Elephants never get dementedI wonder what drugs they’re
on?
David Greenhouse, MD, CMD
Director of Geriatric Education
USC SoM
Stanley
75 yo male seen in the FPC for f/u As part of geriatric curriculum resident
performs Mini-Cog 3 object recall: moon, dog, watch Clock draw test
Long term memory question Why did Kennedy leave office?
Results
1/3 recall after clock draw distraction
“He was having an affair. He was voted out.”
MMSE 20/30
Diagnosis
After some further testing and talking to family, you make the clinical diagnosis of Alzheimer’s type dementia
4.5 million cases today
45.8
6.8
8.7
11.3
13.2
0
2
4
6
8
10
12
14
2000 2010 2020 2030 2040 2050
Year
Millions
Projected Prevalence of AD3rd most expensive disease, $100 billion
Disease Specific Death Rates
Heart disease Down 3 %
Cancer Down 1 %
CVA Down 2.8 %
Alzhemier’s disease Up 5.8 %
Kidney disease Up 1.4
Septicemia Up 2.6 %
Diabetes Up 0.4 %
Knowable, unintended consequences
We all have to die from something. As long as we make gains in treatment of Cardiovascular disease, other diseases will become more prevalent.
Fantastic Voyage
A Look Inside
At the synapse
Loss of acetylcholine neurons starting in hippocampus
Plaques at the Cell Membrane Level
Cholesterol modulates APP processing
Cyp46 = 24S-cholesterol hydroxylase
The Tangled Web
Plaques injury kinase activation
Kinases phosphorylates microtuble tau protein forming tangles
Something New Under the Sun Excitotoxicity
Glutamate Major excitatory neurotransmitter for cognition &
learning Glutamate neuronal loss correlates with degree of
dementia
N-Methyl-D-Aspartate forms ion channel for Ca entry Ca intracellular messenger Inactive receptor blocked by Mg Uncontrolled activation causes cell death
Glutamate in ATD
Glutamate transporter down regulated Increased synaptic glutamate activity
Glutamate promotes APP synthesis β-amyloid inhibits re-uptake of glutamate and
enhances glutamate release Increased NMDA receptor activity increases
phosphorlyation of tau protein
The Stroke Connection
Cognitive performance decreased in those with stroke risk factors Abstract reasoning, visualspatial memory, visual
organization, concentration most affected Snowdon Nun Study
Glutamate & Stroke
Pathophysiologic model
Glutamate
β-AmyloidNeurofibrillary
TangleExcitotoxicity
Cell death
Dementia
Inflammation
Do we have anything to offer?
Non-pharmacologic Strategies
Mental exercises Higher education Physical activity Social activity Diet (fish, low cholesterol)
Think Medical School
Pharmacologic Treatments
Anti-inflammatory agents: NSAIDs Estrogen replacement Antioxidants: vitamin E, selegiline Ginkgo biloba Statins Control vascular risk factors Acetylcholinesterase inhibitors NMDA-receptor antagonists
Anti-Inflammatory Drugs
Observational/epidemiological studies NSIADs associated with reduced risk
Clinical trials Failed to show benefit of prednisone, NSAID,
COX-2
Aisen PS, JAMA 6/4/03; 289; 2819-26
Women’s Health Initiative
Women’s Health Initiative Memory Trial Hazard ratio of 2.05 for probable dementia
1.89 % on E+P vs 0.9% on placebo 12.5 % E+P vs 4.8 % on placebo VCI 50.0 % E+P vs 57.1 on placebo ATD
Yes, more women who developed dementia on placebo developed ATD
No protection for Minimum Cognitive Impairment
Shumaker JAMA 2003; 289: 2651
Vitamin E
Selegiline 5 mg bid or Vitamin E 2000 IU qd Primary outcome: time to death,
institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia
Vit E (670 d) >selegiline (655) >both (585) >placebo (440)
Did not reach statistical significance Cochrane review: insufficient evidence
Sano M, NEJM 1997; 336:1216
This Just In
4740 respondents regarding use of multivitamins, Vit E, Vit C and B-complex
Only people taking combination of Vit E & C had statistically significant protection (HR 0.36) Vit E 1,000 IU and Vit C 500-1,000 mg
Other studies have found reduction in vascular dementia with combination
Zandi, P. Arch Neurol 61 (1): 82-88
Ginkgo biloba
Ginkgo 40 mg PO tid for 6-12 months in mild-moderate dementia
Ginkgo stabilized cognition Serious side effects: coma, bleeding, seizure
LeBars PL JAMA 1997; 278: 1327
Statins
HERS reduced TC and LDL resulted in 50 % decrease in dementia
Epidemiologic studies: Statins decrease risk of AD Jick, Lancet, 30 % reduction in dementia Wolozin, Arch Neuro, 60 % reduction Hajjar statin users had unchanged or improved
MMSE (OR 2.81) Statins decrease β-amyloid deposition
AChEI therapy
Difference in titration, mechanisms of action and metabolism
All have benefits on cognition, behaviors and activities of daily living
Most studied class of medications for ATD Neurostabilizers/neuroprotectors
Donepezil (Aricept)
Introduced 1997; Reversible inhibitor AChE; piperidine
No heptatoxicity Highly protein bound = long half life
Once daily dosing Simple titration
Cytochrome P450 system Long term may up-regulate levels of AChE in CSF
leading to decline in efficacy Least GI side effects
Rivastigmine (Exelon)
Slowly reversible inhibitor of AChE and BuChE; G1 AChE selective (found in hippocampus and
cerebral cortex) Metabolized by target enzymes; not P450
Low protein binding, bid dosing More complicated titration No up-regulation reported Greatest GI side effects
Galantamine (Reminyl)
Phenanthrere from Daffodil stamen Low protein binding, BID dosing More complicated titration Inhibits AChE & modulates nicotinic receptors P450 metabolism Metabolite, sanguinine, 3x power of parent
compound Intermediate GI side effects
AChEI long term benefits
ADAS cog maintained above baseline
Reference
Donepezil (Aricept)
39 wk Rogers, 1998
Rivastigmine (Exelon)
38 wk Farlow, 2000
Galantamine (Reminyl)
52 wk Rasking, 2000
Head to Head Trials
The Evidence is Lacking
MMSE mixed differed
End points different
Rivastigmine v Donepezil
12 week trial, 111 patients, mild to moderate disease
Donepezil better tolerated Similar cognitive and functional outcomes
Too short to really titrate rivastigmine to most effective dosing
Wilkinson DG. Int J Clinic Pract Jul 02; 56(6): 441
Galantamine vs. Donepezil
12 week trial Donepezil better on cognitive and functional
measures Short term and galantamine requires slower
titration to maximize dosing
Galantamine vs Donepezil
Rater blinded, randomized, 12 month, open label, parallel group comparison Galantamine 8 – 24 mg/d Donepezil 5 – 10 mg/d
MMSE remained above baseline for 11 months for galantamine v 6 months for donepezil
No difference in functional measures
McKeith, I Neurology 2003; 60 Suppl 5 A 141
Several years later
Stanley has remained remarkably stable since starting an ACHeI.
On this f/u visit, his daughter relates more forgetfulness and decreased abilities
MMSE 12/30 Daughter “Should we continue the
medication? Do we have any other options?”
New Kid on the Block
Namenda (memantine)
NMDA receptor antagonist
Studies focus on function
Oral, 100 % bioavailable
Minimal metabolism with 57-82 % eliminated unchanged in urine
Does not inhibit P-450
NamendaStabilized at baselinefor 12 weeks. Always above placebo
Namenda dosing
Week 1 5 mg once daily
Week 2 5 mg BID
Week 3 10 mg qam & 5 mg qpm
Week 4, Maintenance 10 mg BID
Add on to Donepezil
404 patient MMSE 5-14 on Donepezil
Randomized to Memantine or placebo in addition to Donepezil
Additional improvements or stabilization in cognition, ADLs, behaviors compared to Donepezil alone
Tariot, P. JAMA Jan 04: 291; 317-324
Time Marches On
MMSE 10/30 Decreased ADLs, incontinent Moved into a Skilled Nursing Home
FAQ
AChEI in late stages Already in Nursing Home One AChEI loses efficacy Other dementias Namenda in early ATD
Donepezil in Advanced Disease
One double blind study and one case report demonstrate efficacy for Donepezil in advanced disease (MMSE 11) Improvements seen in behaviors & ADLs
More long term studies on going My take: use these meds for patients with MMSE >
10 or in those still independent in some ADLs Ambulation, continence, feeding, initiation of activities
Feldman, H. Neurology; 57: 613Tariot, P. JAMDA; July 2003: 216
Other studies in Mod-Severe ATD
Rivastigmine 58 % improvement in irritability, aberrant
behavior, apathy, hallucinations, disruptive night time behavior, agitation, delusions
Galantamine MMSE 12; 6 month trial Cognitive and functional improvements compared
to placebo
Cummings JL. Neurolgy 2000; 54: A469Wilkinson DG Int J Clini Prac 2002; 56(7); 509-14
Donepezil in the Nursing home
208 pt, Mean MMSE 14, frequent behavior problems
24 wk, placebo, blinded study Results
Only improvement seen in agitation/ aggression 61 % concomitant psychotropic
Stabilized MMSE compared to placebo Overall improvement in function in facility
Tariot P. JAGS 2001: 49; 1590-9
Donepezil to maintain ADLs
290 patients in Community or Assisted living, 24 weeks Mean MMSE 12 Psychotropics allowed but stable dosing
Improvement or stabilization of function compared & cognition to placebo
Care givers benefited ~ 1 hr/day
Feldman H. Neurology 2001; 57: 613
Rivastigmine after Donepezil
382 outpatients (MMSE 16) on donepezil changed to rivastigmine in open labeled trial 78 % changed due to lack of efficacy, 3 point
decline in MMSE Improvements seen in cognition, ADLs,
behaviors over baseline
Possible explanations
G1 selectivity BuChE predominance in later disease No up-regulation of AChE with rivastigmine
AChEI & other dementias
Vascular dementia and mixed dementia May have cholinergic deficit Improvement seen in cognition, ADL and
psychiatric inventory compared to placebo 6 month stabilization at baseline
Significant improvements in Lewy Body Dementia
Improvement in dementia associated with Parkinson’s w/o increased symptoms
Erkinjuntti, T. Lancet April 2002; 259:1283-1290Wilkinson, D. Neurology Aug 2003; 61: 479Masterman D.
Namenda & Mixed Dementia
Small studies in mixed vascular dementia similar results as in AD
Memantine for Mild-Moderate ATD
Double-blind, parallel arm, placebo controlled Phase III trial of 24 weeks
403 patients, mean age 77.5 yrs, MMSE 10 to 22
End points: cognition (ADAS-cog), overall function (CIBIC-plus), general function (ADCS-ADL) and behavior (NPI)
Improvement over base line in all areas Only adverse effect -- somnolence
Peskind ER. Poster at AAGP 17th annual meeting
The Future
Statins & ATD Other vitamins ACheI in severe ATD Secretase inhibitors Amyloid protein antibody Glutamate inhibitors for prevention Anti-amyloid aggregators Tau protein phosphorylation inhibitors