Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY).

BACKGROUND: Subcortical microvascular disease represented by brain white matter hyperintensity on magnetic resonance imaging is associated with functional decline in older people with hypertension. The effects of 2 levels of 24-hour average systolic blood pressure (BP) on mobility, white matter disease progression, and cognitive function over 3 years were studied. METHODS: This trial was a prospective, randomized, blinded end-points study in patients ≥75 years of age with systolic hypertension and magnetic resonance imaging evidence of white matter hyperintensity lesions. Patients were randomized to a 24-hour mean systolic BP of ≤130 mm Hg (intensive treatment) versus ≤145 mm Hg (standard treatment) with antihypertensive therapies. Primary study outcomes were changes in mobility (gait speed) and accrual of white matter hyperintensity volume after 3 years. Changes in cognitive function (executive processing) and adverse events were also evaluated. RESULTS: In 199 randomized patients, the mean age of the cohort was 80.5 years, and 54% were women; the average 24-hour systolic BP was 149 mm Hg. Goal BPs were achieved after a median treatment period of 3 to 4 months; at that time, the mean 24-hour systolic BP was 127.7 mm Hg in the intensive treatment group and 144.0 mm Hg in the standard treatment group for an average difference of 16.3 mm Hg. Changes in gait speed were not different between treatment groups (0.40±2.0 versus 0.42±2.7 s in the intensive treatment and standard treatment groups, respectively; P=0.91), whereas changes from baseline in white matter hyperintensity volumes were smaller (0.29%) in the intensive treatment group compared with the standard treatment group (0.48%; P=0.03). Cognitive outcomes also were not different between the treatment groups. Major adverse cardiovascular events were higher in the standard treatment group compared with the intensive treatment group (17 versus 4 patients; P=0.01). Falls, with or without injury, and syncope were comparable in the treatment groups. CONCLUSIONS: Intensive lowering of ambulatory BP reduction in older patients with hypertension did not result in differences in mobility outcomes but was associated with a reduction in accrual of subcortical white matter disease. Over periods >3 years, a reduction in the accumulation of white matter disease may be a factor in conserving function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01650402.

Relationships among clinic, home, and ambulatory blood pressures with small vessel disease of the brain and functional status in older people with hypertension.

BACKGROUND: Subcortical small vessel disease, represented as white matter hyperintensity (WMH) on magnetic resonance images (MRI) is associated with functional decline in older people with hypertension. We evaluated the relationships of clinic and out-of-office blood pressures (BP) with WMH and functional status in older persons. METHODS: Using cross-sectional data from 199 older study participants enrolled in the INFINITY trial, we analyzed the clinic, 24-hour ambulatory, and home BPs and their relationships with WMH burden and mobility and cognitive outcomes. RESULTS: Volume of WMH was associated with clinic and 24-hour ambulatory systolic BP but not home systolic BP. The mobility measure, supine-to-sit time, had a significant association with 24-hour systolic BP and pulse pressure but not with diastolic BP or values obtained by home BP. Cognitive measures of processing speed (Trails Making Test Part A and the Stroop Word Test) were significantly associated with 24-hour systolic BP, but not clinic and home BPs. CONCLUSION: These data demonstrate that ambulatory BP measurements in older people are more strongly associated with WMH and certain measures of functional status compared to home BP measurements. Hence, home BP may not be a useful substitute for ambulatory BP for assessing subcortical small vessel disease and its consequences. Further longitudinal analyses comparing clinic and various types of out-of-office BP measures with small vessel brain disease are needed. Clinicaltrials.gov identifier: NCT01650402.

Longitudinal microstructural changes of cerebral white matter and their association with mobility performance in older persons.

Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ≥75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.

Timed mobility: description of measurement, performance, and dimensionality among older adults.

PURPOSE: To describe the measurement, performance, and dimensionality of five timed mobility activities completed by older adults. MATERIALS AND METHODS: Cross-sectional observational study using correlational and factor analysis to examine the dimensionality of five timed mobility activities performed by 189 older adults in an outpatient setting. RESULTS: The times to complete supine-to-sit, five repetition sit-to-stand, 8 m comfortable gait, four step ascent, and four step descent were correlated significantly with one another (r = 0.294-0.827, p < 0.001). The times were also internally consistent (α = 0.71) and loaded highly on a single factor (0.587-0.888). CONCLUSION: The timed measurements of this study were easily obtained. They can be viewed as unidimensional and representative of a single construct of the international classification of functioning, disability, and health -timed mobility. Implications for rehabilitation For patients who are independent in mobility, timing offers a means of differentiating the performance of individual patients. As the times to complete five mobility activities are interrelated, mobility is supported as a rehabilitation construct and patients who are faster at one activity should be expected to be faster at another.

Functional reach of older adults: normative reference values based on new and published data.

OBJECTIVES: To provide normative reference values for the standing functional reach test for older adults. DESIGN: Observational study and meta-analysis of data from published studies. SETTING: Clinical Research Center. PARTICIPANTS: Older adults: 199 hypertensive from INFINITY study and 7535 from consolidation of INFINITY and 20 other studies. MAIN OUTCOME MEASURE: Functional reach. RESULTS: The mean (standard deviation) for functional reach for the hypertensive older adults was 27.5 (7.2) cm. For the consolidated sample of older adults, a random effects model determined a weighted mean (standard error) functional reach of 27.2 (0.9) cm with a 95% confidence interval of 25.5 to 28.9cm. CONCLUSION: Pending the availability of data from a large population-based study, the summary data presented herein can serve as a reasonable estimate of normal functional reach for older adults.

Consensus statement for diagnosis of subcortical small vessel disease.

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.

Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons.

Several potential vascular risk factors exist for the development and accumulation of subcortical white matter disease in older people. We have reported that in older people followed for up to 4 years white matter hyperintensity (WMH) lesions on magnetic resonance imaging nearly doubled in volume and were associated with alterations in mobility and cognitive function. Herein we review the genetic, metabolic, and vascular risk factors that have been evaluated in association with the development and pathogenesis of WMH in older persons. Our research efforts have focused on systemic hypertension, particularly in the out-of-office setting as 24-hour ambulatory blood pressure (BP) has proven to be a stronger indicator of the progression of WMH in older people and the associated functional decline than doctor's office BP. Based on relations between 24-hour systolic BP levels, the accrual of WMH, and functional decline, we have designed the INFINITY trial, the first interventional study to use ambulatory BP to guide antihypertensive therapy to address this problem in the geriatric population.

Thalamic fractional anisotropy predicts accrual of cerebral white matter damage in older subjects with small-vessel disease.

White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (⩾75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of baseline thalamic FA in multivariate modeling increased this value by 70%, which explains 46.5% of the variance in WMH accrual rate. Thalamic FA might serve as a novel predictor of cerebral small-vessel disease progression in clinical settings and trials. Furthermore, our findings point to the possibility of a causal relationship between thalamic damage and the accrual of WMHs.

Processing speed in normal aging: effects of white matter hyperintensities and hippocampal volume loss.

Changes in cognitive functioning are said to be part of normal aging. Quantitative MRI has made it possible to measure structural brain changes during aging which may underlie these decrements which include slowed information processing and memory loss. Much has been written on white matter hyperintensities (WMH), which are associated with cognitive deficits on tasks requiring processing speed and executive functioning, and hippocampal volume loss, which is associated with memory decline. Here we examine volumetric MRI measures of WMH and hippocampal volume loss together in relation to neuropsychological tests considered to be measures of executive functioning and processing speed in 81 non-demented elderly individuals, aged 75-90. Correlational analysis showed that when controlling for age, both greater WMH volume and smaller hippocampal volume were correlated with slower performances on most tests with the exception of a battery of continuous performance tests in which only WMH was correlated with slower reaction time (RT). We then performed a series of hierarchical multiple regression analyses to examine the independent contributions of greater WMH volume and reduced hippocampal volume to executive functioning and processing speed. The results showed that for the four measures requiring executive functioning and speed of processing, WMH volume and hippocampal volume combined predicted between 21.4% and 37% of the explained variance. These results suggest that WM integrity and hippocampal volume influence cognitive decline independently on tasks involving processing speed and executive function independent of age.

Mobility impairment is associated with reduced microstructural integrity of the inferior and superior cerebellar peduncles in elderly with no clinical signs of cerebellar dysfunction.

While the cerebellum plays a critical role in motor coordination and control no studies have investigated its involvement in idiopathic mobility impairment in community-dwelling elderly. In this study we tested the hypothesis that structural changes in the cerebellar peduncles not detected by conventional magnetic resonance imaging are associated with reduced mobility performance. The analysis involved eighty-five subjects (age range: 75-90 years) who had no clinical signs of cerebellar dysfunction. Based on the short physical performance battery (SPPB) score, we defined mobility status of the subjects in the study as normal (score 11-12, n = 26), intermediate (score 9-10, n = 27) or impaired (score < 9, n = 32). We acquired diffusion tensor imaging data to obtain indices of white matter integrity: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Using a parcellation atlas, regional indices within the superior, middle, and inferior cerebellar peduncles (ICP, MCP, SCP) were calculated and their associations with mobility performance were analyzed. Subjects with impaired mobility showed reduced FA and AD values in the ICP and SCP but not in the MCP. The ICP-FA, ICP-AD and SCP-FA indices showed a significant association with the SPPB score. We also observed significant correlation between ICP-FA and walk time (r = - 0.311, p = 0.004), as well as between SCP-AD and self-paced maximum walking velocity (r = 0.385, p = 0.003) and usual walking velocity (r = 0.400, p = 0.002). In logistic regression analysis ICP-FA and ICP-AD together explained 51% of the variability in the mobility status of a sample comprising the normal and impaired subgroups, and correctly classified more than three-quarters of those subjects. Our findings suggest that presence of microstructural damage, likely axonal, in afferent and efferent connections of the cerebellum contributes to the deterioration of motor performance in older people.

Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons.

BACKGROUND: Brain white matter hyperintensities (WMH) are associated with functional decline in older people. We performed a 4-year cohort study examining progression of WMH, its effects on mobility, cognition, and depression with the role of clinic and 24-hour ambulatory systolic blood pressure as a predisposing factor. METHODS: Ninety-nine subjects, 75-89 years were stratified by age and mobility, with the 67 completing 4-years comprising the cohort. Mobility, cognition, depressive symptoms, and ambulatory blood pressure were assessed, and WMH volumes were determined by quantitative analysis of magnetic resonance images. RESULTS: WMH increased from 0.99±0.98% of intracranial cavity volume at baseline to 1.47±1.2% at 2 years and 1.74±1.30% after 4 years. Baseline WMH was associated with 4-year WMH (p < .0001), explaining 83% of variability. Small, but consistent mobility decrements and some evidence of cognitive decline were noted over 4 years. Regression analyses using baseline and 4-year WMHs were associated with three of five mobility measures, two of four cognitive measures and the depression scale, all performed at 4 years. Increases in ambulatory systolic blood pressure but not clinic systolic blood pressure during the initial 2 years were associated with greater WMH accrual during those years, while ambulatory systolic blood pressure was related to WMH at 4 years. CONCLUSION: Declines in mobility, cognition, and depressive symptoms were related to WMH accrual over 4 years, and WMH was related to out-of-office blood pressure. This suggests that prevention of microvascular disease, even in asymptomatic older persons, is fundamental for preserving function. There may be value in tighter 24-hour blood pressure control in older persons although this requires further investigation.

INtensive versus standard ambulatory blood pressure lowering to prevent functional DeclINe in the ElderlY (INFINITY).

Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages ≥75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of ≤130 mm Hg or standard to achieve a goal 24-hour systolic BP of ≤145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease.

Mobility decline in the elderly relates to lesion accrual in the splenium of the corpus callosum.

In a previous cross-sectional study on baseline data, we demonstrated that the volume of brain white matter hyperintensities (WMH) in the splenium of corpus callosum (SCC) predicted the current mobility function of older persons. The primary aim of this follow-up study was to determine the relation of WMH volume change in SCC (SCC-∆WMH) with change in mobility measures. A secondary aim was to characterize the global and regional progression of WMH. Mobility function and WMH burden were evaluated at baseline and at 2 years in 77 community-dwelling individuals (baseline age, 82 ± 4). Regional WMH in SCC, as well as genu and body of corpus callosum, subregions of corona radiata, and superior longitudinal fasciculus were determined using a white matter parcellation atlas. The total WMH volume increased 3.3 ± 3.5 ml/year, mainly through enlargement. Significant WMH increases were observed in all selected regions, particularly within the corona radiata. While at baseline and follow-up we observed correlations between WMH burden and several measures of mobility, longitudinal change correlated only with change in chair rise (CR). SCC-∆WMH showed the highest correlation (r = -0.413, p = 0.0002) and was the best regional predictor of CR decline (OR = 1.5, r(2) = 0.3). The SCC-∆WMH was more than five times larger in the CR-decline group compared to the no-decline group (p = 0.0003). The SCC-∆WMH (top quartile) showed a higher sensitivity/specificity for CR decline compared to change in total WMH, 63/88% versus 52/84%, respectively. The findings suggest that accrual of WMHs in posterior areas of the brain supporting inter-hemispheric integration and processing of visual-spatial information is a mechanism contributing to age-related mobility deterioration.

Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people.

BACKGROUND: High blood pressure (BP) is a risk factor for cerebrovascular disease, including stroke. Little is known about the importance of BP on the progression of microvascular disease of the brain, which has been associated with functional decline in mobility and cognition in older people. METHODS AND RESULTS: This was a prospective cohort of subjects 75 to 89 years of age to determine relations among vascular risk factors, white matter hyperintensity volume, and functional status. Ninety-nine subjects were enrolled through the use of a balanced 3×3 matrix stratified by age and mobility performance, and 72 subjects completed all sets of baseline and follow-up studies at 2 years. Subjects were excluded if there were medications or systemic or neurological diseases that could compromise mobility. Ambulatory and clinic BP monitoring, magnetic resonance imaging, gait studies, and neuropsychological testing were performed at baseline and after 24 months. Brain classification into normal white matter and T2-hyperintense white matter hyperintensity volume was performed with semiautomated segmentation. Quantitative measures of mobility and cognitive function were obtained longitudinally. Increased ambulatory systolic BP, but not clinic systolic BP, from baseline to 24 month follow-up was associated with increased white matter hyperintensity volume over that same period, as well as measures of executive function/processing speed. Similar associations were observed for 24-hour BP, awake BP, and sleep BP but not for the surge between the sleep and awake time at the 24-month time point. CONCLUSIONS: These data demonstrate for the first time the importance of 24-hour systolic BP in the progression of brain white matter hyperintensity volume burden associated with impairment of cognitive function in older people. The 24-hour systolic BP may be a potential target for intervention in the elderly to reduce vascular disease of the brain and impairment of function.

Mobility assessment: sensitivity and specificity of measurement sets in older adults.

OBJECTIVE: To identify quantitative measurement variables that characterize mobility in older adults, meet reliability and validity criteria, distinguish fall risk, and predict future falls. DESIGN: Observational study with 1-year weekly falls follow-up. SETTING: Mobility laboratory. PARTICIPANTS: Community-dwelling volunteers (N=74; age, 65-94y) categorized at entry as 27 nonfallers or 47 fallers by using Medicare criteria (1 injury fall or >1 noninjury fall in the previous year). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Test-retest and within-subject reliability, criterion and concurrent validity; predictive ability indicated by observed sensitivity and specificity to entry fall-risk group (falls status), Tinetti Performance Oriented Mobility Assessment (POMA), computerized dynamic posturography Sensory Organization Test (SOT), and subsequent falls reported weekly. RESULTS: Measurement variables were selected that met reliability (intraclass coefficient of correlation >.6) and/or discrimination (P<.01) criteria (clinical variables: turn steps and time, gait velocity, step-in-tub time, downstairs time; forceplate variables: quiet standing Romberg ratio sway area, maximal lean anterior-posterior excursion, sit-to-stand medial-lateral excursion, sway area). Sets were created (3 clinical, 2 forceplate) using combinations of variables appropriate for older adults with different functional activity levels, and composite scores were calculated. Scores identified entry falls status and concurred with POMA and SOT scores. The full clinical set (5 measurement variables) produced sensitivity of 80% and specificity of 74% to falls status. Composite scores were more sensitive and specific overall in predicting subsequent injury falls and multiple falls compared with falls status and POMA or SOT score. CONCLUSIONS: Sets of quantitative measurement variables obtained with this mobility battery provided sensitive prediction of future injury falls and screening for multiple subsequent falls by using tasks that should be appropriate to diverse participants.

An obese body mass increases the adverse effects of HIV/AIDS on balance and gait.

BACKGROUND: Balance and gait problems have been detected among patients with HIV/AIDS. The extent to which these problems are exacerbated by either frailty or obesity has not been examined. Objective The purpose of this study was to compare participants who differed in body mass and the presence or absence of HIV/AIDS. DESIGN: This was a cross-sectional study. METHODS: Quantitative measurements were obtained from 86 participants who were HIV-type 1 (HIV-1) seronegative and 121 participants who were seropositive divided into subgroups based on their body mass index (BMI <21, 21-29, or >29 kg/m(2)). RESULTS: Participants who were seropositive were impaired relative to seronegative controls on several indices, including the limit of stability, sway amplitude and sway strategy, gait initiation time, and gait speed during a fast pace condition. Participants who were obese also exhibited impairments, which were evident during assessments of the limit of stability, nonpreferred leg stance time, sway strategy, normal and fast gait speed, fast gait initiation time, and 360-degree turn time. Importantly, the analysis revealed that participants with both attributes were more impaired than those with either or neither attribute: patients who were obese and seropositive were more impaired in fast gait initiation time and cadence, nonpreferred leg stance time, 360-degree turn time, and sway strategy scores. Limitations The validity of BMI as a measure of body mass can be challenged. In addition, the validity of chair rise time and 360-degree turn time as estimates of lower-extremity strength (force-generating capacity) can be argued. CONCLUSIONS: The present findings have an obvious and unfortunate implication: as more patients who are HIV-1 seropositive join the seronegative community in becoming obese, the effects of obesity and their disease may summate and their risk for balance and gait problems may increase.

Brain regional lesion burden and impaired mobility in the elderly.

This study investigated the relationship of brain white matter (WM) lesions affecting specific neural networks with decreased mobility in ninety-nine healthy community-dwelling subjects ≥75 years old prospectively enrolled by age and mobility status. We assessed lesion burden in the genu, body and splenium of corpus callosum; anterior, superior and posterior corona radiata; anterior and posterior limbs of internal capsule; corticospinal tract; and superior longitudinal fasciculus. Burden in the splenium of corpus callosum (SCC) demonstrated the highest correlation particularly with walking speed (r=0.4, p<10(-4)), and in logistic regression it was the best regional predictor of low mobility performance. We also found that independent of mobility, corona radiata has the largest lesion burden with anterior (ACR) and posterior (PCR) aspects being the most frequently affected. The results suggest that compromised inter-hemispheric integration of visuospatial information through the SCC plays an important role in mobility impairment in the elderly. The relatively high lesion susceptibility of ACR and PCR in all subjects may obscure the importance of these lesions in mobility impairment.

The blood-brain barrier: geriatric relevance of a critical brain-body interface.

The blood-brain barrier (BBB) represents the interface between the brain and other body tissues. Its ability to protect the brain from harmful compounds has attracted the attention of clinicians and investigators, but far from being a simple physical barrier, the BBB is a complex, heterogeneous, and dynamic tissue. The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells (BMECs), cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity. Based on the published literature, this study proposes that age- and disease-related BBB alterations play a key role in diminishing the ability of older patients to recover from acute ischemic stroke. Evidence linking deficits in the cerebral microvasculature and BBB integrity to dementia, medication-related cognitive decline, white matter disease (WMD or leukoaraiosis), and related geriatric syndromes including delirium, gait disorders, and urinary incontinence is also reviewed. Priority areas for a future research agenda include strategies to improve clinicians' ability to diagnose, prevent, and manage BBB abnormalities. In future years, in vivo measures such as functional and contrast-enhanced neuroimaging will be used to evaluate BBB integrity in older adults while also assessing the effectiveness of interventions, some targeting inflammatory pathways known to disrupt the BBB, for their ability to prevent or slow the progression of these complex multifactorial geriatric syndromes.