Definition of Dementia

1
Definition of Dementia

• A global impairment of higher cortical functions
  including memory, capacity to solve problems of
  daily living, performance of learned
  perceptuomotor skills, correct use of social
  skills and control of emotional reactions. No
  clouding of consciousness. The course is often
  irreversible and progressive.
• Royal College of Physicians, 1980

2
Dementia Diagnoses in the US
3
(No Transcript)
4
Classification of Dementia

• Cortical
• No motor symptoms (early)
• Processing speed normal (early)
• Amnesia, aphasia, apraxia, agnosia
• Impaired new learning
• Mood usually unaffected
• Behavior can be odd or unusual (FLD or later in
  AD)
• Involvement of basal forebrain, hippocampus and
  cortex
• Examples Alzheimers disease Picks disease
  Lewy Body dementia

• Subcortical
• Presence of motor symptoms
• Hypo- or hyperkinetic
• Dysarthria
• Slow motor speed and information processing
• Impaired planning and problem solving
• Depression, apathy, withdrawal
• No aphasia, apraxia, agnosia
• Basal ganglia, mesencephalon, thalamus affected
• Examples Parkinsons disease Huntingtons
  disease

5
(No Transcript)
6
(No Transcript)
7
(No Transcript)
8
PD Progression of disease with decrease in
striatal 18FDOPA uptake
18FDOPA-PET, Brooks 1993
9
(No Transcript)
10
Huntingtons disease

• Autosomal dominantly inherited
• Unstable and expanded CAG trinucleotide repeat
  in the IT15 gene on chromosome 4
• Symptoms are movement disorder and dementia
• Slowly progressive, resulting in death 10-20
  years after symptom onset

11
(No Transcript)
12
Dopaminergic function in Huntingtons
18F- dopa 11C-raclopride
Turjanski, 2000
13
Huntingtons disease
CMRglc
D2/D3
PSI, 1997
14
HD - Asymptomatic gene carrier
PSI, 1997
15
MOVEMENT DISORDER ATLAS
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
Pick Bodies
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
ADHistory Timeline
7th century BCAge-related mental deterioration
recognized
1980AlzheimersAssociationestablished
Early 1960sAwareness of AD as a single disease
1907AD first described by Dr. Alois Alzheimer
1991APOE implicated
1993First cholinesterase inhibitor approved
Research into treatments continues
700 BC
2000 AD
1992AHCPR develops screening guidelines for AD
200 ADGalen associates morosis (dementia)
with old age
1978?Single entity established senile dementia
of the Alzheimers type (SDAT)
1983Cholinergic deficit identified
1994Brain inflammatory response identified as
pathogenetic
30
(No Transcript)
31
Macro Pathology of the Alzheimer Brain

• Gross atrophy
• shrinkage of brain
• thinning of gyri
• widened sulci

32
Rate of brain atrophy in Alzheimers disease
11 months
MRI, Fox 1996
33
Rate of brain atrophy in healthy subjects
15 months
MRI, Fox 1996
34
(No Transcript)
35
Temporal-Parietal Hypofunction in AD
Normal
AD
36
Micro Pathology of the Alzheimer Brain
Senile Plaque Contain A? peptide
Neuron with Neurofibrillary Tangles
Selkoe
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
(No Transcript)
41
Disease Gene vs Risk-factor Gene
Disease Gene
Risk-factor Gene
42
(No Transcript)
43
(No Transcript)
44
Distribution of Alzheimer's disease forms and
related genetic susceptibility factors
Sporadic cases (gt95
Autosomal Dominant mutation cases (lt5)
From Richard and, Amouyel, 2001
45
(No Transcript)
46
(No Transcript)
47
Possible Mechanismsin the Pathogenesis of AD
Environmental and genetic factors
Plaques
Tangles
Oxidativestress
Inflammatory response
Neuronal injury/death
Dementia
48
INTERMISSION
49
(No Transcript)
50
(No Transcript)
51
What is MCI?

• Common precursor to AD
• Emerging criteria
• Memory test scores 1 SD below age-adjusted
  normals
• No significant objective loss of function
• Do not meet diagnostic criteria for dementia
• 12 per year convert from MCI to AD in 4 years
• Treatments are under investigation

52
MCI-Cerebral atrophy
MCI patient, MMSE27 Healthy volunteer
Age 83 years Age 65 years
MRI, NRU 2001
53
Clinical Progression of AD and MCI
Time (y)
10 y
0 y
Time?
MCIMMSE 2430
Mild ADMMSE 2023

• Mild subjective/objective memory loss
• Normal function

• Forgetfulness
• Repetitive questions
• Daily function impaired

Moderate ADMMSE 1019

• Progression of cognitive deficits
• Short-term memory loss
• Word-finding difficulties

Cognitive function
Severe ADMMSE 09

• Agitation
• Altered sleep patterns
• Total dependence dressing, feeding, bathing

54
Natural history of Alzheimers disease
Early diagnosis
Mild-to-moderate
Severe
30
25
20
Mini-Mental State Examination (MMSE)
15
10
5
0
1 2 3 4 5 6 7 8 9
Time (years)
Reproduced from Feldman and Gracon, 1996
55
Alzheimers Disease Progresses Through Distinct
Stages
Dementia/Alzheimers
Mild Moderate Severe
Stage
Memory loss Language problems Mood
swings Personality changes Diminished
judgment
Behavioral, personality changes Unable to
learn/recall new info Long-term memory
affected Wandering, agitation, aggression,
confusion Require assistance w/ADL
Symptoms
Gait, incontinence, motor
disturbances Bedridden Unable to perform
ADL Placement in long-term care needed
56
Correlation between Cognition and ADLs
Each bar from left to right represents the range
of MMSE scores over which 2575 of Alzheimers
patients in one study showed loss of optimal
(independent) ADL performance
ADL
25
75
Loss of optimal(independent) performance
25
20
15
10
5
0
MMSE score
Galasko et al. Alzheimer Dis Assoc Disord
199711(Suppl 2)S33S39
57
(No Transcript)
58
(No Transcript)
59
Behavioral Disturbances in Alzheimers Disease
and Other Dementias

• Alzheimers disease is the most widely
  encountered cause of psychiatric pathology
  associated with a specific neuropathologic
  substrate
• Merriam et al, JAGS 36 7-12, 1988

60
Behavioral Symptoms in Alzheimers Disease

• Most common reason for institutional placement
• In study by Cummings et al, only 12 of patients
  did not have a behavioral problem.
• Most common reason for caregiver distress
• Caregiver distress ratings correlate highly (r
  .88) with behavioral disturbances

61
Behavioral Symptoms in Alzheimers Disease

• Personality Changes
• Apathy
• Most common behavioral change
• Decreased motivation, indifference
• Associated with frontal hypoperfusion (medial
  frontal, supraorbital, anterior frontal areas)
• Not related to depression

Cummings 1998
62
Behavioral Symptoms in Alzheimers Disease

• Delusions
• Cross sectional studies 20-50
• Longitudinal studies 50-70
• Common Delusions theft, infidelity, Capgras,
  phantom boarder, picture sign
• Associated with decreased metabolism in frontal
  lobes

Cummings 1998
63
Psychotic symptoms in Alzheimers disease

• Delusions 44
• Persecutory 73
• Reference 15
• Jealousy 9
• Misidentification 30
• Not home 51
• Strangers 29
• Reflection is Someone Else 21

• Hallucinations 24
• Visual 85
• Auditory 45
• Tactile 3

Deutsch et al
64
Behavioral Symptoms in Alzheimers Disease

• Depression
• Depressive symptoms are frequent
• Major depressive disorder (MDD) is uncommon
• More common with positive family or personal
  history
• MDD may precede diagnosis of Alzheimers disease
  or vascular dementia

Cummings 1998
65
Behavioral Symptoms in Alzheimers Disease

• Agitation
• Correlates with anxiety in mild patients
• Correlates with psychosis in moderately demented
  patients
• Correlation unclear in severely demented patients
• Associated with decrease in fronto-temporal
  metabolism on imaging studies

Cummings 1998
66
(No Transcript)
67
(No Transcript)
68
(No Transcript)
69
(No Transcript)
70
Cholinergic System of the Human Brain
Parietal Cortex
Occipital Cortex
Frontal Cortex
Basal Forebrain
Hippocampus
71
The Basal Forebrain Cholinergic System Enables or
Gates Important CNS Functions
Cerebral Blood Flow
Cognitive Function
Basal Forebrain Cholinergic Neurons
BF
72
Action of ACh at pre- and postsynaptic nerve
terminals and its removal by AChE
Presynaptic nerve terminal
AChE acetylcholinesterase
Acetyl CoA Choline Acetylcholine
CAT choline acetyltransferase
CAT
N nicotinic M muscarinic
N receptor
M receptor
Postsynaptic nerve terminal
N receptor
M receptor
73
VIDEO
74
Cholinergic deficits in Alzheimers disease

• Reduction in the activity of choline
  acetyltransferase, which synthesises ACh(1)

• Reduction in the number of cholinergic
  neurons in the basal forebrain(2)

75
Nicotinic acetylcholine receptors (nAChR) in the
brain

• ?4?2 nAChR subtype-High affinity
• Pre- and postsynaptic nAChR(3)
• Major excitatory neuronal nAChR(3)
• ?7 nAChR subtype-Low affinity
• Predominantly presynaptic nAChR(1)
• Generates fast calcium currents(1)
• Affects release of glutamate, 5HT, ACh(2)

76
Acetylcholine activates pre- and postsynaptic ?7
nicotinic receptor
Presynaptic nerve terminal
Acetylcholine
?7 nicotinic receptor
Glutamate
Postsynaptic nerve terminal
Glutamate receptor
77
Nicotinic cholinergic neuron density in different
populations
Middle-agedcontrols
Patients with AD
Age-matched controls
? 7600
? 4000
? 1000
Density of nicotinic cholinergic neurons/mm
3
78
?4 and ?7 mRNA expressing neurons associated with
?-amyloid plaque
Wevers et al, 1999
79
Evidence supporting the importance of enhancing
nicotinic receptor function in AD

• AD patients have a reduced number of selected
  subtypes of nicotinic receptors(1)
• Nicotinic receptor antagonists lead to cognitive
  impairment(2)
• Stimulation of nicotinic receptors may enhance
  cognitive functions such as memory and
  learning(3)
• Motor functions are also improved upon nicotinic
  receptor modulation(4)
• Nicotinic stimulation may be neuroprotective(5)

80
Primary Strategy for increasing cholinergic
function block acetylcholinesterase
Acetyl CoA Choline
Presynaptic nerve terminal
CAT
Acetylcholine (ACh)
M receptor
N receptor
ACh
Postsynaptic nerve terminal
Choline acetate
81
Primary medication treatment of AD (secondary
prevention)

• Cholinesterase inhibitors are the mainstay of
  therapy
• Two drugs currently on the market (Aricept and
  Exelon) one about to be launched (Reminyl)
• Though some patients experience immediate
  improvement, most prominent effect is cognitive
  stabilization
• Functional improvement follows cognitive
  enhancement or stabilization
• Positive effects of these agents appear to be
  sustained

82
Pharmacological Comparison of Aricept, Reminyl
and Exelon

• Aricept Reminyl Exelon
• Chemical class Piperidine Alkaloid Carbamate
• Mechanism Reversible Reversible
  Pseudo- irreversible
• Half-life 70 h 5.8 h 2 h
• Hepatic monitoring No No No
• Dosing qd bid bid

Apparent long duration of action (10 h) due to
slow-binding and time-dependent inhibitory
kinetics of carbamates
83
Aricept 30-week, Phase III trialsADAS-cog Results
2.5

2.0




1.5




Clinical improvement Clinical decline
1.0


0.5


0.0

0.5
Least squares mean change frombaseline (SE)
1.0
1.5
US Study Multinational Study Placebo Aricep
t 5 mg/day 10 mg/day
2.0
2.5
3.0
3.5
4.0
0
6
12
18
30
Endpoint
Study week
Placebowashout
ITT-LOCF analysis p?0.001 for Aricept versus
placebo Rogers et al. Neurology 199850136145
Burns et al. Dement Geriatr Cogn Disord
199910237244
84
Raskind Trial Mean ( SE) Change From Baseline
in ADAS-cog
Mean ( SE) Change From Baseline in
ADAS-cogScore
Months
P lt .001 vs placebo.
Raskind et al. Neurology. 2000.
85
Raskind Trial Mean ( SE) Change From Baseline
in ADAS-cog
Raskind et al. Neurology. 2000.
86
Caregiver Time in AD

• As AD progresses, caregivers provide more
  assistance to patient with dressing, feeding,
  bathing and management of incontinence1
• Estimated time spent by caregivers of severe AD
  patients on caregiving activities2
• 10 hours per day
• 290 hours per month

1. Mace et al 2. Max, et al. 1995.
87
Mean Change in Daily Time Spent by Caregiver
Assisting With ADL at 6 Months The Wilcock Study
88
Long-Term Open Label Treatment of AD
6
Clinical improvement
0
Clinical decline
6
12
ADAS-Cog Mean change from baseline (SE)
18
Decline in ADAS-cog score (911 points per year)
based on the natural history of untreated
patients with moderate AD
Aricept-treated patients 95 confidence interval
24
30
36
0
26
50
74
98
122
146
170
194
Study week
No. of subjects 133 124
100 56 46 37
34 28 25
Weeks from the beginning of the double-blind
study Friedhoff et al. Int J Neuropsychopharmacol
19992(Suppl 1)S175
89
Anticholinesterase Dose Titration Schedule
10 mg/day (od) according to individual patient
requirements
5 mg/day (od)
Aricept
12 mg/day (6 mg bid)
9 mg/day (4.5 mg bid)
Exelon
6 mg/day (3 mg bid)
4 mg/day (2 mg bid)
12 mg bid (optional)
8 mg bid
4 mg bid
Reminyl
0
6
12
18
Weeks
90
Reminyl (galantamine) has an allosteric
modulatingaction at nicotinic receptors
Presynaptic nerve terminal
N nicotinic M muscarinic ACh acetylcholine
ACh
M receptor
N receptor
galantamine
Postsynaptic nerve terminal
ACh
91
Summary of Cholinergic Pathology and Therapy in AD

• Alzheimers disease is associated with
  impairment of the cholinergic nervous system(1)

• This leads to
• decrease in ACh(1)
• decrease in specific subtypes of nicotinic
  cholinergic receptors(2)
• Targeting the cholinergic nervous system with
• AchE inhibition and
• nicotinic stimulation/modulation
• may be the optimal cholinergic therapy (3)

92
(No Transcript)
93
Focus of Symptomatic Psychiatric Treatment of AD
(secondary prevention)

• Psychic
• Paranoia
• Delusion/hallucinations
• Anxiety/fear
• Agitation
• Confusion
• Depression

• Vegetative
• Sleep disturbance
• Over or under eating
• Elimination difficulties
• Cognitive
• Limiting impact of cognitive dysfunction
• Enhancing efficacy of remaining cognitive skills

94
Psychotropic Drug Management of AD

• Goal allow caregiver to manage problem behaviors
  at home as long as possible

Anticholinesterase (Primary Therapy)
Antidepressants Depression, Anxiety, Agitation,
Disinhibition
Antipsychotics Psychosis, Anxiety, Agitation,
Aggression
Anxiolytics Anxiety (short-term)
Anticonvulsants (?) Agitation, aggression
95
(No Transcript)
96
PATHOPHYSIOLOGY OF AGGRESSIVITY IN ALZHEIMERS
DISEASE

• Evidence of derangement of serotonergic system
• (1) Clinical response to serotonergic agents
  (trazodone, tryptophan, bupsirone, sertraline,
  fluoxetine) in dementia
• (2) Depleted levels of serotonergic binding in
  neocortex (frontal temporal) found in
  Alzheimers Disease
• (3) Intense neurofibrillary tangle information
  found in dorsal raphe nucleus

97
(No Transcript)
98
(No Transcript)
99
The Roles of the Psychiatrist in AD
Competency
Screening and Diagnosis
Psychiatrist
Support/Aid For Caregiver
Treatment of Psychiatric Symptoms
Long-Term Care Consultation
100
To View or Download this Presentation

• Fletcher-Allen Server Burlington17
• Look in the following Folders
• Groups
• Mental Health
• Neurobiology Course
• File is
• Psychopath Course Lecture-Dementia

101
(No Transcript)
102
AD The Role of the Physician in the Community
Screening
Primary MD
Diagnosis
Treatment
Medication
Therapy (PT and family)
Management
Behavior
Cognitive Decline
Competency
Placement