Citations

Purpose A standard MRI system phantom has been designed and fabricated to assess scanner performance, stability, comparability and assess the accuracy of quantitative relaxation time imaging. The phantom is unique in having traceability to the International System of Units, a high level of precision, and monitoring by a national metrology institute. Here, we describe the phantom design, construction, imaging protocols, and measurement of geometric distortion, resolution, slice profile, signal‐to‐noise ratio (SNR), proton‐spin relaxation times, image uniformity and proton density. Methods The system phantom, designed by the International Society of Magnetic Resonance in Medicine ad hoc committee on Standards for Quantitative MR, is a 200 mm spherical structure that contains a 57‐element fiducial array; two relaxation time arrays; a proton density/SNR array; resolution and slice‐profile insets. Standard imaging protocols are presented, which provide rapid assessment of geometric distortion, image uniformity, T 1 and T 2 mapping, image resolution, slice profile, and SNR. Results Fiducial array analysis gives assessment of intrinsic geometric distortions, which can vary considerably between scanners and correction techniques. This analysis also measures scanner/coil image uniformity, spatial calibration accuracy, and local volume distortion. An advanced resolution analysis gives both scanner and protocol contributions. SNR analysis gives both temporal and spatial contributions. Conclusions A standard system phantom is useful for characterization of scanner performance, monitoring a scanner over time, and to compare different scanners. This type of calibration structure is useful for quality assurance, benchmarking quantitative MRI protocols, and to transition MRI from a qualitative imaging technique to a precise metrology with documented accuracy and uncertainty.

Abstract While cerebrovascular disease can be observed in vivo using MRI, the multiplicity and heterogeneity in the mechanisms of cerebrovascular damage impede accounting for these measures in ageing and dementia studies. Our primary goal was to investigate the key sources of variability across MRI markers of cerebrovascular disease and evaluate their impact in comparison to amyloidosis on cognitive decline in a population-based sample. Our secondary goal was to evaluate the prognostic utility of a cerebrovascular summary measure from all markers. We included both visible lesions seen on MRI (white matter hyperintensities, cortical and subcortical infarctions, lobar and deep microbleeds) and early white matter damage due to systemic vascular health using diffusion changes in the genu of the corpus callosum. We identified 1089 individuals aged ≥60 years with concurrent amyloid-PET and MRI scans from the population-based Mayo Clinic Study of Aging. We divided these into discovery and validation datasets. Using the discovery dataset, we conducted principal component analyses and ascertained the main sources of variability in cerebrovascular disease markers. Using linear regression and mixed effect models, we evaluated the utility of these principal components and combinations of these components for the prediction of cognitive performance along with amyloidosis. Our main findings were (i) there were three primary sources of variability among the CVD measures—white matter changes are driven by white matter hyperintensities and diffusion changes; number of microbleeds (lobar and deep); and number of infarctions (cortical and subcortical); (ii) Components of white matter changes and microbleeds but not infarctions significantly predicted cognition trajectories in all domains with greater contributions from white matter; and (iii) The summary vascular score explained 3–5% of variability in baseline global cognition in comparison to 3–6% variability explained by amyloidosis. Across all cognitive domains, the vascular summary score had the least impact on memory performance (∼1%). Though there is mechanistic heterogeneity in the cerebrovascular disease markers measured on MRI, these changes can be grouped into three components and together explain variability in cognitive performance equivalent to the impact of amyloidosis on cognition. White matter changes represent dynamic ongoing damage, predicts future cognitive decline across all domains and diffusion measurements help capture white matter damage due to systemic vascular changes. Therefore, measuring and accounting for white matter changes using diffusion MRI and white matter hyperintensities along with microbleeds will allow us to capture vascular contributions to cognitive impairment and dementia.

BackgroundTo operationalize the National Institute on Aging – Alzheimer's Association (NIA‐AA) Research Framework for Alzheimer's Disease 6‐stage continuum of clinical progression for persons with abnormal amyloid.MethodsThe Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross‐sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.ResultsAmong 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44–59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short‐term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).InterpretationThe frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145–1156

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

Background: Atrial fibrillation (AF) is an established risk factor for ischemic stroke, but it can be paroxysmal and may go undiagnosed. An artificial intelligence (AI)-enabled ECG acquired during normal sinus rhythm was recently shown to detect silent AF. The objective of this study was to determine if AI-ECG AF score is associated with presence of cerebral infarcts. Methods: Participants from a population-based study ages 30 to 95 years with T2 fluid attenuation inversion recovery (FLAIR) MRI obtained between October 10, 2011, and November 2, 2017 were considered for inclusion. Participants without ECG were excluded. AI-ECG score was calculated using most recent ECG with normal sinus rhythm at the time of MRI. Presence of infarcts was determined on FLAIR MRI scans. Logistic regression was run to evaluate the relationship between AI-ECG AF score and presence of cerebral infarcts. Similar analyses were performed using history of AF rather than AI-ECG AF score as predictor. Age and sex were included as covariates. We also examined whether a high-threshold AI-ECG score was associated with infarcts. In a prior study, an AI-ECG AF score > 0.5 was associated with a cumulative incidence of AF of 21.5% at 2 years and 52.2% at 10 years. Results: This study included 1,373 individuals. Average age was 69.6 years and 53% of participants were male. There were 136 (10%) individuals with ECG-confirmed AF; 1237 (90%) participants had no AF history. Of participants with AF, 23% (n=31) were on anticoagulation, 47% (n=64) were on antiplatelet and 18% (n=24) were on dual therapy. Only 1.3% (n=16) of patients without AF were on anticoagulation and 47% (n=578) were on antiplatelet therapy. Ischemic infarcts were detected in 214 (15.6%) patients. As a continuous measure AI-ECG was associated with infarcts but not after adjusting for age and sex (p=0.46). AI-ECG AF score > 0.5 was associated with infarcts ( p < 0.001); even after adjusting for age and sex ( p = 0.03). History of AF was also associated with infarcts after adjusting for age and sex ( p = 0.018). Conclusion: AI-ECG AF score and history of AF were associated with presence of cerebral infarcts after adjusting for age and sex. This tool could be useful in select patients with cryptogenic stroke but further investigation would be required.

Background: Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of clinical cerebral amyloid angiopathy is less well understood, as are the mechanisms of their impact on cognition. In a community-based dementia-free cohort, we evaluate cross-sectional associations between CMB patterns and cerebral amyloid β (Aβ) deposition, measured by florbetapir PET. Methods: ARIC-PET recruited nondemented individuals from 3 US sites. Participants completed 3T brain MRI with T2*GRE (with CMBs read for presence, frequency, location (lobar vs subcortical), and pattern, as well as florbetapir (Aβ) PET (global cortical standardized uptake value ratio >1.2 as a positive scan). Multivariable (see Table) logistic regression models of Aβ+ scans evaluated CMB presence, frequency, location, and pattern, in separate models. Effect modification by sex, race, APOE status, and cognition (normal vs mild cognitive impairment) was evaluated. Results: Nearly 25% of the 322 individuals included had CMBs. No significant associations were found between CMBs (presence or number) and Aβ positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over a 4-fold higher odds of elevated Aβ vs having no CMBs, without a similar elevated risk in those with isolated subcortical CMBs or mixed subcortical + either lobar CMBs or superficial siderosis. Although no significant interactions were found, a mixed pattern was nonsignificantly protective (OR estimates 0.4-0.6) and lobar only CMBs had a (nonsignificantly) higher risk (OR up to 6.4) of Aβ for three subgroups: women (vs men); Blacks (vs whites), APOE ε4 noncarriers (vs carriers), and cognitively normal (vs MCI). Conclusions: A lobar-only pattern of CMBs is most strongly associated with brain Aβ, with no elevated risk for a mixed CMB pattern. Further study is needed to understand differences in these CMB patterns and their meaning across distinct demographic subgroups.

AbstractIntroductionWe determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total‐tau (t‐tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).MethodsAnalyses included 536 non‐demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t‐tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes.ResultsHigher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t‐tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA.DiscussionCSF NfL predicts changes in white matter integrity, t‐tau reflects non‐specific changes in cortical thickness, and Ng reflects AD‐specific synaptic and neuronal degeneration.

Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls ( H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I ( p = 0.044), Logical Memory II ( p = 0.011), and Trail Making Test –B ( p = 0.032), and APOE ɛ4 genotype was associated with worse performance on Logical Memory I ( p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

AbstractIntroductionThis study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population‐based sample.MethodsParticipants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A–T–) or had prodromal AD (A+T+).ResultsDiagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A–T– and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut‐offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%).DiscussionClinical utility of the CBB for detecting MCI in a population‐based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow‐up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time‐varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow‐up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30–0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05–0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community‐based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.