Influence of Amyloid-β on Cognitive Decline After Stroke/Transient Ischemic Attack

Abstract

C ognitive impairment in the context of stroke or transient ischemic attack (TIA) is a prototype of vascular cognitive impairment (VCI). Our recent in vivo study using carbon-11-labeled Pittsburgh compound B ( 11 C-PiB) positron emission tomography (PET) found that ≈30% of subjects with poststroke/TIA cognitive impairment harbored Alzheimer's pathology.1 Although some studies suggested that in patients with clinical Alzheimer's disease (AD), comorbid cerebrovascular disease was associated with a more rapid cognitive decline, 2,3 it is still unknown whether concurrent presence of Alzheimer's pathology is associated with a faster cognitive deterioration in patients with poststroke/TIA cognitive impairment.In this study, we compared the longitudinal cognitive changes between VCI patients with and without AD-like amyloid-beta (Aβ) deposition measured using 11 C-PiB PET. We hypothesized that over 3 years, PiB-positive VCI (mixed VCI [mVCI]) subjects would experience a more rapid and continuous course of cognitive deterioration, resulting in more severe cognitive impairment than those who were PiB-negative (pure VCI [pVCI]). Methods SubjectsSubjects of this study were participants of the ongoing Stroke Registry Investigating cognitive Decline (STRIDE) study. 1 In the Background and Purpose-We hypothesized that comorbid amyloid-beta (Aβ) deposition played a key role in long-term cognitive decline in subjects with stroke/transient ischemic attack. Methods-We recruited 72 subjects with cognitive impairment after stroke/transient ischemic attack to receive Carbon-11-labeled Pittsburgh compound B positron emission tomography. We excluded subjects with known clinical Alzheimer's disease. Those with and without Alzheimer's disease-like Aβ deposition were classified as mixed vascular cognitive impairment (mVCI, n=14) and pure VCI (pVCI, n=58), respectively. We performed Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment to evaluate global cognition and cognitive domains (memory, visuospatial function, language, attention, and executive function) at 3 to 6 months (baseline) and annually for 3 years after the index event. We compared cognitive changes between mVCI and pVCI using linear mixed models and analysis of covariance adjusted for age and education. Results-Over 3 years, there were significant differences between mVCI and pVCI on change of MMSE score over time (group×time interaction, P=0.007). We observed a significant decline on MMSE score (P=0.020) in the mVCI group but not in the pVCI group (P=0.208 6 were performed on subjects at 3 to 6 months (baseline) after the index event to index general cognition. Then subjects were further invited to return for annual follow-up. This study analyzed the data collected ≤3 years.This substudy included a sample of 72 subjects with cognitive impairment (CDR grade ≥0.5) from the STRIDE study. Clinical diagnoses were made by 2 neurologists specialized in dementia (V.C.T.M. and L.A.). Thirty-six subjects had CDR grade of ≥1 and met the criteria for dementia acco...

Neuronal loss without amyloid‐β deposits in the thalamus and hippocampus in the late period after middle cerebral artery occlusion in cynomolgus monkeys

“…Some rodent studies have found that the Aβ deposits could be induced shortly after stroke but vanish within a few weeks, possibly caused by an increased clearance of pre-existing Aβ deposits, suggesting that cerebrovascular lesions only induce transient but not permanent Aβ deposition (11,14). A clinical study using ELISA to examine serum Aβ levels found that serum Aβ 40 and Aβ 42 levels were increased at day 1, reached peak levels at day 3 and decreased to pre-stroke levels at day 7, indicating that the elevation of serum Aβ levels was also transient (27). In our study, no significant difference was found between monkeys with MCAO and controls in terms of Aβ 40 and, Aβ 42 levels, or the Aβ 40 /Aβ 42 ratio in CSF and plasma at 12 months after MCAO.…”

Poststroke Induction of -Synuclein Mediates Ischemic Brain Damage

“…Of those, PINK1 has been shown to protect neurons from OGD-induced cell death (Zhao et al, 2013), while parkin depletion has been shown to contribute to neuronal death after focal ischemia (Mengesdorf et al, 2002). Furthermore, serum A β levels are a known predictor of short-term neurological deficits after stroke (Liu et al, 2015a) and patients with cerebral A β deposition show more severe and rapid cognitive decline after stroke (Liu et al, 2015b). Mutations or overexpression of α -Syn have been mostly implicated in the pathogenesis of PD, but α -Syn has also been reported to play a neuroprotective role under a cysteine-string protein- α -null-mediated neurodegenerative condition by maintaining synaptic integrity (Chandra et al, 2005; Ruiz et al, 2014).…”

A Methodological Perspective on the Longitudinal Cognitive Change after Stroke

“…Progressive memory decline suggests superimposed Alzheimer disease pathology, and, in fact, underlying amyloid pathology was proposed as a key determinant of delayed cognitive decline in stroke survivors in a recent study [4]. In our study, memory was stable compared to executive function, which suggests that either patients with progressive memory decline were selectively lost during follow-up, or, contrary to the result of the previous study [4], delayed poststroke cognitive decline may not be due to Alzheimer pathology. Further studies should, therefore, explore the mechanisms of domain-specific longitudinal cognitive changes.…”

“…Though most stroke survivors have stable cognitive trajectories [3], some show a delayed cognitive decline [4]. Pathophysiology and clinical determinants of delayed poststroke cognitive decline might differ from those for cognitive impairments occurring relatively early after stroke, and underlying amyloid pathology was proposed as a key determinant of delayed cognitive decline in stroke survivors [4].…”