current management of alzheimer’s disease...current management of alzheimer’s disease william...

7/1/2015

1

Current Management of Alzheimer’s Disease

William Petrie, MD

Risk factors for Alzheimer’s disease

Risk factors for Alzheimer’s disease

Increased systolic B/P(>160) Incraesed cholesterolNoted in 21 year followup Kivipelto et al2001

Increased systolic B/P(>160) Incraesed cholesterolNoted in 21 year followup Kivipelto et al2001

7/1/2015

2

Canadian Study of Health and Aging-5 year followup

Increased Age Fewer years of Education Apoliprotein E4

Canadian study of health and aging

Reduced Risk: Wine drinking Use of NSAIDS Coffee Regular Physical Activity

7/1/2015

3

Canadian study of health and aging- no association

Family history of dementia History of depression Estrogen replacement Head injury Smoking High blood pressure Heart disease Stroke Lindsay et al.

2002

Dutch Study

Risk: Smoking Low Education

No Risk: Family History Head injury Launer et al.

1999

7/1/2015

4

SLEEP

Increased rate of MCI and AD in both short and long sleepers(<6 hours, >9 hrs)

Chen et al. 2015

GAIT

Gait speed Gait Variability

Both predicted dementia

Gillain et al 2015

7/1/2015

5

2015 Risk Factors

Age Family history Susceptibility genes(ApoE) Diabetes(>12 studies) Mid life obesity(6 studies) Mid life hypertension Current Smoking

Other Risk Factors

Years of formal education TBI, esp repetitive Depression, esp recurrent Impaired sleep Hyperlipdemia(+/-)

7/1/2015

6

Progression from MCI to AD

Phosphorylated tau Hippocampal atrophy Medial temporal lobe atrophy Entorhinal atrophy Total tau WMI

Progression from MCI to AD

Depression Diabetes Hypertension Age

7/1/2015

7

DIET

Mediterranean Diet reduced risk of AD by 54%(comparing top 1/3 to bottom1/3)

Hypertension Diet(DASH) reduced AD by 39% compared to bottom third

MIND(Med-DASH Intervention for Neurodegenerative Delay)

Good foods

Green leafy vegetables Other vegetables Nuts/ Berries Beans Whole grains Fish/Poultry Olive oil Wine

7/1/2015

8

Bad Foods

Red Meat Butter/ stick margarine Cheese Pastries Sweets Fried food Fast foods

Treatment of Alzheimer’s Disease

Source: Decision Resources, March 2000.

* Any drug treatment, not limited to acetylcholinesterase inhibitors.

0

1

2

3

4

5

Pat

ien

ts (

mill

ion

s)

Prevalence

4,523,100

Diagnosed

2,261,600

Treated*

904,600

Treated with AChEIs

543,800

Winton, M.J. August 2012: Treatment Algorithms in Alzheimer's Disease

7/1/2015

9

7/1/2015

10

= acetylcholine

Acetyl CoA+

Choline

Acetylcholine

N receptor

Central Cholinergic Transmission

Presynaptic nerve terminal

Postsynaptic nerve terminal

CAT

CAT = choline acetyltransferase

AChE = acetylcholinesterase

N = nicotinic

M = muscarinic

N receptor

M receptor

M receptor

AChE AChE

Major Changes in the CholinergicSystem in Alzheimer’s Disease

• Depletion of acetylcholine (ACh)

• in choline acetyltransferase (ChAT) activity

• Loss of cholinergic neurons

• Acetylcholinesterase (AChE)

• Butyrylcholinesterase (BuChE)

• Loss of muscarinic & nicotinic receptors

7/1/2015

11

FDA-Approved ChEI Treatments for Mild to Moderate Alzheimer’s DiseaseFDA-Approved ChEI Treatments for

Mild to Moderate Alzheimer’s Disease

Mild to moderate AD– Cognex® tacrine (Sept 1993)– Aricept® donepezil (Jan 1997)– Exelon® rivastigmine (June 2000)– Reminyl® galantamine (Feb 2001)

Mild to moderate AD– Cognex® tacrine (Sept 1993)– Aricept® donepezil (Jan 1997)– Exelon® rivastigmine (June 2000)– Reminyl® galantamine (Feb 2001)

Cognex is a registered trademark of Warner-Lambert Company. Aricept is a registered trademark of Eisai Company Ltd. Exelon is a registered trademark of Novartis AG. Reminyl is a registered trademark of Janssen Pharmaceutica.

7/1/2015

12

Commonly used ChE inhibitors in AD

H 3 C O

H 3 C O

O

CH 2

N CH 2

.

DonepezilMechanism: AChE-IInhibition: reversible

C H 3

O

ON

H3 C

C H 3

H3 C

+

Acetylcholine

NH3 C

C H 3

C H 3

O N C H 3

C H 3

O

RivastigmineMechanism: AChE-I/BuChE-I

Inhibition: very slowly reversible

GalantamineMechanism: AChE-IInhibition: reversible

O

N

H OO C H 3

H3 C

7/1/2015

13

Time-course of the Change from Baseline in SIB Score for Patients Completing 24 Weeks of Treatment.

(p = 0.0001)

Aricept (donepezil) 23 mg vs10 mg

MMSE: 0-20; Mod to severeStable dose of ARICEPT 10 mg/day>3 months1434 patients 36% on memantine

Farlow MR, et al. Clin Ther 2010;32:1234-1251.

7/1/2015

14

AD-1

21

7/1/2015

15

Study Week

LS

mea

n c

han

ge f

rom

bas

elin

e sc

ore

DONEPEZIL IN PURE VASCULAR DEMENTIA

Pratt, RD. et al. Am J Geriatr Psychiatry. 2002 March-April; 10(2)Suppl 1:44

Clinical

improvement

Baseline

Clinical

decline

7/1/2015

16

Acetylcholine Can Affect Preand

Postsynaptic Nicotinic Receptors

Postsynaptic nerve terminal

M receptor

N receptor

Presynaptic nerve

terminal ACh

N = nicotinic

M = muscarinic

ACh = acetylcholine

ACh

Newhouse, P. et al. Neurology. Volume 78(2), 10 January 2012, p 91–1012

Nicotine Patch in Mild Cognitive Impairment

A 6‐month double‐blind pilot clinical trial.

N=34 ‐ Nicotine Patch: 5 mg 10 mg 15 mg

N=33 ‐ Placebo:

MMSE=24 – 30

7/1/2015

17

Reminyl Razadyne(galantamine)

Enhances cholinergic functionStimulates the nicotinic

receptor Extracted from the

dewdrops of Amaryllidaciae (daffodils)

7/1/2015

18

7/1/2015

19

Causes of Dementia

Rivastigmine International Lewy Body Dementia Trial: Behavioral Changes

(NPI)NPI 10-item Score–Mean Change from Baseline (OC)

-8

-7

-6

-5

-4

-3

-2

-1

0Baseline Week 12 Week 20

RivastigminePlacebo

*P<0.01 vs placebo (ANOVA/ANCOVA)McKeith IG, et al. American Academy of Neurology 52nd Annual Meeting. April 29-May 6, 2000. San Diego, California.

*

7/1/2015

20

Efficacy of Aricept: Three Year Study

Eisai Data on File: Nordic Study, with 2-Year Open Label Extension

Donepezil and galantamineincrease CSF AChE activity1

(assessed by enzyme antigen immunoassay)

Sustained inhibition of CSF AChE activity by rivastigmine2

(assessed colorimetrically)

Donepezilat 12 months

Galantamine at 6 months

0

50

100

150

200

250

300

350

400

AC

hE

act

ivit

y (%

ch

ang

e)

Rivastigmine at 12 months

–100

–50

0

50

100

150

200

250

AC

hE

act

ivit

y (%

ch

ang

e)

1Adapted from Davidsson et al. 20012Adapted from Darreh-Shori et al. 2002

n=62 n=15

n=7

Effects of long-term ChE inhibition on AChE levels

7/1/2015

21

Aricept Failure Exelon Crossover Study

Auriacombe S, et al. Curr Med Res Opin 2002;18:129-38

Cognitive Efficacy at 5 Years

Data presented are from 2 large open-label extension studies enrolling patients from 4 phase III, randomized, placebo-controlled trials. All patients who were enrolled in the open-label extension studies received up to 12 mg/day rivastigmine. The baseline values used for patients treated with rivastigmine from the outset of the double-blind trials were those from Week 0; for patients treated with placebo in the double-blind trials, the baseline values used for the current analysis were those from the week immediately preceding the beginning of rivastigmine treatment in the open-label extension. The cognitive decline of projected untreated patients was estimated using the algorithm, proposed by Mendiondo et al, a baseline-dependent mathematical model designed to estimate cognitive decline.

20

18

16

14

12

10

8

6

00

MM

SE

Sc

ore

s F

rom

Ba

se

line

1 2 3 4 5

Decline

Improvement

Rivastigmine (up to 12 mg/day)

Projected untreated patients

Yearsn=1998 n=1487 n=1040 n=657 n=298 n=83

Data on file, Novartis Pharmaceuticals Corp.

7/1/2015

22

Exelon (rivastigmine) ‘Patch’

Transdermal System

Role of Glutamate in AD Role of Glutamate in AD

The normal activity of the neurotransmitter glutamate plays an integral role in the neural pathways associated with learning and memory

In AD, abnormal glutamatergic activity can cause neuronal toxicity and may impair learning

The normal activity of the neurotransmitter glutamate plays an integral role in the neural pathways associated with learning and memory

In AD, abnormal glutamatergic activity can cause neuronal toxicity and may impair learning

Source: Greenamyre JT, et al. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:421-430.

7/1/2015

23

Glutamate Hypothesis of Cognitive Deficit

Glutamate Hypothesis of Cognitive Deficit

Neuronal damage/lossfollowing chronic insult

Abnormal glutamatergic activity leads to sustained low-level activation of NMDA receptors

Cognitive deficit

Source: Danysz W, et al. Neurotoxicity Res. 2000;2:85-87.Orgogozo JM, et al. Stroke. 2002;33:1834-1839.

Pharmacology of MemantinePharmacology of Memantine

Uncompetitive (open channel) NMDA-receptor antagonist

Improves performance in learning-impaired animals

Does not alter AChE activity in the presence or absence of AChEIs

Antagonistic effects at the 5HT3 receptor

Uncompetitive (open channel) NMDA-receptor antagonist

Improves performance in learning-impaired animals

Does not alter AChE activity in the presence or absence of AChEIs

Antagonistic effects at the 5HT3 receptor

Adamantane Derivative1-amino-3,5-dimethyladamantane

NH+

3

CH3

H3C

Sources: Parsons CG, et al. Neuropharmacology. 1998;38:735-767. Wenk GL et al. Brain Res. 1994;655:7-11. Namenda package insert, Forest Pharmaceuticals, Inc.Periclou A, et al. Presented at: 26th Annual Meeting of the American Medical Directors Association; March 6-9, 2003; Orlando, Fla.

7/1/2015

24

Memantine Voltage Dependency in Alzheimer’s Disease

Memantine Voltage Dependency in Alzheimer’s Disease

Magnesium

PhysiologicalMagnesium Block

Depolarization SynapticActivity

RestingState

Ca2+ Ca2+

–70 mV –50 mV –20 mV

Low to Moderate AffinityAntagonist Memantine(Ki = 0.5 µM)

Memantine

MM

Ca2+ M

M

Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well toleratedN-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permissionfrom Elsevier.

Results: Cognition—SIBResults: Cognition—SIBThe Memantine Group Exhibited Significantly Superior Cognitive Function Compared With the Placebo Group

*OC analysis. †LOCF analysisAdapted with permission 2004 from: Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. N Engl J Med. 2003;348:1333-1341. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

Mea

n C

han

ge

Fro

m B

asel

ine

in S

IB S

core

-12

-10

-8

-6

-4

-2

0

2

4 12 28

Imp

rovem

ent

Week

Memantine

Placebo

0 End Point

De

terio

ratio

n

126126 117

119106107

8396 126

126

*P=.002 †P<.001P<.001

n =n =

P=.068

Memantine in Moderate to Severe AD Study(Mean age = 76 ± 8; MMSE = 7.9 ± 3.6 (3-14); GDS = 5-6

7/1/2015

25

Results: Cognition—SIBResults: Cognition—SIB

Memantine + Donepezil Produced Sustained Improvement in Cognition Above Baseline Compared With Donepezil Alone

*OC analysis. †LOCF analysis.Adapted from Tariot P, et al. JAMA. 2004;291:317-324.Data on file, Forest Laboratories, Inc.

Memantine + Donepezil in Moderate to Severe AD Study

n =

Placebo+Donepezil

Memantine+Donepezil

0 4 8 12 18

Treatment Week

24

Mea

n C

han

ge

Fro

m

Bas

elin

e in

SIB

Sco

re

End Point

Imp

rovem

en

tD

eterioratio

n

*P<.001†P<.001P=.006P<.001P=.030P=.057

198 192 190 185 181 171 198n = 197 194 180 169 164 153 196

Memantine + Donepezil in Moderate to Severe AD (5 -13 MMSE)

Memantine + Donepezil in Moderate to Severe AD (5 -13 MMSE)

Howard et al. 366;10 nejm.org march 8, 2012

295Subjects(MMSE=5-13)

7/1/2015

26

Treatment Expectations

In Alzheimer’s Disease, clinical success may be:Short-term improvement

(<20%)Stabilization (30%, but only

for 12-18 months)Less than expected decline

(75%)

AD-5

27

7/1/2015

27

Mini-Mental Status Examination

Folstein, M., Folstein, S.E., McHugh, P.R. (1975). “Mini-Mental State” a Practical Method for Grading theCognitive State of Patients for the Clinician. Journal of Psychiatric Research, 12(3); 189-198.

St. Louis University Mental Status Examination (SLUMS)

Takes ~ 7 min to complete

Detects Mild NeurocognitiveImpairment (MNCD)

Higher Specificity than MMSE

MCI: <High School=23.5MCI: >High School=25.5

Dementia:<High School=19.5Dementia:>High School=21.5

Am. J. Geriatr Psychiatry 14:900-910, 2006

7/1/2015

28

Case #1

13

Clock Drawing Test (CDT)Scoring

• Draws closed circle: Score 1 point• Places numbers in correct positions: Score 1 point• Includes all 12 correct numbers: Score 1 point

• Places hands in correct positions: Score 1 point

TOTAL SCORE ( 0 - 4 )• EXAMPLES OF CLOCK DRAWING:

–Adapted from Tuokko H. et al. J. Am. Geriatr. Soc. 40:579-584. 1992

7/1/2015

29

Mini-Cog: Relationship to MMSE• Mini-Cog Cognitive Assessment:

• Scoring:– Results of the 3-item recall: [ ]/3 e.g. [2]/3

– Results of The Clock Drawing Test

– ( ) Draws circle

– ( ) places numbers in correct positions

– ( ) includes all 12 correct numbers

– ( ) places hands in correct positions

– Results of the clock drawing test score [ ]/4 e.g. [3]/4

• Total Mini-Cog score [ ]/7 e.g. [5]/7

• For equivalency with Mini-mental status exam,

multiply numerator by 4.3. MMSE ~ [ ] /30 e.g. [20–22] /30

Treatment Options

Stop donepezil; start another

cholinesterase inhibitor

PotentialOptions

Continue current therapy

Add memantine Discontinue therapy

Increase dosagee.g. Exelon Patch

7/1/2015

30

Other Pharmacological OptionsOther Pharmacological Options

NSAIDs—Clinical trials of COX-2 inhibitors rofecoxib (Vioxx) andcelecoxib (Celebrex) failed to show benefit in AD. Nonselective NSAIDs (ibuprofen, naproxen) have thus far failed to show a benefit

Estrogen (hormone)—Women’s Health Initiative: a smallincreased risk of clinically meaningful cognitive decline

Statins—HMG-CoA reductase inhibition of cholesterol synthesismay reduce microvascular dementias due to reduced stroke. May also modulate APP processing.

Vitamin E (tocopherol)—Antioxidant scavenges toxic freeradicals; safe and well tolerated

Selegiline (MAO-B inhibitor)—Some evidence of improvementwith selegiline in the short term in cognition and activities of daily living; magnitude did not reach clinical importance. No evidence of long-term effects

NSAIDs—Clinical trials of COX-2 inhibitors rofecoxib (Vioxx) andcelecoxib (Celebrex) failed to show benefit in AD. Nonselective NSAIDs (ibuprofen, naproxen) have thus far failed to show a benefit

Estrogen (hormone)—Women’s Health Initiative: a smallincreased risk of clinically meaningful cognitive decline

Statins—HMG-CoA reductase inhibition of cholesterol synthesismay reduce microvascular dementias due to reduced stroke. May also modulate APP processing.

Vitamin E (tocopherol)—Antioxidant scavenges toxic freeradicals; safe and well tolerated

Selegiline (MAO-B inhibitor)—Some evidence of improvementwith selegiline in the short term in cognition and activities of daily living; magnitude did not reach clinical importance. No evidence of long-term effects

AlzheimerImmunotherapy:State of the Art

Discovery Phase I Phase II Phase III Market

Astrazeneca/Dyax: F.hum aAb :AZD-3102

Takeda: Mc aAb40, aAb42Merck &Co: Mc aAb1-42 (ADDLS)Mindset bioph.Inc: Mc aK6-Ab[1-40]Genentech/AcImmune: Mc aAb[1-16]AFFiRiS: active Mimotope truncated/mod. Ab

Roche AG/Morphosys: F.hum HuCAL MabPfizer/Rinat: humz. aAb[X-40]: RN-1219Novartis: CAD106 active Ab[1-6]-cytosTMMERCK: V950AFFiRiS: active Mimotope Ab 1-6; 2 vaccines

Lilly: humz. aAb[16-23]: LY206430Wyeth/Elan: active Ab[1-7]-CRM197

Wyeth/Elan: humz. aAb[1-7]: AAB-001

Modified from B. Permanne

7/1/2015

31

Bapineusumab in Apo-E4 Carriers –Change in ADAS-Cog

Presentation: EFNS (European Federation of Neurological Societies), Stockholm, Sweden, Sept. 8-11, 2012:

ADAS-Cog

www.alz.uci.edu

7/1/2015

32

Age-Related Cognitive Impairment

Virginia Cognitive Aging Project

N=2369-4149

Salthouse TA. J Int Neuropsychological Soc. 2009;15:650–661.

Does Aricept Prevent Onset of Dementia in MCI?

N=259 PBON=253 DPL

PBO=PlaceboDPL=Donepezil

7/1/2015

33

APO-E genotype and AD onset

e2 -- 7% of the population



e3/3 - average age of onset = 74 y/o

e3/4 and e4/4 average age = 69 y/o

Prevention of MCI Dementia in APO-E4 Carriers

N=136 PBON=147 DPLN=141 Vit E

PBO=PlaceboDPL=Donepezil

P=0.04

7/1/2015

34

Apolipoprotein E and AD Pathology

Apolipoprotein E (APOE) genotype is associated with AD risk

APOE-epsilon2 may be protective—APOE-epsilon4 is associated with increased risk

The role of APOE-epsilon2 and APOE-epsilon4 in pathogenesis is not known

APOE is found in -amyloid plaques and neurofibrillary tangles and may affect protein–protein interactions

Bexarotene(Targretin)

Paige E. Cramer et al.Science 335, 1503 (2012)

Nuclear receptor PPA receptor gamma and retinoid X receptor (RXR) Agonist.

7/1/2015

35

Mild Cognitive ImpairmentWHO PROGRESSES?

Mild Cognitive ImpairmentWHO PROGRESSES?

• Small hippocampal volumes (order Neuroquant

with MRI)

• Decreased blood flow to posterior cingulate gyrus

• Increased CSF tau protein and decreased beta- amyloid

(1-42)

• Small hippocampal volumes (order Neuroquant

with MRI)

• Decreased blood flow to posterior cingulate gyrus

• Increased CSF tau protein and decreased beta- amyloid

(1-42)

HippocampalNeurogenesis With

Aerobic Activity

(a, b) running animals have significantlymore dividing cells (BrdU+) than controls.(c, d) Immunofluorescent confocalMicroscopy identify the newly born neurons,neuronal phenotype (NeuN+) appears orange.

Lazarov, O. et al. Trends Neurosci. (2010) 33(12): 569-579. Erickson KI, et al. Proc Natl Acad Sci USA. (2011) 108: 3017–3022.

Aerobic exercise intervention in humans selectively increases volume in the anterior hippocampus.

7/1/2015

36

current management of alzheimer’s disease...current management of alzheimer’s disease william...

Documents