Hippocampal Neurodegenerative Pathology in Post-stroke Dementia Compared to Other Dementias and Aging Controls

Abstract

Neuroimaging evidence from older stroke survivors in Nigeria and Northeast England showed medial temporal lobe atrophy (MTLA) to be independently associated with post-stroke cognitive impairment and dementia. Given the hypothesis ascribing MTLA to neurodegenerative processes, we assessed Alzheimer pathology in the hippocampal formation and entorhinal cortex of autopsied brains from of post-stroke demented and non-demented subjects in comparison with controls and other dementias. We quantified markers of amyloid β (total Aβ, Aβ-40, Aβ-42, and soluble Aβ) and hyperphosphorylated tau in the hippocampal formation and entorhinal cortex of 94 subjects consisting of normal controls (n = 12), vascular dementia, VaD (17), post-stroke demented, PSD (n = 15), and post-stroke non-demented, PSND (n = 23), Alzheimer's disease, AD (n = 14), and mixed AD and vascular dementia, AD_VAD (n = 13) using immunohistochemical techniques. We found differential expression of amyloid and tau across the disease groups, and across hippocampal sub-regions. Among amyloid markers, the pattern of Aβ-42 immunoreactivity was similar to that of total Aβ. Tau immunoreactivity showed highest expression in the AD and mixed AD and vascular dementia, AD_VaD, which was higher than in control, post - stroke and VaD groups (p < 0.05). APOE ε4 allele positivity was associated with higher expression of amyloid and tau pathology in the subiculum and entorhinal cortex of post-stroke cases (p < 0.05). Comparison between PSND and PSD revealed higher total Aβ immunoreactivity in PSND compared to PSD in the CA1, subiculum and entorhinal cortex (p < 0.05) but no differences between PSND and PSD in Aβ-42, Aβ-40, soluble Aβ or tau immunoreactivities (p > 0.05). Correlation of MMSE and CAMCOG scores with AD pathological measures showed lack of correlation with amyloid species although tau immunoreactivity demonstrated correlation with memory scores (p < 0.05). Our findings suggest hippocampal AD pathology does not necessarily differ between demented and non-demented post-stroke subjects. The dissociation of cognitive performance with hippocampal AD pathological burden suggests more dominant roles for non-Alzheimer neurodegenerative and / or other non-neurodegenerative substrates for dementia following stroke.

Keywords: Alzheimer's disease; cerebrovascular disease; mixed dementia; post-stroke dementia; stroke; vascular dementia.

Figure 1

Illustrative images of amyloid pathology in the CA1 sub-region across different markers and across disease groups and aging controls. There is higher expression of amyloid in the AD and AD_VaD groups compared with the VaD, PSD, and PSND and control groups. The level of amyloid immunoreactivity is similar between 4G8 and T-42 but much lower in T-40 and NU-1.

Figure 2

Bar graphs showing the distribution of total Aβ IR across hippocampal sub-regions (A) CA1, (B) CA2, (C) CA3, (D) Subiculum, (E) Entorhinal cortex in Controls, PSND, PSD, VaD, AD and AD_VaD. Bars show ± 2 SEM ^*Mann Whitney U-test was used to compare means of each group. ^*p < 0.05; + p < 0.1 (in comparison with the control group). $*$(red) showed significant difference from PSD group. IR (immunoreactivity).

Figure 3

Bar graphs showing the distribution of Aβ-42 IR across hippocampal sub-regions (A) CA1, (B) CA2, (C) CA34, (D) Subiculum, (E) Entorhinal cortex in Controls, PSND, PSD, AD, VaD, and AD_VaD. Bars show ± 2 SEM ^*Mann Whitney U-test was used to compare means of each group. ^*p < 0.05; + p < 0.1 (in comparison with control group). $*$(red) showed significant difference from PSND group. IR (immunoreactivity).

Figure 4

Bar graphs showing the distribution of Aβ-40 IR across hippocampal sub-regions (A) CA1, (B) CA2, (C) Entorbinal cortex in Controls, PSND, PSD, AD, VaD and AD_VaD. Bars show ± 2 SEM ^*Mann Whitney U–test was used to compare means of each group. ^*p < 0.05; + p < 0.1 (in comparison with the control group). $*$(red) showed significant difference from PSD group. lR (immunoreactivity).

Figure 5

Bar graph shows percentage area and immunoreactivity of soluble Aβ (IR) across the CA1 region (A,B) and Entorhinal cortex (C,D) respectively in Control PSND, PSD, VaD, AD, and AD_VaD. Bars show ± 2 SEM ^*Mann Whitney U-test was used to compare means of each group. ^*p < 0.05 (in comparison with the ^*control group and $*$PSD group). There were no significant differences across groups in the CA1, CA2, and CA3 regions (p > 0.05, Kruskal–Wallis Test).

Figure 6

(A) Hyperphosphorylated tau (AT8) immunoreactivities showing neuropil threads, pretangles and tangles in hippocampal sub-region CAl. AT8 immunoreactivity is relatively higher in AD and AD_VaD compared to other groups. (B) Bar graph showing the distribution of AT8 IR across hippocampal sub-region. (a) CA1, (b) CA2, (c) CA3, (d) Subiculum (e) Entorhinal cortex in Controls. PSND. PSD. AD. VaD and AD_ VaD. Bars show ± 2 SEM ^*Mann Whitney U-test was used to compare means of each group. ^*p < 0.05; (in comparison with the control group). $*$(red) showed significant difference from PSND group.

Figure 7

(A) Box Plots showing the influence of Apo E ε4 on total amyloid deposition across hippocampal sub-regions (a) CA1, (b) CA2, (c) CA3, (d) Subicuhun, and [e] Emorlrinal conex in the post-stroke sub-cohort Mann–Whitney U-test was used to compare the mean 4G8 total immunoreactivity between the Apo E ε4 positive and negative groups respectively. ^*p < 0.05. (B) Box Plot showing the influence of Apo E ε4 on total tau (AT8) deposition across hippocampal sub-regions (a) CA1 (b) CA2 (c) CA3 (d) Subiculum and (e) Entorhinol cortex in the post-stroke sub-cohort. Mann Whitney U-test was used to compare mean AT8 total immunoreactivity between the Apo E ε4 positive and negative groups respectively. ^*p < 0.05.