EVIDENCE BASED STRATEGIES TO PREVENT AGE-RELATED COGNITIVE IMPAIRMENT: SPRINT-MIND RESULTS

MARK A. SUPIANO, M.D. PROFESSOR AND CHIEF, GERIATRICS DIVISIONDIRECTOR, VA SALT LAKE CITY GRECCEXECUTIVE DIRECTOR, UNIVERSITY OF UTAH CENTER ON AGING

DISCLOSURES

• Grant funding– SPRINT-MIND/ASK: NIA R01AG055606

• No relevant financial relationships with any commercial interests to report

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LEARNING OBJECTIVES

• Understand the cognitive impairment continuum and be able to define mild cognitive impairment and dementia

• Recognize that the majority of Alzheimer’s Disease and Related Dementias have a vascular contribution – Vascular Cognitive Impairment

• Become familiar with modifiable approaches to prevent cognitive impairment including new results from the SPRINT-MIND study

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GOOD NEWS: COGNITIVE IMPAIRMENT CAN BE PREVENTED

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STRATEGIES TO PREVENT COGNITIVE IMPAIRMENT - NONMODIFIABLE

• Die young• Pick your parents well• Attain high SES• Maximize years of education

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UNCERTAIN – EQUIPOISE

• Statins– Coming soon, the PRagmatic EValuation of evENTs

And Benefits of Lipid-lowering in oldEr adults –PREVENTABLE – trial

– Examine the equipoise regarding statins for primary CVD, dementia, and disability prevention in adults older than 75 years

– The first statin trial with a non-CVD primary outcome — survival free of dementia or persisting disability

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STRATEGIES TO PREVENT COGNITIVE IMPAIRMENT – MODIFIABLE / 1• Do not smoke• Avoid neurotoxins

– EtOH– Benzodiazepines – Anticholinergic medications

• Avoid head trauma – wear your bike helmet• Treat hearing loss• If diabetic, maintain euglycemia• Increase physical activity• Engage in cognitive stimulating (and social) activities

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STRATEGIES TO PREVENT COGNITIVE IMPAIRMENT – MODIFIABLE / 2

• If hypertensive, with > 15% 10-year CVD risk, control systolic blood pressure to a target of 120 mm Hg

• SPRINT Memory and Cognition INDecreased Hypertension – SPRINT MIND

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SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL: RESEARCH QUESTION

Randomized controlled clinical trial to examine effect of more intensive high blood pressure treatment strategy than is currently recommended

Target Systolic BP

Intensive Treatment Goal SBP < 120 mm Hg

Standard TreatmentGoal SBP < 140 mm Hg

SPRINT design details available at:• ClinicalTrials.gov (NCT01206062)• Ambrosius WT et al. Clin. Trials. 2014;11:532-546

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PRIMARY OUTCOME AND DEATH FROM ANY CAUSE

• The intervention was stopped early after 3.26 year median follow-up

• 25% risk reduction in composite primary outcome (NNT 61)

• 27% risk reduction in all cause mortality (NNT 90)

2019 RMGC 10N Engl J Med 2015;373:2103-2116

WHO PARTICIPATED IN SPRINT-MIND?

• People age 50 years and older with hypertension at high risk of cardiovascular disease (CVD)

• Recruited from 120 clinical sites• Did not include people with

dementia, stroke or diabetes mellitus

• 9,631 participants • Average age 68 years

– 28% were > age 75• 30% Black and 10% Hispanic

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SPRINT-MIND BACKGROUND

• Preventing cognitive impairment becomes increasingly important as people live longer

• While Alzheimer’s Disease is the most commonly diagnosed dementia cause, cognitive impairment due to cerebrovascular causes are important, independent contributors to cognitive dysfunction

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Credit: Jeff Williamson

COGNITIVE IMPAIRMENT CONTINUUM

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Nor

mal

MILD COGNITIVE IMPAIRMENT (MCI)

• Not normal cognitive aging• Clinical state with deficits in short term

memory or another cognitive domain• Montreal Cognitive Assessment (MoCA)

score in 18-25 range• Intact daily functioning• A well-established dementia risk factor

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SPECTRUM OF ADRD ETIOLOGIES

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VASCULAR COGNITIVE IMPAIRMENT (VCI) DEFINITION

• A syndrome where there is evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain

• Encompasses all cognitive disorders from mild deficits to frank dementia and both “vascular dementia” and “multi-infarct dementia”

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VASCULAR COGNITIVE IMPAIRMENT (VCI)

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NO CONCLUSIVE CLINICAL TRIAL FOR THE EFFECT OF BLOOD PRESSURE LOWERING ON DEMENTIA

• Only 4 trials robustly assessed dementia as an outcome; none adjudicated

• Of those 4 trials, only 2 had a duration greater than 3 years

• No trials assessed MCI as an outcome

Adapted from Elias et al. Am J Hypertens. 2018;31(6):631-642

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Study Total N Outcome Follow-upAVEC Trial (2012) 53 Cognitive Function 1 years

ONTARGET (2011) 25,620 Cognitive Function 4.7 years

TRANSCEND Trial (2011) 5,926 Cognitive Function 4.7 years

PRoFESS Trial (2008) 20,332 Cognitive Function 2.4 years

HYVET-COG (2008) 3,336 Dementia 2.2 years

PROBE Study (2006) 160 Cognitive Function 24 weeks

SCOPE (2005) 4,937 Dementia 3.7 years

PROBE Study (2004) 144 Cognitive Function 16 weeks

PROGRESS (2003) 6,105Dementia /

Cognitive Function 3.9 years

Sys-Eur Trial (1998) 2,418 Dementia 2.0 years

MRC Treatment Trial of Hypertension in Older Adults (1996) 2,584 Cognitive Function 4.5 years

HOPE Study (1996) 81 Cognitive Function 24 weeks

SHEP Study (1994) 4,736 Cognitive Function 5 years

Croog et al. (1994) 309 Cognitive Function 22 weeks

Croog et al. (1986) 626 Cognitive Function 24 weeks

EQUIPOISE: LOW SBP ASSOCIATED WITH COGNITIVE HARM• Low SBP was

independently associated with a greater progression of cognitive decline in older patients with dementia and MCI among those treated with antihypertensive drugs (AHDs).

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Mossello JAMA Int Med 2015

SPRINT MIND OBJECTIVE

• Goal was to test whether the adjudicated occurrence of the following will be lower in the SPRINT participants who were randomly assigned to the intensive compared with standard treatment group – All-cause probable dementia (PD)– Mild Cognitive Impairment (MCI)– Composite outcome of PD or MCI

• Cognitive data collection planned at baseline and every two years in follow-up

• Adjudicators masked to treatment arm

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SPRINT MIND TIMELINE

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Mean Follow-up Systolic Blood Pressure

Standard Treatment 135 mmHg (Intervention Period) 136 mmHg (Closeout Visits)136 mmHg (Extended Follow-up Visits)

Intensive Treatment 122 mmHg (Intervention Period) 125 mmHg (Closeout visits)129 mmHg (Extended Follow-up Visits)

SPRINT-MIND SBP THROUGH FOLLOW-UP

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From: Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial

JAMA. 2019;321(6):553-561. doi:10.1001/jama.2018.21442

Probable Dementia by Treatment GroupShaded regions indicate 95% confidence intervals. Median follow-up time was 5.14 years (interquartile range, 3.91-6.00) for the intensive treatment group and 5.07 years (interquartile range, 3.87-5.98) for the standard treatment group. For group comparison of incidence, hazard ratio, 0.83; 95% CI, 0.67-1.04; P=.10.

Figure Legend:

24

Events = 348

Events = 285

ADJUDICATED MCI BY TREATMENT GROUP

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SPRINT-MIND CONCLUSIONS• Intensive blood pressure control significantly

reduced occurrence of MCI by 19% (P=0.01)• Intensive blood pressure control did not

significantly reduce the occurrence of probable dementia (17% reduction, P=0.10)

• Intensive blood pressure control significantly reduces incidence of the composite outcome of MCI or dementia by 15% (P=0.02)

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WHAT ABOUT BRAIN STRUCTURAL CHANGES?

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BRAIN MRI WHITE MATTER LESION VOLUME

• White matter lesions are a risk factor for cognitive decline and dementia

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Mild WML Burden ~4 cm3

SPRINT-MRI RESULTS

• Intensive therapy resulted in 18% LOWER increase in WML volume relative to baseline

• Between-group difference for the change in WML volume of −0.54 cm3 (95% CI, −0.87 to −0.20 cm3)

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CONCLUSIONS AND RELEVANCE

• Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.

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JAMA. 2019;322(6):524-534. doi:10.1001/jama.2019.10551

IMPLICATIONS

• SPRINT is the first RCT intervention to show a reduction in the risk for MCI

• There is no evidence that intensive blood pressure control harms cognition

• SPRINT MIND results are the first to show that what is good for the heart is also good for the brain

• SPRINT MIND demonstrated that a diverse population can be recruited, randomized, and assessed in follow-up for cognition over 5 years with acceptable assessment protocol adherence

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IF NO ADRD CURE, INTERIM GOAL SHOULD BE TO POSTPONE MCI AND ADRD

2019 RMGC 32Zissimopoulos, J Geron 2018

GOOD NEWS! A NEW PARADIGM IN DEMENTIA PREVENTION• The majority of Alzheimer’s Disease and Related

Disorders (ADRD) have a vascular etiology• The incidence of Mild Cognitive Impairment (MCI),

ADRD and White Matter Lesion Volume is decreased among hypertensive patients randomized to achieve a systolic blood pressure (SBP) goal of 120 compared with 140 mm Hg in SPRINT

• Treating CVD risk factors may lead to a further decline in ADRD prevalence

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QUESTIONS...About our logo...

The bristlecone pine tree (Pinuslongaeva) - the earth’s oldest inhabitant with a life span of 4,000 years - is found only in Utah and five other western states. Its extraordinary longevity and ability to adapt and survive in extremely harsh environmental conditions above 10,000 feet embodies the investigative spirit and mission of the Utah Center on Aging.

@Aging_MD

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Bold = Tests in Cognitive Screening Battery

SPRINT MIND NEUROCOGNITIVE BATTERYCOGNITIVE DOMAIN TEST

Global Functioning •Montreal Cognitive Assessment (MoCA)

Executive Function,Speed of Processing

•Digit Symbol Coding Test•Trail Making Test

Learning and Memory • Logical Memory I•Hopkins Verbal Learning Test–R

Visual-Spatial Memory •Modified Rey-Osterreith FigureWorking Memory, Attention, Verbal Fluency

•Digit Span Forward and Backward•Category Fluency-Animals

Language and Naming •Boston Naming Test (15 item)

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SPRINT MIND Screening Cognitive Battery+

SPRINT MIND Extended Cognitive Battery+

Proxy Report (FAQ or Modified Dementia Questionnaire)+

Depression (PHQ-9) and Medications=

Expert Adjudication (w/classification: PD, MCI, No Impairment)

ADJUDICATION COMPONENTS FOR DETERMINING COGNITIVE STATUS

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Intensive Treatment Standard TreatmentRandomized 4,678 4,683Did not complete cognitive assessment during follow-up

369 (7.9%) 366 (7.8%)

Could not adjudicate cognitive status 31 (0.1%) 32 (0.1%)

Included in final analyses for probable dementia

4,278 (91.4%) 4,285 (91.5%)

Intensive Treatment Standard Treatment

Completed Cognitive % In-Person Completed Cognitive % In-Person

Testing (%) Testing Testing (%) Testing

Year 2 Visit 4,255 (95.1%) 97.6 4,256 (94.7%) 96.8

Year 4 Visit / Closeout Visits 3,972 (92.6%) 94.6 3,949 (92.3%) 93.7

Extended Follow-up Visit 2,276 (61.1%) 85.2 2,191 (59.2%) 85.1Completed cognitive testing includes in-person testing, phone battery, or completion of Dementia

Questionnaire by a proxy

COGNITIVE DATA COLLECTION IN FOLLOW-UP

PROTOCOL DEFINITION OF MCI

Year 2

MCI MCI PD

Normal MCI PD

MCI No Test Death No Test Death

Normal No Test Death

Normal

MCI

Normal

Normal N/A

MCI Normal

Not Included in

Protocol Definition

of MCI

MCI

Normal MCI

VISITYear 4 / Closeout Extended FU

Protocol Definition

of MCI

N/A

MCI

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