Iolanda Riba-Llena

Prevalence and Associated Factors of Silent Brain Infarcts in a Mediterranean Cohort of Hypertensives

Silent brain infarcts (SBIs) are detected by neuroimaging in approximately 20% of elderly patients in population-based studies. Limited evidence is available for hypertensives at low cardiovascular risk countries. Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study (ISSYS) is aimed to assess the prevalence and risk factors of SBIs in a hypertensive Mediterranean population. This is a cohort study in randomly selected hypertensives, aged 50 to 70 years old, and free of clinical stroke and dementia. On baseline, all participants underwent a brain magnetic resonance imaging to assess prevalence and location of silent infarcts, and data on vascular risk factors, comorbidities, and the presence of subclinical cardiorenal damage (left ventricular hypertrophy and microalbuminuria) were collected. Multivariate analyses were performed to determine SBIs associated factors. A total of 976 patients (49.4% men, mean age 64 years) were enrolled, and 163 SBIs were detected in 99 participants (prevalence 10.1%; 95% CI, 8.4%–12.2%), most of them (64.4%) located in the basal ganglia and subcortical white matter. After adjustment, besides age and sex, microalbuminuria and increasing total cardiovascular risk (assessed by the Framingham-calibrated for Spanish population risk function) were independently associated with SBIs. Male sex increased the odds of having SBIs in 2.5 as compared with females. Our results highlight the importance of considering both global risk assessment and sex differences in hypertension and may be useful to design future preventive interventions of stroke and dementia.

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability.

Vascular dementia is the second most common type of dementia after Alzheimer’s disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.

Short-Term Blood Pressure Variability Relates to the Presence of Subclinical Brain Small Vessel Disease in Primary Hypertension

Blood pressure (BP) variability is associated with stroke risk, but less is known about subclinical cerebral small vessel disease (CSVD). We aimed to determine whether CSVD relates to short-term BP variability independently of BP levels and also, whether they improve CSVD discrimination beyond clinical variables and office BP levels. This was a cohort study on asymptomatic hypertensives who underwent brain magnetic resonance imaging and 24-hour ambulatory BP monitoring. Office and average 24-hour, daytime and nighttime BP levels, and several metrics of BP variability (SD, weighted SD, coefficient of variation, and average real variability [ARV]) were calculated. Definition of CSVD was based on the presence of lacunar infarcts and white matter hyperintensity grades. Multivariate analysis and integrated discrimination improvement were performed to assess whether BP variability and levels were independently associated with CSVD and improved its discrimination. Four hundred eighty-seven individuals participated (median age, 64; 47% women). CSVD was identified in 18.9%, related to age, male sex, diabetes mellitus, use of treatment, ambulatory BP monitoring–defined BP levels, and ARV of systolic BP at any period. The highest prevalence (33.7%) was found in subjects with both 24-hour BP levels and ARV elevated. BP levels at any period and ARV (24 hours and nocturnal) emerged as independent predictors of CSVD, and discrimination was incrementally improved although not to a clinically significant extent (integrated discrimination improvement, 5.31%, 5.17% to 5.4%). Ambulatory BP monitoring–defined BP levels and ARV of systolic BP relate to subclinical CSVD in hypertensive individuals.

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

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.

Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population

Background Cortical brain infarcts are defined as infarcts involving cortical gray matter, but may differ considerably in size. It is unknown whether small cortical infarcts have a similar clinical phenotype as larger counterparts. We investigated prevalence, determinants, and cognitive correlates of small cortical infarcts in the general population and compared these with large cortical infarcts and lacunar infarcts. Methods Four thousand nine hundred five nondemented individuals (age 63.95 ± 10.99) from a population-based study were included. Infarcts were rated on magnetic resonance imaging and participants were classified according to mean infarct diameter into small (≤15 mm in largest diameter) or large (>15 mm) cortical infarcts, lacunar infarcts, or a combination of subtypes. Spatial distribution maps were created for manually labeled small and large infarcts. Participants underwent cognitive testing. Analyses were performed using multinomial regression and analysis of covariance. Results Three hundred eighty-one (7.8%) persons had any infarct on magnetic resonance imaging, among whom 54 with small (1.1%) and 77 (1.6%) with large cortical infarcts. Small cortical infarcts were mainly localized in external watershed areas, whereas large cortical infarcts were localized primarily in large arterial territories. Age (odds ratio = 1.06; 95% confidence interval = 1.02, 1.09), male gender (1.98; 1.01, 3.92), and smoking (2.55; 1.06, 6.14) were determinants of small cortical infarcts. Participants with these infarcts had worse scores in delayed memory, processing speed, and attention tests than persons without infarcts, even after adjustment for cardiovascular risk factors. Conclusions In the elderly, small cortical infarcts appear as frequent as large infarcts but in different localization. Our results suggest that small cortical infarcts share cardiovascular risk factors and cognitive correlates with large cortical, but also with lacunar infarcts.

Assessment of enlarged perivascular spaces and their relation to target organ damage and mild cognitive impairment in patients with hypertension

Enlarged perivascular spaces (EPVS) have been recently considered a feature of cerebral small vessel disease. They have been related to aging, hypertension and dementia but their relationship with hypertension related variables (i.e. target organ damage, treatment compliance) and mild cognitive impairment (MCI) is not fully elucidated. Our aims were to investigate the relation between basal ganglia (BG) and centrum semiovale (CSO) EPVS with vascular risk factors, hypertension related variables and MCI.

Dementia Rating Scale-2 normative data for middle-and older-aged Castilian speaking Spaniards

Abstract Objectives: The Dementia Rating Scale-2 (DRS-2) is frequently used as a dementia screening tool in clinical and research settings in Spain. The present study describes DRS-2 Total and subscale scores in community-dwelling Spaniards, aged 50–71, and provides normative data for its use in Castilian Spanish-speaking individuals. Methods: The sample consisted of 798 individuals who participated in an observational study on essential hypertension. Mean age was 62.8 years (SD = 5.4), mean education was 8.6 years (SD = 3.4) with 47.9% females. Almost all of them were receiving blood pressure-lowering drugs (93%) and most of them had fairly well-managed blood pressure control (M systolic/diastolic blood pressure = 142.3/77.0 ± 16.0/9.2 mm Hg). We applied a previously described method of data normalization from the Mayo’s Older Americans Normative Studies to obtain the Castilian Spanish DRS-2 norms. Results: Worse performance on Total and subscale scores was associated with older age (p < .05) and fewer years of education (p < .001). Women obtained lower raw Total scores than men (131.68 ± 7.2 vs. 133.10 ± 6.90, p < .005), but had fewer years of education (7.96 ± 3.33 vs. 9.17 ± 3.45, p < .001). This gender difference disappeared after correcting for age and years of education. Total and subscale scores are presented adjusted by age, and normative data are shown for Total scores adjusted by age and years of education. Conclusions: These norms are useful for studying cognitive status and cognitive decline in research and clinical settings in Castilian Spanish-speaking populations.

Microalbuminuria and the Combination of MRI Markers of Cerebral Small Vessel Disease

Background: Kidney function has been related to the presence of individual markers of cerebral small vessel disease (CSVD), as lacunes, white matter hyperintensities (WMH) or microbleeds. We aimed at studying the relationship of kidney dysfunction with the combination of several markers of CSVD. Methods: Subjects are those included in the ISSYS cohort (Investigating Silent Strokes in hypertensives: a magnetic resonance imaging study). A scale ranging from 0 to 4 points was applied based on the presence (one point each) of lacunes, deep microbleeds, moderate to extensive basal ganglia enlarged perivascular spaces (EPVS), and periventricular or deep WMH. We determined the creatinine-based glomerular filtration rate and the urinary albumin-to-creatinine ratio (UACR) as markers of kidney function and studied their association with the scale of CSVD in univariate and ordinal logistic regression analyses. Results: Among the 975 patients included, 28.2% presented one or more CSVD markers, being the most prevalent marker (either alone or in combination) basal ganglia EPVS. The UACR was elevated at increasing the scores of the CSVD scale and remained as independent predictor of the combination of markers (common OR per natural log unit increase in UACR: 1.23, 1.07-1.41) after controlling per age, gender, cardiovascular risk, antihypertensive treatment and hypertension duration. In contrast, no associations were found between the CSVD scores and the creatinine-based estimated glomerular filtration rate. Conclusions: A significant proportion of stroke-free hypertensives present at least one imaging marker of CSVD. UACR but not creatinine-based glomerular filtration rate is associated with the combination of markers of CSVD.

Plasma Matrix Metalloproteinases in Patients With Stroke During Intensive Rehabilitation Therapy

OBJECTIVE To study plasma levels of matrix metalloproteinases (MMPs) as potential markers of recovery during intensive rehabilitation therapy (IRT) after stroke. DESIGN Prospective and descriptive 3-month follow-up study. SETTING Rehabilitation unit and research center. PARTICIPANTS Patients with first-ever ischemic stroke (n=15) enrolled to IRT (≥3h/d and 5d/wk) and healthy volunteers (n=15) (N=30). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES The primary outcome was to measure plasma MMP3, MMP12, and MMP13 levels and evaluate potential associations with motor/functional scales using a battery of tests (National Institutes of Health Stroke Scale, modified Rankin scale, Barthel Index, Fugl-Meyer Assessment, Functional Ambulation Categories, Medical Research Council scale, Chedoke Arm and Hand Activity Inventory, and the 10-m walk test) before IRT and at 1- and 3-month follow-ups. The secondary outcome was to evaluate the use of these MMPs as biomarkers as predictors of patients outcome. RESULTS MMP levels remained stable during the study period and were similar to those in the healthy volunteer group. However, baseline MMP12 and MMP13 levels were strongly associated with stroke severity and were found to be elevated in those patients with the poorest outcomes. Interestingly, plasma MMP3 was independent of baseline stroke characteristics but was found to be increased in patients with better motor/functional recovery and in patients with larger improvements during rehabilitation. CONCLUSIONS MMPs might act as biologic markers of recovery during rehabilitation therapy related to their roles in both injury and tissue remodeling. Future confirmatory investigations in multicenter studies are warranted by our data.

N-terminal pro-brain natriuretic peptide and subclinical brain small vessel disease.

Objective: To study the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with several brain MRI markers of brain vascular disease in a sample of participants free of stroke and dementia. Methods: NT-proBNP plasma level was determined by means of a sandwich immunoassay method in a cohort study comprising 278 hypertensive patients. The presence of silent brain infarcts, brain microbleeds, enlarged perivascular spaces, and white matter hyperintensity volumes was assessed by brain MRI. We performed univariate and multivariate analyses to determine whether NT-proBNP was independently associated with these imaging markers, individually or combined. Results: Median age was 63 years, and 41.4% were women. NT-proBNP remained independently associated with silent brain infarcts (odds ratio [OR] per 1-SD increase in NT-proBNP 2.11, 95% confidence interval [CI] 1.44–3.10), brain microbleeds (OR 1.79, 95% CI 1.15–2.78), basal ganglia enlarged perivascular spaces (OR 1.55, 95% CI 1.12–2.15), and white matter hyperintensity volumes (β 1.60, 95% CI 0.47–2.74), even after controlling for vascular risk factors, cardiovascular risk, atrial fibrillation, previous heart disease, duration of hypertension, and preventive treatments. A score combining several imaging markers was also related to NT-proBNP levels (common OR per 1-SD increase 1.74, 95% CI 1.21–2.50). Conclusions: NT-proBNP is independently associated with silent cerebrovascular lesions and could be a surrogate marker of vascular brain damage in hypertension.