Early symptoms of vascular

dementia is there any space

for Donepezil
Taufik Mesiano

Symposium - Jaknews 2019

9 Maret 2019
 Taufik Mesiano
taufik.mesiano@ui.ac.id
(Born : Jakarta, 1 May 1979)

Education & Training

• Medical Doctor : Faculty of Medicine University of Padjadjaran, 2004
• Neurology Specialty : Faculty of Medicine University of Indonesia, 2010
• Fellowship in Neuroendovascular Therapy, Neurosurgery Dept. Juntendo University -
Tokyo, 2016
• Consultant in Neurovascular : Indonesian Neurology Collegium , 2017
Current Activities & Organization
• Medical Staff at Stroke & Neurovascular Division, Dept. Neurology FMUI-RSCM
• Secretary General of Indonesian Neurology Collegium (KNI)
• Head of Indonesian Neurology Association – Jakarta Chapter
• Coordinator of Public Services Dept. Neurology RSCM
• Member of Stroke Study Group, Indonesian Neurology Association
• Member of American Heart Association / American Stroke Association
• Member of World Stroke Organization
Overview

• Stroke Incidence a bonus demography

• Spectrum post stroke cognitive impairment
• Predispose factor to post stroke VCI
• Management of Post Stroke Dementia
• Role of donepezil in VCI
• Conclusion
Stroke Incidence a bonus
demography for Vascular
Cognitive impairment
National Health Survey 2013
National Stroke Prevalence: 12.1‰

12.2

14.5

17.9
14.6

16.9 HIGHEST CAUSE OF DEATH (2014)

25
21.1
Indonesian population by 2014: 252 millions 20

National Stroke ~ 3,049,200 15 12.9

~6x Brunei population 10 6.7

5.3
~60% of Singapore population 5

National Stroke Registry 2012-2014

Mean age: 58.95±12.05
Stroke Incidence a bonus
demography for Vascular
Cognitive impairment

• Poststroke
multidomain
Survivor impairment of
30 cognitive
Days Disable 30 %

30 %
Institutional care 10 %
365
Day
s Depression 15-30 %

Recurrent Stroke
40 % 1st Year : 6 – 14 %
5 Year : 20 – 37 % World Federation of Neurology, 2007
Stephen et.al, 2017
Stroke Incidence a bonus
demography for Vascular
Cognitive impairment
Symptomatic Infarct
20 – 25 %

Silent Infarct
89 %
CEREBRAL SMALL VESSEL DISEASE

Incidence :
25 % (UK) vs 45 % (Indonesia)
> 65 yo & >> 80 yo
Recurrent Stroke / ICH
Dementia
Mortality
Beiser etal. Stroke 2010; 41: 600-606
Mok et.al 2015. Journal of Stroke 2015;17(2):111-122
Bath PM and Wardlaw JM. International Journal of Stroke Vol 10, June 2015, 469–478
Harris et.al. Indonesia Stroke Registry Data. 2017
Stroke Incidence a bonus
demography for Vascular
Cognitive impairment
Prevalence Vascular Cognitive Impairment
Country Percentage (%)
Nigeria 39.9
Australia 39.4
Chile 39
China 37.1
UK 32
Portugal 55
Singapore 54.8
Korea 49.9
Hongkong 21.8
Ghana 34 Stephen et.al, 2017
Spectrum post stroke
cognitive impairment

Broad spectrum of cognitive impairment among stroke survivor

Single domain Multidomain

Cognitive Impairment Cognitive Impairment
Mild Cognitive Post Stroke Dementia
Impairment

40 - 65 % 8- 30 %
Stroke Survivor Stroke Survivor

• Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive
impairment harmonization standards. Stroke 2006;37:2220-2241.
• Pendlebury ST, Rothwell PM. Prevalence, incidence, and risk factors associated with pre-stroke and post-stroke dementia: a systematic review
• Akinyemi RO, Allan L, Owolabi MO, et al. Profile and determinants of vascular cognitive impairment in African stroke survivors: the CogFAST
Nigeria Study. J Neurol Sci 2014;346:241-249.
Spectrum post stroke
cognitive impairment
• Cross sectional study, Ghana, among stroke survivor
• 147 vs 49
• Cognitive impairment : 72.8 % vs 55.1 % (MOCA)
• NPI :

No Vascular Cognitive 77/147 (52.3%) Visual Impairment 11

Impairment Executive disfunction 6
Vascular Cognitive 50/147 (34 %) Language disfunction 4
Impairment
Post Stroke Dementia 20/147 (13.6%)

Non Amnestik Amnestik

Single Domain 21 (42%) 7 (14%)
Multiple Domain 7 (14%) 15 (30%)

Stephen et.al, Journal of Stroke and Cerebrovascular Diseases, Vol. 26, No. 11 (November), 2017: pp 2553–2562
Spectrum post stroke
cognitive impairment

Duration of Stroke with Cognitive impairment

VCI (%) PSD (%)

1 year 32.8 20.7
2 – 4 years 27.9 2.3
≥ 𝟓 𝒚𝒆𝒂𝒓𝒔 50.0 7.7

Stephen et.al, Journal of Stroke and Cerebrovascular Diseases, Vol. 26, No. 11 (November), 2017: pp 2553–2562
Predispose factor to post
stroke VCI

• Age
• Duration of stroke
• Educational attainment
• NIHSS
• Occupation
• Alcohol
• Environmental enrichment
• Functional limitation
• Area stroke (imaging )
• Cardiovascular risk
• Strategic infarcts
• Area stroke (imaging )
• Medial temporal atrophy
• White matter changes
• Global cerebral atrophy
• Lacunar infarct
• Left Sided lesion
• Cerebral microbleeds
• Cortical lesion
• Silent infarct
• Hemorrhagic

Stephen et.al, Journal of Stroke and Cerebrovascular Diseases, Vol. 26, No. 11 (November), 2017: pp 2553–2562
Renjen P, Gauba C, Chaudhari D (September 29, 2015) Cognitive Impairment After Stroke. Cureus 7(9): e335. DOI 10.7759/cureus.335
Management of Post
Stroke Dementia

• Optimal management in acute phase :

• Thrombolysis and thrombectomy
• Optimum secondary prevention :
• Hypertension ( < 140 / 90 )
• Controlled risk factors
• Antiplatelet
• Statin a

Pharmacology and Non Pharmacology

Lo Coco et al. Vascular Health and Risk Management 2016:12

Management of Post
Stroke Dementia

Pharmacology AD VCI Mix

Donepezil √ √
Galantamin √ √
Memantin √ √
Rivastigmin Not proven
• No specific drug approved for VCI/VaD
• No head to head study

Lo Coco et al. Vascular Health and Risk Management 2016:12

Management of Post
Stroke Dementia

Pharmacology VCI Stroke Recovery

Citicholin + √ 2x500, 9-12 mo
Nimodipin + - 90mg/day
Ginkgo biloba + - 1 x240 mg
O3-FA - √
Non Pharmacology
Diet + Mediterranean,
olive oil, nuts
Cognitive training Cognitive task
Cognitive Not effective Not effective
Rehabilitation
Physical Functional 30 m Mod.Exercise

Lo Coco et al. Vascular Health and Risk Management 2016:12

Role of Donepezil in VCI

• Donepezil range of protecting effects :

• Protecting against amyloid β
• Ischemia
• Glutamate toxicity
• Slowing of progression of hippocampal atrophy;
• Up-regulation of nicotinic acetylcholine receptors.

British Journal of Pharmacology (2017) 174 4224–4232

Role of Donepezil in VCI
Insult
APP Procesing & Deposition of Aβ
Loss of cholinergic neurons
AchE ↗ amyloid fibril formation Aβ
agregation
↘ nicotinic achetylcholine receptor
expression
Excitotoxic cell injury
Free Radical
↘ Density of α 1 receptors
↘ Blood flow in response to
neurotoxicity
Inflammatory cytokines IL-1β , IL-6,
oncostatin M
Mechanism of Injury
Nerve cell death
↗ Aβ production & decrease
processing of APP
Neuronal stress
Loss of α4 & α7 receptors
APP expression & tau phosphorilation
Oxidative stress
Impaired cholinergic and
glutamanergic neurotransmitter
↘ CBF
Accumulation of activated microglia
and reactive astrocytes
British Journal of Pharmacology (2017) 174 4224–4232
Mechanisme of Action Donepezil
↘ Neurotoxic effects Aβ
Maintain cholinergic input to cortical
neuron
↘ AchE-S and ↗ AchE-R
↗ Nicotinic receptor in cortex & ↘
glutamate neurotoxicity
↘ Excitotoxicity via P13k-Akt, NMDA
& nicotinic receptor
Mitigate effects of oxidative stress
α 1 receptor interaction
↗CBF & ↘ ischemia indeced cellular
injury
↘ Inflammatory cytokines & pro-
inflammatory species
 Reperfusi -
X X Trombolisis

• Antagonis Ca Ch.
• Antagonis reseptor
Glutamat (NMDA /
AMPA antagonis)
• Glutamat Inhibitor
X sintesis dan
presinap

• Antioksidan
• Lokal inflamasi
Inhibitor
X • Statin
• Faktor neurotrophic
• Neuromedulator
• Regulator of
receptor structures

Gusev Eugene and Skvortsova V I. Brain

Ischemia. Kluwer Academic/Plenum
Publishers. New York. 2003. p.13
Conclusion

• Stroke Incidence is a bonus demography for

Vascular Cognitive impairment
• Optimal management in acute phase & Optimum
secondary prevention is mandatory to prevent VCI
• AchE inhibitor such as Donepezil had a potential
mechanism of action to reduced VCI symptom and
stroke recovery