Cilostazol and Probucol for Cognitive Decline after Stroke: A Cognitive Outcome Substudy of the PICASSO Trial.
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SUBMITTER: Lim JS
PROVIDER: S-EPMC7900397 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Cilostazol and Probucol for Cognitive Decline after Stroke: A Cognitive Outcome Substudy of the PICASSO Trial.
Lim Jae-Sung JS Kwon Sun U SU Yu Kyung-Ho KH Yu Sungwook S Park Jong-Ho JH Lee Byung-Chul BC Oh Mi Sun MS Kim Yong-Jae YJ Rha Joung-Ho JH Hwang Yang-Ha YH Lee Ji Sung JS Heo Sung Hyuk SH Ahn Seong Hwan SH Seo Woo-Keun WK Park Jong-Moo JM Lee Ju-Hun JH Kwon Jee-Hyun JH Sohn Sung-Il SI Jung Jin-Man JM Kim Hahn Young HY Kim Eung-Gyu EG Cha Jae-Kwan JK Park Man-Seok MS Nam Hyo Suk HS Bae Hee-Joon HJ Kim Dong-Eog DE Park Jaeseol J Kang Yeonwook Y Choi Jimi J Lee Juneyoung J
Journal of stroke 20210131 1
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Project description:Background and purposeCilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression.MethodsA systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742).ResultsWe included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57-0.81]; P<0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29-0.64]; P=0.0001), deaths (OR=0.64 [95% CI, 0.49-0.83], P<0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54-0.99]; P=0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance.ConclusionsCilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.
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Project description:Alzheimer's disease and several variants of frontotemporal degeneration including progressive supranuclear palsy and corticobasal degeneration are characterized by the accumulation of abnormal tau protein into aggregates. Most proteins, including tau, are degraded via the ubiquitin proteasome system, but when abnormal tau accumulates, the function of 26S proteasomes is downregulated. The negative effect of tau aggregates on the function of the proteasome can have deleterious consequences on protein homeostasis and disease progression. Developing therapies aimed at clearing abnormal tau are thus of considerable interest. In the present study, we investigated the effect of cilostazol, an FDA-approved selective phosphodiesterase 3 inhibitor, on a mouse model of tauopathy (line rTg4510). Administration of cilostazol for 30 days enhanced proteasome function via the cyclic adenosine 3',5'-monophosphate/protein kinase A pathway and attenuated tauopathy and cognitive decline in rTg4510 mice. These results suggest that cilostazol, or other FDA-approved drugs acting via the same pathway, has the potential to be repurposed for the treatment of patients with early-stage tauopathy.
| S-EPMC10075247 | biostudies-literature
Project description:ImportanceCognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors' cognitive changes after stroke is uncertain.ObjectiveTo measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories.Design, setting, and participantsProspective study of 23,572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23,057 remained stroke free.ExposureTime-dependent incident stroke.Main outcomes and measuresThe primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score <5 [impaired] vs ≥5 [unimpaired]). For all tests, higher scores indicate better performance.ResultsStroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P < .001). For a 70-year-old black woman with average values for all covariates at baseline, stroke at year 3 was associated with greater incident cognitive impairment: absolute difference of 4.0% (95% CI, -1.2% to 9.2%) at year 3 and 12.4% (95% CI, 7.7% to 17.1%) at year 6.Conclusions and relevanceIncident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.
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Project description:Infarct-induced neurodegeneration increases dementia risk for at least a decade in humans. It can be modeled in wildtype mice, where a cortical stroke results in chronic lymphocytic infiltration into the infarct and delayed cognitive decline. Vascular cell adhesion molecule 1 (VCAM1) on endothelial cells is increased by stroke and facilitates immune cell diapedesis by binding very late antigen 4 (VLA4) on immune cells. We report here that after stroke, chronic but not acute treatment with an anti-VCAM1 blocking antibody reduces B and T lymphocyte infiltration and prevents chronic cognitive dysfunction in wildtype male and female mice. Preservation of cognitive function was also seen with chronic anti-VLA4 treatment despite anti-VLA4’s lack of effect on lymphocyte infiltration. High-depth single-cell RNA sequencing of the chronic infarct and peri-infarct cortex revealed a pronounced decrease in expression of blood vessel growth and maturation genes in endothelial cells that was reversed by both anti-VLA4 and anti-VCAM1. Plasma proteomics also support a vasculoprotective mechanism of anti-VCAM1. Finally, immunostaining demonstrated that both antibodies improve pericyte coverage of the vasculature and prevent extravascular fibrinogen leakage. Together, our findings indicate that vascular structure and function remain abnormal long after stroke and that the VLA4/VCAM1 axis is a promising treatment target for infarct-induced neurodegeneration as blockade restores cerebrovasculature and prevents cognitive decline.
2025-06-25 | GSE300564 | GEO
Project description:ImportanceRecent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage.ObjectiveTo determine the safety and efficacy of cilostazol in mild cognitive impairment.Design, setting, and participantsThe COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020.InterventionsThe participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks.Main outcomes and measuresThe primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events.ResultsThe full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically.Conclusions and relevanceIn this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials.Trial registrationClinicalTrials.gov Identifier: NCT02491268.
| S-EPMC10696485 | biostudies-literature
Project description:Background and purposeIt is unknown whether blacks' elevated risk of dementia is because of racial differences in acute stroke, the impact of stroke on cognitive health, or other factors. We investigated whether racial differences in cognitive decline are explained by differences in the frequency or impact of incident stroke between blacks and whites, controlling for baseline cognition.MethodsAmong 4908 black and white participants aged ≥65 years free of stroke and cognitive impairment in the nationally representative Health and Retirement Study with linked Medicare data (1998-2010), we examined longitudinal changes in global cognition (modified version of the Telephone Interview for Cognitive Status) by race, before and after adjusting for time-dependent incident stroke followed by a race-by-incident stroke interaction term, using linear mixed-effects models that included fixed effects of participant demographics, clinical factors, and cognition, and random effects for intercept and slope for time.ResultsWe identified 34 of 453 (7.5%) blacks and 300 of 4455 (6.7%) whites with incident stroke over a mean (SD) of 4.1 (1.9) years of follow-up (P=0.53). Blacks had greater cognitive decline than whites (adjusted difference in modified version of the Telephone Interview for Cognitive Status score, 1.47 points; 95% confidence interval, 1.21 to 1.73 points). With further adjustment for cumulative incidence of stroke, the black-white difference in cognitive decline persisted. Incident stroke was associated with a decrease in global cognition (1.21 points; P<0.001) corresponding to ≈7.9 years of cognitive aging. The effect of incident stroke on cognition did not statistically differ by race (P=0.52).ConclusionsIn this population-based cohort of older adults, incident stroke did not explain black-white differences in cognitive decline or impact cognition differently by race.
| S-EPMC4480064 | biostudies-literature
Project description:BackgroundPatients with stroke are at a higher risk of cognitive impairment and Alzheimer's disease dementia.ObjectiveTo quantify the role of lifestyle pre-stroke, post-stroke, and changes in lifestyle before and after stroke with cognitive decline in community-dwelling stroke survivors.MethodsUtilizing data from the Chicago Health and Aging Project, a population-based cohort study, we studied 1,078 individuals with stroke (662 incident and 416 prevalent) who underwent cognitive testing during the study period. A healthy lifestyle score was defined by scoring four behaviors: non-smoking, exercising, being cognitively active, and having a high-quality diet. The global cognitive score was derived from a comprehensive battery of 4 standardized tests.ResultsThe mean age at incident stroke was 78.2 years, and 60.1% were women. A healthy lifestyle pre-incident stroke was associated with a slower rate of cognitive decline after stroke. Participants with 3-4 healthy lifestyle factors pre-incident stroke had a slower cognitive decline after stroke by 0.046 units/year (95% CI 0.010, 0.083), or 47.7% slower, than participants with 0-1 healthy lifestyle factor. Lifestyle score post-prevalent stroke was not associated with cognitive decline. Changes in lifestyle behaviors from pre- to post-incident stroke were related to cognitive decline after stroke. Individuals who deteriorated their lifestyle quality after stroke had a faster cognitive decline by 0.051 units/year (β -0.051, 95% CI -0.090, -0.012) than participants with no change in lifestyle score.ConclusionA healthy lifestyle pre-stroke was associated with a slower rate of cognitive decline in stroke survivors, highlighting the importance of primary prevention. After the stroke, changes in lifestyle behaviors may influence the cognitive abilities of older adults as they age.
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Project description:ObjectiveWe compared the effect of clopidogrel plus aspirin vs aspirin alone on functional outcome and quality of life in the Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial of aspirin-clopidogrel vs aspirin alone after acute minor stroke or TIA.MethodsParticipants were assessed at 90 days for functional outcome using the modified Rankin Scale (mRS) and quality of life using the EuroQol-5 Dimension (EQ-5D). Poor functional outcome was defined as mRS score of 2-6 at 90 days and poor quality of life as EQ-5D index score of 0.5 or less.ResultsPoor functional outcome occurred in 254 patients (9.9%) in the clopidogrel-aspirin group, as compared with 299 (11.6%) in the aspirin group (p = 0.046). Poor quality of life occurred in 142 (5.5%) in the clopidogrel-aspirin group and in 175 (6.8%) in the aspirin group (p = 0.06). Disabling stroke at 90 days occurred in 166 (6.5%) in the clopidogrel-aspirin group and in 219 (8.5%) in the aspirin group (p = 0.01). In stratified analysis by subsequent stroke, there was no difference in 90-day functional outcome and quality of life between the 2 groups.ConclusionsIn patients with minor stroke or TIA, the combination of clopidogrel and aspirin appears to be superior to aspirin alone in improving the 90-day functional outcome, and this is consistent with a reduction in the rate of disabling stroke in the dual antiplatelet arm.Classification of evidenceThis study provides Class II evidence that for patients with acute minor stroke or TIA, clopidogrel plus aspirin compared to aspirin alone improves 90-day functional outcome (absolute reduction of poor outcome 1.70%, 95% confidence interval 0.03%-3.42%).
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Project description:Although magnesium is neuroprotective in animal stroke models, no clinical benefit was confirmed in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial of acute stroke patients. The Magnetic Resonance in IMAGES (MR IMAGES) substudy investigated the effects of magnesium on the imaging surrogate outcome of infarct growth.IMAGES trial patients in participating centers were randomized to receive either intravenous magnesium or placebo within 12 hours of stroke onset. Infarct growth was defined as volume difference between baseline diffusion-weighted imaging and day 90 fluid-attenuated inversion recovery image lesions. Patients who died were imputed the largest infarct growth observed.Among the 90 patients included in the primary analysis, there was no difference in infarct growth (median absolute growth, P=0.639; median percentage growth, P=0.616; proportion with any growth, P=0.212) between the 46 treated with magnesium and 44 with placebo. Infarct growth correlated with NIHSS score change from baseline to day 90. There was a trend showing baseline serum glucose correlated with infarct growth with magnesium treatment, but not in the placebo group. The mismatch frequency was reduced from 73% to 47% by increasing the mismatch threshold from >20% to >100% of core volume.Infarct growth, confirmed here as a surrogate for clinical progression, was similar between magnesium and placebo treatment, paralleling the main IMAGES trial clinical outcomes. Glucose was a covariate for infarct growth with magnesium treatment. A more stringent mismatch threshold to define penumbra more appropriately would have excluded half of the patients in this 12-hour time window stroke study.
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