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Eric B. Larson, MD, MPH, MACP Vice President for Research, Group Health

Demented in Seattle: The Evolution of a Community-based Research Program to Become a Learning Laboratory of Aging: Adult Changes in Thought. Eric B. Larson, MD, MPH, MACP Vice President for Research, Group Health Executive Director, Group Health Research Institute Friday Harbor Conference

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Eric B. Larson, MD, MPH, MACP Vice President for Research, Group Health

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  1. Demented in Seattle: The Evolution of a Community-based Research Program to Become a Learning Laboratory of Aging: Adult Changes in Thought Eric B. Larson, MD, MPH, MACP Vice President for Research, Group Health Executive Director, Group Health Research Institute Friday Harbor Conference June 2013

  2. Acknowledgements Funded in part by Grant R13 AG030995 from the National Institute on Aging The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Friday Harbor Psychometrics Workshop 2013

  3. Goals for this Presentation • Narrate the journey leading up to ACT • Provide key background for the week’s work. • Encourage ongoing work with the ACT learning laboratory.

  4. The Evolution of Community Based Dementia Research in Seattle • Phase One: • 1978-80 unfunded research using available patients from Geriatrics and Family Services Clinic (Burton Reifler – founder) • Examples: • Outcome of Dementia Workup in Elderly Outpatients • Coexistence of Depression & Dementia • Depression in Caregivers

  5. Outcome of Dementia Work-up (1984) • First study to focus on outpatients - elderly outpatients • Outcome dramatically different: • “Reversible” – metabolic • – not mass lesions, NPH • Unrecognized, treatable, medical illnesses very common

  6. Depression & Dementia • Depression & dementia – most likely to coexist • Not mutually exclusive: Pseudodementia vs. Dementia • Clinically significant depression common in caregivers, especially spouses (30-60%)

  7. Unfunded Research: Lessons Learned In a "new field" - unfunded research can make valuable contributions It is "fun" - turnaround can be rapid Observations and findings are typically important and can be enduring It is a springboard for funded research, hard to sustain unfunded program!

  8. The Evolution of Community Based Dementia Research in Seattle • Phase Two: • Funded research using available patients in dementia clinics • Examples: • Adverse drug reactions • Falls, fractures, dementia • Sensory impairments & dementia • Mortality rates • Health services utilization

  9. Adverse Drug Reactions • Most common cause of “reversible” (dementia) cognitive impairment • Benzodiazepines, antihypertensives, anticholinergics • Today, much less common

  10. The Evolution of Community Based Dementia Research in Seattle • Phase Two: • Funded research using available patients in dementia clinics • Examples: • Adverse drug reactions • Falls, fractures, dementia • Sensory impairments & dementia • Mortality rates • Health services utilization

  11. Falls and Fracture in Patients with Alzheimer’s Type Dementia Cohort study from UWMC Geriatrics & Family Services Clinic N=157 3 year follow-up Outcomes: 50% fell or became unable to walk; fracture rate 69/1000/yr (3 times greater than expected) Risk factors: Adverse drug reactions -- OR=4.9 for falling, wandering; OR=3.6 for fracture; 6.9 for hip fracture Conclusion: Prevention possible - control wandering, avoid toxic drug reactions, treat co-morbid conditions Buchner and Larson JAMA 1987:1492-5.

  12. The Evolution of Community Based Dementia Research in Seattle Phase Three: Incident case finding Alzheimer’s Disease Patient Registry (ADPR) in HMO Established 1986 in response to RFA to develop the equivalent of a cancer registry for AD & other dementias

  13. Alzheimer’s Disease Patient Registry • Enrolled “New” Cases of AD & Other Dementia from Group Health Cooperative • Source of Well Characterized Cases for Analytic Studies • Database of Medical, Psychological & Epidemiological Data • Annual Follow-up to Monitor Cognitive Decline & Assess Survival • Neuropathological Confirmation of Diagnosis

  14. Group Health Cooperative • Established 1948 amidst resistance of medical community • By mid-1960s, established part of medical community • Largest single sponsor in Washington State • Two hospitals in Seattle area (1986): our study used base population of original “Central” Hospital & its satellite clinics

  15. Rationale • An incident case series in primary care setting Rather than referral center: early recognition, compared to UW ADRC • Cases ascertained from enumerated population with known characteristics • Standardized diagnosis by study physicians • Database for etiologic & risk factor studies

  16. Group Health Cooperative - Attributes • < 1% annual attrition (except deaths) • Enumerated population facilitates selecting comparison subjects (22,000 Aged 60+ in “central” clinics) • Demographically similar to surrounding population

  17. 5 Year Attrition Rates at Group Health Cooperative by Age Attrition Attrition Age(All Causes)(Except Death) 65-69 3.6% 0.4% 70-74 4.2% 0.4% 75-79 5.8% 0.6% 80-84 8.5% 0.9% 85+ 13.9% 1.4%

  18. Genetic Differences in ADCases & Controls • Analytic companion to the ADPR • Enrolled probable AD cases from the ADPR • Randomly selected normal controls, similar age & sex, from Group Health • Focus: diagnostic markers, molecular genetics, & epidemiological risk factors

  19. UW/Group Health Alzheimer’s Disease Patient Registry (ADPR) • Examples of ADPR Research: • Diagnostic marker studies: PMF, skin biopsy amyloid, Alpha 1-antichymotrypsin, apoE • Risk factor studies: solvents, head trauma, depression • Care patterns: symptom reporting, visits • Setting for intervention studies

  20. Prediction of Mortality in Recently Diagnosed Patients with Probable Alzheimer’s Disease Longitudinal follow-up study of 327 newly diagnosed AD patients in a large, stable HMO (median 3.3 years; total 898 person-years) • Patients with AD had increased mortality (9.0 Deaths/100 patient-years vs. 4.3 in age, sex, adjusted community population) • Measures of dementia severity & general debility (especially sensory impairment) & vascular disease were associated with shortened survival. Bowen et al: Neurology 1996;47:433-439

  21. Do Surgical Brain Lesions Present as Isolated Dementia? Population based case series of clinically important subdural hematoma, hydrocephalus not associated with recent bleed, and intracranial tumor not obviously metastatic. Alexander et al: JAGS 1995; 43:138-143

  22. Do Surgical Brain Lesions Present as Isolated Dementia? Over 4.5 years and based on 137,100 person years, average annual incidence was 46.7/100,000 for SDH, 5.8 for hydrocephalus and 53.2 for tumors. Only 59 of 145 presented with cognitive impairment. Alexander et al: JAGS 1995; 43:138-143

  23. Do Surgical Brain Lesions Present as Isolated Dementia?

  24. The Evolution of Community Based Dementia Research in Seattle • Phase Four: Inception Cohort Studies • Group Health N = 2,581 (1994-96) • Non-demented followed every 2 years • Replenishing Cohort N = 852 (2000-02) • Replacement Strategy 2005 --

  25. Phase Four: Inception Cohort Studies • Japanese Americans in King County (1991-2002) • Kame N = 1,900 • Non-demented followed every 2 years; demented every year until death

  26. Age 65 - 69 70 - 74 75 - 79 80 - 84 85 - 89 90 - 94 95+ Rate .8 % 1.4 % 6.3 % 12.7 % 29.7 % 50.2 % 74.3 % Prevalence Rates - Dementia(Kame Project, Seattle 1996)

  27. The Adult Changes in Thought study: Incidence Rate Setting: A random sample of persons enrolled between 1994-96 from a base population of about 23,000 older adults who were members of Group Health Cooperative in Seattle • Sample: 2581 persons who at the time of enrollment were dementia free and not institutionalized; Followed every two years. • Outcomes: Six years follow-up of 2356 subjects with at least one follow-up; • Overall results: 215 cases of dementia; 146 diagnosed as possible or probable Alzheimer's Disease Kukull et al; Arch Neurol 2002;59: 1737-46

  28. Note: The rate is a log scale

  29. Age and Incidence of Alzheimer’s Disease Figure 3. Age and the incidence of Alzheimer disease in 6 studies compared with the Adult Changes in Thought (ACT) cohort study. EURODEM indicates European Studies of Dementia18; MoVIES CDR >0.5, MoVIES Clinical Dementia Rating 0-5 or greater, Monongahela Valley Study10; Rochester, Rochester, Minn, study2; Framingham, Framingham, Mass, study3; East Boston, East Boston, Mass, study41; and Baltimore Longitudinal Aging Study, the Baltimore Longitudinal Study of Aging,5 Baltimore, Md. Walter A Kukull;Dementia and Alzheimer Disease Incidence; Arch Neurol 2002;59, 1737–46;

  30. Age and Sex specific Rates of Dementia Results for Alzheimer's disease were similar but above 90 the incidence rates observed were not stable due to very small sample size in men. Table 4. Age – and Sex-specific rates of dementia, Alzheimer Disease (AD), and non-AD Dementia Cases per 1000 person-years of Observation*

  31. Summary from ACT and from Most Subsequent, Similar Studies Based in Community Populations The number of women affected by AD and related dementias in the U.S. is greater compared to men. That difference, though is not explained by increased risk. Rather because women live longer they are more likely to experience the greater risk of AD and related dementia that occurs with age in greater numbers. Overall the age-related risk of AD and related dementia is not different in women compared with men. Age is the most significant risk for AD and related dementias.

  32. Survival after Initial Diagnosis of Alzheimer's Disease (Larson et al: ANNALS of IM 2004;140:501-509) N = 521 newly diagnosed cases Median Survival: 4.2 years (men); 5.7 years (women) Effects on mortality greatest at younger age of onset Associations: Increased severity of impairment, decreased functional level, history of falls, frontal release signs, abnormal gait and more rapid decline in the year after diagnosis Value: Normative, prognosis and decision making

  33. Footwear Style & Risk of Falls in Older Adults (Koepsell et al: JAGS 2004;52:1-7) N = 1371 monitored for falls for 2 years; 327 cases and 327 controls Athletic and canvas shoes had lowest risk OR: 5.5 for stocking feet; infinity for barefoot; Shoeless adjusted OR = 11.2 (2.4-51.8) Trip or slip? Definitely slip and contrary to findings from gait laboratory studies, athletic shoes associated with relatively low of falls Value: Sid Wolfe (Public Citizen) wrote Tommy Thompson asking that these findings be mailed to all persons in the US with their Social Security checks!!

  34. Cohort Studies: Risk Factors for Cognitive Decline • Chronic disease risk factors: cardiovascular (e.g., exercise, insulin resistance) • Brain reserve: education, leisure time activities • Pharmacoepidemiology: antioxidants, NSAIDS, H2 blockers, others • Mixed dementia and correlation of risk factors with pathologic findings

  35. Evolution of Community Based Studies • Lessons Learned: • Simple observations from descriptive studies in more representative population were valuable, are enduring • Many findings in referral, convenience samples, not reproducible • Alzheimer’s disease, dementia, cognitive impairment—common source of disability, but especially after age 80

  36. World Wide Populations Are Aging • Previous: As mortality decreased demographers and actuaries assumed we were approaching an upper limit of life expectancy. At the upper limit "old age" set in; nothing could be done • More recent evidence indicates POSTPONEMENT OF MORTALITY is widespread • Rather than sensecence being inevitable in multi-cellular species, biodemography suggests greater variations in patterns of aging. • No evidence for an upper limit of life expectancy

  37. News Headlines • Overview: Widespread aging of populations in both developed and developing world has resulted in dramatic increases in persons with AD and related dementias. These trends will challenge social and economic welfare for most countries. The trends may also be seen as welcome for individuals and what they can contribute. • Widespread variation in patterns of aging exist. This widespread variation is a challenge to clinicians but can also be a clue to opportunities for optimization and suggest that senescence need not be considered inevitable. • Primary prevention trials have been disappointing but at least three epidemiologic studies suggest there may already be delayed onset of dementia. • AD or Multi-infarct dementia? Not the dichotomy typical of early onset dementia but variation is key with the complex "ecology" of the aging brain being an individually varying complex convergence of clinical and subclinical diseases (AD, vascular and Lewy Body diseases) • No treatment to date has been proved effective at reducing or removing plaques and tangles. Multiple risk factors for dementia have been identified, many of which are modifiable. • The burden of aging is great for individuals and for societies. Better health of our aging populations may have already relieved the burdens of aging and could be mobilized for further good.

  38. Postponement of Mortality • More people living to 100 - Sweden: 3 in the 1860; 750 in 2008 and of those born in 2007 50-60,000 expected to live to 100 • More people living to each progressive old age milestone: 85, 90, 95. This is driven by progressive increases in survival past age 65, 75 and beyond • Overall we see a postponement of senescence, occurring later in life • "Two scourges of old age are cognitive impairment, often due to Alzheimer's disease and Sensory deprivations" (Vaupel, 2010)

  39. Forecast of Dementia Prevalence Worldwide 2040 2001 2020 42.3 Million Prevalence: 24.3 Million 81.1 Million Ferri, et al. Lancet, 2005

  40. Disappointing Primary Prevention Trial Results • Antioxidants: AREDS, Women’s Health Study, Physicians Health study, Health Protection Study: no consistent benefit • Estrogen: HERS, WSHIMS, COGENT: neutral or harmful • Ginkgo Biloba: GEMS, GuidAge: neutral • NSAIDS:ADAPT (naprosyn and celebcoxib): stopped due to harm

  41. Results of Analyses of Existing Data on Rates of Dementia • Are we already seeing cohort effects of potentially modifiable risk factors: better education, greater wealth, reduced vascular risk? • Manton (2005): National Long Term Care Survey Data (1982-1999) Decline in Severe Cognitive impairment - 5.7-2.9% • Langa et al (2008): U.S. Health and Retirement Study (1993-2002): Compression of Cognitive Morbidity - Prevalence of cognitive impairment - 12.2-8.7%; Higher 2-year mortality in those with cognitive impairment • Schrijvers et al (2012) Rotterdam study suggests incidence of dementia decreased between 1990 and 2005 as did atrophy on MRI associated with better education and control of vascular risk. Rocca et al (2011 reported similar decline (3%/yt) between 1985 and 1984.

  42. Convergence of Neuropathologic Processes in Late-Life • Early efforts, especially when we saw a "younger" population with dementia, were to distinguish AD from vascular dementia (VD). • Key observation: Skoog's 1993 paper describing causes of dementia in 85 yo in Sweden: almost 50% had VD (higher rates in older persons observed originally by Blessed, Tomlinson, and Roth (1970). • Our neuropathologic study (Lim 1999) described community-based autopsy results for persons with AD. NINCDS clinical criteria were quite accurate but of the 95 of 135 cases with neuropathologic AD only 34 had "pure" AD, with remainder having coexisting vascular or Lewy body lesions. • The general trend is for increasing recognition of the importance of "mixed dementias" in late-life dementias even though our efforts in research are to categorize persons into one or the other disease entity.

  43. What Does the Ecology of the Aging Human Brain Tell Us? Unique study: "Ecology of the Aging Human Brain" (Sonnen, 2011) Montine/Sonnen neuropathology lab accumulated 1672 brain autopsies from ACT, HAAS, Nun Study and Oregon Brain Aging Study); 424 met criteria for being cognitively normal at time of death. Results: 47% had moderate to frequent NP density (6% had Braak stage V or VI for NFTs; 15% had medullary Lewy Body disease; 8% and 4% respectively had nigral and isocortical LBD; Cerebral microinfacts were identified in 33% with a high level in 10%. Overall burden of lesions in each individual and their co-morbidity varied widely within each study but was similar among studies. Conclusion: The data show an individually varying complex convergence of subclinical diseases in the brains of older cognitively normal adults. This ecology should help guide biomarker, neuroimaging studies as well as clinical trials that focus on community, and population-based cohorts.

  44. Brain Autopsy Results in 336 Cognitively Normal Subjects Expressed as Summary Neuropathology Slopes

  45. Biodynamics of Aging (2012): Rising Tide of Dementia and Ecology of Aging Brains • Mortality is being postponed; populations are older. • Senescence is not inevitable; biodemography suggests great(er) variations in patterns of aging. • Several neurodegenerative processes commonly occur (together) in late life: in persons without impairment and in those with dementing disorders - another source of variation. • Sources of variation can be basis for prospects for prevention. • What is the evidence for potentially modifiable risk factors for late life dementias?

  46. Potential Impact of Risk Factor Reduction Since no treatment to date has yet been proved effective for reducing plaques and tangles, there may be no "magic bullet" for aging and dementia. What about projected impact of Risk factor reduction? 7 modifiable risk factors analyzed (Barnes and Yaffe, Lancet Neurology 2011): • Cardiovascular disease risk factors (hypertension, lipids, smoking) • Obesity/metabolic dysregulation: • Depression • Physical activity • Low education

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