A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study

Abstract

BackgroundLate-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer’s vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline.MethodsA total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer’s pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid β1–42) and by MR measurements of iron accumulation, a marker for Alzheimer’s-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer’s disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively.DiscussionThe PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.

Longitudinal Brain Atrophy Rates in Transient Ischemic Attack and Minor Ischemic Stroke Patients and Cognitive Profiles

“…Expanding on these studies, The Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) prospective longitudinal cohort study is targeting patients presenting with clinically defined motor or language TIA (50). These subjects are generally younger, not demented and in better physical condition than stroke patients, thereby permitting the acquisition of detailed serial neuropsychological assessments in participants that are not disabled and cooperative with cognitive testing, and avoiding high attrition rates caused by stroke related co-morbidity and frailty that can prohibit the study of cognition over time (10).…”

White matter tract microstructure and cognitive performance after transient ischemic attack

“…Consecutive subjects presenting with first documented TIA, and non-TIA subjects (ages 45–75) were prospectively consented to the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study [ 7 ] approved by the University of Calgary Research Ethics Board. Transient ischemic attack subjects were recruited through the stroke prevention clinic or the emergency department acutely (within 24 hours) and underwent an MRI scan and neuropsychological testing on the same day.…”

Roles of glutamate receptors in a novel in vitro model of early, comorbid cerebrovascular, and Alzheimer’s diseases

“…Considering the numerous genetic risk factors for AD discovered in genome-wide association studies (Carmona, Hardy, & Guerreiro, 2018;Lambert et al, 2013) In rats subjected to endothelin-induced acute vasoconstriction in the striatum together with intra-cerebrovascular injection of the Aβ fragment 25-35 (Amtul et al, 2014), neurodegeneration markers were found at levels higher than caused by either insult alone (Amtul, Frias, Randhawa, Hill, & Arany, 2019;Amtul, Hill, Arany, & Cechetto, 2018;Amtul et al, 2014Amtul et al, , 2015. Still, in addition to using an Aβ fragment that does not accumulate significantly in the AD brain, this approach did not clarify whether the isolated insults produce additive or synergistic effects, a critical matter especially at early stages of comorbid CVD/AD, and/or at the leading edges of disease progression throughout the brain (Araque Caballero et al, 2018;Attems & Jellinger, 2014;Buratti et al, 2015;Caunca, De Leon-Benedetti, Latour, Leigh, & Wright, 2019;Filippi et al, 2019;Frisoni et al, 2013;Molko et al, 2002;Shi & Wardlaw, 2016;Staffaroni et al, 2017;Tariq et al, 2018).…”