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.
Highlights
Stroke accounts for half of the global burden of neurological disorders while remaining the most common cause of acquired disability, and a common cause of cognitive impairment and dementia (Kalaria et al, 2016; Writing Group Members et al, 2016; GBD 2015 Neurological Disorders Collaborator Group, 2017)
Braak stage, CERAD score and Thal stage were significantly higher in the Alzheimer’s disease (AD), AD-vascular dementia (VaD) groups compared to the VaD and post-stroke groups (PSND and post-stroke dementia (PSD)) (p < 0.05)
(2) As expected, concentrations of total amyloid beta and amyloid β-42 were significantly greater in AD and mixed subjects but low in post-stroke subjects consistent with insufficient concentrations for a diagnosis of AD (3) an association between APOE ε4 allele positivity and higher load of amyloid and tau pathology in the subiculum and entorhinal cortex of post-stroke cases (4) hyperphosphorylated tau immunoreactivity did not differ significantly between post-stroke non-demented (PSND) and PSD groups and (5) poor correlation of cognitive measures with the burden of amyloid and tau pathology in post-stroke subjects
Summary
Stroke accounts for half of the global burden of neurological disorders while remaining the most common cause of acquired disability, and a common cause of cognitive impairment and dementia (Kalaria et al, 2016; Writing Group Members et al, 2016; GBD 2015 Neurological Disorders Collaborator Group, 2017). Magnetic resonance imaging studies in a cohort of older African stroke survivors participating in the Cognitive Function After STroke (CogFAST)—Nigeria Study showed that medial temporal lobe atrophy (MTLA) was an independent predictor of post-stroke cognitive impairment and dementia (Akinyemi et al, 2014, 2015). The link between cerebrovascular disease, neurodegeneration and cognition has long been debated (de la Torre and Mussivand, 1993; Kalaria et al, 1993b) Evidence for this link has been provided by experimental models (Kalaria et al, 1993a; Kitaguchi et al, 2009) and from epidemiological studies (Schneider et al, 2004; Petrovitch et al, 2005). Experimental evidence from animal studies has shown that amyloid production may be exacerbated by cerebral hypoxia/ischaemia (Kalaria et al, 1993a; Whitehead et al, 2005)
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