Changes in the age profile until the year 2030 19882030 Number in thousands 100 80 60 40 20 0 400...

Changes in the age profile until the year 2030

1988 2030

Number in thousands

100

80

60

40

20

0

400

Ag

e

1910

0 400 800 400 0 400 800 400 0 400

Men Women

From Maurer K., Ihl R., Fröhlich L., Alzheimer, Springer-Verlag, Heidelberg, 1993

World Population Prospects, The 2002 Revision

Average annual growth rates of the world population

Pe

rce

nta

ge

(%)

4

3

2

1

0

-10–14

3.39

15–59 60+ 80+

Age

2.29

0.72

-0.04

Average Annual Growth (2000-2050 Medium variant)

One way or another w

e will all h

ave to deal w

ith th

e topic „dementia

“!

One way or another w

e will all h

ave to deal w

ith th

e topic „dementia

“!

Prevalence of dementiaP

reva

len

ce

Rat

e (%

)

25

20

15

10

5

065–69 70–74 75–79 80–84

Age

11.1

5.6

World (estimated)

85+

23.6

2.81.4

Jorm et al., Acta Psychiatrica Scandinavica 1987

In the fu

ture, there w

ill be m

ore people in

In the fu

ture, there w

ill be m

ore people in

the higher-risk age groups!

the higher-risk age groups!

The definition of dementia according to ICD-10

Symptoms

Degree of severity

Duration of symptoms

Exclusion criteria

Course

Impairment of higher cortical functions, e.g.

Memory CalculationLearning ability SpeechThinking OrientationDiscriminatory capacity

Impairment of personal activities of daily living

6 months+

Disturbed consciousness

Chronic, progressive

Memory CalculationLearning ability SpeechThinking OrientationDiscriminatory capacity

Types of dementia

Europe North America

Asia

Fratiglioni et al., Drugs Aging 1999

Alzheimer‘s disease Vascular dementia Other

61.4%27.6%

11.0%

74.5%10.0%

15.5%

46.5%38.1%

15.4%

The classification of dementia - an overview

From Ebert D, Psychiatrie systematisch. UNI-MED Verlag: Bremen 2. Aufl, 97/98

Dementia

Degenerative(50%)

1° forms of dementia(90%)

Vascular(15 – 30%)

Mixed(15 – 25%)


Cardiovascular disorders (13%)

Alcohol abuse (8%)

Metabolic diseases, vitamin deficiencies (4%)

Hydrocephalus (4%)

Encephalitis (1%)

Drugs (1%)

Cardiovascular disorders (13%)

Alcohol abuse (8%)

Metabolic diseases, vitamin deficiencies (4%)

Hydrocephalus (4%)

Encephalitis (1%)

Drugs (1%)

Dementia

Degenerative(50%)



Mixed(15 – 25%)


Vascular dementia

Macroangiopathy (infarcts or haemorrhages)

– Strategic single infarcts

Microangiopathy

– Binswanger disease

– Leukoencephalopathy

– Lacunae

– Amyloid angiopathy

– Cerebral Autosomal Dominant Arteriopathy w/Subcortical Infarcts and Leukoencephalopathy CADASIL

• Disease progresses in steps

• At early stages, patient is aware of disease.

• often accompanied by emotional instability, depression, personality changes

= degenerative dementia

= degenerative dementia

Dementia

Degenerative(50%)



Mixed(15 – 25%)


Degenerative dementia

Degenerative dementia

Alzheimer-type dementia

53 %

Parkinson´s disease

25 %

Lewy body dementia

17 %

Others

5 %

Diagnosis and treatment statistics of Alzheimer‘s disease

On average, AD patients live 8 - 10 yrs post diagnosis

AD can last for up to 20 years

treated with modern therapy< 6%

diagnosed (most in later stages)52%

treated9%

patients with AD in Europe~ 8 Mio.

Cognos Report, 2002

The costs of treating dementiawith and w/o drug therapy

Beske F, Geriatrie Praxis 5. 24 – 27, 1993

25

20

1990

Year

Co

sts

in b

illi

on

EU

RO

1995 2000 2005 2010

With therapy Without therapy

Example: Germany

Caregiver costs increase with increasing severity of dementia (Germany)

An

nu

al C

os

ts (

€)

16,000

12,000

8,000

4,000

Community Setting Institutional Setting

Hallauer, 2002

MMSE26–21

MMSE20–15

MMSE14–10

MMSE<10

Potential Reduction in Caregiver Time

Figure adapted according to references

Potential to reduce caregiver time increases with severity of the disease

30

mild moderate severe AD

MMSE Score20 10 0

52h/month (Memantine)3

7h/month (Donepezil)1

12h/month (Galantamine)2

1Dement Geriatr Cogn Disord 2003; Erratum 20032Chemical Business News Base 20013 Wimo et al., Pharmacoeconomics 2003

Socio-economic aspects of moderate to severe Alzheimer’s disease

Caregiver burden and cost of illness is high in

patients with moderate to severe AD.

A treatment which is efficacious in these stages is

expected to reduce caregiver and societal cost.

Memantine treatment has been shown to reduce

caregiver and societal costs (Wimo et al., 2003).

Criteria for assessing the severity of dementia

Mild Work and social activities clearly affected Ability to live independently with adequate personal hygiene Intact discriminative ability retained

Moderate Independent life possible, but w/certain reduction of competence Certain, increasing amount of supervision required

• Severe Activities of daily living are affected Need for constant assistance and care Patient is incapable of maintaining minimal personal hygiene Loss of motor functions

0

Age

Lev

el o

f p

erfo

rman

ce

30 60 90

Long-term memory

Short-term memory

Learning & MemoryLong- and short-term memory over time

Criteria to differentiate age-associated memory impairment

From Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993

Age 50+ years

Complaints of disturbed memory in everyday situations

Criteria to differentiate age-associated memory impairment

From Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993

Memory tests deviate from the performance of younger

healthy subjects by more than one standard deviation

No indication of dementia in relevant, dementia-specific tests

(e.g. not below 24 MMSE points)

Intellectual capacity and social competence adequate for

everyday life

Nature of deficits not progressive

Course of mental capacity and subjective symptoms in dementia patients

Mild

Severity of dementia

After Lehrl, Blaha, Geistig Fit. Vless Verlag 1993

Moderate Severe

Objective mental capacity

Subjective sensationof symptoms

Typical symptoms of the onset of dementia

Disturbed concentration

Feeling of overstrain

Quick exhaustibility

Diffuse anxiety

Depressive mood

Lack of drive

Loss of interest

Typical symptoms of advanced dementia

Significant memory impairment (e.g. agnosia)

Spatial and temporal disorientation

Lack of motivation for house-work

Neglect of personal hygiene

Disturbed social behaviour (e.g. irritability)

Disturbed motor functions

Clinical disease progression

Years From Diagnosis

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9

MM

SE

Sco

reMildMild SevereSevereModerateModerate

CognitiveCognitiveSymptomsSymptoms

DiagnosisDiagnosis

Loss of FunctionalLoss of FunctionalIndependenceIndependence

Behavioral ProblemsBehavioral Problems

Nursing Home PlacementNursing Home Placement

DeathDeath

Reprinted from Clinical Diagnosis and Management of Alzheimer’s Disease, H Feldman and S Gracon;Alzheimer’s Disease:symptomatic drugs under development, pages 239-259, copyright 1996, with permission from Elsevier.

Progressive Loss of Activities of Daily Living

Act

ivit

ies

of

Dai

ly L

ivin

g

Progressive Loss of FunctionMMSE Score

Keep AppointmentsKeep Appointments

Use the TelephoneUse the Telephone

Obtain Meal/SnackObtain Meal/SnackTravel AloneTravel Alone

Use Home AppliancesUse Home AppliancesFind BelongingsFind Belongings

Select ClothesSelect Clothes

DressDress

GroomGroom

25 20 15 10 5 0

0 2 4 6 8 10Years

Maintain HobbyMaintain Hobby

Dispose of LitterDispose of Litter

Clear TableClear TableWalkWalk

EatEat

Mild Moderate Severe

Adapted from Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.

Cerebral atrophy in Alzheimer-type dementia

Top panel w/ kind permission of Prof. Dr. Braak, Klinikum der Johann Wolfgang Goethe University, (Centre for Morphology), Frankfurt, Germany

Diseased

Healthy

Clean-up debris & dead neuronal matter

Structural & nutritional support

Quantitative morphology in Alzheimer-type dementia

Deviation from norm

Hemisphere volumes - 13 to - 18%

Number of neurones in cortical areas Temporal lobes - 22 to - 44% Frontal lobes - 26 to - 60% Hippocampus - 43 to - 57%

After Jellinger 1990. In: Maurer K, Ihl R, Frölich L, Alzheimer. Springer-Verlag: Heidelberg 1993

Number of synapses Mid-frontal - 45 to - 55% Parietal - 45 to - 55%

Number of neurones in subcortical areas N. basalis Meynert up to - 90% N. raphe dorsalis - 36 to - 77%

Volume of the ventricles + 35 to +55%

Number of astroglia + 400 %

Alois Alzheimer1864 - 1915

Historic background of AD

Auguste D.(eter)1850 - 1906

Neurofibrillary tangles and senile plaquesin brain tissue

Right: After Brun A, Englund E. Ann Neurol 19, 253–262, 1986

Hypotheses for the development of dementia

After Frölich L, Psycho 12. 734–740, 1995

Apolipoprotein E risk factor hypothesis

Glutamate toxicity hypothesis

Oxygen radical hypothesis

Glucose metabolism-insulin hypothesis

Cortisol „stress“ hypothesis

Immune hypothesis

Glutamatergic cytotoxicity is the rationale for the effectiveness of

NMDA antagonists, e.g. memantine!

Neurotransmitter disturbances in dementia

Cholinergic system

Glutamatergic system

Noradrenergic system

Dopaminergic system

70%

Less than

30%

NMDAGlutamate ACh

ACh receptor

Acetylcholinesterase

Ca2+Glutamateuptake

Glutamatergic and cholinergic transmission

AChE

Glia

Glia

Neuron 2

Neuron 1

Neuron 3

AChE

Choline+ acetate

Choline+ acetate

e.g. NBM

Parsons and Danysz, unpublished

Neuron 2

Glutamate is involved in physiological and pathophysiological processes

Pathology

Epileptogenesis

Acute neuropathology Hypoxia/Ischaemia Stroke Trauma

Chronic neuropathology Alzheimer‘s disease Huntington‘s disease Parkinson‘s disease

Physiology

Neuronal synaptictransmission

Learning andmemory

Development Plasticity

COOH

COOH

CH2

CH2

CH

H2N

Glutamate

Autoradiographic imaging of glutamate binding sites

Anatomie I, University of Cologne, Germany

Control Alzheimer´s patient

Hippocampus = site of memory

Hippocampus = extremely high density of glutamate

binding sites

Rationale for drug Tx of memory loss:

Target the glutamatergic pathway!!

NMDAreceptor

AMPAreceptor

GlutamateMagnesium

C a2 +

N a +

+ - C a 2 +-+

Relevant signal arrivesGlutamate is released and binds to NMDA & AMPA receptors

Na+ flows through AMPA rec. - NMDA rec. remain blocked by Mg2+

Na + flows leads to partial depolarisationDepolarisation removes Mg 2+ block of NMDA receptors

Ca2+ flows through NMDA channelsIntracellular Ca2+ levels increaseCa2+ levels reach threshold leading to stabilization of plasticity (LTP)

Danysz and Parsons, Int J Geriatr Psychiatry 2003

NMDA receptor and synaptic plasticity

Normal glutamatergic neurotransmission

2+Ca

Signal detection

Learningsignal

Ca

Resting state

Noise

SignalNoise

Magnesium Glutamate NMDA receptorCalcium

Danysz and Parsons, unpublished

Metaboliccompromise

NMDA receptor

Inflammation

ß-amyloid

NMDA Receptor: A common target downstream of converting insults

Danysz et al., Neurotox Res 2000

Neurodegenerative dementia

Pathological activationof NMDA receptors

noise

rest

Ca2+

GlutamateMagnesium

Chronicneurodegeneration

damagedneurons

Ca2+

signal noise

signal not detected

Impairment ofplastic processes

learning

Ca2+

The diagnosis of dementia

After Füsgen I, Demenz. Medizin Verlag: Munich1992

Rationale:

Differentiate 2° dementia

Case history

Supplemented by history reports third party

Clinical status

Laboratory diagnostics

Psychiatric status

Psychometric tests

Examinations using technical equipment

Neurological status

Guidelines for the doctor-patient interview - I

Discriminatory ability, logical thinking

– Conversation about daily events and hobbies

– Explanation of a well-known saying

– Difference and similarity: lake – river; stairs – ladder)

Memory impairment

– Questions about recent events

– Naming 4 terms, terms to be repeated by the patient,

recall test after 3 minutes

Guidelines for the doctor-patient interview - II

Orientation

Speech

– Finding words, fluency of speech, content

– Naming as many animals as possible within 1 min.

State of consciousness

Mood, drive, psychotic symptoms

Guidelines for the doctor-relative interview - I

Daily living relevance of observed impairment

– Forgetting previously well-known names or people

– Losing important objects of everyday use

– Frequent repetition of questions

Thinking capacity

– Difficulty in solving problems and making decisions,

compared to earlier ability

– Increasing avoidance of demanding activities

Guidelines for the doctor-relative interview - II

Chronological course of the symptoms– First onset

– Daily fluctuations

Speech – Difficulty in finding words of everyday speech

– Reduction in fluency of speech

Behavioral problems – Aggressiveness, anxiety, depressive mood, restlessness,

especially in demanding or complicated situations

Clinical examination to rule out 2° dementia - I

Clinical examination

– Cardiovascular system (ECG, blood pressure)

– Pulmonary status (pulmonary function, thoracic X-ray)

– Risk factor profile:

Hypertension, diabetes mellitus,

smoking, alcohol, obesity

From Füsgen I, Demenz. Urban u. Vogel, 2001

Clinical examination to rule out 2° dementia - II

Laboratory diagnostics

– Blood sedimentation rate – Urea/Creatinine

– Blood count – Folic acid and vitamin B12

– Blood sugar – Urinalysis

– Lipid levels – Thyroid function

– Hepatic function (T3, T4, basal TSH)

– Electrolytes

From Füsgen I, Demenz. Urban u. Vogel, 2001

Typical symptoms of the onset of dementia

Disturbed concentration

Feeling of overstrain

Quick exhaustibility

Diffuse anxiety

Depressive mood

Lack of drive

Loss of interest

Differentiation depression vs. dementia - I

DementiaDepression

After Füsgen I, Demenz. Urban u. Vogel, 2001

Rapid onsetDuration < 6 months

Fluctuating performance re. tasks of similar difficulty

OrientedKnows how to find help

Rather slow onset,Duration 6+ months

Steady performance re. tasks of similar difficulty

DisorientedDoes not know how to find help

Differentiation depression vs. dementia - II

After Füsgen I, Demenz. Urban u. Vogel, 2001

DementiaDepression

Objective deficits <

Subjective suffering

Emotional morning low

Libido reduced

Antidepressant therapy successful

Feeling of guiltFear of failure

Blame put on othersDenial

Libido retained

Objective deficits>

Subjective suffering

Swift emotional changes

Antidepressant therapy unsuccessful

Testing depression:The Geriatric Depression Scale (GDS)

47

Identification of cognitive deficits:The clock drawing test

Patient #1

ErrorsQ1 1Q2 1Q3 1Q4 4

Total 7Patient #3


Total 7

Patient #2


Total 2Test sheet

Typical MMSE Scores

29 – 30 pts = Healthy

20 – 24 pts = Mild Dementia

10 – 19 pts = Moderate Dementia

9 pts or less = Severe Dementia

NOTE!

„Ceiling Effect“: Well-educated patients w/mild dementia might be able to compensate for some deficits

NOTE!

„Floor Effect“: MMSE scores less useful in low-score range characteristic of patients w/severe dementia

Identification of cognitive deficits & their severity:The Mini-Mental State Exam MMSE

Act

ivit

ies

of

Dai

ly L

ivin

g

Progressive Loss of FunctionMMSE Score

Keep AppointmentsKeep Appointments

Use the TelephoneUse the Telephone

Obtain Meal/SnackObtain Meal/SnackTravel AloneTravel Alone

Use Home AppliancesUse Home AppliancesFind BelongingsFind Belongings

Select ClothesSelect Clothes

25 20 15 10 5 0

0 2 4 6 8 10Years

DressDress

GroomGroom

Maintain HobbyMaintain Hobby

Dispose of LitterDispose of Litter

Clear TableClear TableWalkWalk

EatEat

Mild Moderate Severe

Adapted from Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.

Identification of cognitive deficits & their severity:

The Mini-Mental State Exam MMSE

Monitoring test - The NOSGER observer‘s rating scale

Imaging diagnostics in dementia

Detection of morphological changes:

– Computed tomography

– Magnetic resonance imaging

Evaluation of functional changes:

– Functional MRI

– Positron emission tomography

– Single photon emission computed

tomography

FDG-PET for diagnosis of dementia

M. Pick – 69y maleMID – 50y male

Healthy control

DAT – 60y male Severe DAT – 64y female

The objectives of dementia therapy - I

Mild Dementia

Improve or stabilize

cognitive performance

Maintain or recover

ability to care for oneself

Maintaineveryday competence

The objectives of dementia therapy - II

Advanced Dementia

Activate patientphysically & mentally

Delay (complete)nursing care

Facilitate careDelay hospitalization

Important approaches to dementia therapy

Psychosocial Therapy

Pharmacotherapy

Mental & Physical Training

Care of Caregivers

Consider social situation of patientCarefully setup timely care plan incl. all available caregivers

Symptomatic therapy (stabilization of neurotransmission)Often improving cognition/emotions/motor functions

Preserve cognitive & motor functions necessary to carry

out activities of daily living as long

as possible.

Psychosocial support to

caregivers should be integral part of any therapeutic

concept

Advice for caregivers of dementia patients

Short, simple sentences

Fixed habits, simple rules

Patient, understanding attitude

Avoid excessive demands

Make sure patient drinks enough fluid

Don’t argue, distract

Antidementia drugs and nootropics –Mode of action

Nootropics

Effect on neuronal metabolismPiracetam

Anti-dementia drugs

DonepezilRivastigmineGalantamine

Cholinesterase inhibitors (AChEIs)Cholinergic neurotransmitter system

Gingko biloba

Vascular dilatationNicergoline

Cerebral blood flow, radical scavenger

NMDA antagonismGlutamatergic neurotransmitter systemMemantine

Severtity of dementia Delay of progression

Mild/Moderate Advanced Symptomatic Pharmacologicallystructure-preserving

Drug

Cognition Motor

function

Drive Vigilance Affect ADL * Ease of care Clinical Experimental

Donepezil ++ + Ø ? + + ? ++ Ø

Rivastigmine ++ + Ø ? + ++ ? + Ø

Galantamine +++ + Ø ? + ++ ? ? Ø

Memantine ++ +++ ++ ++ + ++ ++ ++ ++

Piracetam ++ Ø + ++ + + ? ? ?

Cerebralvasotherapeuticse.g. nicergoline

+ Ø Ø ++ + + ? ? Ø

Modified from: Handbuch der Arzneimitteltherapie I, 2001 (Fox et al.)

+++ much improved; ++ clearly improved; + improved; Ø little/no effect; ? no data* ADL = Activities of Daily Living

Antidementia drugs and nootropics -Positive selection criteria

Herschaft, H., Antidementiva in der Praxis, Uni-Med 2001

Tolerability of donepezil

A d v e r s e e v e n t P la c e b o ( N = 3 1 5 )

D o n e p e z i l 5 m g /d a y ( N = 3 1 1 )

D o n e p e z i l 1 0 m g /d a y ( a f t e r 6 w e e k s a t

5 m g /d a y ) ( N = 2 6 9 )

D o n e p e z i l 1 0 m g /d a y ( a f t e r 1 w e e k a t

5 m g /d a y ) ( N = 3 1 6 )

N a u s e a 6 % 5 % 6 % 1 9 %

D ia r r h e a 5 % 8 % 9 % 1 5 %

In s o m n i a 6 % 6 % 6 % 1 4 %

T i r e d n e s s 3 % 4 % 3 % 8 %

V o m i t in g 3 % 3 % 5 % 8 %

M u s c le c r a m p s 2 % 6 % 3 % 8 %

D o n e p e z il R iv a s t ig m in e G a la n ta m in e M e m a n t in e

A d v a n c e d a g e + m u lt im o rb id it y ? R U ? Ø

S e v e re d e m e n t ia ? ? ? Ø

S e v e re c o n fu s io n Ø Ø Ø C l

E p ile p s y R U R U R U C l

S ic k s in u s s y n d ro m e R U R U R U Ø

S e v e re c a rd io v a s c u la r d is tu rb a n c e s R U R U R U Ø

C a rd ia c a r rh y th m ia s R U R U R U Ø

A s th m a /o b s tru c t iv e lu n g d is e a s e s R U R U R U Ø

S e v e re l iv e r d y s fu n c t io n C I C I C I Ø

Im p a ire d k id n e y fu n c t io n R U R U R U /C I R U

Im p a ire d l iv e r fu n c t io n Ø R U R U /C I Ø

Contraindications and restrictions on use

After: Handbuch der Arzneimitteltherapie I, 2001 (Fox et al.)

Ø no restrictions; ? no data; RU restriction on use; CI contraindication

Effect of memantine on AChE inhibitors

Modified form Wenk et al., (2000) Life Sci. 12, 1079-1083

110

100

50

40

30

20

10

0

Ch

olin

este

rase

act

ivit

y (%

)

Control Donepezil1 µM

Tacrine1 µM

Galantamine2 µM

Memantine5 µM – + – + – + – +

Memantine and AChEIs use different

neurotransmitter systems!

Neuroprotective effect of memantine

Miguel-Hidalgo et al. (1998) Neurobiol. Aging 19: 542

Extent of ß-amyloid-induced damage in the CA1 region

Placebo

Ex

ten

t (

µm

)

1000

Memantine

800

600

400

200

0

Memantine

Placebo

Danysz et al., Neurotox Res 2000

Neurodegenerative dementia


noise

rest

Ca2+

GlutamateMagnesium

Chronicneurodegeneration

damagedneurons

Ca2+

signal noise

Impairment ofplastic processes

learning

Ca2+

Effects of memantine

Ca

Restingstate

Neuroprotection by memantine

Memantine improvesdementia symptoms


2+Ca

Resting state

Increased noise Physiological noise

Signal

Magnesium Glutamate Memantine NMDA receptorCalcium

2+Ca

Noise

Learningsignal

Detectionof signal

Kinetics of NMDA-Receptor Blockade Intermediate between Mg2+ and MK-801

Mg 2+ shows very fast blockade of NMDA receptors and also fast unblockade

MK-801

(+)MK-801 shows very slow blockade of NMDA receptors

and also slow unblockade

Memantine shows fast blockade of NMDA receptors

MemantineMg 2+

Peaks represent responses to

application of NMDA

time

and also relatively fast unblockade

Parsons et al., Neuropharmacology 1993

Improvement of activities of daily living (ADL) with memantine

Görtelmeyer R, Erbler H. Drug Res 42, 904–913, 1992. (n = 82)

*

*

*

*

*

1 0 –1 –2 –3 –4 –5 –6 Time (sec)

Improvement of ADL

Dialing a telephone number

Attaching a sticking plaster

Tying a bow

Closing a safety pin

Fastening buttons

Placebo

Memantine

Improvement of motor skills

Improvement of motor skills

Improvement of cognition

Improvement of cognition

Memantine-induced improvement of ADL in severe dementia

Winblad B, Poritis N, Int. J. Geriat. Psychiatry 14, 135-146, 1999 (M-Best)

*

*

*

*

*

*

*

*

Frequency of improvement (%)

0 20 40 60

Ability to stand up

Ability to move

Ability to wash

Ability to take a bath/shower

Ability to dress

Toilet use

Group activities

Hobbies / interest

Memantine

Placebo

* p < 0,05

63% of severely demented

63% of severely demented

patients on memantine showed

patients on memantine showed

improvement of ADLimprovement of ADL

Improvement in cognition with memantine

Stöffler et al., World Alzheimer’s Congress 2000, Washington, D.C., USA

Memantine

Dec

lin

eIm

pro

vem

en

t

Week 0 Week 12 Week 28

AD

AS

-co

g s

core

2

1

0

-1

-2

-3

-4

Placebo

Memantine-induced benefit re. cognition in moderately severe to severe AD

Reisberg et al., 2000

MemantinePlacebo

p = 0.0018

Observed cases

SIB

Sc

ore

-12

-10

-8

-6

-4

-2

0

2

Week 4 Week 12 Week 28

Means ± SEM

Dec

lin

eIm

pro

vem

en

t

Placebo

Means ± SEM

p = 0.025

Reisberg et al., 2000

Dec

lin

e

Memantine

Memantine-induced benefit re. global clinical impression (moderately severe/severe AD)

CIB

IC-P

lus

Glo

ba

l S

co

re4,0

4,2

4,4

4,6

4,8

5,0

Week 12 Week 28

Observed cases

Increase in drive by memantine

Pantev M, Ritter R, Görtelmeyer R, Zeitschr. f. Gerontopsychologie u. -psychiatrie 6: 103–117, 1993. (n = 66)

Score 0

2

4

6

8

10

12

14

0

Imp

rov

em

en

t

1 2 3 4 Weeks

BGP-Item:

Inactivity

Placebo

Memantine

Long-term treatment with memantine

Görtelmeyer, Pantev, Parsons, Quack: Spektrum der Neurorehabitilation, 1993

Placebo(n = 70)

Memantine(n = 72)

Sc

ore

SC

AG

fa

cto

r:

co

gn

itiv

e i

mp

air

me

nt

0

15

16

17

18

19

2086 16 24 32 40 48 56

Imp

rov

em

en

t

Treatment/weeks

End of double-blind phase

Efficacy of memantine in everyday practice

531 patients

Rüther E. et al., Pharmacopsychiatry 33, 103-108, 2000

Unchanged17%

Worse 6%

Improved77%

100 %

75 %

50 %

25 %

0 %

Patients

Treatment period (month)

0 1 2 3 4 From 5 onwards

Poor

Moderate

Good

Very good

Use of memantine in everyday practice - I

Rieke J, medwelt 47, 251–4, 1996. (n = 1420)

Evaluation of memory

100 %

75 %

50 %

25 %

0 %

Patients



Poor

Moderate

Good

Very good

Use of memantine in everyday practice - II

Rieke J, medwelt 47, 251–4, 1996. (n = 1420)

Evaluation of mood

Poor

Moderate

Good

Very good



100 %

75 %

50 %

25 %

0 %

Patients

Use of memantine in everyday practice - III

Rieke J, medwelt 47, 251–4, 1996. (n = 1420)

Evaluation of motor function

Tolerability of memantine

Rieke J, medwelt 47, 251–4, 1996. (n = 1420)

No data (2.1 %)

Poor (2.1 %)

Moderate (2.0 %)

Very good

56.5%

Good

37.3%

Interactions with memantine

Potential enhancing effect on:

Barbiturates CNS depression: mild sedation coma)

Neuroleptics antipsychotic

Anticholinergics anti-parasympathetic

L-dopa und dopaminergic agonists

(e.g. bromocriptine) anti-Parkinsonian

Amantadine

Modifying effect on:

Dantrolene antispasmodic

Baclofen antispasmodic

Memantine

Structure chemically closely related to that of

memantine

Risk of pharmacopsychosis

Conclusions - I

Dementia is a disease!

Stop regarding

dementia as a taboo

Start treating dementia as

early as possible

Tx of all stages of dementia:

An ethical obligation

A doctor’s duty

Conclusions - II

• Counsel & support caregivers/relatives

• Keep patient in familiar environment as long as possible

• Determine Tx goal by severity of disease

• Bear in mind that slowed-down progression represents Tx success

Conclusions - III

70% of the excitatory synapses in the CNS are glutamatergic ones.

In AD and VaD, the glutamatergic signaling pathway via NMDA receptors is impaired.

The neuroprotective NMDA antagonist memantine is clinically effective in the treatment of dementia.

Appropriate therapy has socioeconomic impact by reducing the costs of nursing and care.

Changes in the age profile until the year 2030 19882030 Number in thousands 100 80 60 40 20 0 400...

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Transcript of Changes in the age profile until the year 2030 19882030 Number in thousands 100 80 60 40 20 0 400...