Low ankle-brachial index and cognitive function after stroke—the PROSpective with Incident Stroke Berlin (PROSCIS-B)

 So you described a risk factor but with nothing provided to fix that, this research was useless.

Low ankle-brachial index and cognitive function after stroke—the PROSpective with Incident Stroke Berlin (PROSCIS-B)

Maria R. V. Stillfried¹, Pia S. Sperber^1,2, Leonie H. A. Broersen¹, Shufan Huo^1,3, Sophie K. Piper⁴, Peter U. Heuschmann⁵, Matthias Endres^1,2,3,6,7, Bob Siegerink^1,8 and Thomas G. Liman^1,2,6,9*

• ¹Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany
• ²German Centre for Cardiovascular Research DZHK, Charité –Universitätsmedizin Berlin, Berlin, Germany
• ³Klinik und Hochschulambulanz für Neurologie, Charité- Universitätsmedizin Berlin, Berlin, Germany
• ⁴German Center for Neurodegenerative Disease DZNE, Berlin Charité-Universitätsmedizin Berlin, Berlin, Germany
• ⁵Institute of Biometry and Clinical Epidemiology, University of Würzburg, Würzburg, Germany
• ⁶German Center for Neurodegenerative Disease DZNE, partner site Berlin Charité-Universitätsmedizin Berlin, Berlin, Germany
• ⁷NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
• ⁸Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
• ⁹Department of Neurology, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany

Introduction: Low ankle-brachial index (ABI) ≤0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population.

Objective: To evaluate the impact of ABI ≤0.9 on cognitive function up to 3 years after first-ever ischemic stroke.

Methods: Data was used from the “PROspective Cohort with Incident Stroke-Berlin” (PROSCIS-B; NCT01363856). ABI was measured at baseline and categorized into normal (1.4–0.9) vs. low (≤0.9). Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental-State-Examination (MMSE) at baseline and with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1–3 years of follow-up. We performed confounder adjusted generalized linear models (GLM) to calculate relative risks (RR) for cognitive impairment at baseline (MMSE≤26; MoCA≤25) and linear mixed models (LMM) to estimate the impact of low ABI on TICS-m over time.

Results: We included 325 patients [mean age: 66 (SD = 13); 38% female, median NIHSS = 2 (IQR = 1–4), ABI≤0.9: 59 (18%)]. Patients with low ABI were at increased risk of cognitive impairment at baseline (adjusted RR for MoCA≤25 = 1.98; 95%-CI:1.24 to 3.16). TICS-m scores were consistently lower over time in patients with low ABI (adjusted ß = −1.96; 95%-CI:−3.55 to −0.37). Independent of ABI, cognitive function did not decline over time (adjusted ß:0.29; 95%-CI:−0.06 to 0.64).

Conclusion: In patients with mild to moderate first-ever ischemic stroke, low ABI is associated with reduced cognitive function over a 3-year follow-up.

Study Registration: https://clinicaltrials.gov; Unique identifier: NCT01363856.

Introduction

The ankle-brachial index (ABI) is a reliable, non-invasive, and inexpensive screening tool for peripheral artery disease (PAD) (1, 2). Low ABI ≤ 0.9 is a sensitive marker for generalized atherosclerosis and independently associated with cognitive impairment and decline in the general population (3, 4).

However, observational studies investigating the impact of low ABI on cognition after stroke are limited, particularly regarding long-term cognitive outcome (5). Stroke occurrence in itself is associated with ensuing cognitive impairment and decline (6). Between 20 and 80% of stroke survivors suffer from cognitive deficits, whereby the severity and recurrence of stroke are related to subsequent cognitive decline (6, 7). Low ABI could be a useful marker to detect cognitive impairment as a stroke-related disability and monitor secondary prevention therapies. A cross-sectional study of 103 hospitalized patients with acute lacunar stroke found that low ABI is associated with cognitive impairment in the acute stroke phase using the Montreal Cognitive Assessment (MoCA; cutoff score at ≤23) (5). Nonetheless, data on low ABI and cognitive function over time after ischemic stroke are lacking.

Aim

We aimed to investigate whether low ABI ≤ 0.9 is associated with reduced cognitive function at baseline and subsequent decline over a three-year follow-up after first-ever ischemic stroke.

Methods

Study design and population

This study is part of the Prospective Cohort with Incident Stroke Berlin (PROSICS-B), an observational, hospital-based prospective cohort study, described in detail elsewhere (8). Between January 2010 and May 2013 stroke patients were recruited at three stroke units of the Charité – Universitätsmedizin Berlin within 7 days after stroke onset (see flow chart in Supplementary Figure 1). Inclusion criteria were patients with (1) first-ever ischemic stroke, primary intracranial hemorrhage, or cerebral venous sinus thrombosis, (2) aged 18 and older, (3) written informed consent by patient or legal guardian prior to study participation. Exclusion criteria were (1) prior stroke (definition according to WHO criteria), (2) patients with brain tumor or brain metastasis, (3) participation in an interventional trial.

Patients were followed up annually with telephone-based interviews for up to 3 years. Patients who had suffered a prior stroke, presented brain tumors, brain metastases or participated in an intervention study were excluded. Only patients with mild to moderate ischemic stroke events, defined by a score of < 16 in the National Institutes of Health Stroke Scale (NIHSS), were included in the analysis. The assessment of ABI and MoCA were introduced to the study as an amendment in January 2011, ~1 year after patient enrollment had started according to the requirements of the ethical committee.

Patient characteristics

Baseline characteristics were assessed upon admission, including sociodemographic characteristics (e.g., age, sex and education, living situation and lifestyle habits), laboratory blood measures, stroke severity, and cardiovascular risk factors (BMI, current smoking and alcohol consumption, history of hypertension, diabetes mellitus and coronary heart disease).

ABI measurement

ABI was measured using a manual cuff and a portable Doppler ultrasound device. Participants were assessed in supine position following a 5-min resting period. The systolic blood pressure was determined for the brachial arteries, posterior tibial and dorsal pedis arteries bilaterally. Measurements were assessed at all three stroke centers following a pre-established standard operating procedure.

In accordance with the guidelines issued by the American Heart Association, ABI was calculated on each side by dividing the higher value of the posterior tibial or dorsal pedis artery systolic blood pressure by the higher systolic blood pressure of both brachial arteries (9). We used the lower ABI value. Low ABI was defined as ≤ 0.9. Participants with abnormally high ABI ≥ 1.4, indicative of non-compressible blood vessel calcification, were excluded (9).

Outcome definitions

Our outcome of interest was cognitive function after stroke at baseline and over a three-year follow-up period. Cognitive function at baseline was assessed using the Montreal Cognitive Assessment (MoCA) and the Mini Mental State Examination (MMSE). Cognitive impairment was defined as a MoCA score ≤ 25 or a MMSE score ≤ 26 (10–12). Cognitive function over time was measured with the Modified Telephone Interview for Cognitive Status (TICS-m), a screening instrument for cognitive dysfunction with 20 items and a maximum score of 50, which was administered annually via telephone interview over a three-year follow-up (13).

Statistical methods

Generalized linear models (GLM) were used to calculate crude and confounder adjusted relative risks (RR) for cognitive impairment at baseline (MoCA ≤ 25; MMSE ≤ 26) in patients with low versus normal ABI and corresponding 95% confidence intervals (CI). We performed linear mixed models (LMM) to calculate effect sizes (ß) and corresponding 95% CI for the crude and confounder adjusted association between low vs. normal ABI and cognitive function over a three-year follow-up, using the annual TICS-m score.

To explore whether the severity of low ABI had an effect on cognitive function in the sense of a dose-response relationship, we further categorized low ABI into mildly low (0.75–0.9) and moderately to severely low ABI (< 0.75) and recalculated our main analyses with these subgroups compared to normal ABI.

Multiple models were used to control for possible sources of confounding. Potential confounding factors were selected a priori according to their presumable impact on both the exposure (ABI) and the outcome (cognitive function). Model 1 adjusted for the sociodemographic variables age (continuous), sex and years of education received (≤ 10 years of schooling, > 10 years of schooling). Model 2 additionally adjusted for the cardiovascular risk factors BMI (kg/m²), current smoking (yes/no), history of diabetes mellitus (yes/no) and hypercholesterolemia (yes/no), and history of coronary heart disease (yes/no) and atrial fibrillation (yes/no). Model 3 moreover adjusted for stroke severity as defined by the NIHSS (in 2 categories: 0–4 and 5–15).

We conducted different sensitivity analyses, described in Methods I of the Supplementary material.

Data were prepared using IBM Statistics for Windows, version 25 (IBM Corp, Armonk, NY). All descriptive and statistical analyses were calculated using Stata version 14.1 (Stata Corp, College Station, TX). Data visualizations were performed in the R project (R 4.0.0) using the ggplot2 package.

Ethics approval

Patients or their legal guardians gave written informed consent prior to study participation. The study was approved by the Charité – Universitätsmedizin Berlin ethics committee (EA1/218/09) and was conducted according to the declaration of Helsinki.

Results

Study population

This analysis included 325 patients with mild to moderate ischemic stroke (NIHSS score < 16) and data on ABI (for detailed information on patient inclusion and exclusion see the flow chart in Supplemental Figure 1).

Mean age at study enrollment was 66 years (SD, 13), 38% (n = 123) were female. Median NIHSS was 2 [inter quartile range (IQR), 1–4], 30% (n = 95) were smokers upon study admission and 19% (n = 58) had a history of hypercholesterolemia. 31% (n = 97) had received a school education for more than 10 years. 18% (n = 59) had ABI ≤ 0.9. Of those, 59% (n = 35) had mildly low ABI (0.75 – 0.9) and 41% (n = 24) had moderately to severely low ABI (< 0.75). Table 1 gives a detailed overview of patient baseline characteristics.

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