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Treatment of
Neurodegenerative Disorders
Stephen P. Salloway, MD, MS
Butler Hospital and
Brown Medical School
Disclosure
Research Support, Consultation and
Honorarium: Eisai, Pfizer, Johnson and
Johnson, Forest, Lilly, Novartis, Aventis,
Athena, Ono, Neurochem, Elan, Myriad
and Sention, NIH, Alzheimer’s Association
Off label discussion of CHEI for mild
cognitive impairment and Memantine for
mild-moderate AD
• Median survival of
women in the
longest-lived
countries has
increased 3 months
per year since 1840
Oeppen J et al. Science. 2002;296:1029-1031
Life Expectancy in Years
Most of Us Will Be Living Out Our Full Lifespan
and a Major Goal Is Healthy (Brain) Aging
Year
Projected Prevalence of AD
4 Million AD Cases Today—
Over 14 Million Projected Within a Generation
16
14.3
14
11.3
12
10
8.7
8
6
4
5.8
6.8
4
2
0
2000
2010
2020
2030
Year
2040
2050
Evans DA et al. Milbank Quarterly. 1990;68:267-289.
Alzheimer’s Disease Risks
• Established
– Age
– Apolipoprotein E ε4 genotype
• 4/4 increases risk 8 fold, any 4 increases risk 3 fold
– Chromosome 1, 14, 21 mutations
– Family history of dementia-RR 3.5
– Family history of Down syndrome-RR 2.7
– Head trauma with LOC-RR 1.8
– History of Depression-RR 1.8
• Others
– Low educational level, female gender
Geldmacher, 2001; Knopman, 2002
5
Cumulative Incidence of Alzheimer’s Disease
60
50
40
Alzheimer's
30
Disease (%)
20
10
0
65
70
75
80
85
Age (years)
Age is the biggest risk factor for AD
90
Teaching Old Dogs New Tricks
• 2 year study, old beagles (7-11
years; n=48) 4 groups divided into 1)
antioxidant-fortified diet, 2) program of
behavioral enrichment, 3) both, or 4)
neither.
• Discrimination and reversal learning
ability decline progressively with
advanced age in beagles, but the rate
of decline was delayed by both
behavioral enrichment and antioxidant
supplementation.
• Behavioral enrichment and
antioxidant supplementation combined
were more effective than either alone.
Milgram et al., Neurobiology of Aging 26 (2005) 77–90.
Keeping Our Synapses Healthy
• Stay mentally and physically
active-read, do crossword
puzzles, play bridge and games,
walk, exercise, go to the gym
• Stay involved with people and
projects- socialize, pursue
hobbies and volunteer work, learn
new things, play music,
participate in church activities
• Control risk factors-weight, BP,
chol, blood sugar, stop smoking
• Eat a balanced diet with Vit Eanimals on calorie restriction live
longer, low calories may decrease
risk of AD. ? Red wine-resveratrol
Defining the Diagnostic Threshold
for Dementia
Cognitive Continuum
Normal
Mild cognitive impairment
Dementia
Mild-Mod AD, Mod-Severe AD
Functional continuum
Normal Aging
• Psychomotor Slowing
– Taking longer to do things
– A 75 year old marathon runner takes twice the time to
complete the race as he or she did at age 25.
– Recalling names or trouble finding specific words
– “What did I come here for?”
• Troublesome signs
– Being repetitive and not just for emphasis
– Not coming up with the names or words later
– Not recalling that conversations or events ever took
place
– Not realizing that there is a memory problem
John A. Kelley in the Boston Marathon
Age 27
Time: 2:37:07 (1st Place)
1935
Age 83
Time: 5:42:54
1991
Ed Whitlock, Age 73
Ed Whitlock’s Fastest Times Since Turning 70
EVENT
TIME
AGE
5,000 meters
18:22
73
10,000 meters 37:33
73
15,000 meters 58:55
72
Marathon
73
2:54:49
• First person over 70 to break the three-hour mark.
• Ran Toronto Waterfront Marathon in 2:54:49, placing 26th out of 1,690 finishers.
• Was a runner in high school and university, then stopped running for 20 years.
• Began running again at age 41.
Subtypes of Mild Cognitive Impairment
MCI
Amnestic
MCI
Multiple Domains
Slightly Impaired
MCI
Single NonMemory Domain
Alzheimer’s Disease
Alzheimer’s Disease
Vascular Dementia (VaD)
? Normal Aging
Frontotemporal Dementia (FTD)
Lewy Body Dementia (LBD)
Primary Progressive Aphasia
(PPA)
Parkinson’s Disease (PD)
Alzheimer’s Disease
 Not all patients with MCI have AD,
but almost all patients with AD pass
through an MCI stage
What is Mild Cognitive Impairment?
• Disorder of short-term memory (> 1.5 SD)
• Misplacing things a lot
• Hard to recall messages, remember details,
and appointments
• Normal functioning overall
• More than a nuisance
• Risk factor for AD (12-15% per year)
Subtle Findings in MCI
MMSE=26
MMSE=21
MCI
AD
1/29/2004
MMSE=26
Volume of AD Cases by Specialty
Specialists providing care
Number of dementia patients
in physician’s practice
180
Other
Psych 7%
8%
120
121
99
Neuro
18%
60
63
48
PCP
67%
0
GP/FP
IM
Neuro
Source: NDTI (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904, 3109, 2912), Moving Annual Total (MAT).
March 2001. Source: Market Measures, February 2000.
Psych
Recommendations for Screening
• At annual physical or when warning signs
appear
• Ask the patient and a knowledgeable informant
about any problems with memory, mood,
behavior or problems driving
• Do a baseline MMSE and clock drawing
• If time is short do the 3 word recall during the
exam and clock drawing
Neurodegenerative Disorders
• Protein dysmetabolism
• Vulnerable cell populations
• Neural systems affected
– Specific regions and neurotransmitters
• Clinical phenotype
– Systems linked to cognitive and behavioral changes
• Disability
• Age dependent onset
• Genetic and environmental risk factors
– ApoE and head injury
The Temporal Course of
Neuropathological Changes of
AD in Down’s Syndrome
Age
10
20
30
40
50
Amyloid
Deposition
Microglial
Changes
Neurofibrillary
Tangles
Neuronal Loss/
Neurochemical
Changes
60
70
Mann DMA. BMJ. 1997(Oct 25);315:1078-1081
Dementia
Figure 4. Appearance of plaques and DAT
70.00
Amyloid Plaques (Braak & Braak)
Proportion (%)
60.00
50.00
DAT - Average of Three Studies
40.00
30.00
20.00
10.00
0.00
46-50
51-55 56-60
61-65
66-70 71-75
Age (years)
Courtesy of Dr. Mark Mintun
76-80 81-85
86-90
Braak Staging of AD
Trans-entorhinal (I-II)
Limbic (III-IV)
Isocortical (V-VI)
Change in Hippocampal Volume from
Normal Aging through AD
Normal
% of nl
>50% of nl
1-50%
1st %
Jack Neurology 1999;52:1397-1403
MCI
AD
conversion rate
9%
26%
50%
PET for the Diagnosis of Dementia
Medicare Guidelines
•Atypical course for AD
and FTD is suspected
• Comprehensive eval
conducted by a
physician experienced in
dementia
• PET reading done by a
physician experienced
in dementia imaging
• No prior SPECT or
PET
• Clinical trials using
PET for dx of early
dementia may be
covered
Amyloid Imaging
 Pittsburgh
compound
Assessment
 Clinical history
 Primary symptoms from patient
and informant
 Onset and course
 Gradual, abrupt
 Were there “events”?
 Determining baseline cognitive
and functional ability
Assessment
Domains
 Cognitive
 Memory, language
 Fluctuations?
 Activities of daily living (ADLs)
 IADLs, BADLs, driving, hobbies
 Behavioral




Mood, irritability, impatience, apathy
Delusions, visual hallucinations, paranoia
Substance use
Sleep, appetite
IADLs = instrumental ADLs; BADLs = basic ADLs
Assessment
 Motor and Gait
 weakness, numbness, lateralizing?
 Parkinsonism
 Bladder control
 Other medical conditions and medications
 Family history: dementia, psychiatric,
neurological
12
Predicted Result of Early Treatment
Cognitive Function
Early Treatment
No Treatment
Time
Modern medicine relies on the premise of early
diagnosis and treatment to prevent or delay morbidity.
Moderate AD
Age 77
Sep 1998
Age 79
Aug 2000
Age 82
Oct 2002
Age 84
2004
MMSE: 19
MMSE: 15
MMSE: 12
MMSE 10
300
250
200
DLBD*
AD
PD*
NC
LBV**
150
100
p-value = 0.0001
(Kruskal-Wallis ANOVA)
50
0
MF ChAT
There is a Pronounced Cholinergic Deficit Early in LBD
*p<0.05 compared to AD; p<0.001 Compared to NC (Dunn’s multiple comparisons test);
**p<0.001 compared to AD and NC (Dunn’s multiple comparisons test); Tiraboschi P, Hansen
LA, Alford M. Neurology. 2000;54:407-411
Cholinesterase Inhibitors for AD
 Tacrine (Cognex)
 Donepezil (Aricept)
 Physostigmine SR (Synapton)
 Rivastigmine (Exelon)
 Metrifonate
 Galantamine
32
Outcomes Measured in Reminyl®
(galantamine HBr) Phase III Trials
Cognition
Outcomes in
Reminyl® trials
Caregiver
burden
Global
change
Behavioral
disturbances
Activities of
daily living
Benefits of CHEI for AD
• Stabilize functioning during the first year
and make subsequent decline more
gradual
• Delay time to nursing home placement
• May decrease behavioral symptoms
• Show some benefit in moderate severe
stages of AD
• The CHEI’s have similar efficacy but may have
differences in tolerability and ease of use
Mean change from baseline ( SE)
Donepezil Pivotal Trials ADAS-cog scores in mild to
moderate AD
2.5
1.5
Clinical
improvement
0.5
Baseline
-0.5
Clinical
decline
-1.5
-2.5
-3.5
Baseline
Donepezil 5 mg/d
Donepezil 10 mg/d
Placebo
6
12
18
Study week
Rogers SL, et al. Neurology.1998;50:136-145.
24
30
38
Long-term Effects of Donepezil on Cognition:
ADAS-Cog Mean Change From Baseline
Improve
-6
0
6
12
Decline in ADAS-Cog score based on
the natural history of untreated patients
with moderate Alzheimer’s disease
Decline
18
0 6 12 14
26
38
50
62
74
86
98
Probability of Remaining at Home
Delay Time to Nursing
Home Placement
1
0.8
Placebo
High Dose
Higher Dose
0.6
0.4
0
100
200
300
400
500
Days
600
700
800
Most Common Side-Effects With
Cholinesterase Inhibitors
• Gastrointestinal
– Nausea, Vomiting, Loose stools, Diarrhea
• Anorexia and weight loss
• Vivid Dreaming
Symptoms are usually transient and dose relatedtitrate slowly and take with food
A small percentage become agitated on CHEI’s
MCI - Amnestic
70
60
50
40
30
20
10
Speed
Attention
Delayed Recall
Recognition
Spatial/Constr
Lang/Naming
Executive
Cognitive Change in the 24 week
Donepezil MCI Trial
3.5
P=.007
P=.044
LS Mean Change
From Baseline
3.0
Donepezil
2.5
Placebo
2.0
1.5
1.0
0.5
0.0
(n=130)(n=132)
ITT-LOCF
*FE=fully evaluable
Salloway et al. Neurology. 2004;63:651-657.
(n=83) (n=100)
FE*
Results of the 36 month
ADCS MCI Conversion Trial
• Conversion rate to dementia was 13% per year,
98% determined to be to AD
• APOE-ε4 + 55.1%. Rate of conversion was
significantly higher in the APOE4 positive group
• There was no significant effect of donepezil or
vitamin E on conversion over the full 3 year study
• Donepezil appeared to decrease the probability of
conversion for up to 18 months and delay the
conversion to dementia by 6 months overall
• The delay to conversion was greatest in the
APOE4 positive group
Lancet 2004;363:
2105-2115
Driving and Dementia
X X X
Normal Driving No driving No driving Local driving Not Driving
at night on highways
only
Driving Evaluation
Gets lost
No strange places
No driving due to crash
Bad Option!
Driving
Spectrum of Neuropsychiatric
Symptoms in AD
Behavior
Apathy
Delusions
Hallucinations
Agitation
Dysphoria
Disinhibition
Mega et al, 1996
Mild
47%
12%
12%
47%
12%
35%
Moderate Severe
80%
92%
25%
31%
15%
8%
55%
85%
45%
62%
40%
54%
Helping Caregivers Cope
•
•
•
•
•
•
•
•
Face the situation directly
Common sense problem solving
Get educated and develop a support network
Structuring the home environment
Familiar, calm environment with a predictable routine
Keep it simple, limit choices
Match activities to capacities and preferences
Avoid arguing and overwhelming situations and
challenges
• Driving and home safety
Use of Glutamatergic Agents
for Rx of Memory Loss
• Glutamate plays an important role in
memory consolidation and LTP
• Therapeutic approaches-NMDA agonists
and antagonists, AMPA receptor
modulators, glycine modulators
• Memantine is a low to moderate affinity,
uncompetitive NMDA-receptor
antagonist, voltage-dependent, fast
blocking/unblocking kinetics
– Blocks the effects of abnormal glutamate
activity that may lead to neuronal cell
damage/loss and cognitive dysfunction
– Preserves physiological activation of NMDA
receptor required for learning and memory
Sources: Rogawski MA, et al. CNS Drug Reviews. 2003;9:275-308.
Danysz W, et al. Neurotoxicity Res. 2000;2:85-97.
Memantine: Mod-Severe
Monotherapy AD Trial
• 28 week trial of memantine 20mg/d vs placebo in
mod-severe AD, MMSE 7.9
• N=252
• Outcomes
– Primary-CIBIC+ and ADL
– Secondary-SIB, MMSE, NPI
• Sig slower decline in the memantine group in
CIBIC, ADL and SIB
• No sig difference in MMSE and NPI
• Caregiver time was sig less in the drug group
NEJM 2003;348:1333-41
Memantine: Mod-Severe
Monotherapy AD Trial
Memantine Plus Aricept for
Mod-Severe AD
• 28 week study, n=403, mean MMSE 10, range 5-14
• Aricept 10 plus memantine 20/d vs Aricept 10 and placebo
– Had to be on Aricept 10 mg for at least 6 months, mean
duration of Aricept Rx-24 mos.
• Outcomes
– Primary- ADL and CIBIC+
– Secondary-SIB, NPI
• Patients on combined Rx declined at a sig slower rate and
showed improvement on the SIB
• Aricept-memantine combination well tolerated
• ? Decreased benefit in the <10 group
JAMA 2004;291:317
Memantine Plus Aricept
for Mod-Severe AD
What about the new preventative and
disease modifying treatments?
•
•
•
•
•
•
Vitamins
Anti-inflammatory agents
Estrogen
Statins
Mood stabilizers
Treatments to reduce amyloid load
– Amyloid vaccine
– Secretase inhibitors
– Heavy metal chelators
• Shunting AD patients
New Targets for Treatment of Alzheimer’s Disease
Three approaches to Altering
Brain Amyloid in Alzheimer’s Disease
1. Reduce β-amyloid production
2. Inhibit β-amyloid fibrillogenesis
3. Promote β-amyloid clearance
New Targets for Treatment of Alzheimer’s Disease
Amyloid Fibril
Nerve Cell
Proteolytic Cleavages of Amyloid
Precursor Protein (APP) That Produce
A Peptide
-amyloid precursor
protein
NH
Extracellular
space
TM
A
peptide
COO
H
2
secretase
Abeta-42
Selkoe DJ et al. JAMA. 2000;283:1615-1617.
Cytoplasm
alpha-secretase
Abeta-40
secretase
Abeta-42
Parietal neocortex, immunized AD
patient in Elan AN-1792 Trial
Parietal neocortex, Nonimmunized
patient at comparable stage of AD
The Meningoencephalitis Induced by Active Amyloid
Immunization With AN-1792 Was T-Cell Mediated
CD3 T-cell antibody stain shows
extensive meningeal reactivity in
response to AN-1792
Hock et al. Neuron. 2003;38:547-554.
CD79a B-cell antibody stain shows
no meningeal reactivity in AN-1792
induced meningoencephalitis
Tau Hyperphosphorylation
Stabilizing
Tau
Molecules
Healthy
Neuron
Microtubule
s
Disintegrating
Microtubule
Diseased
Neuron
Disintegratin
g
Microtubules
Art from ADEAR
Microtubule
Subunits Fall
Apart
Tangled
Clumps of
Tau
Proteins
Improving the Treatment of Dementia
• Develop routine screening for memory loss and behavior
change in older people
• Diagnose and treat signs of dementia early and maintain
persistent treatment
• Educate caregivers about the illness, help them structure
the daily routine and assist them with obtaining support
over the long-term
• Work with determination to develop effective new
treatments that dispel the angst associated with AD
• Build a partnership of civic leaders, scientists, clinicians,
and families to wage a concerted fight against AD
3/15/2004
MMSE=22
Leaves out numbers on left side
3/15/2004
MMSE=22