Early & Continuous Treatment

Early & Continuous Treatment

YUSRIL
 Dementia
 Dementia is a SYNDROME in which there is deterioration in memory,
thinking, behaviour and the ability to perform everyday activities. (WHO)1

 Common symptoms of dementia include the gradual loss of memory,

decline in communication skills and difficulty with thinking and reasoning.
 Dementia is one of the major causes of disability and dependency among
older people worldwide.

Number of people 2
with dementia (millions)

1. http://www.who.int/mediacentre/factsheets/
2. https://www.alz.co.uk/research/WorldAlzheimerReport2015-sheet.pdf
The Global Impact of Dementia

https://www.alz.co.uk/research/WorldAlzheimerReport2015-sheet.pdf
 Dementia
An Umbrela Term

Alzheimer’s Vascular
Disease Dementia
±62% Frontotemporal ±17%
Dementia
2%
Types of
Dementia with
Dementia Parkinson Disease
Lewy Body’s
±4% Dementia
±2%
Others
±13%

Alzheimer Society of Canada. Rising Tide: The Impact of Dementia on Canadian Society. (2010) ISBN 978-0-
9733522-2-1.
http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=2761
ALZHEIMER
DISEASE
????
Alzheimer Disease

• Suatu gangguan neuropsikiatri yang

merupakan bentuk progresifitas dari
dementia, yang berefek pada gangguan
kognitif, behavior, dan fungsional
• penyakit penurunan fungsi otak yang
kompleks dan progresif sehingga daya ingat
seseorang merosot tajam dan tidak dapat
disembuhkan.
 Alzheimers’ Disease (AD)

• A degenerative disease of the brain and the most common cause of dementia
in older people, accounting for 60% to 80% of cases of late-life cognitive
dysfunction.

• AD is contributing to the global non-communicable disease burden, and it is a

leading source of morbidity and mortality in the aging population.

• Indonesia : The estimated number of people with AD (2013) reaches one million
people. The number is expected to increase dramatically to double by 2030,
and to four million by 2050.

Meyer JC, et al. Overview of Alzheimer’s disease and its management. S Afr Pharm J 2016;83(9):48-56
http://www.depkes.go.id/article/view/16031000003/menkes-lansia-yang-sehat-lansia-yang-jauh-dari-demensia.html
Etiologi
– Belum diketahui secara pasti
– Kemungkinan faktor genetik dan lingkungan
sedang diteliti (gen ApoE atau β-secretase)

Faktor Resiko
– Usia
– Genetika
– Hipertensi
– Peningkatan LDL
– Penurunan HDL
– Diabetes
Gejala Alzheimer
AD as a Progressive Disease

Feldman. Clinical Diagnosis and Management of Alzheimer’s Disease. 1996. Elsevier. pp 239-59.
 Tahapan Penurunan Kognitif Menurut MMSE

Mild Difficulty remembering recent events, ability to manage finances, prepare

food, and carry out other household activities declines. May get lost while
(MMSE score
driving. Begins to withdraw from difficult tasks and to give up hobbies.
26–18)

Moderate Patient requires assistance with activities of daily living. Frequently

disoriented with regard to time (date, year, season). Recall for recent
(MMSE score
events is severely impaired. May forget some details of past life and names of
17–10)
family and friends. Functioning may fluctuate from day to day. Patient
generally denies problems. May become suspicious or tearful. Loses ability to
drive safely. Agitation, paranoia, and delusions are common.

Severe Patient loses ability to speak, walk, and feed self. Incontinent of urine and
feces. Requires care 24 hours a day and 7 days a week.
(MMSE score
9–0)

Mini Mental State Examination (MMSE)

GLOBAL DETERIORATION SCALE
Patogenesis
1. Atrofi kortikal
2. Neurofibrillary Tangles (NFTs)
3. Plaque Amyloid
4. Kerusakan saraf kolinergik
5. Penurunan sintesis asetilkolin
 1. Atrophy 2. Amyloid Plaques

3. Neurofibrillary tangles
 Neurofibrillary tangles (NFTs)
Terjadi karena adanya hiperfosforilasi dari protein tau,
sehingga menyebabkan mikrotubul kolaps
4. Terjadinya penurunan aktifitas kolinergik
berpengaruh terhadap keparahan dari
Alzheimer Disease

5. Terjadi penurunan jumlah enzim kolin

asetiltransferase di korteks serebral dan
hipocampus menyebabkan penurunan
sintesis asetilkolin di otak
 Diagnosis
• a detailed patient history
• information from family and
friends
• physical and neurological exams
and lab tests
• neuropsychological tests
• imaging tools such as CT scan,
or magnetic resonance imaging
(MRI). PET scans are used
primarily for research purposes
RESIKO KECENDERUNGANNYA MENDAPAT
DEMENSIA ALZHEIMER’S :

RISK No. Score

1. Orang tua, saudara kandung ada yang 3.0
Alzheimer Demensia
2. Cidera kepala + kehilangan kesadaran 2.0
3. Usia lebih 65 th 1.0
4. Usia lebih 75 th 4.0
5. Usia lebih 85 th 16.0
6. Pendidikan < 7 th 3.6
7. Wanita 1.5
8. Hipertensi Sistolik > 140 mmHg 2.2

Lanjutan 
RESIKO KECENDERUNGANNYA MENDAPAT
DEMENSIA ALZHEIMER’S :

RISK No. Score

9. BMI > 30 kg/m2 2.3

10 Colesterol > 6.5 m mol/L 1.9
11 APO-E3-4 positif 2.4
12 Riwayat Stroke 4.0
13 Riwayat serangan jantung 2.5
14 Diabetes type 2 tak terobati 3.0
15 Kurang olah raga fisik 1.7
16 Merokok terus menerus 2.3

Lanjutan 
RESIKO KECENDERUNGANNYA MENDAPAT
DEMENSIA ALZHEIMER’S :
Total Score :

1. Bila score kurang dari 5 :  Resiko rendah

2. Bila score antara 5-12 :  Resiko sedang
3. Bila score melebihi 12 :  Resiko tinggi

Sumber :
Lancet neurology 5 : 735 – 741
Penelitian longitudinal populasi usia menengah
( middle aged )
Selama 20 tahun oleh :

W. Rodwan Shankle, Daniel Otwen,

M. Kivepelto et.ac, 2006
 Management of
Alzheimer’s Disease
 Tujuan Terapi
• Menjaga fungsi-fungsi pasien selama mungkin
• Menunda perkembangan penyakit

Strategi Terapi
Non farmakologi
Terapi non-farmakologi melibatkan pasien,
keluarga, atau pengasuh khusus untuk
mensupport, menghadapi dan memahami
kondisi pasien
Farmakologi
• Terapi untuk mengatasi gejala penurunan
kognisi atau menunda progresivitas penyakit
• Terapi simptomatik
 Primary Goal Secondary Goal
Treating the symptoms of cognitive Treating psychiatric and
impairment and maintaining the behavioral sequelae.
patient’s functionality for as long as
possible

Non- pharmacological Therapy Pharmacotherapy

FDA Approved Drugs

• Donepezil ( All Stage of AD)
• Galantamine ( Mild-Moderate AD)
• Rivastigmine (Mild-Moderate AD)
• Tacrine ( Mild – Moderate AD)
• Memantine (Moderate-Severe AD)

Abbasi MY, Alam MS. Alzheimer’s Disease Management: Current Therapy and Recent Drug Development, International
Neuropsychiatric Disease Journal. 7(2): 1-19, 2016
Meyer JC, et al. Overview of Alzheimer’s disease and its management. S Afr Pharm J
2016;83(9):48-56
Terapi simptomatik

Selain gejala gangguan kognitif juga terdapat

gejala gangguan non kognitif seperti
depresi,seperti gelisah, pelupa, dan insomnia
• Gejala depresi --- antidepresan (SSRI,TCA)
• Insomnia --- perlu hipnotik, atau antidepresan
yang bersifat sedatif
• Delusi --- curiga, menduga-duga yang salah,
paranoid --- antipsikotik (dicari yang paling
kurang efek sampingnya) --- atipikal (klozapin,
quetiapin, risperidon)
 Early Treatment of AD
 Delays in the diagnosis of Alzheimer’s disease, and, therefore,
delays in treatment, may have a detrimental effect on a
patient’s long-term well-being.

Early treatment Early stage: LESS

loss, MORE can be
Cognitive function

gained
No
treatment

Time
 The Importance of PERSISTENT
Treatment

Continuity of treatment is an important feature of a

long-term Alzheimer’s disease treatment plan
because “drug holidays” or treatment gaps allow
symptoms to rebound, sometimes irreversibly.

Seltzer. Cholinesterase Inhibitors in the Clinical Management of Alzheimer’s Disease: Importance of Early and Persistent Treatment J
Int Med Res. 2006;34(4):339-47
Why later stage of AD have to be treated ?

 To improve patients and caregivers’ quality of life

 To delay the worsening of symptoms of AD

 Decreased Acetylcholine level So, we optimize existing to

maintain ADL, behavior, cognitive and global functions.

 Clinical datas show that Donepezil provides benefits in

patients with severe AD
 Early & Continuous Treatment of AD with Donepezil

Double-blind Open-label
2 Mild to Moderate AD
1
**
0 * Clinical
***
LS Mean Change in MMSE

-1 Overall
improvement
-2 P=0.004
-3
P=0.057
-4
-5 *
Th/ Donepezil (n = 135) Clinical
-6 Decline
Th/ Donepezil delayed start(n = 137)
-7 Projected Placebo (n = 137)
-8 *P<0.05, **P<0.01,
***P<0.001 versus placebo
-9
0 24 52 78 104 130 156 Study Week

 The Winblad’s Study (2006) showed that delayed administration of

Donepezil for 1 year resulted in decreased cognitive function fast.

Winblad B, et al. 3-Year Study of Donepezil Therapy in Alzheimer’s Disease: Effects of Early and Continuous Therapy. Dement
Geriatr Cogn Disord 2006;21:353–363
 Safety of Donepezil

 Donepezil was well tolerated over the 3-year study period, with a long-
term safety profile.

 The majority of AEs were mild to moderate in intensity, with the most
common AEs over the 3 years relating to the digestive system.

 Overall, these data support results of previous studies that concluded that
long-term donepezil therapy is well tolerated and that the incidence of AEs
decreases over time with treatment.

Winblad B, et al. 3-Year Study of Donepezil Therapy in Alzheimer’s Disease: Effects of Early and Continuous Therapy. Dement
Geriatr Cogn Disord 2006;21:353–363
 Donepezil in Moderate to Severe AD
3.2
p = 0.0001 p < 0.0001
3.4 Clinical
p < 0.0001 Improvement
LS mean score ± SE

p = 0.0008
in CIBIC Plus Score

3.6
p = 0.0004
3.8 p < 0.0001
4.0 No Change
4.2
4.4 Clinical
4.6 Donepezil Decline
Plasebo
4.8
0 4 8 12 18 24 Week 24
Study week LOCF
Donepezil n = 133 115 125 120 120 (140)
Placebo n = 137 119 129 127 126 (146)

 The Feldman’s Study (2001) in moderate to severe AD showed the

consistent benefit for Donepezil across the global function

Feldman. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s

diseaseNeurology 2001;57:613-620
 Donepezil in Severe AD

Global Function ( CIBIC Plus)

Colapsed-categories

n =325 5mg Vs Placebo, p=0,129

10mg Vs Placebo, p=0,001

 The Homma’s Study (2008) showed that Donepezil 10mg/d is effective for
improving global function in severe AD.

Homma. Donepezil Treatment of Patients with Severe Alzheimer’s Disease in a Japanese Population: Results
from a 24-Week, Double-Blind, Placebo-Controlled, Randomized TrialDement Geriatr Cogn Disord 2008; 25 :
 Caring for The Caregiver

A critical component of an AD patient’s treatment

plan is to ensure not only the patient but also the
caregiver/s.

One of the most important aspects of the AD patient’s

care is to ensure that the caregiver is taking care of
himself/herself.

Meyer JC, et al. Overview of Alzheimer’s disease and its management. S Afr Pharm J
2016;83(9):48-56
Benefit Donepezil for Caregiver

 Aricept reduces
caregivers’ burden
with less caregiving
time.

52,4 menit / hari.

Feldman. J Am Geriatr Soc. 2003;51(6):737-44.

 Bagaimana cara mencegah
kepikunan / demensia?

• KEPIKUNAN / demensia  tidak dapat

dicegah
• Tapi dapat diperlambat
kemunculannya..
UPAYA MENCEGAH ATAU MENUNDA
DEMENSIA
1. Pelihara Life Style / Gaya hidup :
- Olah raga teratur
- Pola makan yang sehat
- Membaca
- hindari merokok, minuman keras,
ketergantungan obat + zat adiktif

2. Kembangkan kegiatan yang menyenangi

Seni / Arts, dan hobby :
- Musik
- Lukisan
- Barang kerajinan
- Gardening
- Traveling
 7 SAVE YOUR MIND

1. Mind your Brain  use it or lose it

2. Mind your Body  Take Regular Physical Exercise
3. Mind your health checks 3H  Hypertension
Hypercholesterol
Hyperglicemia
4. Mind your diet  Avoid Fatty Foods and obesity
Eat Fish and Food rich anti oxydants

5. Mind your Habits  No Smoking , No Alcohol

6. Mind your Head  Protect from inquiry
7. Mind your Social life  Socialise regularly
 Take Home Message

 Earlier and continuous treatment in patients with mild to- moderate AD has
some beneficial effects on long-term disease development.

 The later stage of AD have to be treated in order to improve the quality of

patients and caregivers’ life and to delay the worsening symptoms of AD.

 Donepezil has shown the efficacy and safety profile for All stages of AD, BPSD
and the benefit for caregiver which is reduces caregivers’ burden with less
caregiving time.

 The long-term donepezil therapy, as a symptomatic treatment for mild-to-

moderate AD, is well tolerated and that the incidence of AEs decreases over
time with treatment. Donepezil also well tolerated in patients with severe AD
 Beta-amyloid Plaques
• dense deposits of βprotein and cellular
material that accumulate outside and around
nerve cells
Amyloid precursor protein (APP) is the
precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Enzymes cut the APP into fragments of
protein, including beta-amyloid.
3. Beta-amyloid fragments come together
in clumps to form plaques.

Beta-amyloid juga dijumpai pada geriatri

normal, tetapi tidak terkonsentrasi pada
korteks/limbik
Terapi Farmakologi

• inhibitor kolinesterase akan meningkatkan

kadar asetilkolin (takrin, donepezil, rivastigmin,
galantamin)
• Antagonis reseptor NMDA : Memantine
• Antioksidan dapat memperlambat progresivitas
penyakit ( Vit E, selegilin (MAO inhibitor))
• Alternatif terapi : ekstrak gingko biloba sebagai
neuroprotektif --- mengurangi kerapuhan kapiler,
efek antioksidan, dan menghambat agregasi
platelet tetapi masih perlu evidence yang lebih
banyak.