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- Aldridge, Chad M., et al.
(författare)
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Genome-Wide Association Studies of 3 Distinct Recovery Phenotypes in Mild Ischemic Stroke
- 2024
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Ingår i: Neurology. - 1526-632X. ; 102:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores. METHODS: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components. RESULTS: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations (p < 5e-6) for cognition (CAMK2D, EVX2, LINC0143, PTPRM, SGMS1, and SMAD2), motor (ACBD6, KDM4B, MARK4, PTPRS, ROBO1, and ROBO2), and global (MSR1 and ROBO2) impairments. DISCUSSION: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.
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| 2. |
- de Havenon, Adam, et al.
(författare)
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Accurate Prediction of Persistent Upper Extremity Impairment in Patients With Ischemic Stroke
- 2022
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Ingår i: Archives of Physical Medicine and Rehabilitation. - : Elsevier BV. - 0003-9993. ; 103:5, s. 964-969
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To develop a simple and effective risk score for predicting which stroke patients will have persistent impairment of upper extremity motor function at 90 days. Design: Post hoc analysis of clinical trial patients hospitalized with acute ischemic stroke who were followed for 90 days to determine functional outcome. Setting: Patient were hospitalized at facilities across the United States. Participants: We created a harmonized cohort of individual patients (N=1653) from the NINDS tPA, ALIAS part 2, IMS-III, DEFUSE 3, and FAST-MAG trials. We split the cohort into balanced derivation and validation samples. Interventions: Not applicable. Main Outcome Measures: The primary outcome was persistent arm impairment, defined as a National Institutes of Health Stroke Scale (NIHSS) arm domain score of 2 to 4 at 90 days in patients who had a 24-hour NIHSS arm score of 1 or more. We used least absolute shrinkage and selection operator regression to determine the elements of the persistent upper extremity impairment (PUPPI) index, which we validated as a predictive tool. Results: We included 1653 patients (827 derivation, 826 validation), of whom 803 (48.6%) had persistent arm impairment. The PUPPI index gives 1 point each for age 55 years or older and NIHSS values of worse arm (4), worse leg (>2), facial palsy (3), and total NIHSS (≥10). The optimal cutpoint for the PUPPI index was 3 or greater, at which the area under the curve was greater than 0.75 for the derivation and validation cohorts and when using NIHSS values from either 24 hours or in a subacute or discharge time window. Results were similar across different levels of stroke severity. Conclusion: The PUPPI index uses readily available information to accurately predict persistent upper extremity motor impairment at 90 days poststroke. The PUPPI index can be administered in minutes and could be used as inclusion criterion in recovery-related clinical trials or, with additional development, as a prognostic tool for patients, caregivers, and clinicians.
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| 4. |
- De Havenon, Adam, et al.
(författare)
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Variability of the Modified Rankin Scale Score between Day 90 and 1 Year after Ischemic Stroke
- 2021
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Ingår i: Neurology: Clinical Practice. - 2163-0402. ; 11:3, s. 239-244
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Tidskriftsartikel (refereegranskat)abstract
- Objective Studies indicate that the functional outcome evolves in the year after ischemic stroke onset. However, the traditional outcome measure in stroke trials is the modified Rankin Scale (mRS) at 90 days from onset. To determine mRS fluctuations in the first year after stroke, we examined data from 3 major stroke trials.MethodsIn a secondary analysis, we evaluated intrapatient mRS between 90 days and 1 year from stroke onset, the mRS shift (ΔmRS = 1 year-day 90), and the trials' primary outcome at day 90 and 1 yearResultsWe included 624 patients from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study, 587 from Albumin Treatment for Acute Ischaemic Stroke, and 611 from Interventional Management of Stroke III, for which the proportion of patients with a ΔmRS change between day 90 and 1 year was 36.5%, 41.7%, and 36.0%. However, the trials' primary outcomes did not differ at 1 year vs 90 days. Similar findings were seen in a second cohort where we pooled the trials and excluded patients with recurrent stroke or death during the follow-up. In those 1,314 patients, 544 (41.4%) had a ΔmRS change, of which 379 (28.9%) had improvement and 165 (12.5%) had worsening, apart from death.ConclusionWe describe the patient-level spectrum of mRS change from day 90 to 1 year after ischemic stroke in 3 high-quality randomized trials. The patient-level shifts consisted of a sufficiently counterbalanced number of mRS improvements and declines, which masked clinical evolution occurring in over one-third of patients. These results may have important implications, both for clinical trial design and outcome adjudication in stroke research and duration of rehabilitative therapy.
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