A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo

Ortega-Cruz, Diana; Uceda-Heras, Alicia; Iglesias, Juan Eugenio; Zea‐Sevilla, María Ascensión; Strange, Bryan A.; Rábano, Alberto

doi:10.1002/alz.12942

Cited by 6 publications

(18 citation statements)

References 67 publications

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“…Conversely, other studies have highlighted the importance of HS in dementia [20,21], which allowed the observation of histological findings proposed as early HS [5,22]. In line with this work, we recently characterized early pathological changes of HS, proposing this pathology forms a wider spectrum than initially defined [23]. Following this re-classification, the prevalence of HS could have been underestimated in previous dementia studies, which reported a frequency of 3-30% following the classical definition [1,2,9].…”

Section: Introductionsupporting

confidence: 79%

“…(A) HS groups defined as a function of HS staging including early and advanced stages (HS+ for those at stage>0) [23]. …”

Section: Resultsmentioning

confidence: 99%

“…To test the regional specificity of the observed effects, we analyzed the association between HS stage and subfield volumes in both head and body of the hippocampus. Hippocampal subfields were analyzed in two groups: CA1+subiculum, in which histological changes occur at earlier HS stages, and CA3+CA4, which may present changes in stage IV [23]. Through the evaluated timespan, volumes of CA1+subiculum were significantly lower in both hippocampal head (Figure 2A) and body (Figure 2B) as a function of respective HS stages (head: F=5.8, p=.035; body: F=8, p=.003).…”

Section: Resultsmentioning

confidence: 99%

“…TDP-43 proteinopathy was evaluated according to LATE staging (0-3) [11], and patients with inclusions in the hippocampus (stage 2 or higher) were categorized as high LATE burden. HS was assessed following our recently proposed staging system (0-IV) including early stages of the pathology [23], evaluated in sections of both head and body of the hippocampus. Subjects presenting stages>0 in any of these two sections were classified as HS+.…”

Section: Methodsmentioning

confidence: 99%

“…We studied data from dementia patients with pre-mortem MRI follow-up, spanning more than 10 years before death, and subsequent neuropathological evaluation. We describe longitudinal differences of whole hippocampus and subfield volumes between subjects with HS (HS+) and without (HS-), following its classical definition, as well as according to our recently proposed evaluation including early stages [23]. Implementing a two-level HS assessment in the head and body of the hippocampus, we explore subfield volumetric changes in these two regions relative to HS.…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior

Ortega-Cruz

Iglesias

Rábano

et al. 2023

Preprint

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INTRODUCTION: Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically-defined features is unknown. We investigated pre-mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia-associated pathologies. METHODS: We analyzed hippocampal volumes from MRI segmentations in 64 dementia patients with longitudinal MRI follow-up and post-mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. RESULTS: Significant HS-associated hippocampal volume changes were observed thoughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's Disease (AD) burden, and specifically driven by CA1 and subiculum. AD burden, but not HS, significantly associated with the rate of hippocampal atrophy. DISCUSSION: HS-associated volume changes are detectable on MRI earlier than 10 years before death. These findings could contribute to the derivation of volumetric cut-offs for in vivo differentiation between HS and AD.

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Section: Introductionsupporting

confidence: 79%

“…(A) HS groups defined as a function of HS staging including early and advanced stages (HS+ for those at stage>0) [23]. …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior

Ortega-Cruz

Iglesias

Rábano

et al. 2023

Preprint

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Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Ortega-Cruz

Iglesias

Rábano

et al. 2023

Alzheimer's & Dementia

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IntroductionHippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically‐defined features is unknown. We investigated pre‐mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia‐associated pathologies.MethodsWe analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow‐up and post‐mortem neuropathological evaluation, including HS assessment in the hippocampal head and body.ResultsSignificant HS‐associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy.DiscussionHS‐associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD.HIGHLIGHTS Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre‐mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

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

et al. 2023

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Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer’s disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

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A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo

Cited by 6 publications

References 67 publications

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior

Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

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

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