Download Goodman - LIFE at UCF

Alzheimer's Disease in the
st
21 Century
Ira J. Goodman, MD
Compass Clinic
Associate Professor of Neurology,
UCF College of Medicine
Alois Alzheimer
•
German Neuropathologist
• Followed 51 year old female for
worsening memory, function, as
well as behavioral changes
• At the time of death 4 years later,
he described the senile plaques and
neurofibrillary tangles that
characterize this disease
Frau Auguste D.
Histopathologic Hallmarks of Alzheimer’s Disease (AD)
Structural Effects of Alzheimer’s Disease (AD) on the Brain
Natural History of Alzheimers
Disease
• Average Duration of Disease = approx.
8 – 10 years but can range from 3 – 20 yrs
• On average lifespan is decreased about
4.5 years in pts with AD
• AD costs approx. $172 billion per year in
US (In elderly, markedly more than cancer
and heart disease)
Clinical Expression of AD
COGNITION
BEHAVIOR
Unique
Symptom
Pattern
of
AD
FUNCTION
Natural History of Alzheimer’s Disease
30
Symptoms
25
Diagnosis
MMSE
20
Loss of functional
independence
Behavioral
problems
Nursing home
placement
15
10
5
Death
0
1
2
3
4
5
6
7
Years of Disease
Feldman & Gracon. Clinical Diagnosis and Management of Alzheimer's Disease.
Gauthier; 1996.
8
Alzheimer’s Disease (AD):
Significant Impact on Caregivers
Alzheimer’s Disease (AD):
Risk Factors
Normal Aging vs.
MCI vs. Dementia
• Benign Forgetfulness – The “Worried Well”
• Depression – “Pseudo Dementia”
• MCI – transition from Normal Aging to
Dementia
• Dementia – Involves at least 2 Cognitive
Domains
Tools used to evaluate
Memory Loss
• SCREENING MEASURES FOR COGNITIVE
IMPAIRMENT
• MMSE *
• Global Deterioration Scale (GDS)
• Clock Draw Test *
• 7 minute screen *
• ADAS – cog
• Functional Activities Questionnaire *
• CIBIC – plus
• Neuropsychiatric Inventory (NPI)
• Geriatric Depression Scale*
• Most important = Caregiver Input
Tools used to evaluate
Memory Loss
• ***For increased sensitivity and diagnosis of dementia
Neuropsychological Testing is recommended
• Also provides a thorough assessment of
emotional/personality functioning
• Patients should undergo formal testing especially to
differentiate those patients with questionable or mild
cognitive impairment versus mild dementia.
• Measures memory, language, IQ, problem solving, visual
spatial skills etc.
• Results are normed for age, education, and culture.
Early Diagnosis of Alzheimer’s
Disease
• Definite AD
– Brain biopsy or autopsy
• Probable AD
– Remains a clinical diagnosis
– Diagnostic testing may include a biomarker to use in
conjunction with other testing and your clinical
impression
– Neuropsychological test results (cognitive scores)
• Possible AD
• Definite Non-AD
Florida Brain Bank Autopsy Series
•
•
•
•
•
•
382 Consecutive Dementia Autopsies
AD-77% (only 54% with “pure” AD)
LBD-26% (66% also with AD)
VaD-18% (77% also with AD)
FTD-5% (33% also with HS)
65% of non-AD were diagnosed with AD
antemortem
Barker et al. ADAD. Vol. 16, 2002.
AD Biomarkers
• APOE- 4
– Requires blood test
– Risk factor, not a biomarker
• AB42/TAU Ratio
– Measured in csf obtained by lumbar puncture
– Overlap with FTD, LBD (though phospho-tau felt to be more
specific for AD (74%  85%))
•
PIB (Pittsburgh Compound B)
–
–
–
–
Requires IV injection and PET Scan
Still investigational
Not practical for Clinical use
New Amyloid Labeling Compounds ( to be launched this year)
• Neural Thread Protein (NTP)
– Requires only Urine Sample
– Appears reliable to distinguish probable AD from definite non-AD
NTP
1. Derived from AD brain
2. Present in AD brain lesions
3. Pathophysiological relevance
» tangles
» plaques
» apoptosis
Forebrain Cholinergic Nuclei
and Their Projections
PC
Thalamus
OC
FC
FC = Frontal cortex
PC = Parietal cortex
S
D
B
H
OC = Occipital cortex
H = Hippocampus
B = Nucleus basalis of Meynert
D = Diagonal bond
S = Septal nucleus
Pedunculopontine n.
Review of Normal
Cholinergic Function
Nicotinic Modulation Model
Galantamine
Cognition and Acetylcholine
Correlation of Cognitive Function with
Cholinergic Dysfunction
6
Patients with AD (n=8)
Healthy age-matched volunteers (n=4)
5
(S) (-)-11C-Nicotine
4
Uptake
nCl/cm3/dose bw-1
3
2
1
0
10 MMSE
Nordberg A. Acta Neurol Scand 1992; Suppl 139:54-58.
20
30
Comparing Approved Agents
Doses/
Day
Titration
(to minimum
effective
dose
Tolerability
(%
Completers)
Tolerability
(nausea
rate)
Tacrine:
Knapp et al, 1994
4
YES
46%
~30%
Donepezil:
Rogers et al 1998
1
NO
79%
11%
Rivastigmine:
Corey-Bloom et al, 1998
2
YES
78%
47%
Galantamine:
Tariot et al, 2000*
2
YES
80%
15%
Memantine
Riesberg et al, 2003
2
YES
77%
*5-month study
Number Needed to Treat
Common Geriatric Syndromes
Drug
Outcome
Duration
Alendronate Hip Fracture 4 years
NNT
15*
Cummings SR et al JAMA 1998;280:2077-82
Statins
https://sites.google.com/site/coretutorsorla
ndo/
MI
4 years
28
1 year
18
1 season
23
LaRosa JC et al JAMA 1999;282:2340-6
ACE/CHF
Death
AIRE Investigators Lancet 1993;342:821-8
Flu Vaccine Influenza
Govaert ME et al JAMA 1994;272:1661-6
*Only with low BMD at baseline. With normal BMD, NNT =

Number Needed to Treat
Donepezil in Mild-Moderate AD
Outcome
Duration
NNT
Clearly Improved
Cognition
6 months
5
1 year
3
1 year
2
1 year
3
Rogers et al, Neurology 1998
Stable Cognition
Winblad et al, Neurology 2000
No ADL Decline
Mohs et al, Neurology, 2000
Avoid Nursing Home
Placement
Lopez et al, JNNP, 2002
AChEI Treatment and Nursing
Home Placement
Likelihood of
Remaining at Home
1.2
AChEI Treated
1.0
No AChEI Treatment
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
72
84
96
Time to Nursing Home Placement (months)
Risk of Placement Differs Significantly (Kaplan-Meier Plot) p=.004
Lopez et al. J Neurol Neurosurg Psychiatry. 2002;73:310-314.
NMDA Receptor Antagonist
• Memantine
– Same class as amantadine,
dextromethorphan, as well as the dissociative
anesthestics ketamine and phencyclidine
Key Facts About Medical Foods
•
•
•
A “medical food” is defined by the Orphan Drug Act & Amendments of 1988
as a substance intended for the dietary management of a specific disease
or condition for which distinctive nutritional requirements, based on
recognized scientific principles, have been established by medical
evaluation
All medical food ingredients must have generally recognized as safe
(GRAS) status or must be approved food additives
Medical foods, dietary supplements, and prescription drugs are
not interchangeable
– Prescription drugs undergo intensive clinical study and are meant in most cases
to treat or prevent a specific disease
– Medical foods must first be shown, by medical evaluation along with scientific
and clinical data, to meet the nutritional needs or metabolic imbalance of a
specific “diseased patient population” before they can be marketed
– Supplements are intended for normal, healthy adults
– Unlike supplements, medical foods are most often available by prescription only
and must be administered under the supervision of a physician
Axona®
• Axona is a medical food intended for the clinical dietary
management of the metabolic processes associated with mild to
moderate Alzheimer’s disease (AD)
• The main ingredient in Axona has achieved self-affirmed generally
recognized as safe (GRAS) status
– Substances used in food that achieve the FDA’s GRAS designation
have a proven record of safety based on scientific evidence
• Axona contains caprylic triglyceride—a proprietary formulation of
medium-chain triglycerides (MCTs)
– MCTs safely increase plasma concentrations of ketone bodies
(predominantly β-hydroxybutyrate), which can provide an alternative
energy source for the brains of AD patients
– MCTs are metabolized differently from long-chain triacylglycerols; they
do not increase blood cholesterol levels and are not stored as fats
Scans of Patients Without and With
Probable Alzheimer’s Disease
(AD)1
Normal FDG PET Scan
AD Patient FDG PET Scan
FDG = 18F-2-deoxy-2-fluoro-D-glucose; PET = positron-emission tomographic scan.
1. National Institute on Aging. http://www.nia.nih.gov/Alzheimers/Resources/HighRes.htm. Accessed May 8, 2009.
Axona® Clinical Study in
Mild to Moderate Alzheimer’s
1
Disease
Significant Improvement in ADAS-Cog for APOE4(–)
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
APOE4 (-)
*
*
*
*
Improvement
Mean Change From Baseline
Patients in Per Protocol and Dosage Compliant
Populations
Axona per protocol
Axona dosage compliant
Placebo per protocol
*P<.05
Placebo dosage compliant
0
45
Time in Days
ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale.
Error bars = standard error of the mean (SEM).
1. Henderson ST, et al. Nutr Metab (Lond). 2009;6(1): 31.
90
Axona® Clinical Study in
Mild to Moderate Alzheimer’s
1
Disease
No Improvement in ADAS-Cog
for APOE4(+) Patients
Improvement
-4
ADAS-Cog
-3
-2
-1
0
1
2
Axona
Placebo
3
4
0
45
90
Days
ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale; APOE = Apolipoprotein Ε.
Error bars = standard error of the mean (SEM).
1. Data on file. Accera, Inc.
Treatment Expectations
• In Alzheimer’s Disease Clinical success is
defined as:
– Improvement
– No Change (as measured by family and
neuropsychological test results)
– Less than expected treatment decline
Current and Future Treatment
Options
• Additional Cholinesterase Inhibitors
• Vaccines – Currently several ongoing
vaccine Clinical Trials targeting amyloid
• Secretase Inhibitors – block formation of
amyloid
• Anti-Neurofibrillary Tangle drugs –
Rember (Methylene Blue), Epothilone D
• Gene Therapy
• Stem Cell Therapy
THANK YOU FOR YOUR
TIME!!