Cognitive assessment protocol design in the ISSYS (Investigating Silent Strokes in hYpertensives: A magnetic resonance imaging Study)

BackgroundSilent brain infarcts are detected by neuroimaging in up to 20% of asymptomatic patients based on population studies. They are five times more frequent than stroke in general population, and increase significantly both with advancing age and hypertension. Moreover, they are independently associated with the risk of future stroke and cognitive decline.Despite these numbers and the clinical consequences of silent brain infarcts, their prevalence in Mediterranean populations is not well known and their role as predictors of future cerebrovascular and cardiovascular events in hypertensive remains to be determined.ISSYS (Investigating Silent Strokes in Hypertensives: a magnetic resonance imaging study) is an observational cross-sectional and longitudinal study aimed to: 1- determine the prevalence of silent cerebrovascular infarcts in a large cohort of 1000 hypertensives and to study their associated factors and 2-to study their relationship with the risk of future stroke and cognitive decline.Methods/DesignCohort study in a randomly selected sample of 1000 participants, hypertensive aged 50 to 70 years old, with no history of previous stroke or dementia.On baseline all participants will undergo a brain MRI to determine the presence of brain infarcts and other cerebrovascular lesions (brain microbleeds, white matter changes and enlarged perivascular spaces) and will be also tested to determine other than brain organ damage (heart-left ventricular hypertrophy, kidney-urine albumin to creatinine ratio, vessels-pulse wave velocity, ankle brachial index), in order to establish the contribution of other subclinical conditions to the risk of further vascular events. Several sub-studies assessing the role of 24 hour ambulatory BP monitoring and plasma or genetic biomarkers will be performed.Follow-up will last for at least 3 years, to assess the rate of further stroke/transient ischemic attack, other cardiovascular events and cognitive decline, and their predictors.DiscussionImproving the knowledge on the frequency and determinants of these lesions in our setting might help in the future to optimize treatments or establish new preventive strategies to minimize clinical and socioeconomic consequences of stroke and cognitive decline.

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“…Our complete cognitive assessment protocol on baseline and follow-up has been published in detail previously [20]. …”

Section: Methodsmentioning

confidence: 99%

Investigating silent strokes in hypertensives: a magnetic resonance imaging study (ISSYS): rationale and protocol design

Riba‐Llena

Jarca²,

Mundet

et al. 2013

BMC Neurol

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“…Our cognitive protocol was published previously elsewhere. 15 The diagnosis of MCI was established following previously published criteria by the neurologist and neuropsychologist who attended the patients, who were masked to other clinical data. 16 In brief, MCI was considered when the subject or caregiver manifest an acquired cognitive impairment that lasted months to years and this alteration was shown on cognitive testing (performance mainly below 1.5 s.d.…”

Section: Cognitive Assessmentmentioning

confidence: 99%

High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals

Riba‐Llena

Nafría

Filomena

et al. 2015

J Cereb Blood Flow Metab

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High blood pressure accelerates normal aging stiffness process. Arterial stiffness (AS) has been previously associated with impaired cognitive function and dementia. Our aims are to study how cognitive function and status (mild cognitive impairment, MCI and normal cognitive aging, NCA) relate to AS in a community-based population of hypertensive participants assessed with office and 24-hour ambulatory blood pressure measurements. Six hundred ninety-nine participants were studied, 71 had MCI and the rest had NCA. Office pulse pressure (PP), carotid-femoral pulse wave velocity, and 24-hour ambulatory PP monitoring were collected. Also, participants underwent a brain magnetic resonance to study cerebral small-vessel disease (cSVD) lesions. Multivariate analysis-related cognitive function and cognitive status to AS measurements after adjusting for demographic, vascular risk factors, and cSVD. Carotid-femoral pulse wave velocity and PP at different periods were inversely correlated with several cognitive domains, but only awake PP measurements were associated with attention after correcting for confounders (beta = -0.22, 95% confidence interval (CI) -0.41, -0.03). All ambulatory PP measurements were related to MCI, which was independently associated with nocturnal PP (odds ratio (OR) = 2.552, 95% CI 1.137, 5.728) and also related to the presence of deep white matter hyperintensities (OR = 1.903, 1.096, 3.306). Therefore, higher day and night ambulatory PP measurements are associated with poor cognitive outcomes.

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“…It is an observational prospective study in hypertensive participants to determine the prevalence of silent or magnetic resonance imaging (MRI)-defined brain infarcts and cognitive impairment. This cohort comprises 1000 non-demented individuals, aged 50 to 70 years, and diagnosed with essential hypertension at least one year before inclusion in the ISSYS study [ 41 ].…”

Section: Methodsmentioning

confidence: 99%

Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study

et al. 2022

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Background and purpose The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10–06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. Results The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10–08) and in MERTK (p value = 1.56 × 10–07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10–06 and p value = 1.3 × 10–02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = − 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = − 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. Conclusions DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation.

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Cognitive assessment protocol design in the ISSYS (Investigating Silent Strokes in hYpertensives: A magnetic resonance imaging Study)

Cited by 13 publications

References 32 publications

Investigating silent strokes in hypertensives: a magnetic resonance imaging study (ISSYS): rationale and protocol design

Investigating silent strokes in hypertensives: a magnetic resonance imaging study (ISSYS): rationale and protocol design

High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals

Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study

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