Lessons from the Oldest Old: The 90+ Study · • KCAL 9 TV 2013 ... AD=Intermediate/High NIA Reagan Criteria None or Insufficient Pathology 40% AD Pathology 60% None or Insufficient

9/10/2018

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Lessons from the

Oldest Old: The 90+ StudyDana Greenia, R.N., M.S.

Co-Investigator

Western Region Chapter

Aging Life Care Association

28th Annual Conference

September 21, 2018Clinic for Aging Research and Education

Institute for Memory Impairments & Neurological Disorders

University of California, Irvine

Madame Jeanne-Louise CalmentArles, France

1875 – 1997Age 122

Madame Jeanne-Louise Calment

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Supercentenarian

If increases in life expectancy continue,

more than half of all children born

today in developed countries can

expect to celebrate their 100th

birthdays

Christensen, Ageing Populations: The Challenges Ahead, Lancet , 2009

Overview

1. The 90+ Study

2. Factors that promote longevity

3. Incidence and Risk Factors for Dementia in the Oldest Old

4. Clinical Pathological Correlations for Dementia

5. Describe the Relationship between Exercise and Falls in 90+ year olds

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U.S. Projected Population GrowthAmong 90+ Year Olds

Population Projections U.S. Census Bureau 2002, Middle Series

0

2,000,000

4,000,000

6,000,000

8,000,000

10,000,000

2001 2010 2020 2030 2040 2050

Year

Mill

ion

s o

f P

eop

le

Age-Specific Incidence of Dementia in Studies with Subjects Aged 90+

The Relative Frequency of

“Dementia of Unknown Etiology” Increases with

Age and is Near 50% in Nonagenarians

• Series of 128 subjects

• Dementia of unknown etiology

– 5% of all cases dying in their 70’s



Crystal, et al, Arch Neurol 2000

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Unknown in 90+ Year Olds

• Risk/Protective Factors Related to Longevity

• Prevalence and Incidence of Dementia

• Risk/Protective Factors Related to Dementia

• Types of Dementia

The Leisure World Cohort StudyUSC

• Prospective Cohort Study Design• Residents of Southern California Retirement Community• 13,978 Enrolled 1981-1985

- Primarily white

- 2/3 female

- Median age at enrollment: 73 years- Well-educated

• Follow-up Surveys1983, 1985, 1992, 1998

The 90+ Study

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UCI Clinic for Aging Research and Education Laguna Woods, CA

The 90+ Study

• 2003: ~ 1,140 survivors of the Leisure World Cohort (13,978 were enrolled) aged 90 years old and older were invited

• Today we have a total of 1,882 participants enrolled • Participants evaluated every 6 months

• neuropsychological tests• physical and neurological examinations • Neuroimaging – Brain Pet scans & MRIs

• Many enrolled in The 90+ Autopsy Study

Assessments• Intake

– Demographics & Medical History

• Neuropsychological Tests

– Memory, Language, Executive function

• Neurological Examination

• Informant Questionnaires

• Genetic studies

– DNA

• Brain Donation

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Physical Performance Measures

The 90+ Study ParticipantsBaseline Results

# of Participants 1882

EducationCollege grad or more 41%

Marital StatusWidowed 77%

Married 14%

% of Women

Mean Age 96Type of Residence

Nursing or group home 40%

Assisted Living 30%

Home alone 30%

Neurological Exam Cognitive Diagnosis Women Men

Normal

Cognitively Impaired, not Demented

Demented

76%

33% 43%

26% 33%

41% 24%

• Russia-2 TV Documentary 2012 • Newport Beach Daily Pilot 2010• Bottom Line Health magazine 2010• New York Times front page 2009• Louie B. Free radio program 2009 • Los Angeles Times front page 2004• KCET Life & Times 2003• My Generation Magazine 2015

• 60 minutes Australia May 2015• CBS 60 minutes May 2014 • Good Day LA 2014 • OC Register Jan, Oct & Nov 2013• KCAL 9 TV 2013• NPR Radio 2012• Italian Public TV 2012• Laguna Woods Globe 2012

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Research Goal

To study potentially modifiable risk factors that may contribute to the

prevention or the delay of the development of Alzheimer’s disease

and dementia

# of participants

719

16

6

4

3

2

9

1

35 States Traveled To Visit Participants

5

Frequency of Medical Histories at Baseline

7

8

11

14

13

15

18

20

21

22

27

29

29

39

43

51%

Diabetes

Rheum Arthr

MI

CAD

Stroke

CHF

Glaucoma

Depression

TIA

Atrial Fib / Arryth

Thyroid

High Chol

Macular Degen

Cancer

Osteoarthritis

HBP

12/2012

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What is Related to Longevity?

Vitamins, Beverages and Longevity

• Vitamin C (diet + supplements)• Vitamin A (diet + supplements)• Vitamin E (supplements)• Calcium (diet)• Soft drinks (cola & other)• Tea (black or green)• Body Mass Index• Activities - Exercise • Activities - Leisure• Caffeine• Alcohol (wine, beer, other)

Corrada 2006; Paganini-Hill 2007, 2011,2015

Studies of Factors Associatedwith Longevity

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BMI and All-Cause MortalityLeisure World Cohort: 1981-2004

-10

0

10

20

30

40

50

60

70

Ch

an

ge i

n R

isk (

Perc

en

t)

BMI at Baseline (Avg Age 73)

BMI at Age 21

BMI Categories

+53%

-3%

+12%

+2%

+15%

Corrada, et al. Am J Epidemiology 2006

N = 13,451

‘Active’ Activities and MortalityLeisure World Cohort: 1981-2004

N = 13,601

-35

-30

-25

-20

-15

-10

-5

0

5

None 15 min 30 min 45 min 1-1.75hrs 2-2.75 hrs 3+ hrs

Ch

an

ge i

n R

isk (

Perc

en

t)

Time Spent per day

‘Active’ Activities Swimming

Biking

Jogging

Tennis

Vigorous walking

Exercising

Dancing-11%

-18%

-24% -25%-23% -22%

‘Other’ Activities and MortalityLeisure World Cohort: 1981-2004

N = 13,601

-40

-35

-30

-25

-20

-15

-10

-5

0

5

0-45 1-1.75 hrs 2-2.75 hrs 3-3.75 hrs 4-4.75 hrs 5-5.75 hrs 6+ hrs

Ch

an

ge i

n R

isk (

Perc

en

t)

Time Spent per day

‘Other’ Activities

-17%

-21%-22%

-25%-26%

-30%

SightseeingFishingGolfGardeningReadingSewingCraftsBoard gamesTheaterConcerts

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Intake of Alcohol and Caffeine

Alcohol (wine, beer, other)

1-2 glasses of alcohol a day reduction in mortality up to 18%

Caffeine

Equivalent to ~2 cups of coffee a day reduction in mortality of 10%

Paganini-Hill, et al. Age & Ageing 2007; Preventive Medicine 2007

What is related to Dementia in the

Oldest-Old

?

What is Dementia?

• A decline in mental ability severe enough to interfere with daily life

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52

8%

2%

2%

4%

14%

17%

Causes of Dementia in the Elderly

Alzheimer’s

Disease

Vascular

Dementia

Lewy Bodies

Mixed Dementia (both AD and

minor strokes)

Fronto-temporal

Parkinson’s disease

Other



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AgingThe Elephant in the Room!

Age is the biggest risk factor for dementia

Oldest old have the highest rates of dementia

Cross-sectional Investigations of Risk

Factors and Dementia

• Vitamin E (supplementation)

• Vitamin C (diet and supplementation)

• BMI

• Alcohol

• Caffeine

• Activities

• Homocysteine levels

• Thyroid function

Vascular Risk Factors andPrevalent Dementia

Vascular risk factors did not distinguish demented and non-demented participants

except hypertension

46% Hypertension

12% Coronary Artery Disease

12% Myocardial Infarction

17% Congestive Heart Failure

22% Atrial Fibrillation

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Background

• Cardiovascular diseases in midlife are commonly associated with an increased risk of dementia later in life. (Kivipelto, Brit Med J 2001; Whitmer, Neurology 2001; Launer, Neurobiol

Aging 2000)

• In contrast, history of hypertension in the oldest-old is associated with a decreased risk of dementia. (Li G, JAGS

2007; Ruitenberg, Geriatr Cogn Disord 2001; MM Corrada, Alzheimers Dement. 2014)

• Whether the apparent change in risk with age is unique to hypertension, or other cardiovascular risk factors behave in a similar manner, is not known.

Prevalence of Cardiovascular Risk Factors at Baseline

6

7

10

10

12

15

15

27

36

58

0 10 20 30 40 50 60

Diabetes

Heart Valve Disease

Congestive Heart Failure

Stroke

Myocardial Infarction

Coronary Artery Disease

Transient Ischemic Attack

Arrhythmia

High Cholesterol

Hypertension

Percent

0.730.78

0.90

1.201.29 1.32

1.53

1.72 1.72

2.15

0.5

Haz

ard

Rat

io (

95

% C

I) (

log

scal

e)

Cox regression adjusting for age (time scale), gender, & education.

Association between Cardiovascular Risk Factors& Risk of Dementia in the Oldest-Old (N=559)

1.0

3.0

2.0

58% 36% 15%27%15% 12% 6%

Prevalence

10% 7% 10%

Medical Histories Analyzed Separately

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0.73

1.72 1.72

2.15

0.5Hyper-tension

HighCholest

CoronaryArtery

Disease

Arrhyth-mia

TransientIschemic

Attack

MyocardialInfarction

Diabetes Stroke HeartValve

Disease

CongestiveHeart

Failure

Hazard

Ratio (

95%

CI)

(lo

g s

cale

)


Association between Cardiovascular Risk Factors& Risk of Dementia in the Oldest-Old (N=559)

58% 36% 15%27%15% 12% 6%

Prevalence

10% 7% 10%

1.0

3.0

2.0

0.74

1.681.60

2.23

0.5

Haz

ard

Rat

io (

95

% C

I) (

log

scal

e)

Association between Cardiovascular Disease& Risk of Dementia in the Oldest-Old (N=559)

Medical Histories Analyzed Together

58% 36% 15%27%15% 12% 6%

Prevalence

10% 7% 10%

1.0

3.0

2.0


Hyper-tension

HighCholest

CoronaryArtery

Disease

Arrhyth-mia

TransientIschemic

Attack

MyocardialInfarction

Diabetes Stroke HeartValve

Disease

CongestiveHeart

Failure

• In people who reach age 90+ without dementia:– Decreased risk - Hypertension

– Increased risk - Congestive heart failure, stroke, and heart valve disease

• The association with dementia changes with age for some but not all vascular diseases.

Conclusions

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• Our results are consistent with other studies

• Hypertension at older ages may be necessary to sustain adequate cerebral perfusion in the oldest-old

• Survival bias is an unlikely explanation for the association between hypertension and a decreased risk of dementia; finding is specific to hypertension and not other vascular diseases.

Discussion

Qiu, Winblad, & Fratiglioni, Lancet Neurol, 2005; Jani and Rajkumar, Post Grad Med J, 2006; de la Torre, Stroke, 2002; Siennicki-Lantz et al., Eur. J. Neurol, 2007

Risk of Dementia in Relation toAge of Onset of Hypertension

1.00

0.88

1.13

0.59

0.45

0.2

2.0

No hx <70 70-79 80-89 90+

Rel

ativ

e R

isk

(95%

CI)

(lo

g sc

ale)

Age of Onset of Hypertension

1.0

low

er r

isk

hig

her

ris

k

Adjusted for age & education Corrada, et al. AAIC 2014

Blood Pressure & DementiaPotential Interpretations

1. “Normal” blood pressure may be different for 90+ year olds

2. Elderly torturous cerebral vessels may require increased pressure for adequate perfusion

3. Low blood pressure may be a marker for other diseases

4. Medication effects – ACE-inhibitors, Ca-channel blockers, others

5. Differential medical care

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The 90+ Autopsy Study

Enrolled 506

Longitudinal follow-up every 6 months

305 have come to autopsy

90+ Autopsy Study Participants

Not Demented Demented

Median

Age (years) 97 97

MMSE 27 12

Brain Weight (g) 1150 1117

Normal BrainAlzheimer’s Brain

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AD Pathological Features

Neuritic Plaques

Extracellular depositsof beta-amyloid

Neurofibrillary Tangles

Intracellular deposits of hyperphosphorylated tau

Pathological Diagnoses by Dementia Status

No Dementia(N=85)

Dementia(N=98)

AD=Intermediate/High NIA Reagan Criteria

None or InsufficientPathology

40%

ADPathology

60%

None or InsufficientPathology

58%

ADPathology

42%

Other pathologies that may contribute to dementia in the

oldest old

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Lewy Body

H&E stained sections of frontal cortex at 200x magnification. A single microinfarct is shown (black arrows) characterized by loss of neurons and neuropil, central cavitation with foamy macrophages and linear extension into deeper layers of cortex. There is subpial sparing of cortical layer I (pink arrow) due to a different arterial supply (meningal arteries vs. deep penetrating cerebral arteries). Scale bar is approximately 70 microns.

200x

J Sonnen collaboration

Microinfarcts

Hippocampal Sclerosis

Neuronal cell loss and gliosis in the CA1 and subiculum of the hippocampus

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Frequency of Dementia by Number of Pathologies (N=183)

Kawas, et al. (under revision)

OBJECTIVE

To explore the relationshipbetween risk of falling at age 90+ and physical activity at

ages 60-70s

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Methods

• Time spent exercising (at ages 60 -70s) was self-reported in 1980s and categorized as none, 15 minutes, 30-45 minutes, or 1+ hour / day.

• 1536 participants (or their informant) of The 90+ Study provided information on falls in the previous year.

• Mean age = 94 years; 78% female; 99% Caucasian

RESULTS

• 52% had fallen in the prior year

• 32% had fallen more than once

• 21% had had a severe fall

• Falling at age 90+ was significantly related to:

–Medical hx: heart disease, TIA/stroke, arthritis, vision disease, dementia, depression

–Medications: hypnotics, anti-psychotics, anti-depressants

–Assistive Devices: cane, walker, wheelchair

RESULTS

• Regular physical activity (30+ minutes /day) at ages 60 -70s was associated with a 35% lower odds of falling in the previous year at age 90+.

• Regular physical activity (30+ minutes /day) at ages 60 -70s was associated with a 45% lower odds of repeated falls in the previous year at age 90+ .

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Conclusion and Relevance

• Falls are extremely common among the oldest-old and often lead to serious injury.

• Prior exercise of 30+ minutes /day was related to a decreased risk of falling at age 90+ even the presence of co-morbidities, certain medications and assistive devices.

• This work is the first to show an association between exercise at ages 60 -70s and lower risk of falling at age 90+.

• Remarkable increase in longevity and numbers

of oldest old world-wide

• Risk of dementia continues to increase with age

• Risk factors change with age

• Multiple pathologies (and risk factors specific to

each) are likely to be important in the

development of dementia in aging

Summary

Did you hear? 95 is the new 65!

The Laguna Beach Independent - O’Malley - 2/1/08

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Acknowledgements

UCI Our CollaboratorsClaudia Kawas Tom Montine - Stanford UniversityMaría Corrada John Trojanowski - U PennAnnlia Paganini Hill Virginia Lee - U PennSandy Pittman Juan Troncoso - JHUNadim Madi Ronald Brookmeyer - UCLARonald Kim Charles DeCarli - UC DavisJaime DeMoss Josh Sonnen - U of UtahChristina WhittleZara MelikyanFarah MozaffarNatalie BryantSzofia BullainShawna PerryMaria KirkwoodColette AquirreMontez HesterMiyoung Kim

Supported by: NIA R01AG21055, P50AG016573, T32AG000096, and the Al and Trish Nichols Chair in Clinical Neuroscience

60 Minutes - May 4, 2014

The 90+ Study Team

.

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Documents

Lessons from the Oldest Old: The 90+ Study · • KCAL 9 TV 2013 ... AD=Intermediate/High NIA Reagan Criteria None or Insufficient Pathology 40% AD Pathology 60% None or Insufficient