.3389/fnagi.2023.1142617. PMC 10034072. PMID 36967829.
  45. ^ Chen HJ, Mitchell JC (June 2021). "Mechanisms of TDP-43 Proteinopathy Onset and Propagation". International Journal of Molecular Sciences. 22 (11): 6004. doi:10.3390/ijms22116004. PMC 8199531. PMID 34199367.
  46. ^ Gendron TF, Rademakers R, Petrucelli L (2013). "TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43". Journal of Alzheimer's Disease. 33 Suppl 1 (Suppl 1): S35–S45. doi:10.3233/JAD-2012-129036. PMC 3532959. PMID 22751173.
  47. ^ Amador-Ortiz C, Dickson DW (2008). "Neuropathology of hippocampal sclerosis". Dementias. Handbook of Clinical Neurology. Vol. 89. pp. 569–572. doi:10.1016/S0072-9752(07)01253-5. ISBN 978-0-444-51898-9. ISSN 0072-9752. PMID 18631779.
  48. ^ Nelson PT, Schmitt FA, Lin Y, Abner EL, Jicha GA, Patel E, et al. (May 2011). "Hippocampal sclerosis in advanced age: clinical and pathological features". Brain. 134 (Pt 5): 1506–1518. doi:10.1093/brain/awr053. PMC 3097889. PMID 21596774.
  49. ^ a b Zarow C, Weiner MW, Ellis WG, Chui HC (July 2012). "Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample". Brain and Behavior. 2 (4): 435–442. doi:10.1002/brb3.66. PMC 3432966. PMID 22950047.
  50. ^ a b Makkinejad N, Schneider JA, Yu J, Leurgans SE, Kotrotsou A, Evia AM, et al. (May 2019). "Associations of amygdala volume and shape with transactive response DNA-binding protein 43 (TDP-43) pathology in a community cohort of older adults". Neurobiology of Aging. 77: 104–111. doi:10.1016/j.neurobiolaging.2019.01.022. PMC 6486844. PMID 30784812.
  51. ^ a b Nelson PT, Schmitt FA, Lin Y, Abner EL, Jicha GA, Patel E, et al. (May 2011). "Hippocampal sclerosis in advanced age: clinical and pathological features". Brain. 134 (Pt 5): 1506–1518. doi:10.1093/brain/awr053. PMC 3097889. PMID 21596774.
  52. ^ Sordo L, Qian T, Bukhari SA, Nguyen KM, Woodworth DC, Head E, et al. (September 2023). "Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old". Acta Neuropathologica. 146 (3): 415–432. doi:10.1007/s00401-023-02606-9. PMC 10412485. PMID 37382680.
  53. ^ Neltner JH, Abner EL, Baker S, Schmitt FA, Kryscio RJ, Jicha GA, et al. (January 2014). "Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing". Brain. 137 (Pt 1): 255–267. doi:10.1093/brain/awt318. PMC 3891448. PMID 24271328.
  54. ^ a b Duong MT, Wolk DA (November 2022). "Limbic-Predominant Age-Related TDP-43 Encephalopathy: LATE-Breaking Updates in Clinicopathologic Features and Biomarkers". Current Neurology and Neuroscience Reports. 22 (11): 689–698. doi:10.1007/s11910-022-01232-4. PMC 9633415. PMID 36190653.
  55. ^ a b c d e Nelson PT, Schneider JA, Jicha GA, Duong MT, Wolk DA (August 2023). "When Alzheimer's is LATE: Why Does it Matter?". Annals of Neurology. 94 (2): 211–222. doi:10.1002/ana.26711. PMC 10516307. PMID 37245084.
  56. ^ Yu L, Boyle PA, Dawe RJ, Bennett DA, Arfanakis K, Schneider JA (January 2020). "Contribution of TDP and hippocampal sclerosis to hippocampal volume loss in older-old persons". Neurology. 94 (2): e142–e152. doi:10.1212/WNL.0000000000008679. PMC 6988988. PMID 31757868.
  57. ^ Young AL, Vogel JW, Robinson JL, McMillan CT, Ossenkoppele R, Wolk DA, et al. (July 2023). "Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies". Brain. 146 (7): 2975–2988. doi:10.1093/brain/awad145. PMC 10317181. PMID 37150879.
  58. ^ Corriveau-Lecavalier N, Botha H, Graff-Radford J, Switzer AR, Przybelski SA, Wiste HJ, et al. (2024). "Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome". Brain Communications. 6 (4): fcae183. doi:10.1093/braincomms/fcae183. PMC 11251771. PMID 39021510.
  59. ^ Grothe MJ, Moscoso A, Silva-Rodríguez J, Lange C, Nho K, Saykin AJ, et al. (April 2023). "Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC". Alzheimer's & Dementia. 19 (4): 1234–1244. doi:10.1002/alz.12763. PMC 9929029. PMID 35971593.
  60. ^ López-Carbonero JI, García-Toledo I, Fernández-Hernández L, Bascuñana P, Gil-Moreno MJ, Matías-Guiu JA, et al. (June 2024). "In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use". Translational Neurodegeneration. 13 (1): 29. doi:10.1186/s40035-024-00419-8. PMC 11149336. PMID 38831349.
  61. ^ Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, et al. (April 2016). "Updated TDP-43 in Alzheimer's disease staging scheme". Acta Neuropathologica. 131 (4): 571–585. doi:10.1007/s00401-016-1537-1. PMC 5946692. PMID 26810071.
  62. ^ Nag S, Yu L, Boyle PA, Leurgans SE, Bennett DA, Schneider JA (May 2018). "TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer's disease". Acta Neuropathologica Communications. 6 (1): 33. doi:10.1186/s40478-018-0531-3. PMC 5928580. PMID 29716643.
  63. ^ Nelson PT, Lee EB, Cykowski MD, Alafuzoff I, Arfanakis K, Attems J, et al. (February 2023). "LATE-NC staging in routine neuropathologic diagnosis: an update". Acta Neuropathologica. 145 (2): 159–173. doi:10.1007/s00401-022-02524-2. PMC 9849315. PMID 36512061.
  64. ^ a b c d Nag S, Schneider JA (September 2023). "Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases". Nature Reviews. Neurology. 19 (9): 525–541. doi:10.1038/s41582-023-00846-7. PMC 10964248. PMID 37563264.
  65. ^ Carlos AF, Tosakulwong N, Weigand SD, Boeve BF, Knopman DS, Petersen RC, et al. (July 2022). "Frequency and distribution of TAR DNA-binding protein 43 (TDP-43) pathology increase linearly with age in a large cohort of older adults with and without dementia". Acta Neuropathologica. 144 (1): 159–160. doi:10.1007/s00401-022-02434-3. PMC 9943023. PMID 35536384.
  66. ^ Mikhailenko E, Colangelo K, Tuimala J, Kero M, Savola S, Raunio A, et al. (June 2024). "Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study". Brain: awae212. doi:10.1093/brain/awae212. PMID 38938199.
  67. ^ Sajjadi SA, Bukhari S, Scambray KA, Yan R, Kawas C, Montine TJ, et al. (January 2023). "Impact and Risk Factors of Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Change in an Oldest-Old Cohort". Neurology. 100 (2): e203–e210. doi:10.1212/WNL.0000000000201345. PMC 9841447. PMID 36302666.
  68. ^ Katsumata Y, Fardo DW, Shade LM, Nelson PT (August 2023). "LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry". Journal of Neuropathology and Experimental Neurology. 82 (9): 760–768. doi:10.1093/jnen/nlad059. PMC 10440720. PMID 37528055.
  69. ^ Huie EZ, Escudero A, Saito N, Harvey D, Nguyen ML, Lucot KL, et al. (2023). "TDP-43 Pathology in the Setting of Intermediate and High Alzheimer's Disease Neuropathologic Changes: A Preliminary Evaluation Across Ethnoracial Groups". Journal of Alzheimer's Disease. 91 (4): 1291–1301. doi:10.3233/JAD-220558. PMC 9974776. PMID 36617779.
  70. ^ Gibson LL, Grinberg LT, Ffytche D, Leite RE, Rodriguez RD, Ferretti-Rebustini RE, et al. (April 2023). "Neuropathological correlates of neuropsychiatric symptoms in dementia". Alzheimer's & Dementia. 19 (4): 1372–1382. doi:10.1002/alz.12765. PMC 10033459. PMID 36150075.
  71. ^ Nichols E, Merrick R, Hay SI, Himali D, Himali JJ, Hunter S, et al. (March 2023). "The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia". The Lancet. Healthy Longevity. 4 (3): e115–e125. doi:10.1016/S2666-7568(23)00019-3. PMC 9977689. PMID 36870337.
  72. ^ Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Grober E, et al. (1994). "Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans". Acta Neuropathologica. 88 (3): 212–221. doi:10.1007/BF00293396. PMID 7810292. S2CID 6265307.
  73. ^ Hokkanen SR, Hunter S, Polvikoski TM, Keage HA, Minett T, Matthews FE, et al. (July 2018). "Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population". Brain Pathology. 28 (4): 548–559. doi:10.1111/bpa.12556. PMC 6099461. PMID 28833898.
  74. ^ Spina S, La Joie R, Petersen C, Nolan AL, Cuevas D, Cosme C, et al. (August 2021). "Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease". Brain. 144 (7): 2186–2198. doi:10.1093/brain/awab099. PMC 8502474. PMID 33693619.
  75. ^ a b Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. (October 2006). "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis". Science. 314 (5796): 130–133. Bibcode:2006Sci...314..130N. doi:10.1126/science.1134108. PMID 17023659. S2CID 8620103.
  76. ^ "Newly recognized form of dementia could now be easier to diagnose". New Scientist. 30 April 2019. Retrieved 30 April 2019.
  77. ^ Chornenkyy Y, Fardo DW, Nelson PT (July 2019). "Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy". Laboratory Investigation; A Journal of Technical Methods and Pathology. 99 (7): 993–1007. doi:10.1038/s41374-019-0196-y. PMC 6609463. PMID 30742063.
  78. ^ Josephs KA, Whitwell JL, Tosakulwong N, Weigand SD, Murray ME, Liesinger AM, et al. (November 2015). "TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features". Annals of Neurology. 78 (5): 697–709. doi:10.1002/ana.24493. PMC 4623932. PMID 26224156.
  79. ^ Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, et al. (September 2019). "Reply: LATE to the PART-y". Brain. 142 (9): e48. doi:10.1093/brain/awz226. PMC 6931389. PMID 31359039.
  80. ^ Josephs KA, Mackenzie I, Frosch MP, Bigio EH, Neumann M, Arai T, et al. (September 2019). "LATE to the PART-y". Brain. 142 (9): e47. doi:10.1093/brain/awz224. PMC 6736234. PMID 31359030.

Further reading

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