Screening For Mild Cognitive Impairment And Alzheimer's Disease

Screening for Mild Cognitive Impairment and Alzheimer's Disease: Relevance of Age and APOE genotype

Senthamizhselvi.K 2nd M.Sc Bioinformatics SRMASC

Dementia Definition  Multiple

Cognitive Deficits:

 Memory

dysfunction especially new learning, a prominent early symptom  At least one additional cognitive deficit aphasia, apraxia, agnosia, or executive dysfunction

 Cognitive

Disturbances:

 Sufficiently

severe to cause impairment of occupational or social functioning and  Must represent a decline from a previous level of functioning

DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE (DSM-IV, APA, 1994)

A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS 1. MEMORY IMPAIRMENT 2, OTHER COGNITIVE IMPAIRMENT B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN IN SOCIAL OR OCCUPATIONAL ACTIVITIES C. COURSE SHOWS GRADUAL ONSET AND DECLINE D. DEFICITS ARE NOT DUE TO: 1. OTHER CNS CONDITIONS 2. SUBSTANCE INDUCED CONDITIONS F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM G. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER

BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD NEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS (Ashford, Mattson, Kumar, 1998; Teter, Ashford, 2002)

 SOCIAL

SYSTEMS

 INSTRUMENTAL

ADLs - EARLY  BASIC ADLs - LATE

 PSYCHOLOGICAL  PRIMARY

LOSS OF SHORT-TERM MEMORY

 LEARNING

 LATER

SYSTEMS

PROCESSES – CLASSICAL, OPERANT

LOSS OF LEARNED SKILLS

 NEURONAL

 CORTICAL

MEMORY SYSTEMS

GLUTAMATERGIC STORAGE  SUBCORTICAL  (acetylcholine, norepinephrine, serotonin)  CELLULAR PLASTIC PROCESSES  APP metabolism – early, broad cortical distribution 

TAU hyperphosphorylation – late, focal effect, dementia related

NEUROPATHOLOGY OF AD  Senile

plaques

beta-amyloid

protein (? Primary

problem)

 Neurofibrillary

tangles

hyper-phosphorylated

synapses, dementia)

 Neurotransmitter

tau (loss of

losses

Acetylcholine

(Ach) – major loss of nicotinic receptors Norepinephrine, serotonin, glutamate, GABAss

 Inflammatory

responses

New Neuropath Mechanisms 

Amyloid PreProtein (APP - ch21) (early changes)  metabolism occurs on cholesterol “rafts” Cholesterol transport by APOE (ch 19), provides, removes  alpha-secretase vs beta/gamma secretase metabolism  influence toward alpha-secretase by Acetylcholine  gamma-secretase (PreSenilin genes, ch14,1)  break down - Insulin Degrading Enzyme (ch10), etc.  prevention of fibril formation by melatonin



Tau hyperphosphorylation (relation to dementia)

Differential Diagnosis: Top Ten (commonly used mnemonic device: AVDEMENTIA)

1. 2. 3. 4. 5. 6. 7. 8. 9. •

Alzheimer Disease (pure ~40%, + mixed~70%) Vascular Disease, MID (5-20%) Drugs, Depression, Delirium Ethanol (5-15%) Medical / Metabolic Systems Endocrine (thyroid, diabetes), Ears, Eyes, Environ. Neurologic (other primary degenerations, etc.) Tumor, Toxin, Trauma Infection, Idiopathic, Immunologic Amnesia, Autoimmune, Apnea, AAMI

Alzheimer’s Disease versus Dementia  50 - 70% of

dementias are due to AD  Probable AD - 30% of cases, 90% neuropath - correct 

20% have other contributing diagnoses

 Possible 

40% have other contributing diagnoses

 Unlikely 

AD - 40% of cases, 70% are AD at neuropath AD - 30% of cases, 30% are AD at neuropath

80% have other contributing diagnoses

 Alzheimer’s disease is a pathological condition  Dementia is a clinical condition frequently caused by AD  The AD dementia has some characteristics and some heterogeneity

UNDERLYING CONTINUUM OF ALZHEIMER SEVERITY (unidimensional) 

CROSS-SECTIONAL MEASURES 

DEMENTIA SEVERITY (cognitive, ADL)  COGNITIVE

SCALE SCORE

 Z-SCORE  PRINCIPAL COMPONENT

  



BRAIN ATROPHY, DYSFUNCTION AUTOPSY MEASURES: plaques, tangles TIME TO DEATH

LONGITUDINAL MEASUREMENT 



ANALYSIS

TIME INTO THE DISEASE PROCESS

CONSIDERABLE HETEROGENEITY IN DISEASE PRESENTATION AND BRAIN DISTRIBUTION

MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology) (Petersen et al., 2001 – Neurology 56:1133)

•

Memory complaint, preferably corroborated by an informant

•

Objective memory impairment Normal general cognitive function Intact activities of daily living

• •

MILD COGNITIVE IMPAIRMENT ISSUES IN DEFINITION (Petersen et al., 2001 – Neurology 56:1133)

Study

Mean Criteria Age

Annual conversion rate to AD % 12

Mayo

81

MCI

Toronto

74

Memory Impairment

14

Columbi a MGH

66

15

72

Questionable dementia CDR 0.5

Seattle

74

Isolated memory loss

12

NYU

71

GDS 3

25

6

ALZHEIMER’S DISEASE Estimate MMSE as a function of time

MMSE score

30 25 20 15 10 5 0 -10

-8

-6

-4

-2

0

2

4

6

8

10

Estimated years into illness

Ashford et al., 199

Age-Associated Memory Impairment vs Mild Cognitive Impairment      

Memory declines with age – need to consider relative to APOE genotype! Age - related memory decline corresponds with atrophy of the hippocampus Older individuals remember more complex items and relationships Older individuals are slower to respond Memory problems predispose to development of Alzheimer’s disease Thus --- screening for MCI / early AD must consider age! 

And should consider APOE genotype!

Early Recognition of AD: Consensus Statement (AAGP, AGS, Alzheimer’s Association)  AD continues to be missed as diagnosis  AD is unrecognized and under-reported patients do not realized families tend to compensate

 Effective treatment and management

techniques are available (AChEIs FDA approved) Several other Small et al., JAMA, 1997

approaches are beneficial

AD is Underdiagnosed  Early

Alzheimer’s disease is subtle – it is easy for family members and physicians to miss the initial signs and symptoms  Less than half of AD patients are diagnosed  Estimates

are that 25% to 50% of cases remain undiagnosed

 Undiagnosed

AD patients often face avoidable social, financial, and medical problems  Early diagnosis and appropriate intervention may lessen disease burden  No definitive laboratory test for diagnosing AD exists Evans DA. Milbank Quarterly. 1990; 68:267-289

AD Can Be Readily Diagnosed A

diagnosis of Alzheimer’s disease can be made with a high degree of certainty Using NINCDS-ADRDA criteria, accuracy in autopsy-verified cases is approximately 90% Diagnosis is a 2-step process: Detection through screening Confirmation through patient history and physical, caregiver interview, brain imaging, and appropriate laboratory

Assessment History Of The Development Of The Dementia       

Ask the Patient What Problem Has Brought Him to See You Ask the Family, Companion about the Problem Specifically Ask about Memory Problems Ask about the First Symptoms Enquire about Time of Onset Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery Ask about Nature and Rate of Progression

 Physical

Examination  Neurological Examination  Laboratory Tests  Neuropsychological / Cognitive

RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE  Family

history of dementia

4.6)  Family history – Downs  Family history - Parkinson’s  Maternal age > 40 years 2.9)  Head trauma (with LOC) 2.7)  History of depression  History of hypothyroidism

3.5 (2.6 2.7 (1.2 - 5.7) 2.4 (1.0 - 5.8) 1.7 (1.0 1.8 (1.3 1.8 (1.3 - 2.7) 2.3 Roca, 1994,(1.0 t’Veldt,-

NEUROPSYCHOLOGICAL TESTING (WAIS, WECHSLER)  MEMORY:

SHORT-TERM, REMOTE  VERBAL FUNCTION, FLUENCY  VISUO-SPATIAL FUNCTION  ATTENTION  EXECUTIVE FUNCTION  ABSTRACT THINKING  ACCOUNT FOR EDUCATION  ACCOUNT FOR PRIOR DISFUNCTIONS

BRIEF CLINICAL TOOLS FOR COGNITIVE ASSESSMENT         

MINI-MENTAL STATE EXAM CLOCK DRAWING ANIMAL NAMING (1 minute) MATTIS DEMENTIA RATING SCALE ALZHEIMER’S DISEASE ASSESSEMENT SCALE (ADAS) ACTIVITIES OF DAILY LIVING GLOBAL CLINICAL SCALE CLINICAL DEMENTIA RATING SCALE GLOBAL DETERIORATION SCALE / FAST

Justification for Brain Scan in Dementia Diagnosis  Differential

Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, Encephalomalacia  Confirmation of atrophy pattern  Estimation of severity of brain atrophy  MRI shows T2 white matter changes  Periventricular,

basal ganglia, focal vs confluent  These may indicate vascular pathology  SPECT,

PET - estimation of regions of physiologic dysfunction, areas of infarction  Helps family to visualize problem

Etiology 

Age (initial genesis vs response to stress)  Bigger factor than for mortality (a = 5 yrs vs 7.5 or 8.2 yrs)  Degree of natural vulnerability of neuroplastic (memory) systems  Stressor response (pathology - vulnerability during activity of repair mechanisms): trauma (head injury), vascular (stroke), surgery, loss, grief, etc.



Genetics (neuroplasticity related - amyloid and cell membrane)  Familial, early onset: APP (21), PS (14, 1) (less than 5%)  Late onset: APOE e4 (ch19) (?50% - 90% of AD)  relation to brain cholesterol metabolism? – cell membranes  APOE e2 may be most protective  many other candidate genes



Relation to vascular factors, cholesterol, BP

Genes and Alzheimer’s disease (60% - 80 % of causation) (all known genes relate to β amyloid)

 Familial

AD (onset < 60 y/o) (<5%)

 Presenilin

I, II (ch 14, 1)  APP (ch 21)  Non-familial

(late onset)

 APOE

studies suggest 40 – 50% due to ε 4  If ε2 is considered, may be 95% of causation  Population studies suggest 10 – 20% cause  Evolution over last 300,000 to 200,000 years  Clinical

 At

least 20 other genes

APO-E genotype and AD risk 46 Million in US > 60 y/o //// 4 Million have AD

(data from Saunders et al., 1993; Farrer et al., 1997)

GenT %pop %AD

#pop

E2/2

0.5M .004M 0.8%

.4 M

5.5M .18M 3.2%

1.5 M

1% 0.1% 4%

#AD

risk If all US

E2/3

12 %

E3/3

60%

35% 27.6M 1.4M 5.1%

2.3 M

E3/4

21%

42%

8.2 M

E4/4

2%

16%

9.6M 1.7M 18% .9M

.6M 67%

30.7M

Are we ready to do genetic testing to predict AD?  The

family members want it They consider recommendations against genetic testing to be “paternalistic”  Family members can make more powerful financial decisions based on this knowledge than the relevance of insurance companies implementing changes in actuarial calculations  Those at risk can seek more frequent testing This is the best opportunity for early recognition  Those at risk will be better advocates for research 

U.S. Census 2000 by age www.census.gov

Males, 138,053,563 Females, 143,368,343

2,500,000 2,250,000

# people

2,000,000 1,750,000 1,500,000 1,250,000 1,000,000

Total = 281,421,906 >60 = 45,809,291 >65 = 35,003,844 >85 = 4,251,678 >100= 62,545

750,000 500,000 250,000 0 0

10

20

30

40

50

Age

60

70

80

90 100

U.S. mortality by age - 1999

www.cdc.gov

Males, 1,175,460

45,000

Number of people

40,000

Females, 1,215,939

35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 0

10

20

30

40

50

Age

60

70

80

90

100

U.S. mortality rate by age 1999 CDC / 2000 census Males, 2t = 8.2yrs Females, 2t = 7.5 yrs Alzheimer incidence

1.0000

Yearly Hazard

0.1000 0.0100 0.0010 0.0001 0

JW Ashford, MD PhD, 2003

10

20

30

40 Age 50

60

70

80

90

100

Proportion of population

Probability Not Demented 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 50

60

70

80

Age

JW Ashford, MD PhD, 2003

90

100

# / yr

U.S. Alzheimer Incidence (4 million / 8yr) male=170,603

16000 14000 12000 10000 8000 6000 4000 2000 0

female=329,115

50

60

70

80 Age

JW Ashford, MD PhD, 2003

90

100

JW Ashford, MD PhD,

(Incidence for a to a + 1 year)

Proportion of population

Probability Not Demented 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

mean rate APOE 4/4 APOE 3/4 APOE 3/3 50

60

70

80

Age JW Ashford, MD PhD, 2003

90

100

Proportion / Year

U.S. AD Incidence by APOE (proportion of cases) 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

4/4 3/4 3/3

50

JW Ashford, MD PhD, 2000

60

70

Age

80

90

100

prob/ yr * live population

Probability of Dementia Onset APOE 4/4-M APOE 4/4-F APOE 3/4-M APOE 3/4-F APOE 3/3-M APOE 3/3-F

0.04 0.03 0.02 0.01 0 50

60

70

80

90

Age (single mortality correction) JW Ashford, MD PhD, 2003

100

Why Diagnose AD Early?  Safety (driving, compliance, cooking, etc.)  Family stress and misunderstanding (blame, denial)  Early education of caregivers of how to handle

patient (choices, getting started)  Advance planning while patient is competent (will, proxy, power of attorney, advance directives)  Patient’s and Family’s right to know  Specific treatments now available  May slow underlying disease process  May delay nursing home placement longer if started

earlier

Need for Better Screening and Early Assessment Tools  Genetic vulnerability testing (trait risk)  Vulnerability factors (education, occupation, head

injury)  Early recognition (10 warning signs)  Screening tools (6th vital sign in elderly)  Positive diagnostic tests

 CSF – tau levels elevated, amyloid levels low  Brain scan – PET – DDNP, Congo-red derivatives

 Mild Dementia severity assessments  Detecting early change over time  predicting progression, measuring rate

Need for a Brief Screening Test for Alzheimer’s Disease  Recent

evidence of benefits of anticholinesterase agents in the treatment of mild Alzheimer’s disease Improvement

of cognition Slowing of progression

Alzheimer Warning Signs Top Ten Alzheimer Association

1. Recent memory loss affecting job 2. Difficulty performing familiar tasks 3. Problems with language 4. Disorientation to time or place 5. Poor or decreased judgment 6. Problems with abstract thinking 7. Misplacing things 8. Changes in mood or behavior 9. Changes in personality 10. Loss of initiative

Available Screening Tests  MMSE

10 -- 15 min

 Too long

 7-Minute Screen

7 – 10 min

 Too complex

 Clock Drawing Test

2 – 4 min

 Not sensitive

 Mini-cog

3 – 5 min

 Complex scoring, unclear adequacy

 Memory Impairment Screen

4 min

 Need for slightly shorter, easier test

 (a suitably accurate test that takes less than

2 minutes is not available)

Anim als nam ed in 1 m in (m m s>19) - CERAD data set

percent of total

12 10 8 6 4 2 0 0

10

20

30

num ber of anim als nam ed Normal Controls, CS = 1, n = 386 Alzheimer patients, CS = 0, n = 380

40

Animals name d in 30 se conds (mms>19) 16

percent of total

14 12 10 8 6 4 2 0 0

5

10

15

number of animals named Normal Controls, n=386

JW Ashford, MD PhD, 2001

Mild Alzheimer Patients, n=380

20

25

Animal naming ROCs (AUC 15: 0.74; 30: 0.83; 45: 0.86; 60: 0.87) 100 90 80

13

70 Sensitivity (%)

15

14

.

17 8

11

10 7

12

60

16

9 animals in 15 secs

11 8

50 10 40

animals in 30 secs

6

animals in 45 secs

7

animals in 60 secs

5

30 20 10 0 0

10

20

30

40

50

60

False Positive Rate (%)

70

80

90

100

Brief Alzheimer Screen (BAS)   

Repeat these three words: “apple, table, penny”. So you will remember these words, repeat them again. What is today’s date?  D = 1 if within 2 days.



Spell the word “WORLD” backwards  S = 1 point for each word in correct order



“Name as many animals as you can in 30 seconds, GO!”  A = number of animals



“What were the 3 words I asked you to repeat?” (no prompts)  R = 1 point for each word recalled

BAS = 3 x R + 2/3 x A + 5 x D + 2 x S

90 80

Mild AD

Percent of Validation Sample

70

Control

60 50 40 30 20 10 0

3-22

JW Ashford, MD PhD, 2001

23

24

25

BAS Score

26

27-39

Mendiondo et al., 2004

BRIEF ALZHEIMER SCREEN (Normal vs Mild AD, MMS>19)

20

True Positive Rate (%) (Sensitivity)

100 27

90

26 25

80

14

13

12

11 10

70

9

60 8

50 40

97

30

6

20 10

animals 1 m

AUC = 0.868

animals 30 s

AUC = 0.828

MMSE

AUC = 0.965

Date+3 Rec

AUC = 0.875

BAS

AUC = 0.983

0 0

10

20

30

40

50

60

70

80

False Positive Rate (%) (1-Specificity) JW Ashford, MD PhD,

90 100

CONCLUSIONS on the BAS 

A single cut-off score provides reasonable sensitivity and specificity for the diagnosis of AD within 2 – 3 minutes



Two cut-off points divide the population into 3 tiers  the first cut-off indicates a low likelihood of dementia  the second indicates a high likelihood of dementia  the remaining group falls into a ‘gray area’ in need of closer scrutiny, follow-up, and more extensive testing



A suitably short screen can be administered yearly to individuals over 60 y/o as a 6th vital sign



Next direction – use of IRT to locate level of impairment

BLT/Ashford Memory Test (to detect AD onset)  New test to screen patients

for AD:

 World-Wide Web – based testing,  CD-distribution  KIOSK administration

 Determine level of ability / impairment  Test takes

about 1-minute  Test can be repeated often (e.g., quarterly)  Any change over time can be detected  Test is at: www.ibaglobal.com/BLT  For info, new tests, see: www.medafile.com, www.brainlane.net

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