DELIRIUM, DEMENTIA, AND DELIRIUM, DEMENTIA, AND AMNESTIC and OTHER AMNESTIC and OTHER

COGNITIVE DISORDERSCOGNITIVE DISORDERS

Second Year Medical SchoolSecond Year Medical School

J. Wesson Ashford, M.D., Ph.D.J. Wesson Ashford, M.D., Ph.D.University of KentuckyUniversity of Kentucky

VAMC, LexingtonVAMC, Lexington

February 12, 2003February 12, 2003

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

Dementia DefinitionDementia Definition

Multiple Cognitive Deficits:Multiple Cognitive Deficits: Memory dysfunctionMemory dysfunction

especially new learning, a prominent early especially new learning, a prominent early symptomsymptom

At least one additional cognitive deficitAt least one additional cognitive deficit aphasia, apraxia, agnosia, or executive aphasia, apraxia, agnosia, or executive

dysfunctiondysfunction Cognitive Disturbances:Cognitive Disturbances:

Sufficiently severe to cause impairment of Sufficiently severe to cause impairment of occupational or social functioning and occupational or social functioning and

Must represent a decline from a previous level Must represent a decline from a previous level of functioningof functioning

Differential Diagnosis: Differential Diagnosis: Top Ten Top Ten

(commonly used mnemonic device: AVDEMENTIA)(commonly used mnemonic device: AVDEMENTIA)1.1. AAlzheimer Disease (pure ~40%, + lzheimer Disease (pure ~40%, + mixed~70%)mixed~70%)

2.2. VVascular Disease, MID (5-20%)ascular Disease, MID (5-20%)3.3. DDrugs, rugs, DDepression, epression, DDeliriumelirium

4.4. EEthanolthanol (5-15%) (5-15%)5.5. MMedical / edical / MMetabolic Systemsetabolic Systems6.6. EEndocrine (thyroid, diabetes), ndocrine (thyroid, diabetes), EEars, ars, EEyes, yes,

EEnviron.nviron.7.7. NNeurologic (other primary degenerations, etc.)eurologic (other primary degenerations, etc.)8.8. TTumor, umor, TToxin, oxin, TTraumarauma9.9. IInfection, nfection, IIdiopathic, diopathic, IImmunologicmmunologic10. 10. AAmnesia, mnesia, AAutoimmune, utoimmune, AApnea, pnea, AAAMIAMI

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

1994)1994)

A.A. Multiple Cognitive DeficitsMultiple Cognitive Deficits1. Memory Impairment 1. Memory Impairment 2. Other Cognitive Impairment2. Other Cognitive Impairment

B. Deficits Impair Social/Occupational B. Deficits Impair Social/Occupational C.C. Course Shows Gradual Onset And DeclineCourse Shows Gradual Onset And DeclineD.D. Deficits Are Not Due to:Deficits Are Not Due to:

1. Other CNS Conditions1. Other CNS Conditions2. Substance Induced Conditions2. Substance Induced Conditions

E. Do Not Occur Exclusively during DeliriumE. Do Not Occur Exclusively during DeliriumF. Not Due to Another Psychiatric DisorderF. Not Due to Another Psychiatric Disorder

Estimate MMSE as a function of time

0

5

10

15

20

25

30

-10 -8 -6 -4 -2 0 2 4 6 8 10

Estimated years into illness

MM

SE

scor

e

AAMI / MCI DEMENTIA

ALZHEIMER’S DISEASE

Alzheimer’s Disease versus Alzheimer’s Disease versus DementiaDementia

50 - 70% of dementias are AD50 - 70% of dementias are AD Probable AD - 30% of cases, 90% correctProbable AD - 30% of cases, 90% correct

20% have other contributing diagnoses20% have other contributing diagnoses

Possible AD - 40% of cases, 70% correctPossible AD - 40% of cases, 70% correct 40% have other contributing diagnoses40% have other contributing diagnoses

Unlikely AD - 30% of cases, 30% are ADUnlikely AD - 30% of cases, 30% are AD 80% have other contributing diagnoses80% have other contributing diagnoses

Vascular DementiaVascular Dementia(DSM-IV - APA, 1994)(DSM-IV - APA, 1994)

A.A. Multiple Cogntive ImpairmentsMultiple Cogntive Impairments1.1. Memory ImpairmentMemory Impairment

2.2. Other Cognitive DisturbancesOther Cognitive Disturbances

B.B. Deficits Impair Social/OccupationalDeficits Impair Social/Occupational

C.C. Focal Neurological Signs and Symptoms Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Cerebrovascular Disease Etiologically Related to the DeficitsRelated to the Deficits

D.D. Not Due to DeliriumNot Due to Delirium

Factors Associated with Multi-infarct Factors Associated with Multi-infarct DementiaDementia

History of stroke (especially in Nursing Home)History of stroke (especially in Nursing Home) Followed by onset of dementia within 3 monthsFollowed by onset of dementia within 3 months

Abrupt onset, Step-wise deteriorationAbrupt onset, Step-wise deterioration Cardiovascular disease - HTD, ASCVD, & Atrial Cardiovascular disease - HTD, ASCVD, & Atrial

FibFib Depression (left anterior strokes), personality Depression (left anterior strokes), personality

changechange More gait problems than in ADMore gait problems than in AD MRI evidence of T2 changes (?? Binswanger’s MRI evidence of T2 changes (?? Binswanger’s

disease)disease) Basal ganglia, putamenBasal ganglia, putamen Periventricular white matterPeriventricular white matter

SPECT / PET show focal areas of dysfunctionSPECT / PET show focal areas of dysfunction Neuropsychological dysfunctions are patchyNeuropsychological dysfunctions are patchy

VASCULAR DEMENTIA CHANGE ON THE MINI-MENTAL STATE EXAM

OVERTIME

< event

< event

< event

0

10

20

30

-5 0 5 10

AVERAGE TIME OF ILLNESS (years)

SC

OR

E

Post-Cardiac SurgeryPost-Cardiac Surgery 53% post-surgical confusion at discharge 53% post-surgical confusion at discharge

(delirium)(delirium) 42% impaired 5 years later (dementia)42% impaired 5 years later (dementia) May be related to anoxic brain injury, apneaMay be related to anoxic brain injury, apnea May be related to narcotic/other medicationMay be related to narcotic/other medication May occur in those patients who would have May occur in those patients who would have

developed dementia anyway (? genetic risk)developed dementia anyway (? genetic risk) Cardio-vascular disease and stress may start Cardio-vascular disease and stress may start

Alzheimer pathologyAlzheimer pathology Any surgery may have a similar effect related to Any surgery may have a similar effect related to

peri-op or post-op anoxia or vascular stressperi-op or post-op anoxia or vascular stress

Newman et al., 2001, NEJMNewman et al., 2001, NEJM

Drug InteractionsDrug Interactions Anticholinergics: amitriptyline, atropine, Anticholinergics: amitriptyline, atropine,

benztropine, scopolamine, hyoscyamine, benztropine, scopolamine, hyoscyamine, oxybutynin, diphenhydramine, oxybutynin, diphenhydramine, chlorpheniramine, many anti-histaminicschlorpheniramine, many anti-histaminics May aggravate Alzheimer pathologyMay aggravate Alzheimer pathology

GABA agonists: benzodiazepines, GABA agonists: benzodiazepines, barbiturates, ethanol, anti-convulsantsbarbiturates, ethanol, anti-convulsants

Beta-blockers: propranololBeta-blockers: propranolol Dopaminergics: l-dopa, alpha-methyl-Dopaminergics: l-dopa, alpha-methyl-

dopadopa Narcotics: may contribute to dementiaNarcotics: may contribute to dementia

Drug ToxicityDrug Toxicity

Anti-cholinergicAnti-cholinergic Peripheral: blurred vision, dry mouth, Peripheral: blurred vision, dry mouth,

constipation, urinary obstructionconstipation, urinary obstruction Central: confusion, memory encoding blockCentral: confusion, memory encoding block

Gaba-agonist:Gaba-agonist: Muscle relaxant, anti-convulsant, sedative, Muscle relaxant, anti-convulsant, sedative,

anti-anxiety, amnesic, confusionanti-anxiety, amnesic, confusion Medication induced electrolyte Medication induced electrolyte

imbalanceimbalance Confusion (watch for in nursing home)Confusion (watch for in nursing home)

DepressionDepression Onset: rapidOnset: rapid Precipitants: psycho-social (not organic)Precipitants: psycho-social (not organic) Duration: less than 3 months to Duration: less than 3 months to

presentationpresentation Mood: depressed, anxiousMood: depressed, anxious Behavior: decreased activity or agitationBehavior: decreased activity or agitation Cognition: unimpaired or poor responsesCognition: unimpaired or poor responses Somatic symptoms: fatigue, lethargy, Somatic symptoms: fatigue, lethargy,

sleep, appetite disruptionsleep, appetite disruption Course: rapid resolution with treatment,Course: rapid resolution with treatment,

but may precede Alzheimer’s but may precede Alzheimer’s diseasedisease

Delirium DefinitionDelirium Definition(more often a problem in medical in-(more often a problem in medical in-

patients)patients) Disturbance of consciousnessDisturbance of consciousness

i.e., reduced clarity of awareness of i.e., reduced clarity of awareness of the environment with reduced ability the environment with reduced ability to focus, sustain, or shift attentionto focus, sustain, or shift attention

Change in cognition (memory, Change in cognition (memory, orientation, language, perception)orientation, language, perception)

Development over a short period Development over a short period (hours to days), tends to fluctuate(hours to days), tends to fluctuate

Evidence of medical etiologyEvidence of medical etiology

DeliriumDelirium Susceptibility may be symptom of early dementia, Susceptibility may be symptom of early dementia,

or delirium may predispose to later dementia or delirium may predispose to later dementia Predisposing factors - Predisposing factors - Age, infections, Age, infections,

dementiadementia Medical conditions Medical conditions

Infections: Infections: G.U. - urinaryG.U. - urinary Respiratory (URI, pneumonia)Respiratory (URI, pneumonia) G.I.G.I.

ConstipationConstipation Drug toxicityDrug toxicity Fracture (especially related to hip fracture)Fracture (especially related to hip fracture)

EthanolEthanol Possibly NeuroprotectivePossibly Neuroprotective

May not kill neurons directly May not kill neurons directly (?Dietary (?Dietary recommendation?)recommendation?)

Accidents, Head InjuryAccidents, Head Injury Dietary DeficiencyDietary Deficiency

Thiamine – Wernicke-Korsakoff syndromeThiamine – Wernicke-Korsakoff syndrome Hepatic EncephalopathyHepatic Encephalopathy Withdrawal Damage (seizures) Withdrawal Damage (seizures)

Delayed Alcohol WithdrawalDelayed Alcohol Withdrawal Watch for in hospitalized patientsWatch for in hospitalized patients

Chronic NeurodegenerationChronic Neurodegeneration Cerebellum, gray matter nucleiCerebellum, gray matter nuclei

Medical / EndocrineMedical / Endocrine Thyroid dysfunctionThyroid dysfunction

Hypothyoidism – elevated TSHHypothyoidism – elevated TSH Compensated hypothyroidism may have normal T4, Compensated hypothyroidism may have normal T4,

FTIFTI HyperthyroidismHyperthyroidism

Apathetic, with anorexia, fatigue, weight loss, Apathetic, with anorexia, fatigue, weight loss, increased T4increased T4

DiabetesDiabetes Hypoglycemia Hypoglycemia (loss of recent memory since episode)(loss of recent memory since episode) HyperglycemiaHyperglycemia HypercalcemiaHypercalcemia Nephropathy, UremiaNephropathy, Uremia Hepatic dysfunction (Wilson’s disease)Hepatic dysfunction (Wilson’s disease) Vitamin Deficiency (B12, thiamine, niacin)Vitamin Deficiency (B12, thiamine, niacin)

Pernicious anemia – B12 deficiency, ?Pernicious anemia – B12 deficiency, ?homocysteinehomocysteine

Eyes, Ears, Eyes, Ears, EnvironmentEnvironment

Must consider sensory deficits might Must consider sensory deficits might contribute to the appearance of the patient contribute to the appearance of the patient being dementedbeing demented

Central Auditory Processing Deficits (CAPD)Central Auditory Processing Deficits (CAPD) Hearing problems are socially isolatingHearing problems are socially isolating Visual problems are difficult to accommodate Visual problems are difficult to accommodate

by a demented patient, ?To do cataract op?by a demented patient, ?To do cataract op? Environmental stress factors can predispose Environmental stress factors can predispose

to a variety of conditionsto a variety of conditions Nutritional deficiencies (tea & toast Nutritional deficiencies (tea & toast

syndrome)syndrome)

Neurological Neurological ConditionsConditions

Primary Neurodegenerative DiseasePrimary Neurodegenerative Disease Diffuse Lewy Body Dementia (? 7 - 50%)Diffuse Lewy Body Dementia (? 7 - 50%)

Note relation to Parkinson’s disease, symptomsNote relation to Parkinson’s disease, symptoms Hallucinations, fluctuating course, neuroleptic Hallucinations, fluctuating course, neuroleptic

hypersensitivity)hypersensitivity) Fronto-temporal dementia (tau gene)Fronto-temporal dementia (tau gene)

Impaired attention, behavioral dyscontrolImpaired attention, behavioral dyscontrol Decrease blood flow, hypometaboism on SPECT / PETDecrease blood flow, hypometaboism on SPECT / PET (Pick’s disease, Argyrophylic grain disease)(Pick’s disease, Argyrophylic grain disease)

Focal cortical atrophyFocal cortical atrophy Primary progressive aphasia (many causes)Primary progressive aphasia (many causes) Unilateral atrophy, hypofunction on EEG, SPECT, PETUnilateral atrophy, hypofunction on EEG, SPECT, PET

Normal pressure hydrocephalusNormal pressure hydrocephalus Dementia with gait impairment, incontinence Dementia with gait impairment, incontinence Suggested on CT, MRI; need tap, ventriculographySuggested on CT, MRI; need tap, ventriculography

Other Neurologic Other Neurologic ConditionsConditions

Subdural hematomaSubdural hematoma Huntington’s diseaseHuntington’s disease Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease

Rapid progressionRapid progression Characteristic EEG changesCharacteristic EEG changes

Multiple sclerosisMultiple sclerosis Corticobasal degeneratonCorticobasal degeneraton Cerebellar degenerationCerebellar degeneration Progressive supranuclear palseyProgressive supranuclear palsey

TumorTumor Primary brain tumorPrimary brain tumor

MMeningioma (treatable)eningioma (treatable) Glioma (usually not responsive to therapy)Glioma (usually not responsive to therapy)

Metastatic brain tumorMetastatic brain tumor

Remote effects of carcinomaRemote effects of carcinoma

ToxinsToxins Heavy metal screen if consideredHeavy metal screen if considered

Trauma

Concussion, ContusionConcussion, Contusion Occult head trauma if recent fallOccult head trauma if recent fall

Subdural hematomaSubdural hematoma Hydrocephalus:Hydrocephalus:

Normal pressure (late effect of bleed)Normal pressure (late effect of bleed) Dementia pugilisticaDementia pugilistica Possible contributor to Alzheimer’s disease initiation Possible contributor to Alzheimer’s disease initiation

and progression (? 4% of cases)and progression (? 4% of cases) Concern re: physical abuse by caretakersConcern re: physical abuse by caretakers

Infectious Conditions Infectious Conditions Affecting the BrainAffecting the Brain

HIVHIV NeurosyphilisNeurosyphilis Viral encephalitis (herpes)Viral encephalitis (herpes) Bacterial meningitisBacterial meningitis Fungal (cryptococcus)Fungal (cryptococcus) Prion (Creutzfeldt-Jakob disease); (mad Prion (Creutzfeldt-Jakob disease); (mad

cow disease)cow disease)

AMNESIC DISORDERAMNESIC DISORDERDSM-IVDSM-IV

A.A. Memory impairmentMemory impairment- inability to learn new information, or- inability to learn new information, or- Inability to recall previously learned information- Inability to recall previously learned information

Memory disturbance significantly impairs Memory disturbance significantly impairs social, social, occupational function, occupational function, deterioration from pastdeterioration from past

Memory not due to delirium, dementiaMemory not due to delirium, dementia Physiological basis or substance inducedPhysiological basis or substance induced

- Distinguish from dissociative disorders, dissociative - Distinguish from dissociative disorders, dissociative amnesia, dissociative identity disordersamnesia, dissociative identity disorders

SpecifySpecify- Transient – less than 1 month- Transient – less than 1 month- Chronic - more than 1 month- Chronic - more than 1 month

Causes of Amnesic Causes of Amnesic DisordersDisorders

AmnesiaAmnesia Dissociative: localized, selective, Dissociative: localized, selective,

generalizedgeneralized Organic - damage to CA1 of hippocampus Organic - damage to CA1 of hippocampus

thiamine deficiency (WKE), hypoglycemia, hypoxiathiamine deficiency (WKE), hypoglycemia, hypoxia

Epileptic eventsEpileptic events Partial complex seizuresPartial complex seizures

Specific brain diseasesSpecific brain diseases Transient global amnesiaTransient global amnesia Multiple sclerosisMultiple sclerosis

Age-Associated Memory Age-Associated Memory ImpairmentImpairment

vsvsMild Cognitive ImpairmentMild Cognitive Impairment

Memory declines with ageMemory declines with age Age - related memory decline corresponds Age - related memory decline corresponds

with atrophy of the hippocampuswith atrophy of the hippocampus Older individuals remember more complex Older individuals remember more complex

items and relationshipsitems and relationships Older individuals are slower to respondOlder individuals are slower to respond Memory problems predispose to Memory problems predispose to

development of Alzheimer’s diseasedevelopment of Alzheimer’s disease

Advances in Advances in Alzheimer’s DiseaseAlzheimer’s Disease

Incidence and prevalenceIncidence and prevalence Search for etiology, geneticsSearch for etiology, genetics Understanding pathophysiologyUnderstanding pathophysiology Better screening tools for early Better screening tools for early recognitionrecognition Improved diagnosisImproved diagnosis Developing interventionsDeveloping interventions Behavioral conditions and Behavioral conditions and managementmanagement

U.S. Census 2000 by age

0

250,000

500,000

750,000

1,000,000

1,250,000

1,500,000

1,750,000

2,000,000

2,250,000

2,500,000

0 10 20 30 40 50 60 70 80 90 100

Age

# p

eo

ple

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

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

U.S. mortality by age - 1999

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

0 10 20 30 40 50 60 70 80 90 100

Age

Nu

mb

er

of

pe

op

le

Males, 1,175,460

Females, 1,215,939

www.cdc.gov

U.S. mortality rate by age1999 CDC / 2000 census

0.0001

0.0010

0.0100

0.1000

1.0000

0 10 20 30 40 50 60 70 80 90 100

Age

proba

bilit

y

Males

Females

U.S. mortality rate by age1999 CDC / 2000 census

y = 9E-05e0.0848x

R2 = 0.9974y = 3E-05e0.0926x

R2 = 0.99730.0001

0.0010

0.0100

0.1000

1.0000

30 40 50 60 70 80 90 100

Age

proba

bilit

y

Males

Females

Expon. (Males)

Expon.(Females)

PREVALENCE of AD PREVALENCE of AD Estimated 4 million cases in US (2000)Estimated 4 million cases in US (2000)

(2000 - 46 million individuals over 60 y/o)(2000 - 46 million individuals over 60 y/o) Estimated 500,000 new cases per yearEstimated 500,000 new cases per year Increase with age (prevalence)Increase with age (prevalence)

1% of 60 - 65 (10.7m) = 107,000 1% of 60 - 65 (10.7m) = 107,000 2% of 65 - 70 ( 9.4m) = 188,0002% of 65 - 70 ( 9.4m) = 188,000 4% of 70 - 75 ( 8.7m) = 350,0004% of 70 - 75 ( 8.7m) = 350,000 8% of 75 - 80 ( 7.4m) = 595,0008% of 75 - 80 ( 7.4m) = 595,000 16% of 80 - 85 ( 5.0m) = 800,00016% of 80 - 85 ( 5.0m) = 800,000

U.S. mortality rate by age1999 CDC / 2000 census

0.0001

0.0010

0.0100

0.1000

1.0000

0 10 20 30 40 50 60 70 80 90 100

Age

prob

abi

lity

MalesFemalesdementia incidence

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

02000400060008000

10000120001400016000

50 60 70 80 90 100

Age

# /

yr

male=170,603

female=329,115

Dementia incidence by individual

00.0020.0040.0060.0080.01

0.0120.0140.016

50 60 70 80 90 100

Age

Pro

po

rtio

na

l ris

k /

yr

male=34%

female=66%

Oeppen & Vaupel, 2002

Oeppen & Vaupel, 2002

ECONOMIC IMPACT OF ECONOMIC IMPACT OF ADAD

2 million AD patients in nursing homes2 million AD patients in nursing homes Projection to Kentucky – 22,000 (6,000 in Eastern Projection to Kentucky – 22,000 (6,000 in Eastern

KY)KY) Nursing homes cost - $120 to $160 per dayNursing homes cost - $120 to $160 per day Annualized cost of nursing homes ranges from Annualized cost of nursing homes ranges from

$40 to $70,000 per year$40 to $70,000 per year Care of AD patients costs $80 billion per yearCare of AD patients costs $80 billion per year With lost wages of patients and families plus With lost wages of patients and families plus

costs for non-nursing home patients:costs for non-nursing home patients: Total costs: $Total costs: $120 billion annually120 billion annually ( (Am J Publ HlthAm J Publ Hlth)) Projection to Kentucky – $1.5 billion annually!Projection to Kentucky – $1.5 billion annually!

EtiologyEtiology Age (Age (initial genesis vs response to stress)initial genesis vs response to stress)

Bigger factor than for mortalityBigger factor than for mortality Design in a plastic (memory) system, energy Design in a plastic (memory) system, energy

demandsdemands Stressor response (Stressor response (adequate repair mechanisms)adequate repair mechanisms)

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

Genetics (amyloid related)Genetics (amyloid related) Familial, early onset: APP (21), PS (14, 1) (less than Familial, early onset: APP (21), PS (14, 1) (less than

5%)5%) Late onset: APOE e4 (ch19) (?50% of AD)Late onset: APOE e4 (ch19) (?50% of AD)

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

many other candidate genesmany other candidate genes Relation to vascular factors, cholesterol, BPRelation to vascular factors, cholesterol, BP Education (? design vs protection)Education (? design vs protection) Environment - Environment - diet, exercise, smokingdiet, exercise, smoking

RELATIVE RISK RELATIVE RISK FACTORS FOR FACTORS FOR

ALZHEIMER’S DISEASEALZHEIMER’S DISEASE Family history of dementiaFamily history of dementia 3.5 (2.6 - 4.6)3.5 (2.6 - 4.6) Family history - Downs Family history - Downs 2.7 (1.2 - 5.7)2.7 (1.2 - 5.7) Family history - Parkinson’sFamily history - Parkinson’s 2.4 (1.0 - 5.8)2.4 (1.0 - 5.8) Maternal age > 40 yearsMaternal age > 40 years 1.7 (1.0 - 2.9)1.7 (1.0 - 2.9) Head trauma (with LOC)Head trauma (with LOC) 1.8 (1.3 - 2.7)1.8 (1.3 - 2.7) History of depressionHistory of depression 1.8 (1.3 - 2.7)1.8 (1.3 - 2.7) History of hypothyroidismHistory of hypothyroidism 2.3 (1.0 - 5.4)2.3 (1.0 - 5.4) History of severe headacheHistory of severe headache 0.7 (0.5 - 1.0)0.7 (0.5 - 1.0) NSAID use or statin useNSAID use or statin use 0.2 (0.05 – 0.83)0.2 (0.05 – 0.83)

Roca, 1994, t’Veldt, 2002

NEUROPATHOLOGY OF NEUROPATHOLOGY OF ADAD

Senile plaquesSenile plaques beta-amyloid protein (? Primary problem)beta-amyloid protein (? Primary problem)

Neurofibrillary tanglesNeurofibrillary tangles hyper-phosphorylated tau (loss of synapses, hyper-phosphorylated tau (loss of synapses,

dementia)dementia)

Neurotransmitter lossesNeurotransmitter losses Acetylcholine (Ach) – major loss of nicotinic Acetylcholine (Ach) – major loss of nicotinic

receptorsreceptors Norepinephrine, serotonin, glutamate, GABAssNorepinephrine, serotonin, glutamate, GABAss

Inflammatory responsesInflammatory responses

New Neuropath New Neuropath MechanismsMechanisms

Amyloid PreProtein (APP - ch21) (early Amyloid PreProtein (APP - ch21) (early changes)changes) metabolism occurs on cholesterol “rafts”metabolism occurs on cholesterol “rafts”

Cholesterol transport by APOE (ch 19)Cholesterol transport by APOE (ch 19) alpha-secretase vs beta/gamma secretase alpha-secretase vs beta/gamma secretase

metabolismmetabolism influence toward alpha-secretase by Acetylcholineinfluence toward alpha-secretase by Acetylcholine gamma-secretase (PreSenilin genes, ch14,1)gamma-secretase (PreSenilin genes, ch14,1) break down - Insulin Degrading Enzyme (ch10), etc.break down - Insulin Degrading Enzyme (ch10), etc. prevention of fibril formation by melatoninprevention of fibril formation by melatonin

Tau hyperphosphorylation (relation to Tau hyperphosphorylation (relation to dementia)dementia) glycogen-synthase-kinase (GSK) 3-betaglycogen-synthase-kinase (GSK) 3-beta inhibition by Ach, lithium, valproic acidinhibition by Ach, lithium, valproic acid

Proteinphosphorylation

Hyper-P-TAU

TAU

Gq/11M1 mAChR

MAPk

M1 AGONIST or ACh

PLC

PKC

GSK-3 beta

PHF

-secretase

APPs

APP

APPs amyloid

/-secretase

Adapted from Fisher, 2000Li+

Genes and Alzheimer’s diseaseGenes and Alzheimer’s disease(60% - 80 % of causation)(60% - 80 % of causation)

(all known genes relate to (all known genes relate to amyloid)amyloid)

Familial AD (onset < 60 y/o) (<5%)Familial AD (onset < 60 y/o) (<5%) Presenilin I, II (ch 14, 1)Presenilin I, II (ch 14, 1) APP (ch 21)APP (ch 21)

Non-familial (late onset)Non-familial (late onset) APOEAPOE

Clinical studies suggest 40 – 50% due to Clinical studies suggest 40 – 50% due to 44 Population studies suggest 10 – 20% causePopulation studies suggest 10 – 20% cause Evolution over last 300,000 to 200,000 Evolution over last 300,000 to 200,000

yearsyears At least 20 other genesAt least 20 other genes

APO-E genotype and AD APO-E genotype and AD onsetonset

e2 -- 7% of the populatione2 -- 7% of the population e3 -- 78% of the population e3 -- 78% of the population e4 -- 15% of the populatione4 -- 15% of the population

e3/3 - average age of onset = 74 y/oe3/3 - average age of onset = 74 y/o e3/4 and e4/4 average age = 69 y/oe3/4 and e4/4 average age = 69 y/o

APO-E genotype and AD riskAPO-E genotype and AD risk46 Million in US > 60 y/o //// 4 Million have AD46 Million in US > 60 y/o //// 4 Million have AD

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

GenT %pop %AD #pop #AD risk If all US

E2/2 1% 0.1% 0.5M .004M 0.8% .4 M

E2/3 12 % 4% 5.5M .18M 3.2% 1.5 M

E3/3 60% 35% 27.6M 1.4M 5.1% 2.3 M

E3/4 21% 42% 9.6M 1.7M 18% 8.2 M

E4/4 2% 16% .9M .6M 67% 30.7M

See: Ashford & Mortimer, 2002, Journal of Alzheimer’s Disease

Biopsychosocial Systems Biopsychosocial Systems Affected by ADAffected by AD(all related to neuroplasticity)(all related to neuroplasticity)

Social SystemsSocial Systems Instrumental ADLs - EarlyInstrumental ADLs - Early Basic ADLs - LateBasic ADLs - Late

Psychological SystemsPsychological Systems Primary Loss Of Memory Primary Loss Of Memory Later Loss Of Learned SkillsLater Loss Of Learned Skills

Neuronal Memory Systems Neuronal Memory Systems Cortical Glutamatergic StorageCortical Glutamatergic Storage Subcortical (acetylcholine, norepi, serotonin)Subcortical (acetylcholine, norepi, serotonin) Cellular Plastic Processes Cellular Plastic Processes

APP metabolism – early, broad cortical distributionAPP metabolism – early, broad cortical distribution TAU hyperphosphorylation – late, focal effect, TAU hyperphosphorylation – late, focal effect,

dementia relateddementia related

Why Diagnose AD Why Diagnose AD Early?Early?

Safety (driving, compliance, cooking, etc.)Safety (driving, compliance, cooking, etc.) Family stress and misunderstanding (blame, Family stress and misunderstanding (blame,

denial) denial) Early education of caregivers of how to handle Early education of caregivers of how to handle

patient (choices, getting started)patient (choices, getting started) Advance planning while patient is competent Advance planning while patient is competent

(will, proxy, power of attorney, advance (will, proxy, power of attorney, advance directives)directives)

Patient’s and Family’s right to knowPatient’s and Family’s right to know Specific treatments now available, may delay Specific treatments now available, may delay

nursing home placement longer if started earliernursing home placement longer if started earlier

Early Recognition of AD: Consensus Early Recognition of AD: Consensus StatementStatement

(AAGP, AGS, Alzheimer’s Association)(AAGP, AGS, Alzheimer’s Association)

AD continues to be missed as AD continues to be missed as diagnosisdiagnosis

AD is unrecognized and under-AD is unrecognized and under-reportedreported patients do not realizedpatients do not realized families tend to compensatefamilies tend to compensate

Effective treatment and management Effective treatment and management techniques are availabletechniques are available

Small et al., JAMA, 1997

Need for Better Need for Better ScreeningScreening

and Early Assessment and Early Assessment ToolsTools Genetic vulnerability testingGenetic vulnerability testing

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

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

derivativesderivatives Mild Dementia severity assessmentsMild Dementia severity assessments Detecting early changeDetecting early change

predicting progression, measuring ratepredicting progression, measuring rate

Alzheimer Warning SignsAlzheimer Warning SignsTop TenTop Ten

Alzheimer AssociationAlzheimer Association

1. Recent memory loss affecting job1. Recent memory loss affecting job2. Difficulty performing familiar tasks2. Difficulty performing familiar tasks3. Problems with language3. Problems with language4. Disorientation to time or place4. Disorientation to time or place5. Poor or decreased judgment5. Poor or decreased judgment6. Problems with abstract thinking6. Problems with abstract thinking7. Misplacing things7. Misplacing things8. Changes in mood or behavior8. Changes in mood or behavior9. Changes in personality 9. Changes in personality 10. Loss of initiative10. Loss of initiative

Need for a Brief Screening Need for a Brief Screening Test for Alzheimer’s Test for Alzheimer’s

DiseaseDisease

Recent evidence of benefits of anti-Recent evidence of benefits of anti-cholinesterase agents in the cholinesterase agents in the treatment of mild Alzheimer’s treatment of mild Alzheimer’s diseasedisease Improvement of cognitionImprovement of cognition Slowing of progressionSlowing of progression

Available Screening TestsAvailable Screening Tests MMSE MMSE 10 -- 15 min10 -- 15 min

Too longToo long

7-Minute Screen7-Minute Screen 7 – 10 min 7 – 10 min Too complexToo complex

Clock Drawing TestClock Drawing Test 2 – 4 min 2 – 4 min Not sensitiveNot sensitive

Mini-cogMini-cog 3 – 5 min 3 – 5 min Complex scoring, unclear adequacyComplex scoring, unclear adequacy

Memory Impairment ScreenMemory Impairment Screen 4 min 4 min Need for slightly shorter, easier testNeed for slightly shorter, easier test

(a suitably accurate test that takes less (a suitably accurate test that takes less than 2 minutes is not available)than 2 minutes is not available)

Feldman H, GraconS. In: Clinical Diagnosis and Management of Alzheimer’s Disease. 1996:239-253.

The Progress of Alzheimer’s DiseaseThe Progress of Alzheimer’s Disease

0

5

10

15

20

25

30

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

Years

MM

SE s

core

Early diagnosis Mild-moderate Severe

Cognitive symptoms

Loss of ADL

Behavioral problems

Nursing home placement

Death

Ashford et al., 1995

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

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10

DISABILITY ("time-index" year units)

PR

OB

AB

ILIT

Y C

OR

RE

CT

PENCILAPPL-REPWATCLOCATIONPENY-REPTABL-REPCLOS-ISRIT-HANDCITYFOLD-HLFSENTENCECOUNTYNO-IFSFLOORSEASONYEARPUT-LAPMONTHADDRESSDRAW-PNTDAYSPEL_ALLDATEAPPL-MEMPENY-MEMTABL-MEM

Mini-Mental State Exam items

Total Item Information Function for the MMSE

0

5

10

15

20

25

30

-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10

Alzheimer's Severity Horographic Function (time-index year units)

Info

rmat

ion

Brief Alzheimer ScreeningBrief Alzheimer Screening Repeat these three words: “apple, table, penny”.Repeat these three words: “apple, table, penny”. So you will remember these words, repeat them again, twice.So you will remember these words, repeat them again, twice. What is today’s date? What is today’s date?

1 point if within 2 days.1 point if within 2 days. ““Name as many animals as you can in 30 seconds, GO!”Name as many animals as you can in 30 seconds, GO!”

1 point for naming 10 animals 1 point for naming 10 animals ““What were the 3 words I asked you to repeat?” (no prompts)What were the 3 words I asked you to repeat?” (no prompts)

1 for each word,1 for each word, TOTAL (max = 5)TOTAL (max = 5)

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

If score of 2 or 3:If score of 2 or 3: Spell World BackwardsSpell World Backwards Draw a Clock (gives some impression of visuospatial problems)Draw a Clock (gives some impression of visuospatial problems)

If continued difficulties, ask questions about ADLsIf continued difficulties, ask questions about ADLs

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

9

20

1413

1211

10

9

6

7

8

2627

25

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

False Positive Rate (%) (1-Specificity)

Tru

e P

osi

tiv

e R

ate

(%

) (

Se

nsi

tiv

ity)

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

BLT/Ashford Memory BLT/Ashford Memory TestTest

(to detect AD onset)(to detect AD onset) New test to screen patients for New test to screen patients for

Alzheimer’s disease using the World-Alzheimer’s disease using the World-Wide Web – based testing and CD-Wide Web – based testing and CD-distributiondistribution

Test only takes 1-minuteTest only takes 1-minute Test can be repeated often Test can be repeated often (quarterly)(quarterly) Any change over time can be detectedAny change over time can be detected Test is at: Test is at: www.ibaglobal.com/BLTwww.ibaglobal.com/BLT For info, see: For info, see: www.medafile.comwww.medafile.com

AssessmentAssessmentHistory Of The Development Of The History Of The Development Of The

DementiaDementia Ask the Patient What Problem Has Brought Him to Ask the Patient What Problem Has Brought Him to

See YouSee You Ask the Family, Companion about the ProblemAsk the Family, Companion about the Problem Specifically Ask about Memory ProblemsSpecifically Ask about Memory Problems Ask about the First SymptomsAsk about the First Symptoms Enquire about Time of OnsetEnquire about Time of Onset Ask about Any Unusual Events Around the Time of Ask about Any Unusual Events Around the Time of

Onset, e.g., stress, trauma, surgeryOnset, e.g., stress, trauma, surgery Ask about Nature and Rate of ProgressionAsk about Nature and Rate of Progression

Physical ExaminationPhysical Examination Neurological ExaminationNeurological Examination

PHYSICAL/PHYSICAL/NEUROLOGICAL NEUROLOGICAL EXAMINATIONEXAMINATION

CHECK BLOOD PRESSURECHECK BLOOD PRESSURE IDENTIFY SYSTEMIC DISORDERSIDENTIFY SYSTEMIC DISORDERS CRANIAL NERVES CRANIAL NERVES

Olfactory dysfunction, poor eye trackingOlfactory dysfunction, poor eye tracking Check for hearing, vision deficitsCheck for hearing, vision deficits

SENSORY DEFICITS SENSORY DEFICITS Proprioception, vibrationProprioception, vibration

DEEP TENDON REFLEXESDEEP TENDON REFLEXES Brisk, check for focal reflexesBrisk, check for focal reflexes

PATHOLOGIC REFLEXESPATHOLOGIC REFLEXES Hyperactive snout reflex, GegenhaltenHyperactive snout reflex, Gegenhalten

CURRENT APPROACHES CURRENT APPROACHES TO SEVERITY TO SEVERITY ASSESSMENTASSESSMENT

MINI-MENTAL STATE EXAMMINI-MENTAL STATE EXAM CLOCK DRAWINGCLOCK DRAWING ANIMAL NAMING (1 minute)ANIMAL NAMING (1 minute) MATTIS DEMENTIA RATING SCALEMATTIS DEMENTIA RATING SCALE ALZHEIMER’S DISEASE ALZHEIMER’S DISEASE

ASSESSEMENT SCALE (ADAS)ASSESSEMENT SCALE (ADAS) ACTIVITIES OF DAILY LIVINGACTIVITIES OF DAILY LIVING GLOBAL CLINICAL SCALEGLOBAL CLINICAL SCALE CLINICAL DEMENTIA RATING SCALECLINICAL DEMENTIA RATING SCALE GLOBAL DETERIORATION SCALE / FASTGLOBAL DETERIORATION SCALE / FAST

NEUROPSYCHOLOGICANEUROPSYCHOLOGICAL TESTING L TESTING (WAIS, (WAIS,

WECHSLER)WECHSLER) MEMORY: SHORT-TERM, REMOTEMEMORY: SHORT-TERM, REMOTE VERBAL FUNCTION, FLUENCYVERBAL FUNCTION, FLUENCY VISUO-SPATIAL FUNCTIONVISUO-SPATIAL FUNCTION ATTENTIONATTENTION EXECUTIVE FUNCTIONEXECUTIVE FUNCTION ABSTRACT THINKINGABSTRACT THINKING ACCOUNT FOR EDUCATIONACCOUNT FOR EDUCATION ACCOUNT FOR PRIOR ACCOUNT FOR PRIOR

DISFUNCTIONSDISFUNCTIONS

LABORATORY TESTS LABORATORY TESTS (routine)(routine)

BLOOD TESTSBLOOD TESTS electrolytes, liver, kidney function tests, electrolytes, liver, kidney function tests,

glucoseglucose thyroid function tests (T3, T4, FTI, TSH)thyroid function tests (T3, T4, FTI, TSH) vitamin B12, folatevitamin B12, folate complete blood count, ESRcomplete blood count, ESR VDRL, HIV (if indicated)VDRL, HIV (if indicated)

EKG (if indicated)EKG (if indicated) CHEST X-RAY (if indicated)CHEST X-RAY (if indicated) URINALYSISURINALYSIS ANATOMICAL BRAIN SCAN – CT (cheapest), MRIANATOMICAL BRAIN SCAN – CT (cheapest), MRI

SPECIAL LABORATORY SPECIAL LABORATORY TESTS TESTS

FUNCTIONAL BRAIN IMAGING FUNCTIONAL BRAIN IMAGING (SPECT, PET)(SPECT, PET)

EEG, Evoked Potentials (P300)EEG, Evoked Potentials (P300) REACTION TIMES (slowed in the elderly, REACTION TIMES (slowed in the elderly,

especially when complex response is especially when complex response is requiredrequired

CSF ANALYSIS - ROUTINE STUDIESCSF ANALYSIS - ROUTINE STUDIES ELEVATED TAU (future possible)ELEVATED TAU (future possible) DECREASED AMYLOID (future possible)DECREASED AMYLOID (future possible)

HEAVY METAL SCREEN (24 hr urine)HEAVY METAL SCREEN (24 hr urine) GENOTYPINGGENOTYPING

APO-LIPOPROTEIN-E (for supporting dx)APO-LIPOPROTEIN-E (for supporting dx) AUTOSOMAL DOMINANT (young onset)AUTOSOMAL DOMINANT (young onset)

Justification for Brain Justification for Brain Scan in Dementia Scan in Dementia

DiagnosisDiagnosis Differential Diagnosis: Tumor, Stroke, Differential Diagnosis: Tumor, Stroke,

Subdural Hematoma, Normal Pressure Subdural Hematoma, Normal Pressure Hydrocephalus, EncephalomalaciaHydrocephalus, Encephalomalacia

Confirmation of atrophy patternConfirmation of atrophy pattern Estimation of severity of brain atrophyEstimation of severity of brain atrophy MRI shows T2 white matter changesMRI shows T2 white matter changes

Periventricular, basal ganglia, focal vs Periventricular, basal ganglia, focal vs confluentconfluent

These may indicate vascular pathologyThese may indicate vascular pathology SPECT, PET - estimation of regions of SPECT, PET - estimation of regions of

physiologic dysfunction, areas of infarctionphysiologic dysfunction, areas of infarction Helps family to visualize problemHelps family to visualize problem

Ashford et al, 2000

Shoghi-Jadid et al., 2002UCLA group, J. Amer. Ger. Psych, 2002

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

67-year-old control Alzheimer patient

PET brain images

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

The family members want itThe family members want it They consider recommendations against genetic They consider recommendations against genetic

testing to be “paternalistic”testing to be “paternalistic” Family members can make more powerful Family members can make more powerful

financial decisions based on this knowledge financial decisions based on this knowledge than the relevance of insurance companies than the relevance of insurance companies implementing changes in actuarial calculationsimplementing changes in actuarial calculations

Those at risk can seek more frequent testingThose at risk can seek more frequent testing This is the best opportunity for early recognitionThis is the best opportunity for early recognition

Those at risk will be better advocates for Those at risk will be better advocates for researchresearch

Specific preventive treatments can be Specific preventive treatments can be developed for each genetic factordeveloped for each genetic factor

BEHAVIORAL BEHAVIORAL PROBLEMS IN PROBLEMS IN

DEMENTIA PATIENTSDEMENTIA PATIENTS MOOD DISORDERS – depression – early in MOOD DISORDERS – depression – early in

ADAD PSYCHOTIC DISORDERSPSYCHOTIC DISORDERS

Particularly paranoia, e.g, people stealing thingsParticularly paranoia, e.g, people stealing things INAPPROPRIATE BEHAVIORS (sexualINAPPROPRIATE BEHAVIORS (sexual AGGRESSION: verbal, physicalAGGRESSION: verbal, physical PURPOSELESS ACTIVITY: verbal, motorPURPOSELESS ACTIVITY: verbal, motor MEAL TIME BEHAVIORSMEAL TIME BEHAVIORS SLEEP DISORDERSSLEEP DISORDERS

NEUROPSYCHIATRIC NEUROPSYCHIATRIC TREATMENTSTREATMENTS

First treat medical problemsFirst treat medical problems Second environmental Second environmental

interventionsinterventions Third neuropsychiatric medicationsThird neuropsychiatric medications

Cognitive impairmentCognitive impairment Psychotic symptomsPsychotic symptoms Depressive symptomsDepressive symptoms Insomnia symptomsInsomnia symptoms Anorexia symptomsAnorexia symptoms Parkinsonian symptomsParkinsonian symptoms