DELIRIUM, DEMENTIA, AND DELIRIUM, DEMENTIA, AND

AMNESTIC and OTHER AMNESTIC and OTHER
COGNITIVE DISORDERS COGNITIVE DISORDERS
Second Year Medical School Second Year Medical School
J. Wesson Ashford, M.D., Ph.D. J. Wesson Ashford, M.D., Ph.D.
University of Kentucky University of Kentucky
VAMC, Lexington VAMC, Lexington
February 12, 2003 February 12, 2003
Slides at: Slides at: www.medafile.com/demdx03a.ppt www.medafile.com/demdx03a.ppt
Dementia Definition Dementia Definition
Multiple Cognitive Deficits: Multiple Cognitive Deficits:
Memory dysfunction Memory dysfunction
especially new learning, a prominent early symptom especially new learning, a prominent early symptom
At least one additional cognitive deficit At least one additional cognitive deficit
aphasia, apraxia, agnosia, or executive dysfunction aphasia, apraxia, agnosia, or executive dysfunction
Cognitive Disturbances: Cognitive Disturbances:
Sufficiently severe to cause impairment of occupational Sufficiently severe to cause impairment of occupational
or social functioning and or social functioning and
Must represent a decline from a previous level of Must represent a decline from a previous level of
functioning functioning
Differential Diagnosis: Top Ten Differential Diagnosis: Top Ten
(commonly used mnemonic device: AVDEMENTIA) (commonly used mnemonic device: AVDEMENTIA)
1. 1. A Alzheimer Disease (pure ~40%, + mixed~70%) lzheimer Disease (pure ~40%, + mixed~70%)
2. 2. VVascular Disease, MID (5 ascular Disease, MID (5--20%) 20%)
3. 3. D Drugs, rugs, D Depression, epression, D Delirium elirium
4. 4. E Ethanol thanol (5 (5--15%) 15%)
5. 5. MMedical / edical / MMetabolic Systems etabolic Systems
6. 6. E Endocrine (thyroid, diabetes), ndocrine (thyroid, diabetes), E Ears, ars, E Eyes, yes, E Environ. nviron.
7. 7. NNeurologic (other primary degenerations, etc.) eurologic (other primary degenerations, etc.)
8. 8. TTumor, umor, TToxin, oxin, TTrauma rauma
9. 9. IInfection, nfection, IIdiopathic, diopathic, IImmunologic mmunologic
10. 10. A Amnesia, mnesia, A Autoimmune, utoimmune, A Apnea, pnea, A AAMI AMI
Diagnostic Criteria For Dementia Of The Diagnostic Criteria For Dementia Of The
Alzheimer Type Alzheimer Type (DSM (DSM- -IV, APA, 1994) IV, APA, 1994)
A. A. Multiple Cognitive Deficits Multiple Cognitive Deficits
1. Memory Impairment 1. Memory Impairment
2. Other Cognitive Impairment 2. Other Cognitive Impairment
B. Deficits Impair Social/Occupational B. Deficits Impair Social/Occupational
C. C. Course Shows Gradual Onset And Decline Course Shows Gradual Onset And Decline
D. D. Deficits Are Not Due to: Deficits Are Not Due to:
1. Other CNS Conditions 1. Other CNS Conditions
2. Substance Induced Conditions 2. Substance Induced Conditions
E. Do Not Occur Exclusively during Delirium E. Do Not Occur Exclusively during Delirium
F. Not Due to Another Psychiatric Disorder F. 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
M
M
S
E

s
c
o
r
e
AAMI / MCI DEMENTIA
ALZHEIMER¶S DISEASE
Alzheimer¶s Disease versus Alzheimer¶s Disease versus
Dementia Dementia
50 50 - - 70% of dementias are AD 70% of dementias are AD
Probable AD Probable AD - - 30% of cases, 90% correct 30% of cases, 90% correct
20% have other contributing diagnoses 20% have other contributing diagnoses
Possible AD Possible AD - - 40% of cases, 70% correct 40% of cases, 70% correct
40% have other contributing diagnoses 40% have other contributing diagnoses
Unlikely AD Unlikely AD - - 30% of cases, 30% are AD 30% of cases, 30% are AD
80% have other contributing diagnoses 80% have other contributing diagnoses
Vascular Dementia Vascular Dementia
(DSM (DSM- -IV IV - - APA, 1994) APA, 1994)
A. A. Multiple Cogntive Impairments Multiple Cogntive Impairments
1. 1. Memory Impairment Memory Impairment
2. 2. Other Cognitive Disturbances Other Cognitive Disturbances
B. B. Deficits Impair Social/Occupational Deficits Impair Social/Occupational
C. C. Focal Neurological Signs and Symptoms or Focal Neurological Signs and Symptoms or
Laboratory Evidence Indicating Cerebrovascular Laboratory Evidence Indicating Cerebrovascular
Disease Etiologically Related to the Deficits Disease Etiologically Related to the Deficits
D. D. Not Due to Delirium Not Due to Delirium
Factors Associated with Multi Factors Associated with Multi- -infarct Dementia infarct Dementia
History of stroke (especially in Nursing Home) History of stroke (especially in Nursing Home)
Followed by onset of dementia within 3 months Followed by onset of dementia within 3 months
Abrupt onset, Step Abrupt onset, Step--wise deterioration wise deterioration
Cardiovascular disease Cardiovascular disease -- HTD, ASCVD, & Atrial Fib HTD, ASCVD, & Atrial Fib
Depression (left anterior strokes), personality change Depression (left anterior strokes), personality change
More gait problems than in AD More gait problems than in AD
MRI evidence of T2 changes (?? Binswanger·s disease) MRI evidence of T2 changes (?? Binswanger·s disease)
Basal ganglia, putamen Basal ganglia, putamen
Periventricular white matter Periventricular white matter
SPECT / PET show focal areas of dysfunction SPECT / PET show focal areas of dysfunction
Neuropsychological dysfunctions are patchy Neuropsychological 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)
S
C
O
R
E
Post Post- -Cardiac Surgery Cardiac Surgery
53% post 53% post--surgical confusion at discharge (delirium) surgical confusion at discharge (delirium)
42% impaired 5 years later (dementia) 42% impaired 5 years later (dementia)
May be related to anoxic brain injury, apnea May be related to anoxic brain injury, apnea
May be related to narcotic/other medication May 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 Cardio--vascular disease and stress may start vascular disease and stress may start
Alzheimer pathology Alzheimer pathology
Any surgery may have a similar effect related to peri Any surgery may have a similar effect related to peri--op or op or
post post--op anoxia or vascular stress op anoxia or vascular stress
Newman et al., 2001, NEJM Newman et al., 2001, NEJM
Drug Interactions Drug Interactions
Anticholinergics: amitriptyline, atropine, Anticholinergics: amitriptyline, atropine,
benztropine, scopolamine, hyoscyamine, benztropine, scopolamine, hyoscyamine,
oxybutynin, diphenhydramine, chlorpheniramine, oxybutynin, diphenhydramine, chlorpheniramine,
many anti many anti--histaminics histaminics
May aggravate Alzheimer pathology May aggravate Alzheimer pathology
GABA agonists: benzodiazepines, barbiturates, GABA agonists: benzodiazepines, barbiturates,
ethanol, anti ethanol, anti--convulsants convulsants
Beta Beta--blockers: propranolol blockers: propranolol
Dopaminergics: l Dopaminergics: l--dopa, alpha dopa, alpha--methyl methyl--dopa dopa
Narcotics: may contribute to dementia Narcotics: may contribute to dementia
Drug Toxicity Drug Toxicity
Anti Anti--cholinergic cholinergic
Peripheral: blurred vision, dry mouth, constipation, Peripheral: blurred vision, dry mouth, constipation,
urinary obstruction urinary obstruction
Central: confusion, memory encoding block Central: confusion, memory encoding block
Gaba Gaba--agonist: agonist:
Muscle relaxant, anti Muscle relaxant, anti--convulsant, sedative, anti convulsant, sedative, anti--
anxiety, amnesic, confusion anxiety, amnesic, confusion
Medication induced electrolyte imbalance Medication induced electrolyte imbalance
Confusion (watch for in nursing home) Confusion (watch for in nursing home)
Depression Depression
Onset: rapid Onset: rapid
Precipitants: psycho Precipitants: psycho--social (not organic) social (not organic)
Duration: less than 3 months to presentation Duration: less than 3 months to presentation
Mood: depressed, anxious Mood: depressed, anxious
Behavior: decreased activity or agitation Behavior: decreased activity or agitation
Cognition: unimpaired or poor responses Cognition: unimpaired or poor responses
Somatic symptoms: fatigue, lethargy, Somatic symptoms: fatigue, lethargy, sleep, appetite sleep, appetite
disruption disruption
Course: rapid resolution with treatment, Course: rapid resolution with treatment,
but may precede Alzheimer·s disease but may precede Alzheimer·s disease
Delirium Definition Delirium Definition
(more often a problem in medical in (more often a problem in medical in- -patients) patients)
Disturbance of consciousness Disturbance of consciousness
i.e., reduced clarity of awareness of the i.e., reduced clarity of awareness of the
environment with reduced ability to focus, sustain, environment with reduced ability to focus, sustain,
or shift attention or shift attention
Change in cognition (memory, orientation, Change in cognition (memory, orientation,
language, perception) language, perception)
Development over a short period (hours to Development over a short period (hours to
days), tends to fluctuate days), tends to fluctuate
Evidence of medical etiology Evidence of medical etiology
Delirium Delirium
Susceptibility may be symptom of early dementia, or Susceptibility may be symptom of early dementia, or
delirium may predispose to later dementia delirium may predispose to later dementia
Predisposing factors Predisposing factors -- Age, infections, dementia Age, infections, dementia
Medical conditions Medical conditions
Infections: Infections:
G.U. G.U. -- urinary urinary
Respiratory (URI, pneumonia) Respiratory (URI, pneumonia)
G.I. G.I.
Constipation Constipation
Drug toxicity Drug toxicity
Fracture (especially related to hip fracture) Fracture (especially related to hip fracture)
Ethanol Ethanol
Possibly Neuroprotective Possibly Neuroprotective
May not kill neurons directly May not kill neurons directly (?Dietary recommendation?) (?Dietary recommendation?)
Accidents, Head Injury Accidents, Head Injury
Dietary Deficiency Dietary Deficiency
Thiamine Thiamine ²² Wernicke Wernicke--Korsakoff syndrome Korsakoff syndrome
Hepatic Encephalopathy Hepatic Encephalopathy
Withdrawal Damage (seizures) Delayed Alcohol Withdrawal Damage (seizures) Delayed Alcohol
Withdrawal Withdrawal
Watch for in hospitalized patients Watch for in hospitalized patients
Chronic Neurodegeneration Chronic Neurodegeneration
Cerebellum, gray matter nuclei Cerebellum, gray matter nuclei
Medical / Endocrine Medical / Endocrine
Thyroid dysfunction Thyroid dysfunction
Hypothyoidism Hypothyoidism ²² elevated TSH elevated TSH
Compensated hypothyroidism may have normal T4, FTI Compensated hypothyroidism may have normal T4, FTI
Hyperthyroidism Hyperthyroidism
Apathetic, with anorexia, fatigue, weight loss, increased T4 Apathetic, with anorexia, fatigue, weight loss, increased T4
Diabetes Diabetes
Hypoglycemia Hypoglycemia (loss of recent memory since episode) (loss of recent memory since episode)
Hyperglycemia Hyperglycemia
Hypercalcemia Hypercalcemia
Nephropathy, Uremia Nephropathy, Uremia
Hepatic dysfunction (Wilson·s disease) Hepatic dysfunction (Wilson·s disease)
Vitamin Deficiency (B12, thiamine, niacin) Vitamin Deficiency (B12, thiamine, niacin)
Pernicious anemia Pernicious anemia ²² B12 deficiency, ?homocysteine B12 deficiency, ?homocysteine
Eyes, Ears, Environment Eyes, Ears, Environment
Must consider sensory deficits might contribute to the Must consider sensory deficits might contribute to the
appearance of the patient being demented appearance of the patient being demented
Central Auditory Processing Deficits (CAPD) Central Auditory Processing Deficits (CAPD)
Hearing problems are socially isolating Hearing problems are socially isolating
Visual problems are difficult to accommodate by a Visual problems are difficult to accommodate by a
demented patient, ?To do cataract op? demented patient, ?To do cataract op?
Environmental stress factors can predispose to a Environmental stress factors can predispose to a
variety of conditions variety of conditions
Nutritional deficiencies (tea & toast syndrome) Nutritional deficiencies (tea & toast syndrome)
Neurological Conditions Neurological Conditions
Primary Neurodegenerative Disease Primary Neurodegenerative Disease
Diffuse Lewy Body Dementia (? 7 Diffuse Lewy Body Dementia (? 7 -- 50%) 50%)
Note relation to Parkinson·s disease, symptoms Note relation to Parkinson·s disease, symptoms
Hallucinations, fluctuating course, neuroleptic hypersensitivity) Hallucinations, fluctuating course, neuroleptic hypersensitivity)
Fronto Fronto--temporal dementia (tau gene) temporal dementia (tau gene)
Impaired attention, behavioral dyscontrol Impaired attention, behavioral dyscontrol
Decrease blood flow, hypometaboism on SPECT / PET Decrease blood flow, hypometaboism on SPECT / PET
(Pick·s disease, Argyrophylic grain disease) (Pick·s disease, Argyrophylic grain disease)
Focal cortical atrophy Focal cortical atrophy
Primary progressive aphasia (many causes) Primary progressive aphasia (many causes)
Unilateral atrophy, hypofunction on EEG, SPECT, PET Unilateral atrophy, hypofunction on EEG, SPECT, PET
Normal pressure hydrocephalus Normal pressure hydrocephalus
Dementia with gait impairment, incontinence Dementia with gait impairment, incontinence
Suggested on CT, MRI; need tap, ventriculography Suggested on CT, MRI; need tap, ventriculography
Other Neurologic Conditions Other Neurologic Conditions
Subdural hematoma Subdural hematoma
Huntington·s disease Huntington·s disease
Creutzfeldt Creutzfeldt--Jakob disease Jakob disease
Rapid progression Rapid progression
Characteristic EEG changes Characteristic EEG changes
Multiple sclerosis Multiple sclerosis
Corticobasal degeneraton Corticobasal degeneraton
Cerebellar degeneration Cerebellar degeneration
Progressive supranuclear palsey Progressive supranuclear palsey
Tumor Tumor
Primary brain tumor Primary brain tumor
M Meningioma (treatable) eningioma (treatable)
Glioma (usually not responsive to therapy) Glioma (usually not responsive to therapy)
Metastatic brain tumor Metastatic brain tumor
Remote effects of carcinoma Remote effects of carcinoma
Toxins Toxins
Heavy metal screen if considered Heavy metal screen if considered
Trauma
Concussion, Contusion Concussion, Contusion
Occult head trauma if recent fall Occult head trauma if recent fall
Subdural hematoma Subdural hematoma
Hydrocephalus: Hydrocephalus:
Normal pressure (late effect of bleed) Normal pressure (late effect of bleed)
Dementia pugilistica Dementia 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 caretakers Concern re: physical abuse by caretakers
Infectious Conditions Infectious Conditions
Affecting the Brain Affecting the Brain
HIV HIV
Neurosyphilis Neurosyphilis
Viral encephalitis (herpes) Viral encephalitis (herpes)
Bacterial meningitis Bacterial meningitis
Fungal (cryptococcus) Fungal (cryptococcus)
Prion (Creutzfeldt Prion (Creutzfeldt--Jakob disease); (mad cow disease) Jakob disease); (mad cow disease)
AMNESIC DISORDER AMNESIC DISORDER
DSM DSM- -IV IV
A. A. Memory impairment Memory 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 social, Memory disturbance significantly impairs social,
occupational function, deterioration from past occupational function, deterioration from past
Memory not due to delirium, dementia Memory not due to delirium, dementia
Physiological basis or substance induced Physiological basis or substance induced
-- Distinguish from dissociative disorders, dissociative amnesia, Distinguish from dissociative disorders, dissociative amnesia,
dissociative identity disorders dissociative identity disorders
Specify Specify
-- Transient Transient ²² less than 1 month less than 1 month
-- Chronic Chronic -- more than 1 month more than 1 month
Causes of Amnesic Disorders Causes of Amnesic Disorders
Amnesia Amnesia
Dissociative: localized, selective, generalized Dissociative: localized, selective, generalized
Organic Organic -- damage to CA1 of hippocampus damage to CA1 of hippocampus
thiamine deficiency (WKE), hypoglycemia, hypoxia thiamine deficiency (WKE), hypoglycemia, hypoxia
Epileptic events Epileptic events
Partial complex seizures Partial complex seizures
Specific brain diseases Specific brain diseases
Transient global amnesia Transient global amnesia
Multiple sclerosis Multiple sclerosis
Age Age- -Associated Memory Impairment Associated Memory Impairment
vs vs
Mild Cognitive Impairment Mild Cognitive Impairment
Memory declines with age Memory declines with age
Age Age -- related memory decline corresponds with atrophy related memory decline corresponds with atrophy
of the hippocampus of the hippocampus
Older individuals remember more complex items and Older individuals remember more complex items and
relationships relationships
Older individuals are slower to respond Older individuals are slower to respond
Memory problems predispose to development of Memory problems predispose to development of
Alzheimer·s disease Alzheimer·s disease
Advances in Alzheimer·s Advances in Alzheimer·s
Disease Disease
Incidence and prevalence Incidence and prevalence
Search for etiology, genetics Search for etiology, genetics
Understanding pathophysiology Understanding pathophysiology
Better screening tools for early recognition Better screening tools for early recognition
Improved diagnosis Improved diagnosis
Developing interventions Developing interventions
Behavioral conditions and management Behavioral conditions and management
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
e
o
p
l
e
Males,
138,053,563
Females,
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
N
u
m
b
e
r

o
f

p
e
o
p
l
e
Males, 1,175,460
Females, 1,215,939
www.cdc.gov
U.S. mortality rate by age
1999 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
p
r
o
b
a
b
i
l
i
t
y
Males
Females
U.S. mortality rate by age
1999 CDC / 2000 census
y = 9E-05e
0.0848x
R
2
= 0.9974
y = 3E-05e
0.0926x
R
2
= 0.9973
0.0001
0.0010
0.0100
0.1000
1.0000
30 40 50 60 70 80 90 100
Age
p
r
o
b
a
b
i
l
i
t
y
Males
Females
PREVALENCE of AD PREVALENCE of AD
Estimated 4 million cases in US (2000) Estimated 4 million cases in US (2000)
(2000 (2000 -- 46 million individuals over 60 y/o) 46 million individuals over 60 y/o)
Estimated 500,000 new cases per year Estimated 500,000 new cases per year
Increase with age (prevalence) Increase with age (prevalence)
1% of 60 1% of 60 -- 65 (10.7m) = 107,000 65 (10.7m) = 107,000
2% of 65 2% of 65 -- 70 ( 9.4m) = 188,000 70 ( 9.4m) = 188,000
4% of 70 4% of 70 -- 75 ( 8.7m) = 350,000 75 ( 8.7m) = 350,000
8% of 75 8% of 75 -- 80 ( 7.4m) = 595,000 80 ( 7.4m) = 595,000
16% of 80 16% of 80 -- 85 ( 5.0m) = 800,000 85 ( 5.0m) = 800,000
U.S. mortality rate by age
1999 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
p
r
o
b
a
b
i
l
i
t
y
Males
Females
dementia incidence
U.S. Dementia Incidence
(4 million / 8yr)
0
2000
4000
6000
8000
10000
12000
14000
16000
50 60 70 80 90 100
Age
#

/

y
r
male=170,603
f emale=329,115
Dementia incidence by individual
0
0.002
0.004
0.006
0.008
0.01
0.012
0.014
0.016
50 60 70 80 90 100
Age
P
r
o
p
o
r
t
i
o
n
a
l

r
i
s
k

/

y
r
male=34%
f emale=66%
Oeppen & Vaupel, 2002
Oeppen & Vaupel, 2002
ECONOMIC IMPACT OF AD ECONOMIC IMPACT OF AD
2 million AD patients in nursing homes 2 million AD patients in nursing homes
Projection to Kentucky Projection to Kentucky ²² 22,000 (6,000 in Eastern KY) 22,000 (6,000 in Eastern KY)
Nursing homes cost Nursing homes cost -- $120 to $160 per day $120 to $160 per day
Annualized cost of nursing homes ranges from $40 to Annualized cost of nursing homes ranges from $40 to
$70,000 per year $70,000 per year
Care of AD patients costs $80 billion per year Care of AD patients costs $80 billion per year
With lost wages of patients and families plus costs for With lost wages of patients and families plus costs for
non non--nursing home patients: nursing home patients:
Total costs: $ Total costs: $120 billion annually 120 billion annually ((Am J Publ Hlth Am J Publ Hlth))
Projection to Kentucky Projection to Kentucky ²² $1.5 billion annually! $1.5 billion annually!
Etiology Etiology
Age ( Age (initial genesis vs response to stress) initial genesis vs response to stress)
Bigger factor than for mortality Bigger factor than for mortality
Design in a plastic (memory) system, energy demands Design in a plastic (memory) system, energy demands
Stressor response ( Stressor response (adequate repair mechanisms) adequate repair mechanisms)
Trauma (head injury), vascular (stroke), surgery, loss, grief, etc. Trauma (head injury), vascular (stroke), surgery, loss, grief, etc.
Genetics (amyloid related) Genetics (amyloid related)
Familial, early onset: APP (21), PS (14, 1) (less than 5%) Familial, early onset: APP (21), PS (14, 1) (less than 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 protective APOE e2 may be most protective
many other candidate genes many other candidate genes
Relation to vascular factors, cholesterol, BP Relation to vascular factors, cholesterol, BP
Education (? design vs protection) Education (? design vs protection)
Environment Environment -- diet, exercise, smoking diet, exercise, smoking
RELATIVE RISK FACTORS RELATIVE RISK FACTORS
FOR ALZHEIMER·S DISEASE FOR ALZHEIMER·S DISEASE
Family history of dementia Family history of dementia 3.5 (2.6 3.5 (2.6 -- 4.6) 4.6)
Family history Family history -- Downs Downs 2.7 (1.2 2.7 (1.2 -- 5.7) 5.7)
Family history Family history -- Parkinson·s Parkinson·s 2.4 (1.0 2.4 (1.0 -- 5.8) 5.8)
Maternal age > 40 years Maternal age > 40 years 1.7 (1.0 1.7 (1.0 -- 2.9) 2.9)
Head trauma (with LOC) Head trauma (with LOC) 1.8 (1.3 1.8 (1.3 -- 2.7) 2.7)
History of depression History of depression 1.8 (1.3 1.8 (1.3 -- 2.7) 2.7)
History of hypothyroidism History of hypothyroidism 2.3 (1.0 2.3 (1.0 -- 5.4) 5.4)
History of severe headache History of severe headache 0.7 (0.5 0.7 (0.5 -- 1.0) 1.0)
NSAID use or statin use NSAID use or statin use 0.2 (0.05 0.2 (0.05 ²² 0.83) 0.83)
Roca, 1994, t¶Veldt, 2002
NEUROPATHOLOGY OF AD NEUROPATHOLOGY OF AD
Senile plaques Senile plaques
beta beta--amyloid protein (? Primary problem) amyloid protein (? Primary problem)
Neurofibrillary tangles Neurofibrillary tangles
hyper hyper--phosphorylated tau (loss of synapses, dementia) phosphorylated tau (loss of synapses, dementia)
Neurotransmitter losses Neurotransmitter losses
Acetylcholine (Ach) Acetylcholine (Ach) ²² major loss of nicotinic receptors major loss of nicotinic receptors
Norepinephrine, serotonin, glutamate, GABAss Norepinephrine, serotonin, glutamate, GABAss
Inflammatory responses Inflammatory responses
New Neuropath Mechanisms New Neuropath Mechanisms
Amyloid PreProtein (APP Amyloid PreProtein (APP -- ch21) (early changes) ch21) (early changes)
metabolism occurs on cholesterol ´raftsµ metabolism occurs on cholesterol ´raftsµ
Cholesterol transport by APOE (ch 19) Cholesterol transport by APOE (ch 19)
alpha alpha--secretase vs beta/gamma secretase metabolism secretase vs beta/gamma secretase metabolism
influence toward alpha influence toward alpha--secretase by Acetylcholine secretase by Acetylcholine
gamma gamma--secretase (PreSenilin genes, ch14,1) secretase (PreSenilin genes, ch14,1)
break down break down -- Insulin Degrading Enzyme (ch10), etc. Insulin Degrading Enzyme (ch10), etc.
prevention of fibril formation by melatonin prevention of fibril formation by melatonin
Tau hyperphosphorylation (relation to dementia) Tau hyperphosphorylation (relation to dementia)
glycogen glycogen--synthase synthase--kinase (GSK) 3 kinase (GSK) 3--beta beta
inhibition by Ach, lithium, valproic acid inhibition by Ach, lithium, valproic acid
Protei
phosphoryl tio
yper-P-
q/11
1 h
Pk
M1 I or h
PLCF
PKC
GSK-3
bet
PHF
E-secret se
E PPs
PP
FAPPs
F yloi
F/K-secret se
Adapt d fr Fis r,
Li+
Genes and Alzheimer·s disease Genes and Alzheimer·s disease
(60% (60% - - 80 % of causation) 80 % of causation)
(all known genes relate to (all known genes relate to FFamyloid) 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 Non--familial (late onset) familial (late onset)
APOE APOE
Clinical studies suggest 40 Clinical studies suggest 40 ²² 50% due to 50% due to II44
Population studies suggest 10 Population studies suggest 10 ²² 20% cause 20% cause
Evolution over last 300,000 to 200,000 years Evolution over last 300,000 to 200,000 years
At least 20 other genes At least 20 other genes
APO APO- -E genotype and AD onset E genotype and AD onset
e2 e2 -- -- 7% of the population 7% of the population
e3 e3 -- -- 78% of the population 78% of the population
e4 e4 -- -- 15% of the population 15% of the population
e3/3 e3/3 -- average age of onset = 74 y/o average age of onset = 74 y/o
e3/4 and e4/4 average age = 69 y/o e3/4 and e4/4 average age = 69 y/o
APO APO- -E genotype and AD risk E genotype and AD risk
46 Million in US > 60 y/o //// 4 Million have AD 46 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
E / 1 .1 . M . M . . M
E / 1 . M .1 M . 1. M
E / 6 .6M 1. M .1 . M
E / 1 .6M 1. M 1 . M
E / 16 . M .6M 6 . M


See: Ashford & Mortimer, 2002, Journal of Alzheimer¶s Disease
Biopsychosocial Systems Biopsychosocial Systems
Affected by AD Affected by AD
(all related to neuroplasticity) (all related to neuroplasticity)
Social Systems Social Systems
Instrumental ADLs Instrumental ADLs -- Early Early
Basic ADLs Basic ADLs -- Late Late
Psychological Systems Psychological Systems
Primary Loss Of Memory Primary Loss Of Memory
Later Loss Of Learned Skills Later Loss Of Learned Skills
Neuronal Memory Systems Neuronal Memory Systems
Cortical Glutamatergic Storage Cortical Glutamatergic Storage
Subcortical (acetylcholine, norepi, serotonin) Subcortical (acetylcholine, norepi, serotonin)
Cellular Plastic Processes Cellular Plastic Processes
APP metabolism APP metabolism ²² early, broad cortical distribution early, broad cortical distribution
TAU hyperphosphorylation TAU hyperphosphorylation ²² late, focal effect, dementia related late, focal effect, dementia related
Why Diagnose AD Early? Why Diagnose AD Early?
Safety (driving, compliance, cooking, etc.) Safety (driving, compliance, cooking, etc.)
Family stress and misunderstanding (blame, denial) Family stress and misunderstanding (blame, 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 (will, Advance planning while patient is competent (will,
proxy, power of attorney, advance directives) proxy, power of attorney, advance directives)
Patient·s and Family·s right to know Patient·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 earlier nursing home placement longer if started earlier
Early Recognition of AD: Consensus Statement Early Recognition of AD: Consensus Statement
(AAGP, AGS, Alzheimer·s Association) (AAGP, AGS, Alzheimer·s Association)
AD continues to be missed as diagnosis AD continues to be missed as diagnosis
AD is unrecognized and under AD is unrecognized and under--reported reported
patients do not realized patients do not realized
families tend to compensate families tend to compensate
Effective treatment and management techniques Effective treatment and management techniques
are available are available
Small et al., JA A, 997
Need for Better Screening Need for Better Screening
and Early Assessment Tools and Early Assessment Tools
Genetic vulnerability testing Genetic 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 tests Positive diagnostic tests
CSF CSF ²² tau levels elevated, amyloid levels low tau levels elevated, amyloid levels low
Brain scan Brain scan ²² PET PET ²² DDNP, Congo DDNP, Congo--red derivatives red derivatives
Mild Dementia severity assessments Mild Dementia severity assessments
Detecting early change Detecting early change
predicting progression, measuring rate predicting progression, measuring rate
Alzheimer Warning Signs Alzheimer Warning Signs
Top Ten Top Ten
Alzheimer Association Alzheimer Association
1. Recent memory loss affecting job 1. Recent memory loss affecting job
2. Difficulty performing familiar tasks 2. Difficulty performing familiar tasks
3. Problems with language 3. Problems with language
4. Disorientation to time or place 4. Disorientation to time or place
5. Poor or decreased judgment 5. Poor or decreased judgment
6. Problems with abstract thinking 6. Problems with abstract thinking
7. Misplacing things 7. Misplacing things
8. Changes in mood or behavior 8. Changes in mood or behavior
9. Changes in personality 9. Changes in personality
10. Loss of initiative 10. Loss of initiative
Need for a Brief Screening Test for Need for a Brief Screening Test for
Alzheimer·s Disease Alzheimer·s Disease
Recent evidence of benefits of anti Recent evidence of benefits of anti--
cholinesterase agents in the treatment of mild cholinesterase agents in the treatment of mild
Alzheimer·s disease Alzheimer·s disease
Improvement of cognition Improvement of cognition
Slowing of progression Slowing of progression
Availa l S r ning T t Availa l S r ning T t
MMSE MMSE 10 10 -- -- 15 min 15 min
Too long Too long
77--Minute Screen Minute Screen 7 7 ²² 10 min 10 min
Too complex Too complex
Clock Drawing Test Clock Drawing Test 2 2 ²² 4 min 4 min
Not sensitive Not sensitive
Mini Mini--cog cog 3 3 ²² 5 min 5 min
Complex scoring, unclear adequacy Complex scoring, unclear adequacy
Memory Impairment Screen Memory Impairment Screen 4 min 4 min
Need for slightly shorter, easier test Need for slightly shorter, easier test
(a suitably accurate test that takes less than 2 (a suitably accurate test that takes less than 2
minutes is not available) minutes is not available)
Fel H, Gr co S. I : Clinical Diagnosis and Management of Alzheimer¶s Disease. 1996:239-253.
The Progress of Alzheimer·s Disease
The 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
Ye rs
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Cogniti e sy pto s
Loss of ADL
Behavioral proble s
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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)
P
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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
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)
I
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Brief Alzheimer Screening Brief Alzheimer Screening
Repeat these three words: ´apple, table, pennyµ. Repeat these three words: ´apple, table, pennyµ.
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 ´Name as as many many animals animals as as you you can can in in 30 30 seconds, seconds, GO!µ GO!µ
11 point point for for naming naming 10 10 animals animals
´What were the 3 words I asked you to repeat?µ (no prompts) ´What were the 3 words I asked you to repeat?µ (no prompts)
1 for each word, 1 for each word,
TOTAL TOTAL (max (max == 55))
A A score score of of 44 or or 55 indicate indicate a a very very low low likelihood likelihood of of dementia dementia..
A A score score of of 22 or or 33 suggests suggests that that more more testing testing is is needed needed..
A A score score of of 00 or or 11 indicate indicate a a very very high high likelihood likelihood of of dementia dementia..
(palm (palm--pilot pilot scoring scoring under under development) development)
If If score score of of 22 or or 33::
Spell Spell World World Backwards Backwards
Draw Draw a a Clock Clock (gives (gives some some impression impression of of visuospatial visuospatial problems) problems)
If If continued continued difficulties, difficulties, ask ask questions questions about about ADLs ADLs
BRIEF ALZHEIMER SCREEN
(Normal vs Mild AD, MMS>19)
9
20
14
13
12
11
10
9
6
7
8
26
27
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)
T
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P
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(
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)
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 Test BLT/Ashford Memory Test
(to detect AD onset) (to detect AD onset)
New test to screen patients for Alzheimer·s New test to screen patients for Alzheimer·s
disease using the World disease using the World--Wide Web Wide Web ²² based based
testing and CD testing and CD--distribution distribution
Test only takes 1 Test only takes 1--minute minute
Test can be repeated often Test can be repeated often (quarterly) (quarterly)
Any change over time can be detected Any change over time can be detected
Test is at: Test is at: www.ibaglobal.com/BLT www.ibaglobal.com/BLT
For info, see: For info, see: www.medafile.com www.medafile.com
Assessment Assessment
History Of The Development Of The Dementia History Of The Development Of The Dementia
Ask the Patient What Problem Has Brought Him to See You Ask the Patient What Problem Has Brought Him to See You
Ask the Family, Companion about the Problem Ask the Family, Companion about the Problem
Specifically Ask about Memory Problems Specifically Ask about Memory Problems
Ask about the First Symptoms Ask about the First Symptoms
Enquire about Time of Onset Enquire about Time of Onset
Ask about Any Unusual Events Around the Time of Onset, e.g., Ask about Any Unusual Events Around the Time of Onset, e.g.,
stress, trauma, surgery stress, trauma, surgery
Ask about Nature and Rate of Progression Ask about Nature and Rate of Progression
Physical Examination Physical Examination
Neurological Examination Neurological Examination
PHYSICAL/NEUROLOGICAL PHYSICAL/NEUROLOGICAL
EXAMINATION EXAMINATION
CHECK BLOOD PRESSURE CHECK BLOOD PRESSURE
IDENTIFY SYSTEMIC DISORDERS IDENTIFY SYSTEMIC DISORDERS
CRANIAL NERVES CRANIAL NERVES
Olfactory dysfunction, poor eye tracking Olfactory dysfunction, poor eye tracking
Check for hearing, vision deficits Check for hearing, vision deficits
SENSORY DEFICITS SENSORY DEFICITS
Proprioception, vibration Proprioception, vibration
DEEP TENDON REFLEXES DEEP TENDON REFLEXES
Brisk, check for focal reflexes Brisk, check for focal reflexes
PATHOLOGIC REFLEXES PATHOLOGIC REFLEXES
Hyperactive snout reflex, Gegenhalten Hyperactive snout reflex, Gegenhalten
CURRENT APPROACHES TO CURRENT APPROACHES TO
SEVERITY ASSESSMENT SEVERITY ASSESSMENT
MINI MINI--MENTAL STATE EXAM MENTAL STATE EXAM
CLOCK DRAWING CLOCK DRAWING
ANIMAL NAMING (1 minute) ANIMAL NAMING (1 minute)
MATTIS DEMENTIA RATING SCALE MATTIS DEMENTIA RATING SCALE
ALZHEIMER·S DISEASE ALZHEIMER·S DISEASE
ASSESSEMENT SCALE (ADAS) ASSESSEMENT SCALE (ADAS)
ACTIVITIES OF DAILY LIVING ACTIVITIES OF DAILY LIVING
GLOBAL CLINICAL SCALE GLOBAL CLINICAL SCALE
CLINICAL DEMENTIA RATING SCALE CLINICAL DEMENTIA RATING SCALE
GLOBAL DETERIORATION SCALE / FAST GLOBAL DETERIORATION SCALE / FAST
NEUROPSYCHOLOGICAL NEUROPSYCHOLOGICAL
TESTING TESTING (WAIS, WECHSLER) (WAIS, WECHSLER)
MEMORY: SHORT MEMORY: SHORT--TERM, REMOTE TERM, REMOTE
VERBAL FUNCTION, FLUENCY VERBAL FUNCTION, FLUENCY
VISUO VISUO--SPATIAL FUNCTION SPATIAL FUNCTION
ATTENTION ATTENTION
EXECUTIVE FUNCTION EXECUTIVE FUNCTION
ABSTRACT THINKING ABSTRACT THINKING
ACCOUNT FOR EDUCATION ACCOUNT FOR EDUCATION
ACCOUNT FOR PRIOR DISFUNCTIONS ACCOUNT FOR PRIOR DISFUNCTIONS
LABORATORY TESTS LABORATORY TESTS (routine) (routine)
BLOOD TESTS BLOOD TESTS
electrolytes, liver, kidney function tests, glucose electrolytes, liver, kidney function tests, glucose
thyroid function tests (T3, T4, FTI, TSH) thyroid function tests (T3, T4, FTI, TSH)
vitamin B12, folate vitamin B12, folate
complete blood count, ESR complete blood count, ESR
VDRL, HIV (if indicated) VDRL, HIV (if indicated)
EKG (if indicated) EKG (if indicated)
CHEST X CHEST X--RAY (if indicated) RAY (if indicated)
URINALYSIS URINALYSIS
ANATOMICAL BRAIN SCAN ANATOMICAL BRAIN SCAN ²² CT (cheapest), MRI CT (cheapest), MRI
SPECIAL LABORATORY TESTS SPECIAL LABORATORY 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, especially REACTION TIMES (slowed in the elderly, especially
when complex response is required when complex response is required
CSF ANALYSIS CSF ANALYSIS -- ROUTINE STUDIES 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)
GENOTYPING GENOTYPING
APO APO--LIPOPROTEIN LIPOPROTEIN--E (for supporting dx) E (for supporting dx)
AUTOSOMAL DOMINANT (young onset) AUTOSOMAL DOMINANT (young onset)
Justification for Brain Scan in Justification for Brain Scan in
Dementia Diagnosis Dementia Diagnosis
Differential Diagnosis: Tumor, Stroke, Subdural Differential Diagnosis: Tumor, Stroke, Subdural
Hematoma, Normal Pressure Hydrocephalus, Hematoma, Normal Pressure Hydrocephalus,
Encephalomalacia Encephalomalacia
Confirmation of atrophy pattern Confirmation of atrophy pattern
Estimation of severity of brain atrophy Estimation of severity of brain atrophy
MRI shows T2 white matter changes MRI shows T2 white matter changes
Periventricular, basal ganglia, focal vs confluent Periventricular, basal ganglia, focal vs confluent
These may indicate vascular pathology These may indicate vascular pathology
SPECT, PET SPECT, PET -- estimation of regions of physiologic estimation of regions of physiologic
dysfunction, areas of infarction dysfunction, areas of infarction
Helps family to visualize problem Helps family to visualize problem
Ashford et al,
2000
Shoghi-Jadid et al., 2002
UCLA group, J. Amer. Ger. Psych, 2002
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Are we ready to do genetic testing to Are we ready to do genetic testing to
predict AD? predict AD?
The family members want it The family members want it
They consider recommendations against genetic testing to be They consider recommendations against genetic testing to be
´paternalisticµ ´paternalisticµ
Family members can make more powerful financial Family members can make more powerful financial
decisions based on this knowledge than the relevance of decisions based on this knowledge than the relevance of
insurance companies implementing changes in actuarial insurance companies implementing changes in actuarial
calculations calculations
Those at risk can seek more frequent testing Those at risk can seek more frequent testing
This is the best opportunity for early recognition This is the best opportunity for early recognition
Those at risk will be better advocates for research Those at risk will be better advocates for research
Specific preventive treatments can be developed for each Specific preventive treatments can be developed for each
genetic factor genetic factor
BEHAVIORAL PROBLEMS BEHAVIORAL PROBLEMS
IN DEMENTIA PATIENTS IN DEMENTIA PATIENTS
MOOD DISORDERS MOOD DISORDERS ²² depression depression ²² early in AD early in AD
PSYCHOTIC DISORDERS PSYCHOTIC DISORDERS
Particularly paranoia, e.g, people stealing things Particularly paranoia, e.g, people stealing things
INAPPROPRIATE BEHAVIORS (sexual INAPPROPRIATE BEHAVIORS (sexual
AGGRESSION: verbal, physical AGGRESSION: verbal, physical
PURPOSELESS ACTIVITY: verbal, motor PURPOSELESS ACTIVITY: verbal, motor
MEAL TIME BEHAVIORS MEAL TIME BEHAVIORS
SLEEP DISORDERS SLEEP DISORDERS
NEUROPSYCHIATRIC NEUROPSYCHIATRIC
TREATMENTS TREATMENTS
First treat medical problems First treat medical problems
Second environmental interventions Second environmental interventions
Third neuropsychiatric medications Third neuropsychiatric medications
Cognitive impairment Cognitive impairment
Psychotic symptoms Psychotic symptoms
Depressive symptoms Depressive symptoms
Insomnia symptoms Insomnia symptoms
Anorexia symptoms Anorexia symptoms
Parkinsonian symptoms Parkinsonian symptoms

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
(commonly used mnemonic device: AVDEMENTIA)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

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

Not Due to Another Psychiatric Disorder . Course Shows Gradual Onset And Decline D.Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV. Deficits Impair Social/Occupational C. Deficits Are Not Due to: 1. Do Not Occur Exclusively during Delirium F. Substance Induced Conditions E. Memory Impairment 2. Other CNS Conditions 2. APA. Other Cognitive Impairment B. 1994) (DSMA. Multiple Cognitive Deficits 1.

ALZHEIMER¶S 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 .

30% are AD  . 70% correct   Unlikely AD .30% of cases.Alzheimer¶s Disease versus Dementia   50 . 90% correct  20% have other contributing diagnoses 40% have other contributing diagnoses 80% have other contributing diagnoses  Possible AD .40% of cases.70% of dementias are AD Probable AD .30% of cases.

APA. Not Due to Delirium . Focal Neurological Signs and Symptoms or Laboratory Evidence Indicating Cerebrovascular Disease Etiologically Related to the Deficits D. 1994) A. Memory Impairment Other Cognitive Disturbances B. Multiple Cogntive Impairments 1. 2. Deficits Impair Social/Occupational C.Vascular Dementia (DSM(DSM-IV .

ASCVD. Step-wise deterioration StepCardiovascular disease .HTD. & Atrial Fib Depression (left anterior strokes). personality change More gait problems than in AD MRI evidence of T2 changes (?? Binswanger·s disease)   Basal ganglia.Factors Associated with Multi-infarct Dementia Multi History of stroke (especially in Nursing Home)  Followed by onset of dementia within 3 months      Abrupt onset. putamen Periventricular white matter   SPECT / PET show focal areas of dysfunction Neuropsychological dysfunctions are patchy .

VASCULAR DEMENTIA CHANGE ON THE MINI-MENTAL STATE EXAM OVERTIME 30 20 10 0 -5 < event < event < event SCORE 0 5 10 AVERAGE TIME OF ILLNESS (years) .

PostPost-Cardiac Surgery        53% post-surgical confusion at discharge (delirium) post42% impaired 5 years later (dementia) May be related to anoxic brain injury. 2001. apnea May be related to narcotic/other medication May occur in those patients who would have developed dementia anyway (? genetic risk) CardioCardio-vascular disease and stress may start Alzheimer pathology Any surgery may have a similar effect related to peri-op or peripostpost-op anoxia or vascular stress Newman et al. NEJM ..

ethanol. chlorpheniramine. atropine. anti-convulsants antiBetaBeta-blockers: propranolol Dopaminergics: l-dopa. diphenhydramine. oxybutynin. many anti-histaminics anti May aggravate Alzheimer pathology     GABA agonists: benzodiazepines. scopolamine. benztropine. hyoscyamine.Drug Interactions  Anticholinergics: amitriptyline. alpha-methyl-dopa lalpha-methylNarcotics: may contribute to dementia . barbiturates.

antiantiantianxiety. dry mouth. memory encoding block   GabaGaba-agonist:  Muscle relaxant. sedative.Drug Toxicity  AntiAnti-cholinergic Peripheral: blurred vision. amnesic. urinary obstruction  Central: confusion. confusion Confusion (watch for in nursing home)  Medication induced electrolyte imbalance  . anti-convulsant. constipation.

appetite disruption Course: rapid resolution with treatment. but may precede Alzheimer·s disease .Depression         Onset: rapid Precipitants: psycho-social (not organic) psychoDuration: less than 3 months to presentation Mood: depressed. anxious Behavior: decreased activity or agitation Cognition: unimpaired or poor responses Somatic symptoms: fatigue. sleep. lethargy.

or shift attention    Change in cognition (memory.e.Delirium Definition (more often a problem in medical in-patients) in-  Disturbance of consciousness  i. tends to fluctuate Evidence of medical etiology . perception) Development over a short period (hours to days). language. orientation.. reduced clarity of awareness of the environment with reduced ability to focus. sustain.

.I. infections.urinary  Respiratory (URI.U.Delirium  Susceptibility may be symptom of early dementia. dementia  Medical conditions  Infections:  G. pneumonia)  G.  Constipation  Drug toxicity  Fracture (especially related to hip fracture) . or delirium may predispose to later dementia  Predisposing factors .Age.

gray matter nuclei  Chronic Neurodegeneration  . Head Injury Dietary Deficiency  Thiamine ² Wernicke-Korsakoff syndrome Wernicke- Hepatic Encephalopathy Withdrawal Damage (seizures) Delayed Alcohol Withdrawal  Watch for in hospitalized patients Cerebellum.Ethanol      Possibly Neuroprotective  May not kill neurons directly (?Dietary recommendation?) Accidents.

increased T4 Hyperthyroidism         Diabetes Hypoglycemia (loss of recent memory since episode) Hyperglycemia Hypercalcemia Nephropathy. ?homocysteine . Uremia Hepatic dysfunction (Wilson·s disease) Vitamin Deficiency (B12.Medical / Endocrine  Thyroid dysfunction   Hypothyoidism ² elevated TSH  Compensated hypothyroidism may have normal T4. thiamine. FTI Apathetic. with anorexia. fatigue. niacin)  Pernicious anemia ² B12 deficiency. weight loss.

Ears.Eyes. 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) .

Argyrophylic grain disease)  FrontoFronto-temporal dementia (tau gene)     Focal cortical atrophy   Primary progressive aphasia (many causes) Unilateral atrophy. fluctuating course. behavioral dyscontrol Decrease blood flow. hypometaboism on SPECT / PET (Pick·s disease.Neurological Conditions  Primary Neurodegenerative Disease  Diffuse Lewy Body Dementia (? 7 .50%)   Note relation to Parkinson·s disease. hypofunction on EEG. ventriculography  Normal pressure hydrocephalus   . incontinence Suggested on CT. SPECT. symptoms Hallucinations. need tap. MRI. PET Dementia with gait impairment. neuroleptic hypersensitivity) Impaired attention.

Other Neurologic Conditions Subdural hematoma  Huntington·s disease  Creutzfeldt-Jakob disease Creutzfeldt 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 .

Contusion  Occult head trauma if recent fall Subdural hematoma Hydrocephalus:  Normal pressure (late effect of bleed) Dementia pugilistica Possible contributor to Alzheimer¶s disease initiation and progression (? 4% of cases) Concern re: physical abuse by caretakers .Trauma       Concussion.

Infectious Conditions Affecting the Brain HIV  Neurosyphilis  Viral encephalitis (herpes)  Bacterial meningitis  Fungal (cryptococcus)  Prion (Creutzfeldt-Jakob disease). (mad cow disease) (Creutzfeldt .

Inability to recall previously learned information    Memory disturbance significantly impairs social. Memory impairment . deterioration from past Memory not due to delirium.Distinguish from dissociative disorders.Chronic . or .more than 1 month . dementia Physiological basis or substance induced . dissociative amnesia.inability to learn new information. occupational function. dissociative identity disorders  Specify .AMNESIC DISORDER DSMDSM-IV A.Transient ² less than 1 month .

hypoxia   Epileptic events  Partial complex seizures Transient global amnesia Multiple sclerosis Specific brain diseases   . hypoglycemia.damage to CA1 of hippocampus  thiamine deficiency (WKE). selective. generalized Organic .Causes of Amnesic Disorders  Amnesia   Dissociative: localized.

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 .AgeAge-Associated Memory Impairment vs Mild Cognitive Impairment      Memory declines with age Age .

genetics Understanding pathophysiology Better screening tools for early recognition Improved diagnosis Developing interventions Behavioral conditions and management .Advances in Alzheimer·s Disease        Incidence and prevalence Search for etiology.

000 1.000.343 # people Total = 281.000 1.000 1.000 500.000 2.256.421.250.U.368.000 750.008.750.000 2.000 1.000 250. 138.053.906 >65 = 35.587 Age .250.753 >85 = 4. 143.563 Females.500.000.000 0 0 10 20 30 40 50 60 70 80 90 100 Males. Census 2000 by age 2.500.S.

939 Number of people 40.000 30.cdc. 1.U. 1.000 Males.000 0 0 10 20 30 40 50 60 70 80 90 100 Age www.000 5.1999 45.000 10.215.000 15. mortality by age .175.S.000 35.000 20.000 25.gov .460 Females.

0010 0.0001 0 10 20 30 40 50 60 70 80 90 100 Males Females Age .0100 0. mortality rate by age 1999 CDC / 2000 census 1.0000 probability 0.S.U.1000 0.

U.0000 probability 0.0010 0.S.9973 70 80 90 100 Age .9974 y = 3E-05e 0.0100 0.0848x R 2 = 0.1000 0.0926x R 2 = 0. mortality rate by age 1999 CDC / 2000 census 1.0001 30 40 50 60 Males Females y = 9E-05e 0.

46 million individuals over 60 y/o) Estimated 500.4m) ( 5.000 188.65 65 .70 70 .75 75 .0m) = = = = = 107.000 800.4m) ( 8.000 350.000 new cases per year Increase with age (prevalence) 1% of  2% of  4% of  8% of  16% of  60 .7m) ( 7.000 595.000 .PREVALENCE of AD    Estimated 4 million cases in US (2000)  (2000 .7m) ( 9.80 80 .85 (10.

0010 0.0001 0 10 20 30 40 50 60 70 80 90 100 Males Females dementia incidence Age .0100 0.0000 probability 0.U.1000 0.S. mortality rate by age 1999 CDC / 2000 census 1.

U.115 # / yr 50 60 70 Age 80 90 100 .S.603 female=329. Dementia Incidence (4 million / 8yr) 16000 14000 12000 10000 8000 6000 4000 2000 0 male=170.

004 0.Dementia incidence by individual 0.01 0.014 0.002 0 50 male=34% female=66% Proportional risk / yr 60 70 80 90 100 Age .006 0.012 0.008 0.016 0.

Oeppen & Vaupel. 2002 .

2002 .Oeppen & Vaupel.

.

000 in Eastern KY) Nursing homes cost .$120 to $160 per day Annualized cost of nursing homes ranges from $40 to $70.5 billion annually! .ECONOMIC IMPACT OF AD      2 million AD patients in nursing homes  Projection to Kentucky ² 22.000 per year Care of AD patients costs $80 billion per year With lost wages of patients and families plus costs for nonnon-nursing home patients:   Total costs: $120 billion annually (Am J Publ Hlth) $120 Hlth) Projection to Kentucky ² $1.000 (6.

surgery. smoking . vascular (stroke). loss. cholesterol. exercise. grief. energy demands Stressor response (adequate repair mechanisms)  Trauma (head injury). etc. PS (14.diet.  Genetics (amyloid related)   Familial. 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.Etiology  Age (initial genesis vs response to stress)    Bigger factor than for mortality Design in a plastic (memory) system. early onset: APP (21). BP Education (? design vs protection) Environment .

3 .7 (0.8 (1.0 .2.Parkinson·s Maternal age > 40 years Head trauma (with LOC) History of depression History of hypothyroidism History of severe headache NSAID use or statin use 3.7) 1.7 (1.6 .6) 2.2.Downs Family history .1.5.7) 2.RELATIVE RISK FACTORS FOR ALZHEIMER·S DISEASE          Family history of dementia Family history .2 (0.3 (1. 2002 .5.4 (1.5.05 ² 0.7) 2.0 .0 . t¶Veldt.2.2 .5 .7 (1.8 (1.4) 0.8) 1. 1994.4.83) Roca.0) 0.9) 1.5 (2.3 .

GABAss   Inflammatory responses .NEUROPATHOLOGY OF AD  Senile plaques  betabeta-amyloid protein (? Primary problem) hyperhyper-phosphorylated tau (loss of synapses. serotonin. dementia)  Neurofibrillary tangles   Neurotransmitter losses Acetylcholine (Ach) ² major loss of nicotinic receptors  Norepinephrine. glutamate.

1) gamma break down . lithium. valproic acid  .  prevention of fibril formation by melatonin  Tau hyperphosphorylation (relation to dementia) glycogen-synthaseglycogen-synthase-kinase (GSK) 3-beta 3 inhibition by Ach.Insulin Degrading Enzyme (ch10). etc.ch21) (early changes)   metabolism occurs on cholesterol ´raftsµ  Cholesterol transport by APOE (ch 19) alphaalpha-secretase vs beta/gamma secretase metabolism  influence toward alpha-secretase by Acetylcholine alpha gamma-secretase (PreSenilin genes. ch14.New Neuropath Mechanisms  Amyloid PreProtein (APP .

.F yloi FAPPs PP E PPs M1 I or h 1 h q/11 F/K-secret se E-secret se PHF PLCF Pk yper-P- PKC Protei phosphoryl tio GSK-3 bet Li+ Adapt d fr Fis r.

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Genes and Alzheimer·s disease (60% .80 % of causation) (all known genes relate to Famyloid)  Familial AD (onset < 60 y/o) (<5%) Presenilin I. II (ch 14.000 years   At least 20 other genes . 1)  APP (ch 21)   NonNon-familial (late onset)  APOE Clinical studies suggest 40 ² 50% due to I4  Population studies suggest 10 ² 20% cause  Evolution over last 300.000 to 200.

78% of the population e4 -.15% of the population e3/3 .7% of the population e3 -.average age of onset = 74 y/o e3/4 and e4/4 average age = 69 y/o   .APOAPO-E genotype and AD onset    e2 -.

. Journal of Alzheimer¶s Disease .6M 1. M 1. 1997) GenT E / E / E / E / E / 1 pop 1 AD . M . Farrer et al. M . M . .. M .1 . 1993.. 2002.6M 6 See: Ashford & Mortimer. M 1 .1 M . #AD M risk If all . M 1 16 6 .1 #pop .6M 1. M . M .APOAPO-E genotype and AD risk 46 Million in US > 60 y/o //// 4 Million have AD (data from Saunders et al. M .

focal effect.Early Basic ADLs .Late Primary Loss Of Memory Later Loss Of Learned Skills Cortical Glutamatergic Storage Subcortical (acetylcholine. dementia related . norepi. broad cortical distribution TAU hyperphosphorylation ² late.Biopsychosocial Systems Affected by AD (all related to neuroplasticity)  Social Systems   Instrumental ADLs . serotonin) Cellular Plastic Processes    Psychological Systems    Neuronal Memory Systems    APP metabolism ² early.

power of attorney. etc. may delay nursing home placement longer if started earlier . advance directives) Patient·s and Family·s right to know Specific treatments now available. proxy.) Family stress and misunderstanding (blame.Why Diagnose AD Early?       Safety (driving. getting started) Advance planning while patient is competent (will. compliance. cooking. denial) Early education of caregivers of how to handle patient (choices.

.Early Recognition of AD: Consensus Statement (AAGP. 997 . JA A. AGS. Alzheimer·s Association)   AD continues to be missed as diagnosis AD is unrecognized and under-reported underpatients do not realized  families tend to compensate   Effective treatment and management techniques are available Small et al.

amyloid levels low Brain scan ² PET ² DDNP.Need for Better Screening and Early Assessment Tools     Genetic vulnerability testing Early recognition (10 warning signs) Screening tools (6th vital sign in elderly) Positive diagnostic tests   CSF ² tau levels elevated. measuring rate . Congo-red derivatives Congo-   Mild Dementia severity assessments Detecting early change  predicting progression.

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

Need for a Brief Screening Test for Alzheimer·s Disease  Recent evidence of benefits of antianticholinesterase agents in the treatment of mild Alzheimer·s disease Improvement of cognition  Slowing of progression  .

easier test Clock Drawing Test  MiniMini-cog  Memory Impairment Screen   (a suitably accurate test that takes less than 2 minutes is not available) . unclear adequacy Need for slightly shorter.15 min t MMSE  Too long 7-Minute Screen  7 ² 10 min 2 ² 4 min 3 ² 5 min 4 min Too complex Not sensitive Complex scoring.Availa l S r      ning T 10 -.

5 9 Ye rs Fel H.5 7 7.5 3 3. I : Clinical Diagnosis and Management of Alzheimer¶s Disease.5 8 8.5 5 5.The Progress of Alzheimer·s Disease 30 Early iagnosis Cogniti e sy pto s 25 20 Mil .5 1 1. 1995 .o erate Se ere MMSE score Loss of ADL 15 Behavioral proble s 10 5 rsing ho e place ent Death 0 0 0. 1996:239-253.5 4 4.5 6 6. Ashford et al..5 2 2. Gr co S.

4 0.5 0.7 0.6 0.AD all (easiest to hardest at p=.5) Mini-Mental State Exam items 1 0.9 PROBABILITY CORRECT 0.8 0.2 0.3 0.1 0 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 DISABILITY ("time-index" year units) 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 20 Information 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) .

needed. What is today·s date?  1 point if within 2 days. twice. 1 point for naming 10 animals 1 for each word. A score of 4 or 5 indicate a very low likelihood of dementia. repeat them again. A score of 0 or 1 indicate a very high likelihood of dementia. A score of 2 or 3 suggests that more testing is needed. dementia. table. dementia. (palm(palm-pilot scoring under development) ´Name as many animals as you can in 30 seconds. So you will remember these words. pennyµ. GO!µ  ´What were the 3 words I asked you to repeat?µ (no prompts)  TOTAL (max = 5)      If score of 2 or 3:   Spell World Backwards Draw a Clock (gives some impression of visuospatial problems)  If continued difficulties.Brief Alzheimer Screening       Repeat these three words: ´apple. ask questions about ADLs .

983 .BRIEF ALZHEIMER SCREEN (Normal vs Mild AD.875 AUC = 0.828 AUC = 0.868 AUC = 0.965 AUC = 0. MMS>19) 100 True Positive Rate (%) (Sensitivity) 20 27 26 25 14 10 12 11 13 90 80 70 9 60 50 40 30 6 20 10 0 0 10 20 30 40 50 60 70 80 90 100 False Positive Rate (%) (1-Specificity) 8 97 animals 1 m animals 30 s MMSE Date+3 Rec BAS AUC = 0.

medafile.com/BLT For info.ibaglobal.com . see: www.BLT/Ashford Memory Test (to detect AD onset)       New test to screen patients for Alzheimer·s disease using the World-Wide Web ² based Worldtesting and CD-distribution CDTest only takes 1-minute 1Test can be repeated often (quarterly) Any change over time can be detected Test is at: www.

e. surgery Ask about Nature and Rate of Progression   Physical Examination Neurological Examination . trauma. stress.g. 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.Assessment History Of The Development Of The Dementia        Ask the Patient What Problem Has Brought Him to See You Ask the Family..

poor eye tracking Check for hearing. vibration Brisk. vision deficits Proprioception. Gegenhalten    SENSORY DEFICITS  DEEP TENDON REFLEXES  PATHOLOGIC REFLEXES  .PHYSICAL/NEUROLOGICAL EXAMINATION    CHECK BLOOD PRESSURE IDENTIFY SYSTEMIC DISORDERS CRANIAL NERVES   Olfactory dysfunction. check for focal reflexes Hyperactive snout reflex.

CURRENT APPROACHES TO SEVERITY ASSESSMENT          MINIMINI-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 .

REMOTE SHORTVERBAL FUNCTION.NEUROPSYCHOLOGICAL TESTING (WAIS. FLUENCY VISUOVISUO-SPATIAL FUNCTION ATTENTION EXECUTIVE FUNCTION ABSTRACT THINKING ACCOUNT FOR EDUCATION ACCOUNT FOR PRIOR DISFUNCTIONS . WECHSLER)         MEMORY: SHORT-TERM.

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LABORATORY TESTS (routine)      BLOOD TESTS  electrolytes. HIV (if indicated) EKG (if indicated) CHEST X-RAY (if indicated) XURINALYSIS ANATOMICAL BRAIN SCAN ² CT (cheapest). ESR  VDRL. folate  complete blood count. MRI . TSH)  vitamin B12. T4. FTI. kidney function tests. liver. glucose  thyroid function tests (T3.

SPECIAL LABORATORY TESTS     FUNCTIONAL BRAIN IMAGING (SPECT. Evoked Potentials (P300) REACTION TIMES (slowed in the elderly.ROUTINE STUDIES   ELEVATED TAU (future possible) DECREASED AMYLOID (future possible)   HEAVY METAL SCREEN (24 hr urine) GENOTYPING   APO-LIPOPROTEINAPO-LIPOPROTEIN-E (for supporting dx) AUTOSOMAL DOMINANT (young onset) . PET) EEG. especially when complex response is required CSF ANALYSIS .

Encephalomalacia Confirmation of atrophy pattern Estimation of severity of brain atrophy MRI shows T2 white matter changes   Periventricular. Subdural Hematoma.Justification for Brain Scan in Dementia Diagnosis     Differential Diagnosis: Tumor. focal vs confluent These may indicate vascular pathology   SPECT. areas of infarction Helps family to visualize problem .estimation of regions of physiologic dysfunction. PET . Normal Pressure Hydrocephalus. Stroke. basal ganglia.

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Ashford et al, 2000

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

Shoghi-Jadid et al., 2002

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Are we ready to do genetic testing to predict AD?  The family members want it  They consider recommendations against genetic testing to be ´paternalisticµ     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 .

people stealing things      INAPPROPRIATE BEHAVIORS (sexual AGGRESSION: verbal. physical PURPOSELESS ACTIVITY: verbal.BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS   MOOD DISORDERS ² depression ² early in AD PSYCHOTIC DISORDERS  Particularly paranoia. motor MEAL TIME BEHAVIORS SLEEP DISORDERS . e.g.

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

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