DELIRIUM, DEMENTIA, AND AMNESTIC and OTHER COGNITIVE DISORDERS

Second Year Medical School J. Wesson Ashford, M.D., Ph.D.

University of Kentucky VAMC, Lexington February 12, 2003

Slides at: www.medafile.com/demdx03a.ppt

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

Cognitive Disturbances:

Differential Diagnosis: Top Ten

1. Alzheimer Disease (pure ~40%, + mixed~70%) 2. Vascular Disease, MID (5-20%) 3. Drugs, Depression, Delirium

(commonly used mnemonic device: AVDEMENTIA)

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

Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA,

1994)
A.

B.
C. D.

E. F.

Multiple Cognitive Deficits 1. Memory Impairment 2. Other Cognitive Impairment Deficits Impair Social/Occupational Course Shows Gradual Onset And Decline Deficits Are Not Due to: 1. Other CNS Conditions 2. Substance Induced Conditions Do Not Occur Exclusively during Delirium Not Due to Another Psychiatric Disorder

ALZHEIMERS DISEASE
Estimate MMSE as a function of time
30 MMSE score 25 20 15 10 5 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 Estimated years into illness

AAMI / MCI

DEMENTIA

Alzheimers Disease versus Dementia

50 - 70% of dementias are AD Probable AD - 30% of cases, 90% correct

20% have other contributing diagnoses 40% have other contributing diagnoses 80% have other contributing diagnoses

Possible AD - 40% of cases, 70% correct

Unlikely AD - 30% of cases, 30% are AD

Vascular Dementia
(DSM-IV - APA, 1994)
A.

Multiple Cogntive Impairments

1. 2.

Memory Impairment Other Cognitive Disturbances

A. B.

Deficits Impair Social/Occupational Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Related to the Deficits Not Due to Delirium

C.

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

VASCULAR DEMENTIA CHANGE ON THE MINI-MENTAL STATE EXAM OVERTIME 30 20 10 0 -5

< event < event < event

SCORE

10

AVERAGE TIME OF ILLNESS (years)

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 Newman et al., related to peri-op or post-op anoxia or2001, 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

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

(more often a problem in medical inpatients)

Delirium Definition

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

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 Cerebellum, gray matter nuclei

Chronic Neurodegeneration

Medical / Endocrine

Thyroid dysfunction

Hypothyoidism elevated TSH Hyperthyroidism

Compensated hypothyroidism may have normal T4, FTI 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

Neurological Conditions

Primary Neurodegenerative Disease

Diffuse Lewy Body Dementia (? 7 - 50%)

Note relation to Parkinsons disease, symptoms Hallucinations, fluctuating course, neuroleptic hypersensitivity) Impaired attention, behavioral dyscontrol Decrease blood flow, hypometaboism on SPECT / PET (Picks disease, Argyrophylic grain disease)

Fronto-temporal dementia (tau gene)

Focal cortical atrophy

Primary progressive aphasia (many causes) Unilateral atrophy, hypofunction on EEG, SPECT, PET Dementia with gait impairment, incontinence Suggested on CT, MRI; need tap, ventriculography

Normal pressure hydrocephalus

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

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 Transient global amnesia Multiple sclerosis

Specific brain diseases

Age-Associated Memory Impairment vs Mild Cognitive Impairment

Memory declines with age 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

Advances in Alzheimers Disease

Incidence and prevalence Search for etiology, genetics Understanding pathophysiology Better screening tools for early recognition Improved diagnosis Developing interventions Behavioral conditions and

U.S. Census 2000 by age

2,500,000 2,250,000 2,000,000 1,750,000 1,500,000 1,250,000 1,000,000 750,000 500,000 250,000 0 0 10 20 30 40 50 60 70 80 90 100

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

# people

Total = 281,421,906 >65 = 35,008,753 >85 = 4,256,587

Age

U.S. mortality by age - 1999

45,000 Males, 1,175,460 Females, 1,215,939

Number of people

40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 0 10

20

30

40

50

60

70

80

90

100

Age

www.cdc.gov

U.S. mortality rate by age 1999 CDC / 2000 census

1.0000 probability 0.1000 0.0100 0.0010 0.0001
0 10 20 30 40 50 60 70 80 90 100

Males Females

Age

U.S. mortality rate by age 1999 CDC / 2000 census

1.0000 probability 0.1000 0.0100 0.0010 0.0001
30 40 50 60

Males Females Expon. (Males) Expon. (Females)

y = 9E-05e R2 = 0.9974 0.0926x y = 3E-05e R2 = 0.9973

70 80 90 100

0.0848x

Age

PREVALENCE of AD

Estimated 4 million cases in US (2000)

(2000 - 46 million individuals over 60 y/o)

Estimated 500,000 new cases per year Increase with age (prevalence)

1% of 60 - 65 (10.7m)

= 107,000 = 188,000 = 350,000

2% of 65 - 70 ( 9.4m) 4% of 70 - 75 ( 8.7m)

U.S. mortality rate by age 1999 CDC / 2000 census

1.0000 0.1000 0.0100 0.0010 0.0001
0 10 20 30 40 50 60 70 80 90 100

Males Females dementia incidence

probability

Age

U.S. Dementia Incidence (4 million / 8yr)

16000 14000 12000 10000 8000 6000 4000 2000 0 male=170,603 female=329,115

# / yr

50

60

70 Age

80

90

100

Dementia incidence by individual

0.016 0.014 0.012 0.01 0.008 0.006 0.004 0.002 0 50

Proportional risk / yr

male=34% female=66%

60

70

80

90

100

Age

Oeppen & Vaupel, 2002

Oeppen & Vaupel, 2002

2 million AD patients in nursing homes

ECONOMIC IMPACT OF AD
Projection to Kentucky 22,000 (6,000 in Eastern KY)

Nursing homes cost - $120 to $160 per day Annualized cost of nursing homes ranges from $40 to $70,000 per year Care of AD patients costs $80 billion per year With lost wages of patients and families plus costs for non-nursing home patients:

Total costs: $120 billion annually (Am J Publ Hlth)

Age (initial genesis vs response to stress)

Etiology

Bigger factor than for mortality Design in a plastic (memory) system, energy demands Stressor response (adequate repair mechanisms)

Trauma (head injury), vascular (stroke), surgery, loss, grief, etc.

Genetics (amyloid related)

Familial, early onset: APP (21), PS (14, 1) (less than 5%) Late onset: APOE e4 (ch19) (?50% of AD)

relation to brain cholesterol metabolism? APOE e2 may be most protective

many other candidate genes

Relation to vascular factors,

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 Roca, 1994, tVeldt, 2002

NEUROPATHOLOGY OF AD

Senile plaques

beta-amyloid protein (? Primary problem) hyper-phosphorylated tau (loss of synapses, dementia)

Neurofibrillary tangles

Neurotransmitter losses
Acetylcholine (Ach) major loss of nicotinic receptors Norepinephrine, serotonin, glutamate, GABAss

Inflammatory responses

Amyloid PreProtein (APP - ch21) (early changes)

New Neuropath Mechanisms

metabolism occurs on cholesterol rafts

Cholesterol transport by APOE (ch 19)

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

amyloid

APPs APP

APPs

M1 AGONIST or ACh

M1 mAChR

Gq/11

/-secretase -secretase

PHF

PLC

MAPk

Hyper-P-TAU

PKC

Protein phosphorylation

TAU

GSK-3 beta

Li+

Adapted from Fisher, 2000

Genes and Alzheimers disease

(60% - 80 % of causation) (all known genes relate to amyloid) Presenilin I, II (ch 14, 1) APP (ch 21)

Familial AD (onset < 60 y/o) (<5%) Non-familial (late onset)

APOE
Clinical studies suggest 40 50% due to 4 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 onset

e2 -- 7% of the population e3 -- 78% of the population e4 -- 15% of the population

e3/3 - average age of onset = 74 y/o e3/4 and e4/4 average age = 69 y/o

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 E2/2 E2/3 E3/3 E3/4 E4/4 1% 0.1% 12 % 60% 21% 2% 4%

#pop

#AD

risk If all US .4 M 1.5 M 2.3 M 8.2 M 30.7M

0.5M .004M 0.8% 5.5M .18M 3.2%

35% 27.6M 1.4M 5.1% 42% 16% 9.6M 1.7M 18% .9M .6M 67%

See: Ashford & Mortimer, 2002, Journal of Alzheimers Disease

Biopsychosocial Systems Affected by AD

(all related to neuroplasticity)

Social Systems

Instrumental ADLs - Early Basic ADLs - Late Primary Loss Of Memory Later Loss Of Learned Skills Cortical Glutamatergic Storage Subcortical (acetylcholine, norepi, serotonin) Cellular Plastic Processes

Psychological Systems

Neuronal Memory Systems

APP metabolism early, broad cortical distribution TAU hyperphosphorylation late, focal effect, dementia related

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

Early Recognition of AD: Consensus Statement (AAGP, AGS, Alzheimers Association)

AD continues to be missed as diagnosis AD is unrecognized and underreported

patients do not realized families tend to compensate

Effective treatment and management techniques are Small et al., JAMA, 1997 available

Need for Better Screening and Early Assessment Genetic vulnerability Tools testing

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

predicting progression, measuring rate

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

Need for a Brief Screening Test for Alzheimers Disease

Recent evidence of benefits of anticholinesterase agents in the treatment of mild Alzheimers disease
Improvement of cognition Slowing of progression

Available Screening Tests

MMSE

10 -- 15 min 7 10 min 2 4 min 3 5 min

Too long Too complex Not sensitive Complex scoring, unclear adequacy Need for slightly shorter, easier test

7-Minute Screen

Clock Drawing Test

Mini-cog

Memory Impairment Screen 4 min (a suitably accurate test that takes less than 2 minutes is not available)

The Progress of Alzheimers Disease

30 25 20 Early diagnosis Cognitive symptoms Mild-moderate Severe

MMSE score

Loss of ADL

15 10 5 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 Behavioral problems Nursing home placement Death

Years
Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimers Disease. 1996:239-253.

Ashford et al., 1995

AD all (easiest to hardest at p=.5)

1 0.9 PROBABILITY CORRECT 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 DISABILITY ("time-index" year units)

Mini-Mental State Exam items

PENCIL APPL-REP WATC LOCATION PENY-REP TABL-REP CLOS-IS RIT-HAND CITY FOLD-HLF SENTENCE COUNTY NO-IFS FLOOR SEASON YEAR PUT-LAP MONTH ADDRESS DRAW-PNT DAY SPEL_ALL DATE APPL-MEM PENY-MEM TABL-MEM

Total Item Information Function for the MMSE

30 25 Information 20 15 10 5 0 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10
Alzheimer's Severity Horographic Function (time-index year units)

Brief Alzheimer Screening

Repeat these three words: apple, table, penny. So you will remember these words, repeat them again, twice. What is todays date?

1 point if within 2 days.

Name as many animals as you can in 30 seconds, GO!

1 point for naming 10 animals

What were the 3 words I asked you to repeat? (no prompts)

1 for each word, A score of 4 or 5 indicate a very low likelihood of dementia. A score of 2 or 3 suggests that more testing is needed. A score of 0 or 1 indicate a very high likelihood of dementia. (palm-pilot scoring under development)

TOTAL (max = 5)

If score of 2 or 3:

Spell World Backwards

BRIEF ALZHEIMER SCREEN

(Normal vs Mild AD, MMS>19)

100
True Positive Rate (%) (Sensitivity)

20 27 26 25 14 10 9 8 97 6
animals 1 m animals 30 s MMSE Date+3 Rec BAS AUC = 0.868 AUC = 0.828 AUC = 0.965 AUC = 0.875 AUC = 0.983

90 80 70 60 50 40 30 20 10 0 0

11

12

13

10

20

30

40

50

60

70

80

90 100

False Positive Rate (%) (1-Specificity)

New test to screen patients for Alzheimers disease using the World-Wide Web based testing and CD-distribution Test only takes 1-minute Test can be repeated often
(quarterly)

BLT/Ashford Memory Test (to detect AD onset)

Any change over time can be detected Test is at:

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

PHYSICAL/NEUROLOGICA L EXAMINATION

CHECK BLOOD PRESSURE IDENTIFY SYSTEMIC DISORDERS CRANIAL NERVES

Olfactory dysfunction, poor eye tracking Check for hearing, vision deficits Proprioception, vibration Brisk, check for focal reflexes Hyperactive snout reflex, Gegenhalten

SENSORY DEFICITS

DEEP TENDON REFLEXES

PATHOLOGIC REFLEXES

CURRENT APPROACHES TO SEVERITY ASSESSMENT MINI-MENTAL STATE EXAM

CLOCK DRAWING ANIMAL NAMING (1 minute) MATTIS DEMENTIA RATING SCALE ALZHEIMERS DISEASE ASSESSEMENT SCALE (ADAS) ACTIVITIES OF DAILY LIVING GLOBAL CLINICAL SCALE CLINICAL DEMENTIA RATING SCALE GLOBAL DETERIORATION SCALE / FAST

NEUROPSYCHOLOGICAL TESTING (WAIS,

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

WECHSLER)

LABORATORY TESTS (routine)

BLOOD TESTS electrolytes, liver, kidney function tests, glucose thyroid function tests (T3, T4, FTI, TSH) vitamin B12, folate complete blood count, ESR VDRL, HIV (if indicated) EKG (if indicated) CHEST X-RAY (if indicated) URINALYSIS ANATOMICAL BRAIN SCAN CT (cheapest), MRI

FUNCTIONAL BRAIN IMAGING (SPECT, PET) EEG, Evoked Potentials (P300) REACTION TIMES (slowed in the elderly, especially when complex response is required CSF ANALYSIS - ROUTINE STUDIES

SPECIAL LABORATORY TESTS

ELEVATED TAU (future possible) DECREASED AMYLOID (future possible)

HEAVY METAL SCREEN (24 hr urine) GENOTYPING

APO-LIPOPROTEIN-E (for supporting dx) 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

Ashford et al, 2000

UCLA group, J. Amer. Ger. Psych, 2002

Shoghi-Jadid et al., 2002

67-year-old control

Alzheimer patient

PET brain images

2-(4-methylamino-phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound)

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

BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS

MOOD DISORDERS depression early in AD PSYCHOTIC DISORDERS

Particularly paranoia, e.g, people stealing things

INAPPROPRIATE BEHAVIORS (sexual AGGRESSION: verbal, physical PURPOSELESS ACTIVITY: verbal, motor MEAL TIME BEHAVIORS SLEEP DISORDERS

NEUROPSYCHIATRIC TREATMENTS

First treat medical problems Second environmental interventions Third neuropsychiatric medications
Cognitive impairment Psychotic symptoms Depressive symptoms Insomnia symptoms Anorexia symptoms