4 November 2004 Dr.

Supparearg Disayabutr

Dementia
Chronic or progressive dysfunction of cortical and subcortical function Interfere daily functioning and the quality of life

Epidemiology
Prevalence 1.5% at age 65 yrs Double every 4 yrs to 30% at 80 yrs Overall incidence increases with age and is about 1% per year

Karen Ritchie, Simon Lovestone. The Lancet. 2002; 360: 1759-66

Survival
Average survival = 8 years from Dx Longer survival - Patient with AD - Women in both AD and VaD

Karen Ritchie, Simon Lovestone. The Lancet. 2002; 360: 1759-66

Diagnostic criteria (DSM-IV)

A. Multiple cognitive deficits
1. Memory impairment 2. One or more of the following : a. Aphasia b. Apraxia c. Agnosia d. Impaired executive function

B. Significant impairment in social or occupational function and decline from a previous functional level C. Not occurring during the course of delirium

Causes of dementia
Primary dementia
- Alzheimers disease

- Picks disease (frontotemporal dementia)

- Dementia with Lewy bodies (DLB)

- Parkinsons disease
- Progressive supranuclear palsy

Causes of dementia
Secondary dementia
- Vascular dementia
- Trauma - Intracranial condition (eg. tumor, subdural hematoma, hydrocephalus) - Metabolic and endocrine disturbances (eg.

hypothyroidism, hyperthyroidism, hypoglycemia,

hyperglycemia, uremic encephalopathy, anoxic) - Deficiency states (eg.Vitamin B12)

- Infection (eg. AIDS, syphilis)

Vascular dementia
Second most common caused of

dementia
Prevalence from autopsy studies* 7-10%

Cognitive loss with vascular brain lesion

with temporal link between stroke and

dementia
Jellinger KA. J Neural Transm Suppl. 2002(62): 1-23

Risk factors of VaD

Age
Male sex Hypertension MI Dyslipidemia Diabetes CAD Smoking

History of stroke
Prestroke cognitive decline E4 allele of APOE Hypoxic event during acute stroke

Generalized atherosclerosis

Vascular disorder

Vascular disorder
Large vessel injury
Multiple or single (cortical or cortico-subcortical infarcts)

Small vessel injury

Multiple basal ganglia and white matter lacunae or extensive white matter lesion

Six subtypes of VaD

1. Multi-infarct dementia (MID)
2. Strategic single infarct dementia

3. Small-vessel disease with dementia

4. Hypoperfusion dementia

5. Hemorrhagic dementia
6. Other VaD
Parnetti L. Rev Neurol (Paris). 1999; 155(9): 754-8.

Criteria for VaD

Sensitivity and specificity are vary in all clinical criteria
- HIS
- DSM-IV - ICD-10

- NINDS-AIREN
- CAD-DTC

False-positive cases are usually AD plus CVD Lack of uniform diagnostic criteria

Clinical features
Cognitive loss, often predominantly
subcortical

Vascular brain lesions by imaging

A temporal link between stroke and

dementia
Exclusion of other causes

Roman GC. J Am Geriatr Soc. 2003 May; 51(Suppl): S296-304.

Clinical features
In VaD, executive dysfunction is

commonly seen
But memory impairment is mild or may

not be present*
Clinical presentation varies with location of infarcts Lack of uniform diagnostic criteria
Mare Fisher, Stroke April 2004; 1010-17 Roman GC, J Am Geriatr Soc 2003; 51Suppl: S296-304

Neuropsychiatric disorders

Clinical approach
Underlying disease Functional impairment
History and physical examination - Cognitive and behavioral changes

- Existing illness and medication

MMSE
1 2

Laboratory evaluation Neuroimaging

3

Mental-status testing

Laboratory evaluation
CBC

Thyroid function
Vitamin B12 level Screening for inflammatory and infectious disease Genetic testing : controversial

Neuroimaging
To rule out structural brain lesion If no abnormal neurological examination CT is adequate If there is motor dysfunction MRI may be identified lesion that cannot be detected by CT

Physiologic imaging (PET, SPECT)

David S. N Eng J Med. 1996; 335: 330-336.

Neuroimaging

PET studies show hypometabolism in a characteristic pattern in the common dementias, (including AD, Parkinsons disease with dementia, LBD, MID, FTD, and progressive supranuclear palsy)
Sid Gilman. N Eng J Med. 1998; 338: 889-96.

Neuroimaging
A 1015 patients, prospective, population based cohort study*

To study the association between silent

brain infarcts and risk of dementia

Presence of silent brain infarcts** at

baseline doubled risk of dementia

Periventricular WML increased risk of

dementia
*Sarah E. N Eng J Med. 348; 13: 1215-22. ** = Evidence of one or more infarcts without a Hx of stroke or TIA

Neuroimaging
A 1015 patients, prospective, population based cohort study*

Silent thalamic infarcts were associated

with a decline in memory performance

Nonthalamic infarcts were associated with

a decline in psychomotor speed

*Sarah E. N Eng J Med. 348; 13: 1215-22.

*Sarah E. N Eng J Med. 348; 13: 1215-22.

Neuroimaging
A 141 patients, retrospective study *

Compare the prevalence of cerebral WML in 3 groups of patient : not fulfill criteria

for dementia, AD and VaD

*Yih Yiow Sitoh. Age and ageing. 2004; 33: 65-70.

Neuroimaging
A 141 patients, retrospective study * (1)
59% 5% 36% 25% 3% 25%

Significant
Not sig.

(2)

Compare associated clinical features (1) and psychometric performance (2) in demented patients with and without WML
*Yih Yiow Sitoh. Age and ageing. 2004; 33: 65-70.

Management
Primary prevention Secondary prevention
1. Early diagnosis and Rx of acute stroke 2. Prevention of stroke recurrence 3. Slowing of progression (Rx of risk factors)

Aim of treatment

1. Slow progression 1 2. Symptomatic 2 3. Rx of neuropsychiatric symptoms 3

Pharmacotherapy in VaD
Propentofylline
Nimodipine

Memantine
Cholinesterase inhibitors
Donepezil
Galantamine Rivastigmine

Propentofylline
Glial modulator

Beneficial effects on learning and

memory in mild to moderate VaD *

But no longer under development

Kittner B. Ann N Y Acad Sci. 1997; 826: 307-16. Mielke R. Alzheimer Dis Assoc Disord. 1998; 12(Suppl 2):29-35.

Nimodepine
Dihydropyridine calcium antagonist Effect on autoregulation of cerebral

blood flow, specific effect on small vv

Providing some degree of

neuroprotection
Insufficient evidence that useful in

symptomatic Rx of VaD *
Lopez-Arieta BJ. Cochrane Database Syst Rev.2001; 1: CD000147.

Memantine
N-methyl-D-aspartate receptor
antagonist

In MMM300* and MMM500** studies :

Memantine improve cognitive function by ADAS-cog scores esp. in small-vessel group without cortical infarction
* Orgogozo J-M.Stroke. 2002; 33: 1834-39. ** Wilcock G. Internat Clin Psycho-pharmacol. 2002; 17: 297-305.

Cholinergic dysfunction and cholinesterase inhibitors in VaD

Localized stroke interrupt cholinergic
bundle that extend from nucleus basalis

to cerebral cortex and amygdala

Loss of cholinergic neurons in 40% of

VaD with reduced acetylcholine activity in

cortex, hippocampus, striatum and CSF

Donepezil
Piperidine derivative

Reversible central acetylcholinesterase

inhibitor Black S.* and Wilkinson D.** studies showed that Donepezil treatment group have cognitive function improvement

by ADAS-cog and MMSE and well

tolerated in both 5, 10 mg/d
* Black S. Stroke. 2003; 34: 2323-32. ** Wilkinson D. Neurology.2003; 61: 479-486.

Galantamine
Acetylcholinesterase inhibitor and

modulates central nicotinic receptors

Galantamine showed long-term benefits

across several measures of efficacy

(cognition, behaviour, and activities of

daily living) in patients with dementia of

the Alzheimer type

Galantamine
In 6-month trial of Erkinjuntti T. study
Include 592 patients with probable VaD or AD plus CVD, recieved galantamine 24 mg/d Both groups, galantamine showed efficacy on all outcome (ADAS-cog, CIBIC, DAD) In open-label extension, can maintained

cognitive abilities at baseline for 12 month

* Erkinjuntti T. Lancet. 2002; 359: 1283-1290.

Rivastigmine
Acetylcholinesterase inhibitor and
butyrylcholinesterase inhibitor

Improve cognition, caregiver stress and

behavior in small open-label study of

patients with subcortical VaD

Timo Erkinjuntti. Stroke. 2004; 35: 1010-1017.

Rx of neuropsychiatric symptom
Drugs with anticholinergic effect
should be avoid

Non-pharmacological management
should be attempted first