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. 2011 May;134(Pt 5):1506-18.
doi: 10.1093/brain/awr053.

Hippocampal sclerosis in advanced age: clinical and pathological features

Peter T Nelson  1 , Frederick A Schmitt, Yushun Lin, Erin L Abner, Gregory A Jicha, Ela Patel, Paula C Thomason, Janna H Neltner, Charles D Smith, Karen S Santacruz, Joshua A Sonnen, Leonard W Poon, Marla Gearing, Robert C Green, John L Woodard, Linda J Van Eldik, Richard J Kryscio
Affiliations

Hippocampal sclerosis in advanced age: clinical and pathological features

Peter T Nelson et al. Brain. 2011 May.

Abstract

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.

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Figures

Figure 1
Figure 1
Estimated probability of a pathologically confirmed ‘definite’ Alzheimer’s disease (black curve) and the probability of a hippocampal sclerosis pathology (red curve; n = 106) as a function of age at death. ‘Definite’ Alzheimer’s disease cases (n = 286) had moderate or high densities of neuritic amyloid plaques and Braak stage V or VI. Note that after the age of 95 years, the probability for Alzheimer’s disease-type pathological diagnosis begins to decline but the probability for pathologically confirmed hippocampal sclerosis increases dramatically.
Figure 2
Figure 2
Features of HS-Ageing and TDP-43 immunohistochemistry. A 97-year-old female (Case 1) had hippocampal features that, with haematoxylin and eosin staining, met criteria for hippocampal sclerosis on the right (A) but not the left (B) side. Green arrows show CA1, blue arrows show subiculum. Immunohistochemistry for TDP-43 showed clear evidence of aberrant TDP-43 on the left side (C), confirming that the process was bilateral. Case 2 (D) is an 88-year-old male with bilateral hippocampal sclerosis pathology but not Alzheimer’s disease or cerebrovascular disease, without aberrant TDP-43 staining. Shown here is the normal pattern of TDP-43 staining in neurons in the CA1 field of the hippocampus. Case 3 (E) is from a 34-year-old female with history of seizures and right mesial temporal sclerosis. Shown is a portion of the dentate granule cells, which like the rest of the hippocampectomy specimen (and all the other hippocampal sclerosis–seizures cases) showed no evidence of aberrant TDP-43 in cytoplasm or neurites. Case 4 (F) is from a 97-year-old APOE 3/3 male with Alzheimer’s disease and bilateral hippocampal sclerosis. Shown is a representative high-power field from frontal lobe (Brodmann area 9), with sparse aberrant TDP-43 immunohistochemistry including an intraneuronal inclusion (arrow) and a few scattered neurites (smaller arrows). Four of 14 stained frontal cortices from cases with HS-Ageing–TDP also showed scattered immunopositivity in frontal cortex. Scale bars = 1 mm (A, B and F), 50 microns (C–E). HS = hippocampal sclerosis.
Figure 3
Figure 3
Linear mixed modelling of world list delay (A), verbal fluency (B) and MMSE (C) scores over time (n = 118 patients) with the goal of developing a biomarker for HS-Ageing. Cognitive assessment scores were modelled starting with the final evaluation and working back for 10 years using the non-linear mixed effects regression model (Martins et al., 2005; Nelson et al., 2009). This approach was used because starting at ‘baseline’ and moving forward required potential insertion of bias to cope with variance in the number of years before the advent of cognitive decline. Eventual HS-Ageing pathology and Alzheimer’s disease (with Braak stage V or VI) pathology, are the two main factors investigated and the fitted curves were plotted accordingly. The data from this three-parameter logistic model suggested an approach that could use cognitive testing as a biomarker for HS-Ageing because verbal fluency scores were higher, but word list delay lower in patients with HS-Ageing pathology (red line) than those with pure Alzheimer’s disease pathology (blue line). Note that MMSE scores provide weaker discriminatory power than the other two tests although, as in the other tests, the impact of HS-Ageing and Alzheimer’s disease are additive in individuals with both pathologies (green line). AD = Alzheimer's disease; HS = hippocampal sclerosis.
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