No evidence for amyloid pathology as a key mediator of neurodegeneration post-stroke - a seven year follow-up study

Abstract

Background Cognitive impairment (CI) with mixed vascular and neurodegenerative pathologies after stroke is common. The role of amyloid pathology in post-stroke CI is unclear. We hypothesize that amyloid deposition, measured with Flutemetamol ( 18 F-Flut) positron emission tomography (PET), is common in 7-year stroke survivors diagnosed with CI and, further, that quantitatively assessed 18 F-Flut-PET uptake after seven years correlates with amyloid-β peptide (Aβ 42 ) levels in cerebrospinal fluid (CSF) at one year, and with measures of neurodegeneration and cognition at seven years post-stroke. Methods 208 patients with first-ever stroke or TIA without pre-existing CI were included during 2007 and 2008. At one- and seven-years post-stroke, cognitive status was assessed, and categorized into dementia, mild cognitive impairment or none. Etiologic sub-classification was based on magnetic resonance imaging (MRI) findings, CSF biomarkers and clinical cognitive profile. At seven years, patients were offered 18 F-Flut-PET, and amyloid-positivity was assessed visually and semi-quantitatively. The associations between 18 F-Flut-PET standardized uptake value ratios (SUVr) and measures of neurodegeneration (medial temporal lobe atrophy (MTLA), global cortical atrophy (GCA)) and cognition (Mini-Mental State Exam (MMSE), Trail-making test A (TMT-A)) and CSF Aβ 42 levels were assessed using linear regression. Results In all, 111 patients completed 7-year follow-up, and 26 patients agreed to PET imaging, of whom 13 had CSF biomarkers from one year. Thirteen out of 26 patients were diagnosed with CI seven years post-stroke, but only one had visually assessed amyloid positivity. CSF Aβ 42 levels at one year, MTA grade, GCA scale, MMSE score or TMT-A at seven years did not correlate with 18 F-Flut-PET SUVr in this cohort. Conclusions Amyloid binding were not common in 7-year stroke survivors diagnosed with CI. Quantitatively assessed amyloid did not correlate with other measures related to neurodegeneration and cognition. Therefore amyloid pathology may not be a key mediator of neurodegeneration seven years post-stroke.

Increased brain atrophy over 3 years in stroke survivors is linked to early post-stroke cognitive impairment

“…Many authors have proposed that incipient Alzheimer's pathology is contributing to the hippocampal atrophy, and that pre-existing protein deposition leads to the observed atrophy. However, this has not been borne out on PET amyloid imaging studies of stroke 30,31 , nor did we find an association between hippocampal volume and amyloid status in a small PET amyloid sub-study at 3 years 32 . Vascular risk factors are increasingly considered as primary drivers of hippocampal degeneration 9,10 .…”

Post-Stroke Cognitive Impairment and Dementia

“…161 Also, imaging studies combining positron emission tomography with tracers directed at Aβ did not find amyloid pathology to be a key factor for the development of PSCID. 162,163…”

Cognitive decline according to amyloid uptake in patients with poststroke cognitive impairment

“…[25][26][27] Previous studies of the prevalence of Ab in PSCI and its effect on the prognosis of PSCI were limited because patients were enrolled even though they underwent initial neuropsychological testing 3 to months after their stroke events, patients with pre-existing dementia were not clearly excluded, cohorts were small, patient assessments were made using computerized tomography results without MRI, a variety of stroke etiologies were used (eg, TIA, hemorrhage, and infarction), and over half of the studies used Pittsburgh compound B as an investigative amyloid tracer, which was not approved for clinical practice. [4,8,9,28,29] Because of these limitations, there is no consensus yet regarding the contribution of Ab to PSCI and the impact of Ab on the PSCI prognosis. We hypothesized that Ab deposition may accelerate neuroinflammation related to stroke, which in turn could result in rapid PSCI progression.…”

“…In addition, as a variety of factors are known to contribute to PSCI, it is unclear if Aβ is a predictor of its progression or poststroke dementia, even though Aβ positivity is known to be a strong predictor of progression or conversion to AD from MCI [25–27] . Previous studies of the prevalence of Aβ in PSCI and its effect on the prognosis of PSCI were limited because patients were enrolled even though they underwent initial neuropsychological testing 3 to 6 months after their stroke events, patients with pre-existing dementia were not clearly excluded, cohorts were small, patient assessments were made using computerized tomography results without MRI, a variety of stroke etiologies were used (eg, TIA, hemorrhage, and infarction), and over half of the studies used Pittsburgh compound B as an investigative amyloid tracer, which was not approved for clinical practice [4,8,9,28,29] . Because of these limitations, there is no consensus yet regarding the contribution of Aβ to PSCI and the impact of Aβ on the PSCI prognosis.…”

“…[4] On the other hand, amyloidpathology prevalence in PSCI was found not to increase in cognitively healthy stroke survivors, suggesting that factors other than amyloid pathology were likely contributors to the development of PSCI. [8] Moreover, Hagberg et al [9] reported that amyloid binding was uncommon and that amyloid deposition did not correlate with cognition in a 7-year longitudinal study. Therefore, this study was designed to examine how cognitive-impairment progression in PSCI is related to amyloid pathology.…”