Diagnosis of Azlheimer'S Disease

Diagnosis of Azlheimer'S Disease

MILD COGNITIVE IMPAIRMENT DIFFERENTIAL DIAGNOSIS J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimers Center VAMC, Palo Alto, California May 14, 2004 MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology) (Petersen et al., 2001 Neurology 56:1133) 1. Memory complaint, preferably corroborated by an informant 2. 3. 4. 5. Objective memory impairment Normal general cognitive function Intact activities of daily living Not demented - Earlier descriptions by:

Jonker, Hooyer, 1990 Flicker, Ferris, Reisberg, 1991 Zaudig, 1992 MILD COGNITIVE IMPAIRMENT ISSUES IN DEFINITION (Petersen et al., 2001 Neurology 56:1133) Study Mean Criteria Age Annual conversion rate to AD % Mayo 81 MCI

12 Toronto 74 Memory Impairment 14 Columbi a 66 Questionable dementia 15 MGH

72 CDR 0.5 Seattle 74 Isolated memory loss 12 NYU 71 GDS 3 25 6 100%

90% 80% Percentage 70% 60% AD MCI Non-Affected 50% 40% 30% 20% 10% 0% Markov Chain model Age

Yesavavage et al., 2002 ALZHEIMERS 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 AAMI / MCI 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 Alzheimers disease Thus --- screening for MCI / early AD must consider age! And should consider APOE genotype! Early Recognition of AD: Consensus Statement (AAGP, AGS, Alzheimers 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 approaches are beneficial Small et al., JAMA, 1997


mixed~70%) 2. Vascular Disease, MID (5-20%) 3. Drugs, Depression, Delirium 4. Ethanol (5-15%) 5. Medical / Metabolic Systems 6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ. 7. Neurologic (other primary degenerations, etc.) 8. Tumor, Toxin, Trauma 9. Infection, Idiopathic, Immunologic 10. Amnesia, Autoimmune, Apnea, AAMI 11. VA consider PTSD, Gulf War Syndrome 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 Alzheimers Disease versus Dementia 50 - 70% of dementias are AD Probable AD - 30% of cases, 90% correct 20% have other contributing diagnoses Possible AD - 40% of cases, 70% correct 40% have other contributing diagnoses

Unlikely AD - 30% of cases, 30% are AD 80% have other contributing diagnoses Vascular Dementia (DSM-IV - APA, 1994) A. Multiple Cogntive Impairments 1. Memory Impairment 2. Other Cognitive Disturbances B. Deficits Impair Social/Occupational C. Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Related to the Deficits D. Not Due to Delirium Factors Associated with Multi-infarct Dementia History of stroke (especially in Nursing Home) Followed by onset of dementia within 3 months Abrupt onset, Step-wise deterioration

Cardiovascular disease - HTD, ASCVD, & Atrial Fib Depression (left anterior strokes), personality change More gait problems than in AD MRI evidence of T2 changes (?? Binswangers disease) Basal ganglia, putamen Periventricular white matter SPECT / PET show focal areas of dysfunction Neuropsychological dysfunctions are patchy SCORE VASCULAR DEMENTIA CHANGE ON THE MINI-MENTAL STATE EXAM OVERTIME 30 20 10 0 < event < event < event -5 0 5 AVERAGE TIME OF ILLNESS (years) 10 Post-Cardiac Surgery 53% post-surgical confusion at discharge (delirium) 42% impaired 5 years later (dementia) May be related to anoxic brain injury, apnea May be related to narcotic/other medication May occur in those patients who would have developed dementia anyway (? genetic risk) Cardio-vascular disease and stress may start Alzheimer pathology Any surgery may have a similar effect related to

peri-op or post-op anoxia or vascular stress Newman et al., 2001, NEJM Drug Interactions Anticholinergics: amitriptyline, atropine, benztropine, scopolamine, hyoscyamine, oxybutynin, diphenhydramine, chlorpheniramine, many anti-histaminics May aggravate Alzheimer pathology GABA agonists: benzodiazepines, barbiturates, ethanol, anti-convulsants Beta-blockers: propranolol Dopaminergics: l-dopa, alpha-methyldopa Narcotics: may contribute to dementia Drug Toxicity Anti-cholinergic Peripheral: blurred vision, dry mouth, constipation, urinary obstruction Central: confusion, memory encoding block Gaba-agonist:

Muscle relaxant, anti-convulsant, sedative, anti-anxiety, amnesic, confusion Medication induced electrolyte imbalance Confusion (watch for in nursing home) Depression Onset: rapid Precipitants: psycho-social (not organic) Duration: less than 3 months to presentation Mood: depressed, anxious Behavior: decreased activity or agitation Cognition: unimpaired or poor responses Somatic symptoms: fatigue, lethargy, sleep, appetite disruption Course: rapid resolution with treatment, but may precede Alzheimers disease Delirium Definition (more often a problem in medical in-patients)

Disturbance of consciousness i.e., reduced clarity of awareness of the environment with reduced ability to focus, sustain, or shift attention Change in cognition (memory, orientation, language, perception) Development over a short period (hours to days), tends to fluctuate Evidence of medical etiology Delirium Susceptibility may be symptom of early dementia, or delirium may predispose to later dementia Predisposing factors - Age, infections, dementia Medical conditions

Infections: G.U. - urinary Respiratory (URI, pneumonia) G.I. Constipation Drug toxicity Fracture (especially related to hip fracture) Ethanol Possibly Neuroprotective May not kill neurons directly (?Dietary recommendation?) Accidents, Head Injury Dietary Deficiency Thiamine Wernicke-Korsakoff syndrome Hepatic Encephalopathy Withdrawal Damage (seizures) Delayed Alcohol Withdrawal Watch for in hospitalized patients Chronic Neurodegeneration

Cerebellum, gray matter nuclei Medical / Endocrine Thyroid dysfunction Hypothyoidism elevated TSH Compensated hypothyroidism may have normal T4, FTI Hyperthyroidism Apathetic, with anorexia, fatigue, weight loss, increased T4 Diabetes

Hypoglycemia (loss of recent memory since episode) Hyperglycemia Hypercalcemia Nephropathy, Uremia Hepatic dysfunction (Wilsons disease) Vitamin Deficiency (B12, thiamine, niacin) Pernicious anemia B12 deficiency, ? homocysteine Eyes, Ears, Environment Must consider sensory deficits might contribute to the appearance of the patient being demented Central Auditory Processing Deficits (CAPD) Hearing problems are socially isolating Visual problems are difficult to accommodate by a demented patient, ?To do cataract op? Environmental stress factors can predispose to a variety of conditions Nutritional deficiencies (tea & toast syndrome) Neurological Conditions Primary Neurodegenerative Disease

Diffuse Lewy Body Dementia (? 7 - 50%) Note relation to Parkinsons disease, symptoms Hallucinations, fluctuating course, neuroleptic hypersensitivity) Fronto-temporal dementia (tau gene) Impaired attention, behavioral dyscontrol Decrease blood flow, hypometaboism on SPECT / PET (Picks disease, Argyrophylic grain disease) Focal cortical atrophy Primary progressive aphasia (many causes) Unilateral atrophy, hypofunction on EEG, SPECT, PET Normal pressure hydrocephalus Dementia with gait impairment, incontinence Suggested on CT, MRI; need tap, ventriculography Other Neurologic Conditions Subdural hematoma Huntingtons disease Creutzfeldt-Jakob disease

Rapid progression Characteristic EEG changes Multiple sclerosis Corticobasal degeneraton Cerebellar degeneration Progressive supranuclear palsey Tumor Primary brain tumor Meningioma (treatable) Glioma (usually not responsive to therapy) Metastatic brain tumor Remote effects of carcinoma Toxins Heavy metal screen if considered

Trauma Concussion, Contusion Occult head trauma if recent fall Subdural hematoma Hydrocephalus: Normal pressure (late effect of bleed) Dementia pugilistica Possible contributor to Alzheimers disease initiation and progression (? 4% of cases) Concern re: physical abuse by caretakers Infectious Conditions Affecting the Brain

HIV Neurosyphilis Viral encephalitis (herpes) Bacterial meningitis Fungal (cryptococcus) Prion (Creutzfeldt-Jakob disease); (mad cow disease) AMNESIC DISORDER DSM-IV A. Memory impairment - inability to learn new information, or - Inability to recall previously learned information Memory disturbance significantly impairs social, occupational function, deterioration from past Memory not due to delirium, dementia Physiological basis or substance induced - Distinguish from dissociative disorders, dissociative amnesia, dissociative identity disorders

Specify - Transient less than 1 month - Chronic - more than 1 month Causes of Amnesic Disorders Amnesia Dissociative: localized, selective, generalized Organic - damage to CA1 of hippocampus thiamine deficiency (WKE), hypoglycemia, hypoxia Epileptic events Partial complex seizures Specific brain diseases Transient global amnesia Multiple sclerosis Etiology of Alzheimers Disease

Age (initial genesis vs response to stress) Bigger factor than for mortality Design in a plastic (memory) system, energy demands Stressor response (inadequate repair mechanisms) Trauma (head injury), vascular (stroke), surgery, loss, grief, immunological response, etc. Genetics (amyloid related) Familial, early onset: APP (21), PS (14, 1) (less than 5%) Late onset: APOE e4 (ch19) (40% to 90% of AD) relation to brain cholesterol metabolism? APOE e2 may be most protective many other candidate genes Relation to vascular factors, cholesterol, BP Education (? design vs protection) Environment - diet, exercise, toxin, smoking, infectious agent AD Is Often Misdiagnosed Patient initially diagnosed with AD Patients first diagnosis other than AD 35%

14% 14% No 72% 9% 7% Yes 28% 21% Dementia (not AD) Depression Stroke No diagnosis Normal aging Other

Source: Consumer Health Sciences, LLC. Alzheimers Caregiver Project. 1999. AD is Underdiagnosed Early Alzheimers 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 McKhann G et al. Neurology. 1984;34:939-944. Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164.

A diagnosis of Alzheimers 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 studies 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 RELATIVE RISK FACTORS FOR ALZHEIMERS DISEASE Family history of dementia 3.5 (2.6 - 4.6) Family history Downs 2.7 (1.2 - 5.7) Family history - Parkinsons 2.4 (1.0 - 5.8) Maternal age > 40 years 1.7 (1.0 - 2.9) Head trauma (with LOC) 1.8 (1.3 - 2.7)

History of depression 1.8 (1.3 - 2.7) History of hypothyroidism 2.3 (1.0 - 5.4) History of severe headache 0.7 (0.5 - 1.0) NSAID use or statin use 0.2 (0.05 0.83) Roca, 1994, tVeldt, FACTORS INFLUENCING ALZHEIMERS DISEASE (age at onset, rate of progression) age sex genotype (presenilin, APO-E) education environment (head injury)

surgery psychological problems: depression, agitation, anxiety, sleep disturbance medication PHYSICAL/NEUROLOGICAL EXAMINATION CHECK BLOOD PRESSURE IDENTIFY SYSTEMIC DISORDERS CRANIAL NERVES Olfactory dysfunction, poor eye tracking Check for hearing, vision deficits SENSORY DEFICITS Proprioception, vibration DEEP TENDON REFLEXES Brisk, check for focal reflexes PATHOLOGIC REFLEXES Hyperactive snout reflex, Gegenhalten NEUROPSYCHOLOGICAL TESTING (WAIS, WECHSLER) MEMORY: SHORT-TERM, REMOTE VERBAL FUNCTION, FLUENCY



EEG, Evoked Potentials (P300) REACTION TIMES (slowed in the elderly, especially when complex response is required CSF ANALYSIS - ROUTINE STUDIES ELEVATED TAU (future possible) DECREASED AMYLOID (future possible) HEAVY METAL SCREEN (24 hr urine) GENOTYPING APO-LIPOPROTEIN-E (for supporting diagnosis) AUTOSOMAL DOMINANT (young onset) 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 UCLA compound Shoghi-Jadid et al., 67-year-old control Alzheimer patient PET brain images 2-(4-methylamino-phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound) Genes and Alzheimers disease (60% - 80 % of causation) (all known genes relate to amyloid) Familial AD (onset < 60 y/o) (<5%) Presenilin I, II (ch 14, 1) APP (ch 21) Non-familial (late onset) APOE Clinical studies suggest 40 50% due to 4 If is considered, may be 95% of causation Population studies suggest 10 20% cause Evolution over last 300,000 to 200,000 years 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% 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% JW Ashford, MD PhD, 2003 4% #AD

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 Specific preventive treatments can be developed for each genetic factor 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 JW Ashford, MD PhD, 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 JW Ashford, MD PhD, 2003 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 Cache County, probability of incident dementia Circles females Squares - males Open ApoE-e44 Gray ApoE-e4/x Black ApoE-ex/x Miech et al., 2002 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) Patients and Familys 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 Alzheimers Disease Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimers 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 p e r c e n t o f to ta l 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 todays 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

Percent of Validation Sample 80 Mild AD 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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