Vascular Dementia:

Distinguishing Characteristics,
Treatment,
and Prevention

PENDAHULUAN
VaD : penyebab kedua paling sering setelah
demensia pada usia lanjut
Abad 19-20 : oklusi arteri serebral -->degenerasi
: penyebab demensia
Willis (1972) :
- postapopletic dementia
- dullness of mind, forgetfulness, stupidity dan
foolishness--> tanda VaD
- Stupidity bersama palsy dan apopleksi -->
Mixed demensia

 1984 : jenis VaD :

- Atrofi otak arterioskelotik --> miliary
apopleksis
- Stroke lakuner infark
- demensia sifilitik, infiltrasi inflamasi difus
1907 : Binswanger varian AD dengan White
Matter Lucencies subkortikal dan
pelebaran ventrikel

 Emil Kraepelin (1910) demensia

aterosklerotik : demensia senil dan AD
Demensia aterosklerotik : pengurangan
jaringan otak 50-100ml pada poststroke
-->demensia

Karakteristik serebrovaskuler VaD

Penyebab VaD(>>): lesi CVD akibat kelainan
vaskuler dan sirkulasi:
- perdarahan (HT, angiopati amiloid, hematologi,
SAH, hidrosefalus obstruktive postperdarahan,
hematom subdural)
- iskemia (iskemia komplit akibat oklusi arteri
penyebab nekrosis, likuifaktion, dan cavitasi
atau iskemia inkomplit akibat hipoperfusi
sekunder sampai stenosis arteriola maduller
dan kardial atau kelainan sirkulasi)
- campuran iskemia dan perdarahan (vena
kortikal dan sinus trombosis).

VaD Iskemik
Dibagi dua :
1. Large-vessel disease (onset akut) :
- Multiple infark diesease (MID)
- Strategic stroke
2. Small-vessel forms (onset sub akut)
- Single strategic lacuna

Etiologi
Hipertensi, atherosklerosis, DM,
hiperlipidemia dan embolisme kardiogenik
(termasuk fibrilasi atrium), vaskulitis
autoimun atau infektius dan vaskulopati
nonspesifik.

Mixed dementia
Tidak tepat
Koinsidensi dengan parkinson, demensia
Lewi Body

VaD VERSUS AD

Dapat koinsidensi
Faktor resiko vaskuler serupa
Perbedaan : onset dan progresinya
Petunjuk utama :
- memori
- fungsi kognitif (kekacauan pikiran,
tingkah laku dan emosi)
- gait

8
4

: VaD
: AD

Faktor Risiko

Stroke iskemik pada usia >65 thn : 2533% demensia :

usia tua, tingkat pendidikan dan pendapatan
yang rendah, merokok, tekanan darah yang
rendah atau hipotensi ortostatik, stroke
berulang dan stroke yang lebih luas, lesi di
substansia alba yang lebih besar, stroke di
hemisfer kiri, dan komplikasi stroke akut yang
berupa hipoksia dan iskemia (kejang, aritmia
jantung, pneumonia aspirasi, hipotensi)
disfagia, masalah-masalah gait, dan gangguan
buang air kecil; perokok; tekanan darah
rendah, hipotensi ortostatik, WML dan atrofi
kortikal.

Kriteria Diagnostik (VaD)

3 elemen penting :
- ganguan kognitif
- lesi serebrovaskuler
- onset demensia dalam 3 bulan gejala
stroke

Tes fungsi eksekutif

kemampuan untuk melakukan perilaku bertujuan
yang kompleks; untuk memulai, melakukan
sesuatu secara bertahap, dan memonitor
perilaku yang kompleks; dan untuk
memecahkan masalah.
Gangguan kontrol eksekutif : kekacauan pikiran,
tingkah laku dan emosi.
Topis : sistem profontal, dorsofrontal,
orbitofrontal atau singulata, striatum, pallidum,
thalamus atau talamokortikal di substansia alba

Tes fungsi eksekutif

Trail-Making Test
Behavior dysfunction scale
Executive Interview (EXIT25)
CLOX

TERAPI

DONEPEZIL
Penelitian klinis terbesar pdrt VaD dibagi 3
klpk dengan pemberian Donepezil
5,10mg & plasebo, follow up 24 bulan
diukur dengan ADAS-COG, MMSE,
CIBIC-plus, CDR, ADFA dan Change
Scale
Klpk donepezil perbaikan bermakna
secara statistik
Efek samping : dosis 10 mg >>

GALANTAMINE
Kolinesterase inhibitor reversibel dan
modulator reseptor Ach nikotinik di otak.
Penelitian multisenter selama 24 bln-->
perbaikan bermakna

Rivastigmine
Golongan AChI dan ChI
Penelitian terbaru dengan pemberian
Rivastigmine perbaikan dalam fungsi
eksekutif, perilaku dan Relative Stress
Score dibandingkan aspirin.

MEMANTINE
Antagonis reseptor NMDA :
- melindungi neuron dari efek merusak
yang diinduksi oleh eksitotoksisitas pada
iskemia otak
- neuroprotektor
Dosis : 10 mg/hr

Pencegahan
Pencegahan faktor resiko CVD / stroke
yaitu : hipertensi, penyakit jantung,
merokok, abnormalitas lipid, DM,
homosistein.

Kesimpulan
Ciri khas VaD yaitu onset mendadak,
gangguan fungsi eksekutif dan progresi
yang berfluktuasi datau perlahan tapi
meningkat
Vad dan AD mempunyai faktor risiko yang
sama
ChI sebagai obat lini pertama
Memantine, CCB, nootropik, pentoksifilin
dan antiplatelet -->efikasi

DEMENSIA
Definisi
Prevalensi
Kriteria diagnosis
Klasifikasi etiologi
Patofisiologi berdasar etiologi
Pemeriksaan
Perbandingan gejala
Gejala neuropsikiatrik

Demensia
Suatu sindrom penurunan kemampuan
intelektual progresif yang menyebabkan
deteorisasi kognisi dan fungsional,
sehingga mengakibatkan gangguan fungsi
sosial, pekerjaan dan aktivitas sehari-hari
(AAzI, 2003)

Relative frequencies of the main

dementias
5%

5%
Alzheimers disease

Pure DLB 3%

Vascular dementia
Dementia with Lewy bodies
Frontotemporal dementia

DLB with
AD 12%

Other dementias

Mixed
vascular
dementia
and AD 10%

60%

Pure vascular
dementia 5%

white matter dementias

subcortical (secondary) dementias
transmissible encephalopathies

Depression

5-15 %

Alcohol-related dementia

1-10 %

Metabolic disturbances

1-10 %

Toxic disturbances

1-10 %

Brain tumors

1-2 %

Hydrocephalus

1-5 %

Brain trauma

1-2 %

Anoxia brain injury

1-2 %

Subdural hematoma

1-2 %

Central nervous system infections

1-2 %

Gearing et al (1995); Kosunen et al (1996); Nagy et al (1998)

Diagnosis banding demensia :

Delirium (onset mendadak, derajat defisit
kognitif fluktuatif)
Depresi (pseudodemensia)
Schizophrenia (latar belakang perilaku
psikotik)
Hipotiroidisme
Normal pressure hydrocephalus
Defisiensi vitamin B 12
Gangguan amnesik (kelemahan memori tetapi
tidak ada defisit kognitif)

PATOFISIOLOGI DEMENSIA
(MEYER-RAGE., 1992)
Primary degeneration aetioloy
Ischaemic aetiology
(alzheimers, Pick,s disease)
(stroke, multi-infarkdementia)

Disturbed regulation of
DNA Trancription
(disturbed template activity)

Qualitative exhaution of
neuronal reserve capacity
for CNS performance

Decreased glcolytic turnover

Decreased Ac-CoA synthetics

Decrased CAT activity
Decreased acetylcholine synthesis
Decrased cholinergic activity

DEMENT IA

Metabolic aetiology
(intoxication, hipoxia,
Circulatory colapse)

Disturbed energy supply

through decreased
recupertaive capacity of
CNS metebolisme

Standard Assesment of The Dementia Patient

Laboratory Tests:
Complete blood count
Erythrocyte sedimentation rate
Electrolyte, blood glucose, BUN
Serun calcium and phosphorus
TSH
Serum Vitamin B12 level
Fluoroscent treponemal antibody absorbtion
test (FTA-ABS)
Neuroimaging:
CT or MRI

Standard Assesment of The Dementia Patient

Useful systemic Assessments:
Electrocardiograms
Chest X-ray
Urinalysis
Optional tests:
Lumbar puncture
EEG and quantitative EEG
SPECT
PET
Serum antiphospholipid antibody
Serum or urine drug tests
Radionuclide cisternography
Serum HIV antibodies

Distinguishing Characteristics of Cortical and Subcortical Dementias

Function
Cortical Dementia
Psychomotor speed Normal

Subcortical Dementia
Slowed

Language

Involved

Spared

Memory:
-Recall
-Recognition
-Remote

-impaired
-impaired
-temporal gradient present

-impaired
-spared
-temporal gradient absent

Executive function

Less involved

More involved

Depression

Less common

More common

Apathy

Less common

More common

Motor system

Spared until late

Involved early

Anatomy

Cerebral cortex

Subcortical structures and dorsolateral

prefrontal cortex projecting to head of
caudate nucleus

Examples

Alzheimers disease

Huntingtons disease, HIV

encephalopathy, lacunar state

Contrasting Features of
Dementia and Delirium
Feature

Delirium

Dementia

Onset

Acute or sub acute

Insidious

Course

Fluctuating

Persistent

Duration

Limited

Chronic

Attention

Impaired

Intact until advanced

stages

Language

Incoherent

More coherent

Speech

Slurred dysarthria

Dysarthria uncommon

Visual Hallucinations

Common

Uncommon

Tremor

Common

Uncommon

Myoclonus

Common

Occurs in only a few types

of dementia

Electroencephalogram

Prominent abnormalities

Mild changes

Gejala neuropsikiatrik
pada demensia

Demen
sia

Defisit
Neuro
transmiter

Gejala
Neuro
Psikia
trik

Gejala neuropsikiatrik
Gejala positif
Psikosis
Mania
Depresi
Agitasi
Anxietas
Iritabel
Disinhibisi

Gejala negatif
Apati
Kelemahan persepsi
terhadap stimuli emosi
Penurunan rentang
ekspresi terhadap
emosi normal
Penurunan mood,
affect, vocal inflection
(Jeffrey, 2003)

Vascular Dementia
Dementia due to cerebrovascular disease in
general

Multiinfarct dementia
Single infarct in eloquent areas,
episodes of hypotension
Leukoaraiosis, incomplete infarction
Cerebral hemorrhage

BambangHartono

Vascular Dementia
(VaD)
Accounts for about 20% of cases of dementia
Another 20% of cases are a combination of AD
and vascular causes
Usually affects people between 60 and 75 years
old
Slightly more common in men

Source: The DementiaDirectory. Vascular Dementia.

Available at http://www.zarcrom.com/users/alzheimers/odem/d4.html.

Vascular dementia

Abrupt onset and stepwise progression

Might involve small, large or any vessel/s
History of stroke/s.
Hypertension, diabetes and elevated Homocysteine
are strong risk factors.
Cognitive abnormalities depending on the areas
affected
Sub-cortical symptoms (slow processing, depression,
emotional incontinence, somatic complaints)
Hachinski Ischemic Score (HIS) vs ADDTC criteria

Prevalence of Dementia
10%

5%

AD pathology

5%
48%

AD with vascular
pathology
AD with vascular
encephalopathy
Pure VaD
Other

32%

Jellinger KA et al. J Neural Transm. 2002;109:813-836

Tomlinson et al estimated that at least 100 ml of brain tissue would need to be

lost before dementia was produced. Further studies showed, however, that the
site of the cerebral infarction is more important than the volume of tissue lost

Amar et al, 1996

Table 1. Risk Factors For Vascular Dementia

Non-reversible risk factors
Reversible risk
factors
Increasing age*
Genetic predisposition (eg.
Hypertension
CADASIL)
Coronary artery
disease
Geographic origin (eg. AfricanAmerican, Asian)
Atrial fibrillation
Prior strokes (particularly if large,
Diabetes mellitus
multiple, or in vulnerable locations)
Hyperlipidemia
Low education level
Hyperglycemia
*Only well established risk factor
Smoking

Age

Table 4. Risk factors for vascular dementia

Increased incidence with age, especially after
age 60 yr

Sex

Higher rates in men

Race

Higher rates in Asian and black populations

Education

Possible protective effect

Hypertension

Major risk factor

Stroke

Number, volume, and location of stroke and

strategic silent infarcts; preexisting atrophy

Hyperlipidemia Risk factor for stroke

Coronary
artery disease

Risk factor for stroke

Diabetes

Risk factor for stroke

Cigarette
smoking

Risk factor for stroke

Keluhan mengarah demensia

ESESSMEN KLINIK:
Anamnesis,MMSE/CDT,FAQ/ADL

Tidak

Penurnan fx kognisi dan kemampuan fungsional

Ya

Curiga demensia

Delirium a depresii
Tidak
Ya

Bukan demensia

Ragu

demensia

Kriteria Dx
Probable VaD
NINCDS-AIREN

Neeuroimaging
Skor iskemik hachinski
Pem : CDT,TMT, EXIT25,CDR
AD

Obati

VaD

Tatalaksana/follow up

Rujuk spesialis

Demensia deg.lain

Keluhan mengarah demensia

Gangguan kognisi
(bahasa,praksis,pengambilan keputusan,
orientasi/spasial,memori)
Gangguan kepribadian dengan awitan
mendadak/fluktuatif
Defisit neurologis
Faktor-faktor CVD

Table 3. Overview of clinical assessment of vascular

dementia
1.History (onset, course, and nature of cognitive deficits;
information from caregiver on personality and behavior
changes)
2.Cognitive assessment
3.Behavioral evaluation*
4.General physical examination
5.Assessment of functional losses
6.Examination for focal neurologic signs
7.Routine investigations directed toward providing evidence
of cerebrovascular disease and its risk factors
8.Brain imaging**
9.Other specialized investigations (eg, echocardiography,
cerebrospinal fluid examination, functional brain imaging,
neuropsychologic evaluation)

The American Academy of Neurology

recognizes four main guidelines for
vascular dementia diagnosis.
1.These guidelines are the National Institute of
Neurological Disorders and Stroke--Association
Internationale pour la Recherche et
l'Enseignement en Neurosciences (NINDSAIREN) criteria
2.Alzheimer's Disease Diagnostic and Treatment
Centers (ADDTC) criteria
3.Modified Hachinski Ischemic Score (MHIS)
4. Diagnostic and Statistical Manual of Mental
Disorders, fourth edition revised (DSM-IV-TR).

NINCDSADRDA criteria for AD

Criteria for clinical diagnosis of AD include
dementia
deficits in two or more areas of cognition
progressive
no disturbance of consciousness
onset ages 4090 years
absence of other systemic or brain disease that could
account for the condition
Other (1)

Other (2)

Unlikely

Possible AD

Definite AD

McKhann et al (1984)

The DSM-IV for VaD

Sign and Simpton neurologic focal
The cognitive deficite caused a significant
impairmant in social & occup, fungtion
The deficits do not occur during course the
delirium
Course characterized by sustained
periods sudden significant cognitive and
func. losses

The ICD-10 criteria for VaD

Unequal distribution of deficits in higher
cognitif fungtion and other relatif spared
Evidence for focal brain damage ;
unilateral spastic weakness, increasse
tendo reflexes, extensor plantar respon,
pseudobulbar palsy
Evidence from the history, examination, or
CV test of significant CV dissease

Research Definition of VaD

A) Dementia
B) Cerebrovascular disease
C) A and B must be reasonably related.
Based on Romn GC, Tatemichi TK, Erkinjuntti T, et al: Vascular
dementia: Diagnostic criteria for research studies. Report of
the NINDS-AIREN International Workshop held at the National
Institutes of Health, Bethesda, Md, April 19-21, 1991.
Neurology 1993;43:250-260.

Research Definition of VaD

Based on Romn GC et al (Neurology 1993;43:250-260)

Dementia and CVD must be reasonably

related:
1. Onset of dementia within 3 months following
stroke (post-stroke dementia)
2. Exclude pre-stroke dementia: 5.5%-16.3% of
cases of post-stroke dementia had symptoms
of AD
3. Abrupt deterioration of cognitive function
4. Fluctuating, stepwise progression

Research Definition of VaD

Based on Romn GC et al (Neurology 1993;43:250-260)

Cerebrovascular disease:
MUST include confirmation by brain imaging
including: multiple large-vessel strokes (MID),
single strategic infarct (thalamus, PCA, ACA),
lacunes (multiple, basal ganglia, white matter);
extensive periventricular white matter lesions
Presence of focal neurological signs consistent
with stroke with or without history of stroke.
Use of Hachinski Ischemic Scale not
recommended.

Research Definition of VaD

Based on Romn GC et al (Neurology 1993;43:250-260)

Clinical features consistent with VaD:

Early gait disturbances, frequent falls

Parkinsonian features
Early urinary symptoms
Personality change, mood disorders (vascular
depression), psychomotor retardation
Abnormal executive function

Research Definition of VaD

Based on Romn GC et al (Neurology 1993;43:250-260)

Clinical features inconsistent with VaD:

Early and severe memory deficit
Worsening of language (transcortical
sensory aphasia)
Apraxia, agnosia,
Absence of focal neurological signs
No evidence of CVD on brain CT or MRI

Assessment of a patient with suspected

vascular dementia should include :
1.Establishment of the diagnosis of dementia,
2.Identification of the extent and severity of
cognitive impairment
3.Determination of the presence of risk factors
4.Documentation of evidence of
cerebrovascular disease
5.Determination of the etiologic role of
cerebrovascular disease
6.Evaluation of the functional status of the
patient and the interpersonal and community
supports available.

Gabriel Gold,M.D,et al, 2002

Sub-types of Vascular
Dementia
Cortical vascular dementia or multi-infract dementia
Large vessel disease
Cardiac embolic events
Subcortical vascular dementia or small vessel dementia
Small vessel disease
Strategic infract dementia
Large vessel disease
Cardiac embolic events
Small vessel disease
Source: Alzheimers Disease and related Disorders Annual.
2000 Editors: Gauthier S., Cummings JL.

Subtipe VaD
VaD Post stroke
- demensia infark strategis
- MID
- Stroke perdarahan
VaD subkortikal
- Lesi iskemik substansi alba
- Infark lakuner subkortikal
- Penyakit Binswanger
Mixed demensia : AD dan CVD

Lokasi infark vaskuler yang

mempengaruhi beratnya gangguan
kognitif

Ganglia basalis
Thalamus
The deep white matter
Area limbik
Area asosiasi heteromodal

Multi-infarct dementia
the most common
caused by a number of small strokes, called
ministrokes, these strokes may be silent
The strokes cause damage to the cortex of the
brain - the area associated with learning,
memory and language.
Symptoms : trouble remembering things
(especially recent events), find it difficult to
communicate or follow a conversation, or appear
generally confused, epileptic fits or partial or total
paralysis of a limb, depression, hallucinations

Single "Strategic" Infarct Dementia

It is currently recognized that small but strategically
located infarcts in thalamus, basal forebrain, or caudate
also produce acute-onset VaD.
The clinical features of strategic infarct VaD vary with
location of lesions in cortical or subcortical regions.
Memory impairment, impaired executive function,
confusion, and fluctuating levels of consciousness may
occur. Behavioral changes may include apathy, lack of
spontaneity, and perseveration.

Subcortical Ischemic VaD

(SIVD)
Small-vessel disease, causing lacunes and incomplete white
matter ischemia.
Lesions in subcortical VaD tend to injure specific prefrontal
subcortical circuits.
Clinically, a prominent cognitive feature is the executive
dysfunction syndrome, affecting performance in activities of
daily living (ADL) as a result of faulty goal formulation,
initiation, planning, and organization. Abstract thought is also
affected, but memory deficits are less severe than in AD.
Recognition and cuing effect remain relatively intact. Mood
changes with depression, personality changes, and labile
emotionality are common.
Onset is usually slow and subtle; acute. Focal motor signs,
gait disorder, urinary urgency, and psychomotor slowing

SIVD
Oklusi arteriolar
Infark deep white matter(inkomplit)
Lesi subkortikal
(ggl basalis, white matter & brainstem)

Binswanger's disease

subcortical vascular dementia

rare
Associated with stroke-related changes
The white matter deep
caused by high blood pressure, thickening of the
arteries and inadequate blood flow
Symptoms : slowness and lethargy, difficulty
walking, emotional ups and downs and lack of
bladder control early in the course of the
disease, with gradually progressive dementia
developing later.

Computed tomography of the brain of patient with

multi-infarct dementia showing multiple cortical
infarct

Multiple cortical infarcts are commonly the result of thromboembolic disease--for

example, from a cardiac or carotid source--but can also be caused by cerebral
vasculitis.

Multi-infarct dementia (MID), a common cause of dementia in

the elderly, occurs when blood clots block small blood vessels in
the brain and destroy brain tissue. Probable risk factors are high
blood pressure and advanced age
MID, which often develop in a stepwise manner, include
confusion, problems with recent memory, wandering or getting
lost in familiar places, loss of bladder or bowel control
(incontinence), emotional problems such as laughing or crying
inappropriately, difficulty following instructions, and problems
handling money. Usually the damage is so slight that the change
is noticeable only as a series of small steps.
ages of 60 and 75
men more often than women.

Autopsy series from dementia clinics report that

coexisting vascular pathology
occurs in 24% to 28% of ADcases.
mixed dementia as cognitive decline sufficient to
impair independent functioning in daily life resulting
from the coexistence of AD and cerebrovascular
pathology, documented either by clinical criteria or
by neuroimaging findings.

Langa et al, 2004

Interaction of AD and VaD

There is also emerging evidence that the cascade
of events leading to the development of AD brain
plaques and tangles may be due to ischemia
resulting from cerebrovascular disease.
The association of the apolipoprotein E (APOE)
4 genotype with an increased risk for both AD
and cardiovascular disease further suggests a
potential link between atherosclerosis,
cerebrovascular disease, and AD.
Amyloid deposition in cerebral blood vessels due to
AD increases the risk for hemorrhagic strokes
Langa et al, 2004

Patofisiologi VaD
Ischemia
Hipoperfusion
Hemorrhage
Heterogeneous brain lessions
Reduction of
Cerebral flow

Alteration of O2
metabolism

VaD

Inflamatory
mechanism

Higher Cortical Functions and Association Cortices

Attending
Selecting
Recognizing
Imitating
Remembering

Association cortices = cognition

Bob Chaudhuri, MD

Atherosklerosis
Atherosclerosis is a disease affecting the
arterial blood vessel. It is commonly
referred to as a "hardening" or "furring" of
the arteries. It is caused by the formation
of multiple plaques within the arteries
Banning (2004)
Damage of endothelia cell
stress oksidatif hipotesis
LDL reseptor hipotesis

Pathologically, the atheromatous plaque is divided

into three distinct components:
The atheroma is the nodular accumulation of a soft,
flaky, yellowish material at the center of large
plaques, composed of macrophages nearest the
lumen of the artery, sometimes with
Underlying areas of cholesterol crystals, and
possibly also
Calcification at the outer base of older/more
advanced lesions.

Arteriosclerosis ("hardening of the artery")

results from a deposition of tough, rigid collagen
inside the vessel wall and around the atheroma.
This increases the stiffness, decreases the
elasticity of the artery wall. Arteriolosclerosis
(hardening of small arteries, the arterioles) is the
result of collagen deposition, but also muscle
wall thickening and deposition of protein
("hyaline

Neuropathology of VaD
Microvascular brain damage
Perivascular subcortical white matter
damage
Microinfarction

Because of the variety of pathogenic mechanisms involved in

vascular dementia, clinical manifestations can be
heterogeneous
Table 1. Signs and symptoms often present in vascular
dementia
Abnormal executive functioning (difficulty with tasks that require
conscious control and planning)
Impaired psychomotor performance
Changes in personality and mood
Disturbances in gait (slow and unsteady)
Hyperreflexia, extensor plantar response
Urinary incontinence
Hemiparesis, including lower facial weakness
Hemisensory deficits
Visual problems (field defect, diplopia)
Pseudobulbar syndrome (eg, dysarthria, dysphagia, emotional
incontinence)

Table 5. Strategies for prevention of vascular dementia

Target high-risk groups: elderly persons; patients with
hypertension, diabetes, atrial fibrillation, past transient
ischemic attack, or stroke; smokers
1. Treat hypertension optimally
2. Treat diabetes
3. Control hyperlipidemia
4. Urge smoking cessation
5. Prescribe anticoagulants, such as warfarin sodium (Coumadin)
for atrial fibrillation, as indicated
6. Prescribe antiplatelet agents for patients with past transient
ischemic attack or nonhemorrhagic stroke
7. Intervene early (within 3 hr) in selected patients with stroke to
achieve reperfusion with thrombolytic agents
8. Provide intensive rehabilitation after stroke
9. Perform carotid endarterectomy for severe carotid stenosis
10.Recommend lifestyle changes (dietary changes to control risk
factors, weight loss, exercise, stress reduction, decreased salt
intake)

VCI

Vascular Cognitive Impairment

All cases of cognitive impairment of
cerebrovascular origin without a
requirement for dementia and not
requiring prominent memory loss
Hachinski, Dementia, 1994; 5:130-2

BambangHartono

VCI

Vascular Cognitive Impairment

This new term is aimed at emphasizing the
importance for treatment and prevention
by including the entire range of the
dementia process, from the very early
stage (i.e. brain-at-risk) through a whole
spectrum of cognitive impairment
Hachinski, Dementia, 1994; 5:130-2

BambangHartono

Normal Pressure Hydrocephalus

PATHOLOGY - COMMUNICATING
Insufficiency of transcortical subarachnoid space or
other absorption defect at the arachnoid villi
leading to reduced conductance of CSF outflow.
Generally occurs slowly so that pressures are
only intermittently elevated.
Patients usually do not have classic hydrocephalic
signs such as HeadAche, papilledema, lethargy,
etc.

Etiology of NPH
(1)

Thickening of the Arachnoid villi/Obstruction of subarachnoid space

- Subarachnoid hemorrhage
- Meningitis
- Head trauma
- Elevated levels of CSF protein
- Idiopathic
(2) Intra-Ventricular Obstruction (Non-communicating)
- Tumors
- Stenosis of Aqueduct of Sylvius
- Arachnoid Cysts

NPH - Signs/Symptoms
1.

Gait Apraxia - The gait is slow, unsteady, and wide based.

Steps are usually short, and patients have difficulty picking
their feet off the ground to ambulate (so-called magnetic gait).
Turning is difficult and takes several steps(Compromised
microcirculation, due to increased intraparenchymal
pressure_
2. DementiaCognitive decline is clinically multidimensioned and
involves impaired attention, poor memory, and poor executive
function
3. Urinary impairment
Neuroanatomically, the gait dysfunction and urinary impairment
are believed to relate to the stretched fibers innervating the
legs and sphincters that project through the vicinity of the
frontal horns of the ventricular system.

Diagnosis of NPH
(1) CT Scan
Anterior ventricular horns > 30% of the diameter of the cranial cavity
Inferior horns are wider than 2 mm.
(2) LP
A lumbar puncture usually reveals normal CSF pressure.
Furthermore, removal of 20 to 50 ml of CSF may cause clinical
improvement in cognitive and gait dysfunction .
(3) Differentiate from other Dementia
Alzheimer's disease - no gait dysfunction
Multi-infarct dementia - similar clinical presentation to NPH but MRI
shows signs of multiple strokes

Treatment of NPH
(1) Surgical - Chance to Cut = Chance to Cure
BUT - to whom do we give this chance?
Expert based medicine:
- Dementia < 2 years' duration
- Typical gait and Urinary dysfunction
- No evidence of multi-infarct dementia
Complications occur in 30%, w/ 5% being serious sequela
- Hematomas
- Intracranial infections
- CVA
- Shunt malformations
How well does it work? 25%-80% get long term benefit

Evidence
Surgical Management (Shunting)
- No Randomized Trials available, Cochrane Database of Systematic
Reviews. (3):CD003157, 2002
- The predictive value of ventricular CSF removal in normal pressure
hydrocephalus. Neurological Research. 19(4):357-60, 1997
Aug.

Digoxin + NPH
- Nothing on MedLine Search.

Acetazolamide + NPH
- Nothing concerning Rx on MedLine Search. (2 articles about its use
in predicting response to shunting w/ NPH).

Figure 2 Development and noninvasive treatment of bilateral subdural hygromas

following placement of a programmable shunt for idiopathic normal pressure
hydrocephalus

Gallia GL et al. (2006) The diagnosis and treatment of idiopathic normal pressure hydrocephalus
Nat Clin Pract Neurol 2: 375381 10.1038/ncpneuro0237

Diagnosis of Dementia
Multiple cognitive deficits manifested by
impaired
memory plus:

Impaired language or
Apraxia or
Agnosia or
Impaired executive function

Deficits:
Significant enough to impair function
Interferes with work or social activities

Not delirium

What is mixed dementia?

1. AD with concomitant CVD
- AD with CV lesions on imaging
- combined clinical features of both AD
and VaD
2. Likely that early-onset AD patients have
vascular lesions (in contrast with late
onset AD?)
3Continuum from pure CVD, through
mixed, to pure AD

Mixed dementia
Symptoms of both neurodegenerative and
vascular dementia
Presence of microangiopathic disease,
White matter disease
Same risk factors as for
neurodegenerative and vascular
dementia.
Imaging: Atrophy, lacunar infarcts and
white matter disease

AD & Stroke (CVD)

ApoE allele epsilon 4 mrpk FR untuk AD
dan Stroke iskemik
Peran CVD menentukan beratnya
simptom AD
AD & CVD dapat berinteraksi secara
kumulatif menyebabkan gangguan kognitif

Treatment mixed dementia

Acetylcholinesterase inhibitors
and
Stroke prevention

Effects of Aspirin
1.

2.

Antithrombotic effect

Inhibition of COX by the irreversible acetylation of a

specific serine moiety

Aspirin is 170-fold more potent in inhibiting COX-1 than
COX-2

Antioxidant effect

Decrease the progression of atherosclerosis

Improves endothelial dysfunction in atherosclerotic

vessel

3.

Antiinflammatory effect hs CRP (ASH 2003)

Aspirin

Ireversibel inhibits COX dan mencegah sintesis thromboxane A2.

Pengaruh terhadap platelet setelah + 7-10 hari.
Tidak bisa mencegah agregasi yg disebabkan trombin.
Hanya sebagian menginhibisi agregasi yg diinduksi adenosine diphosphate (ADP).

CLOPIDOGREL

C
ADP
ADP

GPllb/llla

Activation

(Fibrinogen receptor)
COX (cyclo-oxygenase)
ASA
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)

COX
TXA 2

1. Jarvis B, Simpson K. Drugs 2000; 60: 34777.

Collagen thrombin
TXA 2

*The preganglionic neuron originates in the CNS; it forms synapse

with the postgangionic neuron which locates its cell body in
ganglia. All preganglionic neurons release acetylcholine as their
transmitter.
*Sympathetic system is catabolic; the ganglia are located lateral
to the vertebral column in the thoracic and lumber regions. Most
of the sympathetic system utilizes norepinephrine.
*Parasympathetic system is anabolic; the ganglia are located
closer to the target organs. All of the parasympathetic
postganglinic fibers release acetylcholine

Docking and Exocytosis of ACh

1. ACh molecules aew stored in neurosecretory vesicles in the terminal bulbs.
2. A nerve pulse from presynaptic axon opens the voltage-gated calcium channels in
the terminal bulbs.
3. Elevated cytosolic calcium levels stimulate secretion.
(a) Phosphorylation of synapsin in the membrane of neurosecretory vesicles that the
vesicles no longer binds to the cytockeleton.
(b) Rapid docking and fusion of neurosecretory vesicles with the plasma membrane in
the terminal bulbs.
4. Docking at the active zone within the presynaptic neuronal membrane.

Ach is
hydrolytically
destroyed in the
brain by 2 ChE :
AChE & BuChE

AchE is the main enzime

involved in the
breakdown of Ach in the
normal brain

Correcting cholinergic loss in AD

Muscarinic receptor
Nicotinic receptor
ACh
ACh metabolites

1
Lecithin

Choline
Acetyl
CoA

AChE
AChEIs

Dopaminergic (DA) neurons)

originate from the ventral
mesencephalon and are divided into
laterally and medially situated
groups. The lateral group projects
from the substantial nigra and
innervates the putamen, caudate,
and nucleus accumbens of the
septal area. Destruction of lateral DA
neurons contributes to symptoms of
Parkinson's disease. The medially
situated DA neurons primarily
innervate the limbic system and
neocortex. This mesolimbic DA
pathway is an important substrate of
mood, affect and mechanisms of
addiction. As with NA neurons, most
of the ascending DA neurons pass
through the MFB.

Drug Activation of Dopaminergic

Neurons
neuron in the VTA as well as a
GABAergic interneuron and a
GABAergic projection neuron with
a recurrent collateral. Whereas,
nicotine increases the firing rate of
dopaminergic neurons in the VTA
by activating nicotinic acetylcholine
receptors located on these cells,
other drugs of abuse activate
dopaminergic neurotransmission
by inhibiting GABAergic
transmission in the VTA.
Stimulation of m opioid receptors,
GABAA receptors, or CB1
cannabinoid receptors on VTA
GABAergic neurons reduces
GABA transmission, which
increases the firing rate of
dopaminergic neurons via
disinhibition.

Mechanism of action of
memantine (2)
Pathological activation of
NMDA-receptors

Possible neuroprotection
by memantine

Rest

Rest

Learning

Ca2+

Memantine improves
plastic processes

Glutamate
Magnesium
M Memantine

M
Ca2+

Ca2+

Signal
detected

Signal
Noise

Noise

Noise

Glutamatergic hypothesis of
dementia
Glutamate is the main fast excitatory transmitter in regions
associated with cognition and memory
Cortical and subcortical structures that contain glutamatergic
receptors are structurally damaged in AD
Glutamate acts as an excitotoxin, causing neuronal death when
chronically released
Animal data suggest that NMDA-receptor antagonists provide
neuroprotection
Clinical signs of dementia correlate with deficits of glutamatergic
association fibres

CHOLINESTERASE INHIBITOR
Blocking cholinesterase induced
hydrolysis of Ach
The subsequent increase in Ach
concentration in central synapses
The enhancement of cholinergic function
ChEI are not cure-they cannot restore lost neurons;they are
used to enhance the function of the remaining cholinergic
neurons

Who Should Receive

Acetylcholinesterase Inhibitors
Mild to moderate Alzheimers disease
(MMSE > 10) until of no further benefit
Modest slowing down of cognitive decline
in up to 60-70% patients for 12-18 months
May improve behaviour, reduce carer
stress and benefit function

Cholinesterase inhibitors and

behavioural management
Cholinesterase inhibitors reduce
behavioural disturbance in AD
Cholinesterase inhibitors may be a safer
alternative to neuroleptics in DLB
Muscarinic agonists reduce BPSD despite
little or no effect on cognition
Bodick et al (1997); McKeith et al (2000); Tariot et al (2000)

ChEI
1. Donopezil
2. Rivastigmine
3. Galantamine

Donepezil

Reversible acetylcholinesterase (AChE) inhibitor

Half life < 70 hours
Once-daily dosing
Two doses: 5 mg/day and 10 mg/day
Greater efficacy at 10 mg/day
Subjected to Cochrane review
Evidence for improvement in cognition, global state and possibly
function
Side-effects similar to other AChEIs nausea and vomiting most
common
Side-effects often mild and attenuate with time
Nightmares may occur
Cochrane review

Rivastigmine

Pseudo-irreversible acetylcholinesterase (AChE) inhibitor

Half life ~2 hours / effects on AChE ~10 hours
Twice-daily dosing
Dose-titration regimen
Greater efficacy (and more side-effects) at higher doses
Evidence for improvements in cognition, global state and possibly
function
Evidence for benefits in those with vascular risk factors
Side-effects similar to other AChEIs nausea and vomiting most
common
Few interactions with other drugs
Pharmacoeconomic modelling suggests modest cost savings
Pseudo-irreversibility

Galantamine
Competitive reversible acetylcholinesterase (AChE)
inhibitor
Allosteric modulator of nicotinic receptors
Half life ~2 hours / effects on AChE ~10 hours
Slow dose-titration reduces side-effects
Evidence for improvement in cognition, global state and
possibly function
No effect of APOE
Benefit maintained to 12 months
Side-effects similar to other AchEIs nausea and vomiting
most common
Allosteric modulation of nicotinic receptors

Mechanism of action of
memantine (1)
Both memantine and magnesium allow the physiological activation of the
NMDA-receptor due to their:
voltage dependency
rapid unblocking kinetics
BUT
Memantine does not leave the NMDA-receptor channel as easily as
magnesium following tonic low level activation of NMDA-receptors
Memantines voltage-dependency is not as pronounced as
magnesiums

Mechanism of action of
memantine (1)
Both memantine and magnesium allow the physiological activation of the
NMDA-receptor due to their:
voltage dependency
rapid unblocking kinetics
BUT
Memantine does not leave the NMDA-receptor channel as easily as
magnesium following tonic low level activation of NMDA-receptors
Memantines voltage-dependency is not as pronounced as
magnesiums

Mechanism of Action of Currently Available Cholinesterase

Inhibitors
Property

Donepezil

Rivastigmine

Galantamine

Enzyme inhibition

AChE

AChE & BuChE

AChe

Brain regions selective

No

Yes

No

Allosterice modulation

Yes

Unknown

Yes

When Should Treatment be Stopped?

There is no definitive answer to this piece of the question. Some
experts recommend the discontinuation of drug therapy if there is
a lack of clinical improvement after 3 to 6 months, yet, the
definition of clinical improvement in AD patients is highly
ambiguous and subjective. Most would agree that prevention of
disease progression is a reasonable outcome, and that true
clinical improvement is highly unlikely. To that end, an evaluation
of patient response should be undertaken. Drug-free periods may
offer the best means of evaluation. It is suggested that
symptomatic deterioration during a drug-free period of up to 6
weeks might be used as an indication to reintroduce and continue
treatment.

Aggressive identification and treatment of cardiovascular

risk factors in middle aged and older individuals may
represent an important strategy for decreasing the
incidence of dementia and for slowing the progression of
cogniClinicians should address treatment and/or lifestyle
changes for the risk factors for patients with early AD,
VaD, or mixed dementia as a potential strategy
for improving quality of life and delaying the progression
of cognitive decline.

Langa et al, 2004

Trail making part A

Trail making part B

Table 1. Differentiating Features of Delirium and

Dementia
Features
Delirium
Dementia
Onset

Acute

Insidious

Course

Fluctuating

Progressive

Duration

Days to weeks Months to years

Consciousness Altered

Clear

Attention

Impaired

Normal, except for

severe dementia

Psychomotor
changes

Increased or
decreased

Often normal

Reversibility

Usually

Rarely

Psychosis

Delirium

+++

Orientation to place & time +++

Recent memory

Halucinations

Visual or auditory or both Auditory

Major stress

Delusions

Catatonic behavior

Incoherent thinking

Emotional turmoil

Distractible

Lack of sleep

Normal Forgetfulness vs Early Dementia

Brodaty 1998

Description

Dementia

Normal Elderly

Forgets

Whole experience

Part experience

Forgets words/names

Progressive

Occasional

Delayed recall

Often

Rarely

Follows commands

Gradually unable

Usually able

Ability to use notes,

reminders

Gradually unable

Usually able

Follow a story on TV,

book

Gradually unable

Retains usual ability

Calculations

Gradually unable

May be slower

Self care

Gradually unable

Usually able

Symptom
Psychomotor
agitation

Alzheimer's
disease

Vascular
dementia

Diffuse Lewy
body

Frontotemporal

+++

+++

+++

Aggresive
behaviour

++

++

++

Delusions

++

++

+++

+++

Depression

++

+++

++

Anxiety

++

+++

Apathy/
retardation

++

+++

++

++++

Sleep changes

++

++

++

+++

+++

+++

Hallucinations

Appetite
Changes
Sexual
disinhibition

Depression

Onset: rapid
Precipitants: psycho-social (not organic)
Duration: less than 3 months to presentation
Mood: depressed, anxious
Behavior: decreased activity or agitation
Cognition: unimpaired or poor responses
Somatic symptoms: fatigue, lethargy, sleep,
appetite disruption
Course: rapid resolution with treatment,
but may precede Alzheimers disease

Clinical features of depression

in AD
Lack of reactivity to pleasant events
Poor self-esteem
Pessimism
Loss of interest
Physical complaints
Psychomotor retardation
Sadness
Assessment

Difficulties

Harwood et al (1998); Katz (1998);

Longsdon and Teri (1995)

Investigations for the Causes of Depression

and Cognitive Impairment
Investigation

Conditions

Full blood count / ESR

Anaemia, infections, e.g. subacute bacterial

endocarditis, vasculitis

Urea and electrolytes

Hypokalaemia, hyponatraemia, uraemia

Blood sugar level

Diabetes

B12, folate levels, homocysteine

Pernicious anaemia, malnutrition

Thyroid function tests

Hyper/hypothyroidism

Calcium/phosphate

Hyper/hypocalcaemia

Urinalysis

Urinary tract infection, renal disease

Liver function tests

Hepatitis, liver cancer

Chest X-ray

Lung cancer, pneumonia

Brain CT Scan (no contrast)

Exclude CVA, neoplasia, subdural

Syphilis serology

Neurosyphilis

Investigations for the Causes of Depression

and Cognitive Impairment
These Additional Tests Should be Considered in
the Following Circumstances:
Investigation

Conditions

EEG

When prolonged delirium or encephalopathy is a concern

ECG

In patients with prominent complaints of fatigue and

breathlessness

Brain MRI

To exclude cerebral vasculitis, posterior brainstem lesions

HIV

Exposure to potentially contaminated blood products, highrisk sexual practices, intravenous drug abuse

SPECT / PET

May assist in early onset AD and DD with VaD

Drug levels

Digoxin, phenytoin, carbamazepine, theophylline

Carotid Doppler

To exclude carotid vessel disease in VaD

Lumbar puncture

If chronic meningitis or encephalitis suspected

Kriteria Depressi DSM-IV

1. Felt depressed
2. Loss of interest
3. appetite loss and weight loss
4. insomnia or hipersomnia
5. lack of energy
6. poor self esteem
7.concentration disturbances
8. suicide

Score > 5

DEPRESI

Pathofisiologi depression post

stroke
Organik brain lession

Decrease of serotonin
Noradrenalin
Dopamin

Stroke

Depression

Neurological Conditions
Primary Neurodegenerative Disease
Diffuse Lewy Body Dementia (? 7 - 50%)
Fronto-temporal dementia (tau gene)

Focal cortical atrophy

Primary progressive aphasia (many causes)
Unilateral atrophy, hypofunction on EEG, SPECT, PET

Normal pressure hydrocephalus

Dementia with gait impairment, incontinence
Suggested on CT, MRI; need tap, ventriculography

Other Neurologic Conditions

DISTRIBUTED COGNITIVE FUNCTION

Cognitive function

Neural basis

1.

Attention/concentration

2.

Memory

Reticular activating system (brain stem

and thalamic nuclei), and multimodal
association areas (prefrontal, posterior
parietal and temporal lobes)
Limbic system (especially
hippocampus and diencephalon)

3.

Higher-order intellectual function,

social behaviour, and personality

Frontal lobes

Cognitive Impairment

Concentration and attention

Memory
Speed of information processing
Mental flexibility
Executive functioning
Neurolinguistic
May be associated with other psychiatric syndromes
(e.g., depression, anxiety, psychosis)

Assessment
1.
2.
3.
4.
5.
6.
7.
8.

Dementia vs pseudodementia
Acute vs Chronic
Global vs Focal
Irreversible vs Reversible dementia
Deficits
Comorbid problems
Strengths
Effect on family/ carer

Assessment of the cognitively

impaired patient
History
Duration of perceived impairment (preferably
at least 6 months)
Specific difficulties STM, spatial, lists,
topographical
Impact on the patients life and functioning (eg
stopped driving, retired)

Examination
Physical examination
Examine for reversible risk factors for
vascular dementia.
Examine for Parkinsonian features
Cognitive examination
MMSE (Folstein et al)
Clock drawing test

CLOCK DRAWING TEST

CDT is strongly
associated with MMSE
Patients are asked to draw a clock with all the numbers, and
make the hands point to certain time, eg, 20 minutes before
2 o'clock.
The clocks shown above are considered poor (0), fair (1),
good (2), and excellent (3).
Source: Reprinted with permission from Strub RL, Black FW. The Mental Status Examination in Neurology. 3rd ed. Philadelphia, PA: FA Davis;
1993.

Impairment Level and CDR Score (0, 0.5, 1, 2, 3)

None
0
Memory

Questionable
0.5

Mild
1

Moderate
2

Severe
3

No memory loss or
slight inconsistent
forgetfulness

Consistent slight
forgetfulness; partial
recollection of events;
"benign" forgetfulness

Moderate memory loss;

more marked for recent
events; defect interferes
with everyday activities

Severe memory loss;

only highly learned
material retained; new
material rapidly lost

Severe memory loss;

only fragments remain

Orientation

Fully oriented

Fully oriented except for

slight difficulty with time
relationships

Moderate difficulty with

time relationships;
oriented for place at
examination; may have
geographic
disorientation elsewhere

Severe difficulty with

time relationships;
usually disoriented to
time, often to place

Oriented to person only

Judgment &
Problem
Solving

Solves everyday
problems & handles
business & financial
affairs well; judgment
good in relation to past
performance

Slight impairment in
solving problems,
similarities, and
differences

Moderate difficulty in
handling problems,
similarities, and
differences; social
judgment usually
maintained

Severely impaired in
handling problems,
similarities, and
differences; social
judgment usually
impaired

Unable to make
judgments or solve
problems

Community
Affairs

Independent function at
usual level in job,
shopping, volunteer and
social groups

Slight impairment in
these activities

Unable to function
independently at these
activities although may
still be engaged in
some; appears normal
to casual inspection

No pretense of
independent function
outside home
Appears well enough to
taken to functions
outside a family home

No pretense of
independent function
outside home
Appears too ill to be be
taken to functions
outside a family home

Home and
Hobbies

Life at home, hobbies,

and intellectual interests
well maintained

Life at home, hobbies,

and intellectual interests
slightly impaired

Mild but definite

impairment of function
at home; more difficult
chores abandoned;
more complicated
hobbies and interests
abandoned

Only simple chores

preserved; very
restricted interests,
poorly maintained

No significant function in
home

Needs prompting

Requires assistance in
dressing, hygiene,
keeping of personal

Requires much help

with personal care;
frequent incontinence

Personal Care

Fully capable of self-care

Lab Studies:
- Complete blood cell count with differential - Helpful to
diagnose infection and anemia
- Electrolytes - To diagnose low or high levels
- Glucose - To diagnose hypoglycemia, diabetic ketoacidosis, and
hyperosmolar nonketotic states
- Renal and liver function tests - To diagnose liver and renal
failure
- Thyroid function studies - To diagnose hypothyroidism
- Urine analysis - Used to diagnose urinary tract infection
- Urine and blood drug screen - Used to diagnose toxicological
causes
- Thiamine and vitamin B-12 levels - Used to detect deficiency
states of these vitamins
- Tests for bacteriological and viral etiologies - To diagnose
infection
- Sedimentation rate
- Drug screen including alcohol level

KLASIFIKASI DEMENSIA
BERDASAR ANATOMIS
A. KORTIKAL
Dementia of alzheimer, picks disease
B. SUBKORTIKAL
Dementia of Parkinson, huntington, wilson,
supranuclear palsy.
C. CAMPURAN (vaskuler)
Multiple infarct dementia, creutzfeld-jacob,
Korsakoff syndrom
Whitehouse, 1986

Jenis-jenis Demensia
1.
2.
3.
4.
5.
6.

Demensia jenis alzheimer

Demensia vasculer (dahulu: multi infarct dementia)
Demensia karena kondisi medik umum lain: infeksi
HIV, trauma kepala, parkinson, huntington, picks,
creutzfeld-jacob, penyakit lain.
Demensia karena penggunaan substansi tertentu
dalam jangka lama.
Demensia karena etiologi multipleks
Demensia yang tidak terspesifikasi.

Harsono, 1995