A.1.

Demensia
INARTDWFDCD04
Types of Dementia
Primary Dementia (cortical
dementia)
Alzheimers disease
Picks disease
Frontal lobe dementia syndrome
Mixed dementia with an Alzheimers component

Vascular dementia
Multi-infarct dementia
Strategic infarct dementia
Lacunar state
Binswangers disease
Mixed vascular dementia
Types of dementia
Dementia associated w/ Lewy body
disease
Dementia due to infection
Dementia due to structural brain
abnormalities
Some potentially reversible
conditions mimicking dementia
Hypothyroidism
Depression
Vitamin B12 deficiency
CLINICAL DIAGNOSTIC
CRITERIA
DSM-1V - Diagnostic &
Statistical Manual of Mental
Disorders IV --- Psychiatric Aid,
1994
NINCDS - ACDRDA - National
Institute of Neurological and
Communicable Diseases - A.D.
& Related Diseases Association

(Nickham et al, 1984)

Faktor Resiko Demensia

(Reference : Journal Nature, vol. 415, Jan 2002 )

INARTDWFDCD04 A.3.
TREATMENT SCHEMES IN MCI

Normal Cognitive
Functioning MCI DEMENTIA

Prevention of
MCI

Symptomatic treatment
Of MCI

Delaying onset of
AD
Treatment Strategies in AD
Normal Cognitive MCI DEMENTIA
Function

Primary prevention

Secondary prevention
Tertiary prevention
Epidemiologi
-risk factor
Phropylatic
Neuroprotection Molecular biology
Pathogenesis/pathological substrate
Disease modifying strategies
C.1.

Alzheimers
Disease
INARTDWFDCD04
 Alzheimers Disease
Alzheimers disease is a progressive,
degenerative brain disease
characterized by:
Loss of memory and other cognitive
functions
Decline in ability to perform activities of
daily living
Changes in personality, behavior, and
judgment
Increase in resource utilization, caregiver
demands, and medical care
Tariot P, Winblad B. In: Alzheimers Disease: Advances in Etiology, Pathogenesis and Therapeutics.
New York: John Wiley & Sons Ltd; 2001:707-723.
Asal Mula Alzheimer
Demensia

C.2.
INARTDWFDCD04
Neuropatologi AD

C.4.
INARTDWFDCD04
Factors affecting cognitive
function in the elderly

Alzheimers disease
Education and early
background
Cerebrovascular disorders
Other brain disorders
Cardiovascular disorders
Other disorders (physical,
psychiatric)
Risk Factors in A.D.
Family history of A.D.
Increasing age
Head trauma
Genetics
E4 allele of apoE
E4 homozygotes >50% risk of having A.D. by age 70
E2 allele of apoE
Protective
Down syndrome
B-amyloid gene in chromosome 21
 Alzheimers Disease &
Vaskuler Demensia
Cholinergic deficit

AD Probable
Probable Mixed
Mixed Possible
Possible Probable
Probable VaD
Possible
Possible

Amyloid plaques Mixed Stroke/TIA

Genetic factors AD/CVD Hypertension
Neurofibrillary tangles Amyloid plaques Diabetes
Genetic factors Hypercholesterolemia
Neurofibrillary tangles Heart disease
Stroke/TIA
Hypertension
Diabetes
A.5. Hypercholesterolemia
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S115-123.
Heart disease
INARTDWFDCD04
Progresifitas Demensia

Reference : Mc Dowell et al, Aging, vol. 13, 2001.

A.6.
INARTDWFDCD04
 Perkembangan Konsep &
Pengobatan Demensia
1860s Senile dementia normal aging No need to treat

1890s Senile dementia abnormal Treat with vasodilators

process due to arteriosclerosis

1970s Senile dementia = AD Cholinergic hypothesis

cholinomimetics in AD

Arteriosclerotic dementia = MID Treat by

1970s
preventing further cerebrovascular
damage
1990s
VaD is more than MID Prevent/treat risk factors
2000 Cholinergic hypothesis of VaD Rationale for the use of
cholinomimetics in VaD
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S115-123.
A.4.
INARTDWFDCD04
 Disfungsi Kolinergik
FOKUS TERAPI TERKINI
Faktor Lingkungan Penuaan/Faktor yang
Genetik
Tidak diketahui

Lanjutan Patologis

Plak Neuritik Neurofibillary

Tangles
Defisit Neurotransmiter
(NFT)
pada celah sinaps

FOKUS TERAPI Kolinergik FOKUS TERAPI

Defisit / Disfungsi

Gejala Penurunan Kognitif pada Demensia

A.7.
INARTDWFDCD04 Adapted from: Evans D A. et al.: JAMA. 262, 1551-2556, 1989
D.1.

Vaskuler
Demensia
INARTDWFDCD04
 Penyebab Vaskuler Demensia
NONSTROKE

Merokok PeminumAlkohol DM Peny.Jantung Hipertensi Obesitas

STROKE D.2.
INARTDWFDCD04
Pengaruh Hipertensi pada VaD

INARTDWFDCD04 D.4.
Kadar Asetilkolin Pasien VaD

INARTDWFDCD04 D.7.
 Radiologi pada VaD
Terdapat penurunan fungsi neurotransmitter
asetilkolin (jalur kolinergik) pada pasien VaD di
4 area yaitu Korteks, Hipokampus, Cairan Otak
& Striatum
Terapi AChE Is memberikan hasil bermakna
pada penatalaksanaan VaD

Sesudah Therapi Sebelum Therapi Sesudah Therapi Sebelum Therapi

D.8. Selden NR, et al. Brain. 1998;121:2249-2257.

Swartz RH, Black SE. J Neurol Sci. 2002;203-204(C):281.
Sandra Black, American Heart Assc., 2003; 2323 2332;34.
INARTDWFDCD04
Cholinergic deficits in
dementia

Cholinergic deficits well

established in Alzheimers
disease
Animal studies suggest that
cholinergic dysfunction is
present in cerebrovascular
disease
Preclinical data suggest similar
Cholinergic Changes in AD

The most prominent

neurotransmitter abnormalities are
cholinergic
Reduced activity of choline
acetyltransferase (synthesis of
acetylcholine)1
Reduced number of cholinergic
neurons in late AD (particularly in
basal forebrain) 2
1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-

Guan
Selective
1239.
3. ZZ et al. J Neurochem.loss of nicotinic receptor
2000;74:237-243.
Relation Between VaD and
AD
VaD and AD share a number of features
Cognitive, functional, and behavioral changes
Risk factors (eg, age, education,
hypertension)
Brain lesions (eg, atrophy, white matter lesions,
cerebral infarcts)
Pathogenic mechanisms (eg, apoptosis, delayed
neuronal death, inflammation)
Cholinergic dysfunction (central to AD) is seen in
VaD
A large subset of patients have AD coexistent with
cerebrovascular disease (CVD), also known as
mixed dementia
Togashi H, et al. Neurosci Lett. 1994;166:117-120. Saito H et al. Clin Exp Pharmacol Physiol. 1995;22(suppl 1):S257-
S259.
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13(suppl 3):S115-S123. Wallin A et al. Acta Neurol Scand.
1989;80:518-523. Gottfries CG et al. Dementia. 1994;5:163-167. Tohgi H et al. J Neural Transm. 1996;103:1211-1220.
Key Differentiating Factors
AD
Insidious onset VaD
Progressive deterioration Sudden onset
No early focal neurological Fluctuating, stepwise course
signs Early focal neurological signs
Early cognitive AD VaD
symptoms
Impaired executive X
functions
Ineffective
memory/learning
Forgetfulness X
Poor recognition X
Cortical symptoms X
Visuospatial
Desmond difficulties
DW et al. Alzheimer 3):S21-S29; Moroney JTXet al.
Dis Assoc Disord. 1999;13(Suppl
Neurology. 1997;49:1096-1105.
Acetylcholinesterase Inhibitors
Drugs used to treat Alzheimers
disease act by inhibiting
acetylcholinesterase activity
These drugs block the esterase-
mediated metabolism of
acetylcholine to choline and acetate.
This results in:
Increased acetylcholine in the synaptic
cleft
Increased availability of acetylcholine
for postsynaptic and presynaptic
Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.
Reminyl (galantamine HBr) :
Mechanisms of Action
Increases amount of acetylcholine
available in synaptic cleft by inhibiting
breakdown of acetylcholine
By modulating activity at nicotinic
receptors, it may increase release of
acetylcholine from surviving
presynaptic nerve terminals

Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.

Reminyl (galantamine
HBr): Proposed Mechanisms
of Action
Presynaptic
nerve
terminal
Muscarinic
receptor

Postsynapti
c nerve
ACh
terminal
Nicotini Acetylcholinestera
c se
receptor (AChE)

Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170. Nordberg A, Svensson A-L. Drug
Safety. 1998;19:465-480.
Benefits of nicotinic
enhancement with Reminyl
Postsynaptic nAChR:
maximised response to ACh, larger depolarisation
up-regulation of nAChR expression
Presynaptic nAChR:
increased neurotransmitter release
modulation of Glu, GABA, 5HT systems
recovery of lost plasticity
All nicotinic receptors:
protection from amyloid toxicity
protection from apoptosis and general neuroprotection

A. M., Laboratory of Molecular Neurobiology, Mainz, Germany

 GAL GBR 2 :
A long term comparison of
Reminyl (Galantamine Hbr)
versusG.Donepezil
Wilcock et al. Drugs Ageing
2003: 20 (10): 777-789
GAL-GBR-2
Trial Design
A rater-blinded, randomized, 12-
month,
open-label, parallel-group comparison
of Reminyl (galantamine HBr) versus
Donepezil, employing a flexible-dose
design in patients with moderate-to-
severe Alzheimers disease

Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789

GAL-GBR-2
Inclusion Criteria

Male or female outpatients with probable AD as

determined by NINCDS-ADRDA criteria
Moderate-to-severe dementia as evidenced by an
MMSE score of 918 inclusive at screening
A history of cognitive decline that was gradual in
onset and progressive over a period of at least 12
months
A responsible caregiver for regular daily visits
A signed informed consent form from both the
patient
(or relative, guardian, or legal representative) and
caregiver
Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789
 GAL-GBR-2
Baseline Demographics
Reminyl
(galantamine HBr) Donepezil
(N = 94) (N = 88)
Mean age (y) 74.1 72.8
(Range) (5388) (5488)
Female 53 (56.4%) 60 (68.2%)
Caucasian 94 (100%) 87 (98.9%)
Mean screening 15.1 14.8
MMSE (14.515.7) (14.215.3)
(95% CI)

Severity (MMSE) 13 (13.8%) 12 (13.6%)

Severe (91) 80 (85.1%) 75 (85.2%)
Moderate (12 1 (1.1%) 1 (1.1%)
18)
Mild (> 18)
Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789
GAL-GBR-2: Moderate
Subgroup
MMSE: Change From
Baseline
* 2.5
Reminyl (galantamine HBr)
* 2
(n = 81)
Donepezil (n = 75)
Mean MMSE change
( SE) from baseline

1.5
1
0.5 NS
#
0
0.5
1
1.5
2
2.5 *
0 13 2 39 52
Weeks6
* p < 0.0001 vs baseline; # p < 0.01 vs baseline;

p < 0.05 between group difference; p < 0.005 between-group difference; NS = p > 0.1.
Moderate subgroup (MMSE
12).
Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789
 GAL-GBR-2: Moderate
Subgroup
MMSE Responder Analysis
MMSE unchanged or improved vs
Reminyl (galantamine HBr)

baseline
80 * (n = 76)
79. 78. Donepezil (n = 67)
70 2 6
Patients responding

60 65.
to therapy (%)

2 56. 57. 58.

50
3 9 0
40
30
29. 30.
20 9 7
10
0
Week 13 Week 26 Week 52 LOCF

Moderate subgroup (MMSE 12).

* p < 0.01, p < 0.001 between-group analysis.

Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789

GAL-GBR-2: Choice Reaction
Time
Speed and Accuracy
Reminyl (galantamine HBr)
(n = 41) Improvement
15 *
Donepezil (n = 39)

10

10
Week 6 Week 13 Week 26 Week 52
* p < 0.005 vs baseline.

Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789

GAL-GBR-2
Adverse EventsReminyl

(galantamine Donepezil
HBr) (n = 88)
(n = 94)
Completers* 78 (80.4%) 71 (78.0%)
Patients maintained on 69 (71.1%) 63 (69.2%)
maximum dose*
Safety population n = 97 n = 91
All adverse events 88 (90.7%) 85 (93.4%)
Serious adverse events 18 (18.6%) 14 (15.4%)
Severe adverse events 18 (18.6%) 18 (19.8%)
Drug-related adverse 56 (57.7%) 52 (57.1%)
events
* ITT population.
Discontinuation due to 13 (13.4%) 12 (13.2%)
AE 2 (2.1%) 3 (3.3%)
Wilcock G. et al. Drugs Ageing 2003: 20 (10): 777-789
GAL-GBR-2
Conclusions
This is the first long-term, head-to-head
comparison of
2 active treatments in Alzheimers disease
Both treatments maintained functional abilities
over
12 months, as measured by the BrADL
Significant advantages were found with Reminyl
(galantamine HBr) compared with Donepezil on
cognition
at Week 52, as measured by the MMSE
Only REMINYL maintained cognition at baseline
levels
for G.
Wilcock 1 et
year, asAgeing
al. Drugs measured by the
2003: 20 (10): MMSE
777-789
Reminyl (galantamine

HBr): Dosing
Simple, one-step dose escalation
8 mg/day starting dose for 4 weeks (4
mg bid)
16 mg/day maintenance dose for at
least
4 weeks (8 mg bid)
The flexibility to increase to 24 mg/day
(12 mg bid)
Taken preferably with morning and
evening meals
Erkinjuntti Trial:
Conclusions
In addition to the long-term benefits previously
demonstrated in patients with Alzheimers disease,
galantamine also maintained cognitive function and
delayed the emergence of behavioral symptoms for
a full year in patients with AD with CVD or probable
vascular dementia
Furthermore, galantamine is generally safe and well
tolerated by patients with either AD with CVD or
probable vascular dementia treated over the course
of a year
As in Alzheimers disease, the incidence of
gastrointestinal adverse events may be reduced by
slower dose escalation
Adapted from Erkinjuntti T et al. Lancet. 2002 Apr 13;359(9314):1283-90. Erkinjuntti T et al. Poster presented at the
54th Annual Meeting of the American Academy of Neurology, April 13-20 2002, Denver, Colorado
TERIMA KASIH .
Faktor Resiko VaD

D.5.
INARTDWFDCD04
F.1. Studi
Perbandingan
Gol AChE-Is

INARTDWFDCD04
 STAGES OF ALZHEIMERS DISEASE
TRANS- LIMBIC NEOCORTICAL
ENTORHINAL

IMMEDIATE
MEMORY
MCI
SEMANTIC
MEMORY

EXECUTIVE
FUNCTIONS

EPISODIC
MEMORY

PRECLINICAL EARLY MILD

MMSE 30-24 MMSE 26-20
 DEMENSIA VASKULAR
Penderita Stroke beserta faktor resiko tekanan darah tinggi,
diabetes, peningkatan kadar kolesterol dan merokok mempunyai
kolerasi kuat mengalami Demensia Vaskuler
Pasien Demensia Vaskular adalah 1/3 pasien demensia di dunia
Pasien Demensia Vaskular diderita oleh 30 35% pasien paska
stroke setelah serangan pertama
Demensia Vaskular menurunkan 50 % tingkat harapan hidup

TIA
Defisit Kolinergik
Demensia Vaskuler
Stroke & Menejemen Komprehensif, Supplement BKM XV,2:59-69(1999)

INARTDWFDCD04 D.6.
Pathology of AD

There are 3 consistent

neuropathologic hallmarks:
Amyloid-rich senile plaques
Neurofibrillary tangles
Neuronal degeneration
These changes eventually lead to
clinical symptoms, but they begin
years before the onset of symptoms
Selkoe DJ. JAMA. 2000;283:1615-1617.