Behnam Sabayan

Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: A meta-analysis of transcranial Doppler studies

BACKGROUND AND PURPOSE Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimers disease and vascular dementia, using transcranial Doppler studies. METHODS A literature search was conducted in Pubmed, EMBASE and Web of Science. After initial screening of 304 articles and removing duplicates, a total of 53 articles, published between 1980 and 2010, were reviewed. Finally 12 articles were included in the meta-analysis. For each study, effect sizes (ES) indicating the standardized mean differences of the hemodynamic measures between two groups were calculated. Using random effect models, pooled estimates of ES were measured. RESULTS Patients with Alzheimers disease (ES=-1.09, 95% CI -1.77 to -0.44, p=0.004) and vascular dementia (ES=-1.62, 95% CI -2.26 to -0.98, p<0.001) had significantly lower cerebral blood flow velocity compared with healthy aged-matched controls. In addition, pulsatility index was significantly higher in both Alzheimers disease (ES=0.5, 95% CI 0.28-0.72, p<0.001) and vascular dementia patients (ES=2.34, 95% CI 1.39-3.29, p<0.001). Patients with Alzheimers disease had lower pulsatility index (ES=-1.22, 95% CI -1.98 to -0.46, p=0.002) compared to subjects with vascular type of dementia. CONCLUSIONS Patients with Alzheimers disease and vascular dementia have a pronounced disturbance in their cerebrovascular hemodynamics. The severity of disturbances in cerebral hemodynamics is significantly lower in Alzheimers disease compared to vascular dementia.

High Blood Pressure and Resilience to Physical and Cognitive Decline in the Oldest Old: The Leiden 85-Plus Study

To evaluate the association between various blood pressure (BP) measures at age 85 and future decline in physical and cognitive function the oldest old.

Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study

Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years). Design Prospective cohort study. Setting PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study, a collaboration between centres in Ireland, Scotland, and the Netherlands. Participants 5461 participants, mean age 75.3 years, who were at risk of cardiovascular disease. Blood pressure was measured every three months during an average of 3.2 years. Visit-to-visit variability in blood pressure was defined as the standard deviation of blood pressure measurements between visits. Main outcome measures Four domains of cognitive function, testing selective attention, processing speed, and immediate and delayed memory. In a magnetic resonance imaging substudy of 553 participants, structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities were measured. Results Participants with higher visit-to-visit variability in systolic blood pressure had worse performance on all cognitive tests: attention (mean difference high versus low thirds) 3.08 seconds (95% confidence interval 0.85 to 5.31), processing speed −1.16 digits coded (95% confidence interval −1.69 to −0.63), immediate memory −0.27 pictures remembered (95% confidence interval −0.41 to −0.13), and delayed memory −0.30 pictures remembered (95% confidence interval −0.49 to −0.11). Furthermore, higher variability in both systolic and diastolic blood pressure was associated with lower hippocampal volume and cortical infarcts, and higher variability in diastolic blood pressure was associated with cerebral microbleeds (all P<0.05). All associations were adjusted for average blood pressure and cardiovascular risk factors. Conclusion Higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age.

High Blood Pressure, Physical and Cognitive Function, and Risk of Stroke in the Oldest Old: The Leiden 85-Plus Study

Background and Purpose— Epidemiological studies have shown mixed findings on the association between hypertension and stroke in the oldest old. Heterogeneity of the populations under study may underlie variation in outcomes. We examined whether the level of physical and cognitive function moderates the association between blood pressure and stroke. Methods— We included 513 subjects aged 85 years old from the population-based Leiden 85-plus Study. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure were measured at baseline. Activities of daily living and Mini-Mental State Examination were assessed to estimate level of physical and cognitive function, respectively. Five-year risk of stroke was estimated with Cox regression analysis. Results— In the entire cohort, there were no associations between various measures of blood pressure and risk of stroke except for the inverse relation between pulse pressure and stroke risk (hazard ratio [HR], 0.80 [95% confidence interval [CI], 0.66–0.98]). Among subjects with impaired physical functioning, higher systolic blood pressure (HR, 0.74 [95% CI, 0.59–0.92]), mean arterial pressure (HR: 0.68 [95% CI, 0.47–0.97]), and pulse pressure (HR, 0.71 [95% CI, 0.55–0.93]) were associated with reduced risk of stroke. Likewise, among subjects with impaired cognitive functioning, higher systolic blood pressure was associated with reduced risk of stroke (HR, 0.80 [95% CI, 0.65–0.98]). In subjects with unimpaired cognitive functioning, higher diastolic blood pressure (HR: 1.98 [95% CI, 1.21–3.22]) and mean arterial pressure (HR, 1.70 [95% CI, 1.08–2.68]) were associated with higher risk of stroke. Conclusions— Our findings suggest that impaired physical and cognitive function moderates the association between blood pressure and stroke.

Blood pressure and 10-year mortality risk in the Milan Geriatrics 75+ Cohort Study: role of functional and cognitive status

BACKGROUND Optimal blood pressure targets in older adults are controversial. OBJECTIVE to investigate whether the relation of blood pressure with mortality in older adults varies by age, functional and cognitive status. DESIGN longitudinal geriatric outpatient cohort. SETTING Milan Geriatrics 75+ Cohort Study. SUBJECTS One thousand five hundred and eighty-seven outpatients aged 75 years and over. METHODS The relations of systolic (SBP) and diastolic blood pressure (DBP) with mortality risk were analysed using Cox proportional hazards models. Blood pressure, Mini-Mental State Examination (MMSE) and Basic Activities of Daily Living (ADL) were assessed at baseline. All analyses were adjusted for socio-demographic factors, co-morbidities and medications. RESULTS One thousand and forty-six patients died during 10-year follow-up. The relationships of SBP and DBP with mortality risk were U-shaped; SBP of 165 mmHg and DBP of 85 mmHg were associated with the lowest mortality. Patients with SBP < 120 mmHg and patients with SBP 120-139 mmHg had 1.64-fold (95% confidence intervals, CI 1.21-2.23) and 1.32-fold (95% CI 1.10-1.60) higher mortality risk than patients with SBP 160-179 mmHg (P values 0.001 and 0.004, respectively). In patients with SBP below 180 mmHg, higher SBP was associated with lower mortality in patients with impaired ADL and MMSE but not in those with preserved ADL and/or MMSE (P for interaction 0.033). Age did not modify the correlation of SBP with mortality. CONCLUSIONS The correlations of SBP and DBP with mortality were U-shaped. Higher SBP is related to lower mortality in subjects with impaired ADL and MMSE. ADL and MMSE may identify older subjects who benefit from higher blood pressure.

Framingham Stroke Risk Score and Cognitive Impairment for Predicting First-Time Stroke in the Oldest Old

Background and Purpose— Predictive value of the conventional risk factors for stroke attenuates with age. Cognitive impairment has been implicated as a potential predictor for stroke in older subjects. Our aim was to compare the Framingham stroke risk score with cognitive functioning for predicting first-time stroke in a cohort of the oldest old individuals. Methods— We included 480 subjects, aged 85 years, from the Leiden 85-plus Study. At baseline, data on the Framingham stroke risk score and the Mini-Mental State Examination (MMSE) score were obtained. Risk of first-time stroke was estimated in tertiles of Framingham and MMSE scores. Receiver operating characteristic curves with corresponding areas under the curves (AUCs) and 95% confidence intervals (CIs) were constructed for both Framingham and MMSE scores. Results— Subjects with high Framingham risk score compared with those with low Framingham risk score did not have a higher risk of stroke (hazard ratio, 0.77; 95% CI, 0.39–1.54). Conversely, subjects with high levels of cognitive impairment compared with those with low levels of cognitive impairment had a higher risk of stroke (hazard ratio, 2.85; 95% CI, 1.48–5.51). In contrast to the Framingham risk score (AUCs, 0.48; 95% CI, 0.40–0.56), MMSE score had discriminative power to predict stroke (AUCs, 0.65; 95% CI, 0.57–0.72). There was a significant difference between AUCs for Framingham risk score and MMSE score (P=0.006). Conclusions— In the oldest old, the Framingham stroke risk score is not predictive for first-time stroke. In contrast, cognitive impairment, as assessed by MMSE score, identifies subjects at higher risk for stroke.

Cognitive Impairment and Risk of Stroke: A Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background and Purpose— Cognitive impairment is linked to vascular risk factors and brain vascular pathologies. Several studies have tested whether subjects with cognitive impairment have higher risk for stroke. The aim of this study was to systematically review available evidence on the association between cognitive impairment and risk of stroke to obtain precise effect estimates of the association and to identify which cognitive domains associate most with incident stroke. Methods— PubMed, EMBASE, and Web of Science were searched from January 1, 1980, to October 1, 2013, without language restriction. Only prospective cohort studies were included. From each study, data on the association between cognitive impairment and stroke estimated with hazard ratios or relative risks with 95% confidence interval (CI) were extracted. For each study, risk of stroke per SD lower performance in various cognitive tests was calculated. Results— Twelve studies were included, comprising 82 899 participants of whom 3043 had an incident stroke. The pooled relative risk per SD lower global cognitive performance was 1.19 (95% CI, 1.12–1.27). Each SD lower score in executive function or attention was associated with 1.14-fold (95% CI, 1.06–1.24) higher risk of stroke. Lower scores in memory were associated with 1.07-fold (95% CI, 1.02–1.12) higher risk of stroke, and lower scores in language were associated with 1.08-fold (95% CI, 1.02–1.16) higher risk of stroke. Conclusions— Cognitive impairment is associated with higher risk of stroke. The associations were not significantly different for executive function, memory, and language.

Phoshphodiesterase-5 Inhibitors: Novel Weapons Against Alzheimer's Disease?

ABSTRACT Although Alzheimers disease (AD) poses a major health problem in both developing and developed countries, no definite treatment is available for its cure; hence efforts are being focused on introducing disease-modifying agents for slowing down its course. Recent studies on the effects of sildenafil on different organs have shown that PDE-5 inhibitors may offer new horizons in therapeutic treatment of pulmonary hypertension, multiple sclerosis, neuropathic pain, and age-related memory impairment. In this paper we introduce PDE-5 inhibitors as novel disease-modifying agents against AD and review the different impacts of PDE-5 inhibition on various pathogenic mechanisms leading to AD, including neuronal apoptosis, neurovascular dysfunction, neurotransmitter modulation, and impairment of neurogenesis.

Cardiac hemodynamics are linked with structural and functional features of brain aging: the age, gene/environment susceptibility (AGES)-Reykjavik Study.

Background Advanced heart failure is linked with structural and functional alterations in the brain. It is unclear whether a graded decrease in cardiac function puts older subjects at risk for brain aging. We investigated the association between cardiac hemodynamics and features of brain aging in community‐dwelling older subjects. Methods and Results With data from a sub‐study (n=931 subjects, mean age 75.9 years, 47.7% male) of the Age, Gene/Environment Susceptibility (AGES)‐Reykjavik Study, we investigated the association of MRI measures of cardiac hemodynamics, including left ventricular stroke volume (LVSV) and cardiac output (CO) to brain characteristics. In multivariable analyses, each 10 mL lower LVSV was associated with 4.4 mL (95% CI 1.9 to 6.9) lower total parenchymal brain volume (TBV) and 3.7 mL (95% CI 1.8 to 5.7) lower gray matter volume (GMV). Likewise, each unit (L/min) lower CO was associated with 3.9 mL (95% CI 0.4 to 7.4) lower TBV and 3.9 mL (95% CI 0.4 to 7.4) lower GMV. Lower LVSV was associated with worse performance in processing speed (P=0.043) and executive function (P<0.001). Lower CO was associated with worse performance in processing speed (P=0.015) and executive function (P=0.003). Each 10 mL lower LVSV and each unit lower CO associated with a higher risk of mild cognitive impairment or dementia (odds ratio: 1.24, 95% CI 0.99 to 1.57 and odds ratio: 1.40, 95% CI 0.99 to 2.00, respectively). Conclusions A graded decrease in cardiac functioning is associated with features of brain aging. Older persons with cardiac or cognitive signs and symptoms may have both cardiac and cerebral diseases and should be evaluated accordingly.

Blood Pressure Control and Cognitive Impairment—Why Low Is Not Always Better

The linkbetweenbloodpressure and cognitive impairment is a complex beast. Several observational investigations have studied the association between blood pressure and cognitive function and yielded mixed results.1 Various explanations suchasheterogeneity in demographic and clinical characteristicsof studypopulations have been proposed for such discrepancies.Methodological limitations of clinical trials on antihypertensive therapy in relation to cognitive outcomes have added further complexity to this issue. While a meta-analysis of placebo-controlled trials showed amarginal benefit of lowering blood pressure in reducing the risk of dementia,2 the short-term follow-up and inclusion of healthy participants with low levels of comorbidities and high levels of cognitive functioning have limited the generalizability of these findings.3 Normal regulation of blood pressure is necessary for adequate organ perfusion and prevention of vascular damage. As shown in the Figure, high blood pressure in midlife, low blood pressure in old age, and excessive blood pressure fluctuation can all contribute to cognitive impairment. Hemodynamic stress, imposed by high blood pressure, results in endothelial dysfunction and damages cerebral vessels, which ultimately impairs thestructural and functional integrityof the brain.5 It has been shown that the degree of vascular damage in the systemic and cerebral circulation is linked with lower cerebral blood flow.6 Long-lasting cerebral hypoperfusion results inneuronal energycrisis andcell death.At the same time, damage of the brain can lead to dysregulation of blood pressure and a further decline in cerebral blood flow. Therefore, what is consideredanormal or lowbloodpressure in individualswithcognitive impairmentmaynotnecessarilymeanawellcontrolledbloodpressure. Instead, itmayhinder sufficientperfusion of a damaged brain. In this issue of JAMA Internal Medicine, Mossello et al7 showed that lowerdaytimesystolic bloodpressure in 172older personswithcognitive impairmentwasassociatedwitha faster cognitivedecline. Therewasno associationbetweenother office or ambulatory measures of blood pressure and accelerated cognitive decline. When participants were stratified for antihypertensive medication use, the association was present only in the group receiving treatment (72% of the total population). As a strength, this studyhas specifically focused on patients with cognitive impairment. Furthermore, the investigators applied ambulatory blood pressure monitoring, whichmighthelp to capture the circadiancomplexityof variation in blood pressure. Nonetheless, caution needs to be exercised when interpreting the results. Given the observational design, it cannot be concluded that antihypertensive therapy is directly responsible for the link between low daily systolic blood pressure and cognitive decline. It is likely that individuals receiving antihypertensive therapy had higher loads of overt and covert cardiovascular pathologies, which could independently lead to accelerated cognitive decline. To address this issue of confounding by indication, randomized clinical trials are warranted. An increasingbodyof evidence implies that a “one size fits all” approach in antihypertensive therapy needs to be replacedwith an individualized approach based on chronological age, biological age or the degree of systemic and cerebrovasculardamage,andhemodynamicstatus.8Wethink it is time tomove from the concept of “the lower thebetter” to the concept of “hemodynamic optimization” to decelerate the pace of cognitive decline by a proper management of blood pressure. There is anurgentneed for interventional studies among high-risk groups, applying various classes of antihypertensivemedications, to shed further light on the optimal control of blood pressure in older persons with and at risk of cognitive impairment. Related article page 578 Figure. The Circuit of Blood Pressure Dysregulation and Cognitive Impairment