Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old

Sordo, Lorena; Qian, Tianchen; Bukhari, Syed; Nguyen, Katelynn M.; Woodworth, Davis C.; Head, Elizabeth; Kawas, Claudia H.; Corrada, María M.; Montine, Thomas J.

doi:10.1007/s00401-023-02606-9

Cited by 13 publications

(6 citation statements)

References 59 publications

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“…In addition, we found that the differences in hippocampal atrophy were better detected when examining only the volume of the smallest hippocampus rather than total bilateral hippocampal volume. HS-A commonly presents unilaterally, and here we show that this may mean disproportionate atrophy in the hippocampus in one hemisphere vs. the other [8] , [15] . Thus, examining total hippocampal volume alone could mask the extent of the atrophy in the affected hemisphere of individuals with HS-A and therefore, it is important to consider the laterality of the presentation of HS-A in its assessment.…”

Section: Discussionmentioning

confidence: 49%

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging

Nguyen

Qian

et al. 2023

Aging Brain

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Section: Discussionmentioning

confidence: 49%

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging

Nguyen

Qian

et al. 2023

Aging Brain

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“…For example, Forrest et al showed that ARTAG, and a novel Tau pathology termed age-related tau oligodendrogliopathy (ARTOG), were associated with LATE-NC ( 94 ). Sordo et al ( 74 ) and Katsumata et al ( 92 ) confirmed that ARTAG was associated with LATE-NC. Yokota et al ( 95 ) reported that the presence of amygdala granular-fuzzy astrocytes was associated with LATE-NC as well as with Tau-immunoreactive argyrophilic grain pathology.…”

Section: Late-nc and Comorbidities That Are Enriched In Brains With L...mentioning

confidence: 89%

“…For example, the clinical literature usually refers to a seizure disorder when applying the term HS, and pathology that is labeled HS is also seen in completely different circumstances related to brains affected by anoxia, hypoglycemia, and various infections that target the hippocampus ( 121–123 ). We and others have proposed a term that is more specific for HS in the context of LATE-NC, which is “hippocampal sclerosis of aging,” or HS-A ( 92 , 113 , 124 ). The term HS-A is useful and we will apply it subsequently in this present review but it has the drawbacks of not being consensus-based and also is still not specifically defined in terms of the precise histopathologic features other than LATE-NC, cell loss, and gliosis in the hippocampal formation.…”

Section: Late-nc and Comorbidities That Are Enriched In Brains With L...mentioning

confidence: 99%

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

Nelson,

Fardo,

et al. 2024

Journal of Neuropathology &Amp; Experimental Neurology

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Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although “pure” LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions (“synergies”) between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.

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“…Participants with ALS/FTLD-TDP, on the other hand, had greater odds of HS-A but lower odds of ADNC, LB, and CAA, compared to NACC participants without brain TDP-43. The association between TDP-43 and HS-A, is well known for both FTLD-TDP [ 7 , 31 , 71 ] and LATE-NC [ 4 , 32 , 60 , 72 ]. A novel contribution from this study, however, is the similarities in odds of HS-A for ALS/FTLD-TDP, LATE-NC, and even in the “Other TDP-43” group, compared to those without TDP-43.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer’s Coordinating Center database

Woodworth,

Nguyen,

Sordo

et al. 2024

Acta Neuropathol

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TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer’s Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies (“Other TDP-43”). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer’s disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.

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Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old

Cited by 13 publications

References 59 publications

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer’s Coordinating Center database

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