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