Abdul Gofir

Bagian Neurologi FK-UGM

Klinik Memori & Unit Stroke
RS Sardjito
 The word dementia is used to describe the condition where
one has a progressive decline in memory and other
cognitive functions that results in a change in the ability to
conduct one's usual activities
 Dementias are neurodegenerative diseases which cannot
be cured
 Each type characterized by specific effects on cognitive
and motor function
 Diagnosis of dementia is not generally given in absence of
impairment in social functioning and independent living.
 Dementia seriously affects a person’s ability to carry out
daily activities
 People with dementia lose their abilities at different rates
 Eventually, patients may need total care
Dementia symptoms may include:
 asking the same questions repeatedly,

 becoming lost in familiar places,

 being unable to follow directions,

 getting disoriented about time, people, and

places, and
 neglect of personal safety, hygiene, and
nutrition.
◦ 50 - 70% of dementias are due to AD
◦ Probable AD - 30% of cases, 90% neuropath - correct
 20% have other contributing diagnoses
◦ Possible AD - 40% of cases, 70% are AD at neuropath
 40% have other contributing diagnoses
◦ Unlikely AD - 30% of cases, 30% are AD at neuropath
 80% have other contributing diagnoses
◦ Alzheimer’s disease is a pathological condition
◦ Dementia is a clinical condition frequently caused by AD
 The AD dementia has some characteristics and some
heterogeneity
 Mild Cognitive Impairment
Petersen RC

 Memory complaint corroborated

by an informant
 Normal general cognitive
function
 Normal activities of daily living
 Memory impairment in relation
to age and education
 Not demented
Transitional state between the cognitive changes of
normal aging and the fully developed features of
dementia
Peterson, RC. Seminars in Neurology 2001;27(1):22-31

Original Criteria
Memory complaint, preferably qualified by an informant
Memory impairment for age and education
Preserved general cognitive function
Intact activities of daily living
Not demented
Adapted from Reisberg B et al. Am J Psychiatry
1982;139:1136-1139
 PSP & related disorders  Infections
 Huntington’s ◦ HIV
 Post-anoxic ◦ Syphilis
 NPH ◦ Lyme’s
 B12 ◦ CJD
 Hypothyroidism  Encephelopathy
 Hypercalcemia ◦ Uremic
◦ Hepatic
 Alcohol/thiamine
Mild cognitive
impairment Alzheimer’s disease
Amnestic

Mild cognitive
impairment Alzheimer’s
Multiple domains disease
slightly impaired
? normal aging

Frontotemporaldementia
Mild cognitive Lewy body dementia
impairment Primary progress. aphasia
Single non- Parkinson’s disease
Alzheimer’s disease
memory
domain
 MCI: Conversion to AD

Longitudinal studies Year Conversion rate

follow-up to AD (%)

MCI Normal

Petersen et al 1999* 4 12 1-2

Kluger et al 1999 6-7 67.2 11.9
Rubin et al 1989 3-7 69
Flicker 1991 2 71.9
Wolf et al 1998 2.7 19.8
Petersen et al 1995 4.5 55
Grundman et al 1996 3 44

* Rate per year

 Clinical features
◦ presence of any quantifiable abnormalities
beyond memory
◦ Test of delayed verbal recall and executive
functions
 Apolipoprotein E4 genotype
 Neuroimaging (hippocampal volumes)
 PET (alterations in entorhinal cortex
and/or posterior cingulate cortex)
 CSF levels of A-beta, Tau Protein
   perfusion1
◦ hippocampal-amygdaloid
◦ posterior cingulate
◦ anterior thalamus
◦ anterior cingulate
 No predictors2
  Ratio between CFS tau and blood flow in the
posterior cingulate3

1Johnson et al, 1998; 2McKelvey et al, 1999; 3Okamura et al, 2002

  beta-amyloid
 ↑ protein Tau
  APP Ratio in platelets

Andreasen et al., 2000; Riemenschneider et al., 2003;

Rosenberg et al, 2000; Di Luca et al, 2003; Borroni et al,
2004)
 Prevalensi Alzheimer cenderung meningkat
sejalan dengan usia harapan hidup.
 Disabilitas dan mortalitas merupakan masalah
utama
 Alzheimer merupakan penyakit degeneratif yang
utama, 2/3 dari demensia.
 Faktor risiko meliputi faktor genetik dan
nongenetik
(Lindsay, et al. 2004, Harvey 2003, Hacker 2004, Hendrie, 1998).
Insidensi
meningkat sesuai
harapan hidup
(Nussbaum and Ellis,
2003)
 Suatu sindrom penurunan intelektual progresif
yang menyebabkan deteriorasi kognisi dan
fungsional.
 Menganggu gangguan fungsi sosial, pekerjaan
dan ADL (AAzI, 2003)
 Diagnosis definite, probable dan posible
(NICDS-ADRA)
tangles

plaques
 Memori kumpulan beberapa kemampuan
mental, melibatkan beberapa sistem yang otak
 Sistem memori : episodik, semantik, prosedural
dan working memori
 Bersifat eksplisit, deklaratif atau implisisit,
nondeklaratif

(Budson and Price, 2005).

 Mutasi amyloid precursor protein (APP)
 Presenilin
 Apolipoprotein
 Protein tau
 Apolipoprotein E
 Pasien Trisomi 21 dewasa berkembang menjadi
Alzheimer
 Mutasi amyloid precursor protein (APP) pada
kromosom 21 pd Alzheimer onset awal
 Peningkatan degradasi produk peptida Aß 1-42

(Mulder, et al., 2000)

 APP merupakan protein trans membran, 770
asam amino, fungsi belum diketahui
 Dipecah oleh enzim α, β dan γ secretase
 α secretase menghasilkan short Aβ40 yang non
toksik
 β secretase menghasilkan peptida amyloid β1-
40
 γ secretase menghasilkan amyloid β1-42
(Nestler, et al., 2001)
 Kerusakan neuron oleh Aß 42-43 dalam bentuk
insoluble/agregat
 Antigen bagi mikroglia (foreign bodies)
 Respon berlebihan mikroglia menyebabkan
proses neurotoksik dan inflamasi
(Nestler, et al., 2001)
Rute mutasi gen pada penyakit Alzheimer

(Nestler, et al., 2001).

 Alzheimer onset awal, kromosom 14 dan 1, terdiri
467 asam amino
 65% presenillin 1 sisanya presenilin 2
(Martin, 1999).
 Fungsi presenilin
◦ Transduksi signal bersama APP, traficking protein,
pemecahan kromosom
◦ Deferensiasi neuron dan mendeteksi protein plasma
◦ Mengatur apoptosis, homeostasis intraseluler, stabilisasi
cytoskeleton dan adhesi sel
(Shastry, 2001)
 Mutasi gen presenilin berhubungan dengan
peningkatan Aβ 42-43
 Kofaktor γ secretase
(Nestler, et al., 2001)

 Peningkatan Aβ 42-43 ditemukan pada

Alzheimer dengan mutasi PS-1 dn PS-2
(Stege and Bosman, 1999)
 apoE memiliki 4 allele ε2, ε3 dan ε4
 ε4 pada kromosom 19 meningkatkan Alzheimer
onset awal dan sporadis, meningkatkan bentuk
solubel Aβ1-40 menjadi insoluble
 ε2, ε3 memiliki efek penghambatan amyloid
patologis
 13-19% populasi

(Martin, 1999; Stege and Bosman, 1999).

 Fenotipe apoE terlibat dalam transpor kolesterol
dan mengikat Aβ shg mencegah agregasi toksik
 Peningkatan lipid perifer, penurunan
metabolisme glukosa otak, aktifasi glia,
inflamasi dan stress oksidatif, penurunan
pembersihan Aβ dan pemebentukan NFT

(Lane and Farlow, 2005)

 Phosphoprotein mikrotubulus penyusun NFT
 Fungsi
◦ Pertumbuhan neurit, stabilisasi mikrotubulus dan
melindungi neuron dari Aβ yang merusak cytoskeleton
◦ Polimerisasi dan stabilisasi axon
 Penderita Alzheimer diredistribusi ke dalam
filmen helix dalam bentuk distropic neurit shg
terjadi gangguan rangka

(Stege and Bosman, 1999)

 Proses neuropatologi, plak amyloid dan NFT
menemukan sedikit hubungan dengan tingkatan
gangguan kognitif
 Disfungsi sinaps merupakan proses patologis
dengan penurunan kognitif
 Proses disfungsi terjadi sebelum kematian sel
 Berawal di kortek transentorhinal/entorhinal dan
di dentrit
(Coleman, et al., 2004).
 Penurunan densitas dan kapasitas sinaps
Alzheimer
 Disfungsi sinaps menyebabkan defek sintesis
neurotransmiter, transpor, reuptake dan release
 Defek metabolisme APP mengawali disfungsi
sinaps karena APP bertanggung jawab pada
stabilisasi sinaps

(Coleman, et al., 2004).

 Kaskade APP C terminal memicu respon
inflamasi
 Peningkatan aktifitas dan ekspresi asetilkolin
esterase
 Peningkatan forforilasi tau
 Penurunan synaptophysin
 Penurunan fungsi sinaps
 Jalur kolinergik berasal dari forebrain, rostral
forbrain, talamus
 Disintesis oleh acetyl Coa dan choline, dgn
reseptor nikotinik presinaps, muskarinik (M2)
dan post sinaps (M1)
 Alzheimer terjadi kehilangan neuron kolinergik di
nukleus basalis Maynert dan nukleus subkortikal
(Gauthier, 2003)
Proyeksi neuron kolinergik dari nukleus basalis
Maynert dan septum pelucidum ke hipokampus dan
neokortek (Gauthier, 2002).
 Deposit Aß dapat mengganggu fungsi sinaps
kolinergik dengan adanya gangguan uptake
choline, pelepasan asetilkolin, ekspresi reseptor
nikotinik/muskarinik dan disfungsi neurotropin

(Terry and Buccfusco, 2003), (Yang and Feng, 2004)

 Diet tinggi karbohidrat, rendah EFA dengan
modulasi apoE, penurunan lipoprotein lipase
dan penghambatan EFA ke glia dan neuron
 Kerusakan oligodendrosit pada Alzheimer
menganggu metabolisme kholesterol,
meningkatkan ion Fe yang memacu stress
oksidatif

(Lane and Farlow, 2005)

 Possible Alzheimer’s disease
◦ Fulfillment of the above criteria with variation in the onset of
symptoms or manifestations or in clinical course; or a single, but
gradually progressive, cognitive impairment without an identifiable
cause
◦ Another brain disorder or systemic disease that is sufficient to
produce dementia, but that is not considered to be the underlying
cause of the dementia in the patient
 Definite Alzheimer’s disease
◦ Fulfillment of the above clinical criteria and histologic evidence of
Alzheimer’s disease based on examination of brain tissue obtained
at biopsy or autopsy

(NINCDS-ADRDA)
 Characterized by the abundance of extracellular neuritic
(senile) plaques (NP) and intracellular neurofibrillary
tangles (NFT)
◦ The NP contain deposits of b-amyloid peptide (Ab) –
primarily found as star shaped masses of amyloid fibrils
◦ The NFT are primarily composed of a
hyperphosphorylated, microtubule-associated protein
called tau
◦ Neither NP nor NFT are specific for AD
 Massive neuronal loss occurs in hippocampus, frontal and
temporal cortices thought to be due to toxic action of NFT
and NP
 Contain b amyloid deposits – two
forms:
◦ Ab42 –prone to aggregate
◦ Ab40 – predominant form Ab

 Contain apolipoprotein E (ApoE),

another Alzheimer’s susceptibility gene

 Dystrophic neurons : within the plaque

and surrounding it – neurons are
dilated and contain numerous
abnormalities

 Associated with activated microglia and

reactive astrocytes

 Probably evolves gradually over a

substantial period of time
• The tau is
hyperphosphorylated
• Not known which kinases
are responsible for
initiating the
hyperphosphorylation
• The tangles may
represent a cytological
response to the
accumulation of Ab

www.rndsystems.com
tangles

plaques
  Large, nonmembrane bound
bundles of abnormal fibers
contained in neurons from
brain regions typically affected
in AD
 Consist of pairs of filaments
wound into helices (paired
helical filaments – PHF)
 Composed of microtubule-
associated protein tau

Neurofibrillary tangles
 CSF : total tau and amyloid beta1-42 (Ab42) 
improve diagnosis accuracy

Parnetti,l.et al. Neuro Sci 24:3:199-200,2003

CSF/phospho-tau  sensitivity 85,2% & specificity 85,0%- AD bio-

marker

Increase Ab42 – >70% MCI  later developed AD

A combined CSF-tau and IMSPECT  predict transition MCI to AD

Arai, Nippon Ronen Igakkai zasshi,40:22-6, 2003

 Tau Have Diagnostic
 Phospho-tau sensitivity and specificity
at pre-D stage
 Beta amyloid

 ApoE  is not a useful as a diagnostic test

 Mutations in APP gene and PS genes
 PCR
 Sequencing
 AD is the results of the formation of amyloid β peptide
(Aβ42) neurotoxic loss of mental function
 Transgenic model: express DNA encode the protein
brain plaques similar to AD
 Combination of Vaccination with amyloid β peptide and
immunotherapy with a humanized monoclonal antibody
 most plaques disappeared (Qu,et al 2003)
 DNA-Vaccination (amyloid gene): gene gun and gene
vaccination (Johnston et al. 2004)

www.hum-molgen.org: Dec 21,2004