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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%)
2° forms of dementia(10%)
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%)
1° forms of dementia(90%)
Vascular(15 – 30%)
Mixed(15 – 25%)
2° forms of dementia(10%)
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%)
1° forms of dementia(90%)
Vascular(15 – 30%)
Mixed(15 – 25%)
2° forms of dementia(10%)
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
ErrorsQ1 1Q2 1Q3 1Q4 4
Total 7
Patient #2
ErrorsQ1 1Q2 0Q3 1Q4 0
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
Pathological activationof NMDA receptors
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
Pathological activationof NMDA receptors
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
Treatment period (month)
0 1 2 3 4 From 5 onwards
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
Treatment period (month)
0 1 2 3 4 From 5 onwards
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.
Recommended