In collaboration with: Cardiovascular Risk, Cerebral Micro-vascular Disease, and their Consequences Lewis A. Lipsitz, MD In collaboration with: Farzaneh Sorond, MD. PhD Vera Novak, MD, PhD William Milberg, PhD Ihab Hajjar, MD

Aging and BP Elevation

Effect of Aging and CV Risk Factors on the Brain Impaired BP Regulation Cerebral Hypoperfusion Cerebral Microvascular Ds.

190 SUP STD BREAK STD/AMB STG STD AMB MED LUNCH STD 170 150 SBP (mm Hg) old 130 young 110 90 7 8 9 10 11 12 1 Time (hours)

Consequences of HTN and Impaired BP Regulation in the Elderly Orthostatic and postprandial hypotension Syncope, falls, and fractures Cerebral ischemic damage (micro-angiopathy) to white matter in watershed areas of periventricular and frontal subcortical regions of the brain. Executive dysfunction Gait disorders Depressive Symptoms

Cerebral Microangiopathy (a.k.a.White Matter Lesions (WML) and leukoariaosis)

Watershed Areas of the Brain Wong, HH et al, Stroke 2001; ooo = watershed

Cerebral Microvascular Disease Moody, DM, et al Neuroradiology 2004

Conceptual Model The Evidence Cardiovascular Risk Hypertension, Diabetes 6 5 1 Cerebral Hypoperfusion 4 2 Cerebral Microangiopathy 3 Frontal Subcortical Syndrome Executive Dysfunction, Slow Gait, Depression

Evidence for Association Between CV Risk and Cerebral Hypoperfusion (Cross-sectional studies)

Cerebral Autoregulation Normotensive Hypertensive Treated Hypertensive

CASL at 3 Tesla MRI To measure vasomotor reactivity Control baseline hypercapnia hypocapnia baseline CASL at 3 Tesla MRI To measure vasomotor reactivity Control Hypertensive

Control DM

Evidence for Association between Cerebral Hypoperfusion and White Matter Lesions (Cross-sectional) Rotterdam Scan Study (J Cereb Blood Flow Metab, 2007): In 892 popn.-based Sx aged 60-91, low total brain perfusion associated with higher WML volume (MRI). SMART Study (J. Neurol, 2004): In 228 Sx w/ CVD, high tot. CBF associated w/ lower prevalence and severity of WMLs by MRI. Copenhagen Study (Stroke, 2002): Among 21 85 yo Sx, MRI showed lower CBF and CO2 reactivity in WMH than normal WM. Molecular pathology of WML in 456 postmortem brains shows increased hypoxia-related proteins (Stroke, 2006)

Orthostatic BP and Cerebral Infarction Kario, JACC, 2002

T2-weighted MR images (left), CBF (center), and CMRO2 images (right) for a control subject (top row) and for an asymptomatic subject with WML (subject 7, bottom row) Hatazawa, J. et al. Stroke 1997;28:1944-1947 Copyright ©1997 American Heart Association

Cerebral Blood Flow and White Matter Damage Diabetics Controls Novak, Diabetes Care, 2006

Evidence for Association Between Cerebral White Matter Lesions and Symptoms. Cognition: LADIS study (Arch Intern Med, 2007): prospective study of 639 independent seniors (74+5 yrs), showed severe WML assoc’d w/ cognitive and functional (mostly motor) decline over 1 yr. Gait: Whitman (Neurology 2001): In 70 Sx, aged 74-88, decline in Tinetti scores over 4 yrs. assoc’d w/ increase in vol. of WML. Mood: Rotterdam study (J Neurol Neurosurg Psych 2002): Among 2093 Sx aged 72 + 6 yrs, depressive sx assoc’d w/ reduced CBFV (TCD) and CO2 reactivity.

Cerebral Microvascular Disease This slide illustrates that this approach is successfull across quite large anatomical variability. In particular it works quite well in presence of atrophy, which is often seen in MS patients. Guttmann et al., Neurology, 2000,54:1277-1283

Evidence for Association between CV Risk, and Frontal Subcortical Symptoms (x-sectional and longitudinal)

Relation between CV Risk and Frontal Executive Dysfunction Pugh, JAGS 2003; 51:1439

Relation Between SBP and Executive Impairment Kuo, J Geront 2004; 59A: 1191

Cognitive Dysfunction and Poor Diabetes Control Munshi, et al, Diabetes Care, 2006.

Charleston Heart Study: Baseline functional measures by HTN and control status (1984-1985) p-value is comparing the hypertensive vs normotensives or the analysis of variance comparing normotensives, controlled, and uncontrolled

LSM change of outcome measure by HTN status (1984-1993) Values are the least square mean (LSM) from the final Proc Mixed models with covariate adjustments (age, race, BMI, education, baseline measure, physical activity, and comorbidities **: P-values are from the Proc Mixed procedure testing the hypothesis Hº: rate of change is different between the hypertensive and normotensives participants

LSM change of outcome measure by control status (1984-93) Values are the least square mean (LSM) from the final Proc Mixed models with covariate adjustments (age, race, BMI, education, baseline measure, physical activity, and comorbidities). Blue P-value is derived from the Proc Mixed procedure testing the hypothesis Hº: rate of change is different between normotensives and controlled hypertensives. Pink P-value is derived from the Proc Mixed procedure testing the hypothesis Hº: rate of change is different between normotensives and uncontrolled hypertensives.

A frontal subcortical phenotype A frontal subcortical phenotype? Impaired Executive Function, Gait, and Mood P**=0.01 *Groups: 0: no impairment; 1: one of slow gait (<0.7 m/sec), slow trail B (<117sec), and depressive SX (>10); 2: 2 of the 3 impairments; 3: all 3. ** p value for trend (DF=1) adjusted for age, stroke, sex, and antihypertensive treatment

DoesTreatment of CV Risk Factors (HTN) Improve CBF and Cognition? Syst-Eur Trial (Lancet, 1998, Arch Int Med 2002): In 2902 elderly people with Syst HTN, Rx w/ nitrendipine for 3.9 yrs reduced the incidence of dementia by 62%. PROGRESS Study (Arch Intern Med 2003): Among 6105 elderly people with CVD, Perindopril/Indapamide reduced cog decline assoc’d w/ recurrent stroke by 34%. Cochrane analysis of Sx w/o CVD in SCOPE, SHEP, & Syst-Eur showed no combined effect.

ACE Inhibitors may improve CBF in Elderly Hypertensives Lipsitz, HTN, 2005

Managing CV Risk Requires Executive Function A cognitive ability that involves: Planning, organizing Sequencing Multi-tasking Controlled by the frontal lobes. Necessary for management of DM, HTN, and other risks.

The Heart-Brain Connection