The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence ...in their effects on cognition.
Participants in the National Alzheimer's Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer's disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised - Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test TMT-A and Digit Symbol Substitution Test DSST), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers.
Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) RR = 1.094, p = 0.0327; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers.
Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.
Large and complex studies are now routine, and quality assurance and quality control (QC) procedures ensure reliable results and conclusions. Standard procedures may comprise manual verification and ...double entry, but these labour-intensive methods often leave errors undetected. Outlier detection uses a data-driven approach to identify patterns exhibited by the majority of the data and highlights data points that deviate from these patterns. Univariate methods consider each variable independently, so observations that appear odd only when two or more variables are considered simultaneously remain undetected. We propose a data quality evaluation process that emphasizes the use of multivariate outlier detection for identifying errors, and show that univariate approaches alone are insufficient. Further, we establish an iterative process that uses multiple multivariate approaches, communication between teams, and visualization for other large-scale projects to follow.
We illustrate this process with preliminary neuropsychology and gait data for the vascular cognitive impairment cohort from the Ontario Neurodegenerative Disease Research Initiative, a multi-cohort observational study that aims to characterize biomarkers within and between five neurodegenerative diseases. Each dataset was evaluated four times: with and without covariate adjustment using two validated multivariate methods - Minimum Covariance Determinant (MCD) and Candès' Robust Principal Component Analysis (RPCA) - and results were assessed in relation to two univariate methods. Outlying participants identified by multiple multivariate analyses were compiled and communicated to the data teams for verification.
Of 161 and 148 participants in the neuropsychology and gait data, 44 and 43 were flagged by one or both multivariate methods and errors were identified for 8 and 5 participants, respectively. MCD identified all participants with errors, while RPCA identified 6/8 and 3/5 for the neuropsychology and gait data, respectively. Both outperformed univariate approaches. Adjusting for covariates had a minor effect on the participants identified as outliers, though did affect error detection.
Manual QC procedures are insufficient for large studies as many errors remain undetected. In these data, the MCD outperforms the RPCA for identifying errors, and both are more successful than univariate approaches. Therefore, data-driven multivariate outlier techniques are essential tools for QC as data become more complex.
Background and Purpose- Depression and anxiety are common after stroke/transient ischemic attack (TIA). These conditions are associated with poor functional outcome and worse quality of life. ...However, few studies have explored predictors of poststroke risk of generalized anxiety, especially in patients without comorbid depressive symptoms. We aimed to explore predictors of high risk of generalized anxiety after stroke/TIA. Methods- Consecutive stroke and TIA referrals to the Sunnybrook Stroke Prevention Clinic over a 2-year period (April 2012-April 2014) who spoke English, were not severely aphasic, and who consented to complete neuropsychological testing were included in this analysis. Generalized anxiety and depressive symptoms were assessed using the Generalized Anxiety Disorder 7-item scale and Center for Epidemiological Studies Depression Scale, respectively. Results- Two hundred and fifty-eight patients completed the Generalized Anxiety Disorder 7-item scale, of whom 56 (22%) were at high risk for generalized anxiety (scores ≥10). Younger age (odds ratio=0.96; 95% CI, 0.93-0.99; P=0.004) and greater depressive symptoms (odds ratio=1.20; 95% CI, 1.14-1.26; P≤0.001) were significant predictors of being at high risk for generalized anxiety after stroke/TIA. Younger patients (≤50 years) were significantly more likely to be at high risk for both depression and generalized anxiety than older patients (30% versus 12%, χ
1, N=258=10.98, P=0.001). Our model explained 56% of the variance in risk of generalized anxiety after stroke. In patients without severe depressive symptoms (n=193, 75%), age and severity of depressive symptoms remained the only factors associated with risk of generalized anxiety. Conclusions- Anxiety is common after stroke/TIA and is highly correlated with poststroke depressive symptoms and age, even among those without severe depressive symptoms. Given the greater frequency of both generalized anxiety and depressive symptoms in young survivors, routine screening for depression and further evaluation of anxiety after stroke/TIA is warranted.
Poststroke/transient ischemic attack obstructive sleep apnea (OSA) is prevalent, linked with numerous unfavorable health consequences, but remains underdiagnosed. Reasons include patient ...inconvenience and costs associated with use of in-laboratory polysomnography (iPSG), the current standard tool. Fortunately, home sleep apnea testing (HSAT) can accurately diagnose OSA and is potentially more convenient and cost-effective compared with iPSG. Our objective was to assess whether screening for OSA in patients with stroke/transient ischemic attack using HSAT, compared with standard of care using iPSG, increased diagnosis and treatment of OSA, improved clinical outcomes and patient experiences with sleep testing, and was a cost-effective approach.
We consecutively recruited 250 patients who had sustained a stroke/transient ischemic attack within the past 6 months. Patients were randomized (1:1) to use of (1) HSAT versus (2) iPSG. Patients completed assessments and questionnaires at baseline and 6-month follow-up appointments. Patients diagnosed with OSA were offered continuous positive airway pressure. The primary outcome was compared between study arms via an intention-to-treat analysis.
At 6 months, 94 patients completed HSAT and 71 patients completed iPSG. A significantly greater proportion of patients in the HSAT arm were diagnosed with OSA (48.8% versus 35.2%,
=0.04) compared with the iPSG arm. Furthermore, patients assigned to HSAT, compared with iPSG, were more likely to be prescribed continuous positive airway pressure (40.0% versus 27.2%), report significantly reduced sleepiness, and a greater ability to perform daily activities. Moreover, a significantly greater proportion of patients reported a positive experience with sleep testing in the HSAT arm compared with the iPSG arm (89.4% versus 31.1%). Finally, a cost-effectiveness analysis revealed that HSAT was economically attractive for the detection of OSA compared with iPSG.
In patients with stroke/transient ischemic attack, use of HSAT compared with iPSG increases the rate of OSA diagnosis and treatment, reduces daytime sleepiness, improves functional outcomes and experiences with sleep testing, and could be an economically attractive approach. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02454023.
The neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy ...(EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide.
REPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney
test and multiple linear regression.
Sixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (
= 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range IQR, 2.54-21.81) in patients with placebo (
= 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error SE, 60%) in the white matter (
= 0.03) and by 340% (SE, 140%) in the basal ganglia (
= 0.02) in the nerinetide group compared with placebo after adjusting for confounders.
This study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth.
ClinicalTrials.gov NCT02930018.
This study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.
Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible ...mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by 18F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer’s disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer’s disease prevention and treatment.
•In cognitively normal adults, less amyloid-β accumulation in ARB than ACE-I users.•In Alzheimer'’s disease, ARBs and ACE-Is not different in effects on amyloid-β.•ApoE genotype may moderate effects of ARBs and ACE-Is on amyloid-β.
Abstract INTRODUCTION We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial ...fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS PVS was significantly associated with sEF ( c = ‐0.125 ± 0.054, 95% bootstrap confidence interval CI ‐0.2309, ‐0.0189, p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.
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