department of neurology דמנציה ומחלת אלצהיימר - 2014 alois alzheimer auguste d
TRANSCRIPT
Department of Neurology
2014דמנציה ומחלת אלצהיימר - Alois Alzheimer
Auguste D.
Department of Neurology
85שכיחות של אנשים מעל גיל
0.1 0.2 0.2 0.3 0.4 0.6 0.9 1.42.2
3
4.6
6.16.7
8.1
12.8
15.3
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050
YEAR
Prev
alen
ce >
85
yr in
mill
ions
Department of Neurology
שינויים מורפולוגיים במוח בזקנה
-1161 גרם ל- 1394ירידה במשקל המוח מ( )50-100ירידה במספר תאי העצב )נוירונים
ביליון( ירידה במספר הדנדריטים ובצפיפות הסינפסות נוכחות של רבדים )פלקים( סניליים המכילים
עמילואיד, ליפופוסצין, וברזל( ובחילוף %28ירידה בזרימת הדם המוחית )
החומרים המוחי בייחוד של גלוקוזשינויים בנוירוטרנסמיטורים מוחיים
Department of Neurology
Age
32 39 46 53 60 67 74 81 88
% P
erfo
rman
ce
0
20
40
60
80
100
inductive reasoningverbal meaningimmed recallword fluency
Normal Cognitive Decline With Age
Department of Neurology
שכחהפיזיולוגית
דמנציה)שטיון(
Department of Neurology
• Benign Senile Forgetfulness• Age - Associated Memory Impairment
AAMI• Age- Related Cognitive Decline - ARCD• Mild Cognitive Impairment - MCI• Pre Alzheimer’s Disease
שמות שונים לירידה פיזיולוגית בזיכרון
Department of Neurology
MILD COGNITIVE IMPAIRMENT- MCI- )Petersen, 1995()Petersen, 1995(
• Age above 50 Y.Age above 50 Y.• Subjective feeling of memory decline and slowingSubjective feeling of memory decline and slowing• Memory decline of 1.5 SD in objective evaluationMemory decline of 1.5 SD in objective evaluation• No dementia or function deteriorationNo dementia or function deterioration• Prevalence is ~16% over age 65Prevalence is ~16% over age 65• The rate of progression to AD 10-15% in a year !!The rate of progression to AD 10-15% in a year !!
Department of Neurology
Aging, AAMI (ARCD), MCI, and AD
Cognitive PerformanceCognitive Performance
FrequencyFrequency
YoungYoung
Adapted from Ferris and Kluger. Aging, Neuropsychology and Cognition, 1996.
ElderlyElderly
1 SD
A
B
ADAD MCIMCI AAMIAAMI
Department of Neurology
Longitudinal Course of MCI to AD
AAMI / ARCD
MCI
AD
Age
Cog
nitiv
e D
eclin
e
Department of Neurology
לדמנציהMCIשכיחות מעבר מ
MCI MCI AD 12%/yrAD 12%/yr Control Control AD 1-2%/yrAD 1-2%/yr
50
60
70
80
90
100
50
60
70
80
90
100
Initial 12 24 36 48exam Months
Initial 12 24 36 48exam Months
Department of Neurology
שטיוןDementia
הסתמנות קלינית המאופיינת באובדן •של יכולת קוגניטיבית ורגשית המביא להפרעה בתפקוד היום-יומי ובאיכות
החיים
Department of Neurology
Department of Neurology
Common Causes of Dementia
Alzheimer's 56.8%
Vascular 13.3%Other dementia 19.7%
Depression 4.5%
Alcohol 4.2%
Medication 1.5%
Department of Neurology
Vascular Dementia
Department of Neurology
Vascular Dementia
Multi Infarct Dementia
Hypoperfusion - Cardiac Arrest, S/P CABG Water-shade Infarction
Small Vessels Disease-Binswanger Disease
Department of Neurology
אבחנה מבדלת של דמנציה -מחלות זיהומיותSyphilis , HIV , PML -מחלות מטבוליותB12 Def , Hypothyroidism ,תרופותהרעלות, אלכוהול-מחלות אינפלמטוריות ווסקוליטידיות SLE , Sjogren PAN,
Sarcoid מחלות ממאירות - גליומה, לימפומה, גרורות -טראומה מוחית Chronic Subdural Hematoma -מחלות הפריוןCJD - Creutzfeldt-Jakob DiseaseNPH - Normal Pressure Hydrocephalus
Department of Neurology
Some Medications AreAssociated with Cognitive Decline
Anticholinergic Antiepileptic Benzodiazepines Barbiturates Narcotics H2 antagonists
(stomach upset)
β blockers Sympathomimetics
(bronchodilators) Digoxin Dopamine antagonists
(atypical antipsychotics) Dopamine agonists
Department of Neurology
אבחנה מבדלת של דמנציה -מחלות זיהומיותSyphilis , HIV , PML -מחלות מטבוליותB12 Def , Hypothyroidism ,תרופותהרעלות, אלכוהול-מחלות אינפלמטוריות ווסקוליטידיות SLE , Sjogren PAN,
Sarcoid מחלות ממאירות - גליומה, לימפומה, גרורות -טראומה מוחית Chronic Subdural Hematoma -מחלות הפריוןCJD - Creutzfeldt-Jakob DiseaseNPH - Normal Pressure Hydrocephalus
Department of Neurology
Normal Pressure HydrocephalusNPH
Hakim Triad:– Dementia
– Ataxia
– Incontinence
Department of Neurology
מחלת אלצהיימר
Department of Neurology
מחלת אלצהיימר - 80 מעל גיל 40 עד % 65 בגיל %5שכיחות
-בארץ100,000 מיליון חולים בארה”ב, 4כ
סיבה רביעית לתמותה בעולם המערבי
ביליון דולר 60הוצאות טיפול בחולים עד בארה"ב
Department of Neurology
Alzheimer’s Disease - Diagnostic Criteria According to DSM-IV
Memory impairment and at least
one of the following:
– Aphasia
– Apraxia
– Agnosia
– Disturbance in executive functioning
Significant impairment in social or occupational functioning.
Gradual onset and continuous cognitive decline.
No other CNS and systemic conditions that cause progressive deficit in memory and cognition.
No depression or schizophrenia.
Department of Neurology
Alzheimer’s Disease- Warning signs
Difficulty learning new information
Language problems
Problems with orientation
Difficulty performing complex tasks
Diminishing reasoning
Changes in personality, mood or behavior
Department of Neurology
גיל
נשים < גברים
גורמים גנטיים
השכלה נמוכה
מצב לאחר חבלת ראש
יתר ל”ד
עודף שומנים
מחלת לב איסכמית
גורמי סיכון למחלת אלצהיימר
Department of Neurology
Alzheimer’s Disease
Diagnostic Evaluation
Complete history
Physical and neurological examination
Neuropsychological examination
Selected laboratory tests
Neuroimaging
Laboratory Tests
CBC
Biochemistry
TSH
Vit - B12, Folic acid
VDRL, HIV
Department of Neurology
התמצאותזיכרון מיידיריכוז וחישובזיכרון לטווח קצר מרכיבי שפה
ניקוד מקסימלי - 30דמנציה <24
Complete history
Physical and neurological examination
Neuropsychological examination
Selected laboratory tests
Neuroimaging
Mini Mental State Examination
Alzheimer’s Disease
Diagnostic Evaluation
Department of Neurology
Folstein’s Mini-Mental State Inventory
Department of Neurology
31.8.98
8.3.99
18.10.99
ציורי שעון של חולת אלצהיימר
Department of Neurology
Clinical course of Alzheimer’s disease
Time (years)
0 1 2 3 4 5 6 7 8 9
MM
SE
0
5
10
15
20
25
30
early diagnosis mild-moderate severe
symptoms
diagnosis
dependence
behavioral problems
nursing home
death
Department of Neurology
Brain Atrophy in Alzheimer’s Disease
Normal Alzheimer’s
שיפוט
Normal Alzheimer’s
שפה
זכרון
שיפוט
שפה
Department of Neurology
Brain Atrophy in Alzheimer’s Disease
Department of Neurology
MRI in Alzheimer’s Disease
Department of Neurology
MRI and SPECT in AD
MRI
SPECT
MRI+SPECT
Department of Neurology
PET Scan in Alzheimer’s Disease
Department of Neurology
What Causes Alzheimer’s Disease ?
Vascular Trauma Toxic (e.g. Aluminum) Infection Free Radicals
Theories
Department of Neurology
Pathology of Alzheimer’s Disease
Neurofibrillary Tangles
Senile plaques
Department of Neurology
Pathology of Alzheimer’s DiseaseSenile Plaques Neurofibrillary Tangles
APP and Amyloid TAU
Department of Neurology
Amyloid and APP in Alzheimer’s Disease
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIAT
APP
Amyloid 1-43
Department of Neurology
Amyloid and APP Processing in Alzheimer’s Disease
Department of Neurology
Tau Protein in Neurofibrillary Tangles in Neurons
NFT
Department of Neurology
TAU protein in Alzheimer’s Disease
Proline-Rich Flanking Domain
1 2 3 4H2N COOH
* *** * *1 441
Microtubule-associated protein- MAP
1-4 Repeat domains- binding to microtubule
*- Phosphorylation sites in AD
Department of Neurology
Abnormal Metabolism of Tau in Alzheimer’s Disease
Department of Neurology
Biological Markers for Diagnosis of Alzheimer’s Disease
Total TAU protein levels in CSF A1-40 and A1-42 levels in CSF Phosphorylated Tau (P-Tau) in CSF Tau - A1-42 Index
Melanotransferrin (P97) in Serum Neuronal thread proteins in Serum
Department of Neurology
Amyloid Scan with PET or MRI or SPECT
Klunk et al.University of Pittsburgh
School of Medicine Ann Neurol 4.2004
Department of Neurology
גנטיקה של מחלת אלצהיימר
Department of Neurology
Genetic of Alzheimer’s disease
TTTyyypppeee CCChhhrrrooommmooosssooommmeee GGGeeennneee PPPrrroooddduuucccttt AAAgggeee
AD1 222111 AAAPPPPPPmmmuuutttaaatttiiiooonnnsss
555000sss
AAADDD222 111999 AAApppoooEEE---eee444pppooolllyyymmmooorrrhhhiiisssmmm
666000sss aaannndddooollldddeeerrr
AAADDD333 111444 PPPrrreeessseeennniiillliiinnn 111mmmuuutttaaatttiiiooonnnsss
444000sss aaannnddd555000sss
AAADDD444 111 PPPrrreeessseeennniiillliiinnn 222mmmuuutttaaatttiiiooonnnsss
555000sss
Department of Neurology
Genetic Loci of Alzheimer’s Disease
Department of Neurology
7878%%
7%7%
1515%%
APO E POLYMORPHISM
Department of Neurology
Apolipoprotein E and Alzheimer’s Disease
Genotype Frequency E3E3 60% E3E4 27% E3E2 10% E4E4 2% E2E2 <0.05%
ApoE4 Allele Frequencies)%( Normals LOAD EOAD
15% 42% 19% 1 ApoE1 ApoE4= 2.2-4.4 Increased Risk for AD 4= 2.2-4.4 Increased Risk for AD 2 ApoE2 ApoE4= 5.1-17.9 Increased Risk for AD4= 5.1-17.9 Increased Risk for AD
Department of Neurology
Apolipoprotin E 4 effect in Alzheimer’s Disease
Department of Neurology
Genetic Loci of Alzheimer’s Disease
Department of Neurology
DOWNהקשר בין תסמונת ( ומחלת אלצהיימר21)טריזומיה
Department of Neurology
Genetic Loci of Alzheimer’s Disease
Department of Neurology
APP Mutations Causing Alzheimer’s Disease
Department of Neurology
Genetic Loci of Alzheimer’s Disease
Department of Neurology
Presenilin Mutations in Alzheimer’s Disease
Department of Neurology
The Amyloid Theory
Amyloid
APP Mutations Head Trauma
Presenilins Mutations
Trisomy 21
OxidativeStress
ApoEe4 Tau Tau + Pi
Tangles
Plaques
Department of Neurology
The Amyloid Theory
Amyloid
Senile PlaquesNeurofibrillary Tangles
Tau Tau + P
Neuron Death
Alzheimer’s Disease
Cerebral CortexBasal Forebrain
Neurotransmitter Deficits (Ach)
Department of Neurology (Cummings JL. 2004)
Amyloid β mechanisms in Alzheimer’s Disease
Department of Neurology (Cummings JL. 2004)
Amyloid β mechanisms in Alzheimer’s Disease
Department of Neurology
תודה רבה
Department of Neurology
• Prevention • Cure• Delay disease progression• Reduce behavioral abnormalities• Reduce disability• Reduce caregiver distress• Delay nursing home placement
Therapy in Alzheimer’s Disease: Goals
Department of Neurology
המחיר הכלכלי של מחלת אלצהיימר Mild AD- 18,408 $/ patient per year Moderate AD – 30,096 $/ patient per year Severe AD – 36,132 $/ patient per year
Prevention of 2 point decline in MMSE– Save 3,700 $/patient per year
Improvement of 2 point in MMSE-– Save 7,000 $/patient per year
Department of Neurology
Treatment Outcomes in Alzheimer’s Disease
Time
Fu
nc
tio
nal
ab
ility
Slowing of diseaseprogressionTreatment
Symptomaticbenefit
Maintenance of function
Cure
Natural Progression
)Ferris, 8/03(
Department of Neurology
Pharmacological Therapy
Therapeutic Strategies in Alzheimer’s Disease
Supportive - Non Pharmacological Therapy
Department of Neurology
Amyloid Production and Aggregation
Pharmacological Therapy in
Alzheimer’s Disease
Disease Specific
NeuroprotectionNerve Cell Death
Cholinergic DrugsNeurotransmitter Deficits
Cognitive and behavioral
disturbances
Psychotropic Drugs
Department of Neurology
Anti-Amyloid Therapy
Prevention of Amyloid deposition:– Amyloid Immunization – Secretase Inhibitors
Dissolving of Amyloid: Organic Solvents Reducing of Amyloid Damage:
– Anti Apoptotic Agents– Anti Oxidants– Nerve Growth Factors – Inhibitors of Tau Phosphorylation
Department of Neurology
טיפולים נסיוניים במחלת אלצהיימר-חיסון ע"י בטא-עמילואיד
Transgenic “AD” mouseover-expressing APP with FADlinked codon 717 mutation
With increasing agedevelops extensiveamyloid deposits
Age 13months,cognitivedecline,neuronalpathology
Immunized at 6 weeks with A1-42
Develops antibodiesagainst A1-42
Normalold age,no amyloiddeposits
Schenk et al. Nature 400: 173-177, 1999
Department of Neurology
Immunization with a-beta in Alzheimer’s disease Treatment
Schenk D et al. 1999- Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
Janus C et al. 2000- A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.
Department of Neurology
חתכי רקמה בהיפוקמפוס של עכברי הניסוי
ללא חיסון
עם
42A β
חיסון עם
42A β
Department of Neurology
Clinical effects of Aβ immunizationin patients with AD in- an interrupted trial S. Gilman et al. , for the AN1792)QS-21(-201 Study Team* NEUROLOGY 2005;64:1553–1562
Double blind study – 300 P Aβ 72 control Most patients received 2 injections out of 6 59 )19.7%( developed the predetermined
antibody response 18 patients out of 300 )6%( developed
severe meningoencephalitis
טיפולים נסיוניים במחלת אלצהיימר-חיסון ע"י בטא-עמילואיד
Department of Neurology
Elan AD Vaccine Clinical Trial
Trial was suspended As some predicted, a major problem was
vaccine toxicity 15 patients out of about 360 developed
“cerebral inflammation” These complications were likely related
to direct or indirect A1-42 toxicity
)Wisniewski, 8/03(
Department of Neurology
Secretases Inhibition in Alzheimer’s disease Treatment
(Koo et al. 2002)
Department of Neurology
Nerve Cell Death
Neuroprotection in Alzheimer’s Disease
Anti-Oxidants:
– Vitamin E
– Selegiline
– Ginko Biloba
Anti Inflammatory:
– NSAIDS
– Prednisone
Anti-Exitatory:
– Anti glutamate Memantine (Ebixa)
Department of Neurology
Treatment of Mild Cognitive Impairment Patients
פעילות מוחית: קריאה, משחקי מחשבה, נגינה, ריקודפעילות גופנית תזונה נכונההורדת כולסטרולהורדת יתר ל”דהורדת גורמי סיכון למחלות לב? נטילת חומצה פולית?נטילת תרופות נוגדי דלקת
Department of Neurology
The Cholinergic Theory Cholinergic deficit
progressive loss of cholinergic neurones
progressive decrease in available ACh
impairment in ADL, behaviour and cognition
Hippocampus
Cortex
N. basalis Meynert
Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978
Department of NeurologyACh receptors
CholineAcCoA
The Cholinergic Synapse
Presynaptic
Postsynaptic
ACh
ACh-Esterase
ACh
A Ch
Cholinomimetics
Muscarinic agonists
Nicotine
Precursors:
Phosphatidylcholine
Phosphatidylserine
ACh-E InhibitorsACh
Department of Neurology
Cholinergic Drugs
Acetyl Choline Esterase Inhibitors• Donepezil (Aricept)
(Memorit)
(Asenta)• Rivastigmine (Exelon)• Galantamine )Reminyl(• Tacrine )Cognex(
• Metrifonate (Pro-Mem)• Physostigmine (Synapton)
Department of Neurology
The A.B.C. of Alzheimer’s Disease Treatment
Improvement in 3 key domainsImprovement in 3 key domains
AAActivity of Activity of Daily livingDaily living
BBBehaviorBehavior
CCCognitionCognition
Department of Neurology
The A.B.C. of Alzheimer’s Disease Treatment
Improvement in 3 key domainsImprovement in 3 key domains
AAActivity of Activity of Daily livingDaily living
BBBehaviorBehavior
CCCognitionCognition
Department of Neurology
Department of Neurology
*p<0.05 Exelon® vs placebo**p<0.01 Exelon® vs placebo***p<0.001 Exelon® vs placebo Doraiswamy et al., 2000
0 13 26 39 52
–4
–2
0
2
4
6
8
Study week
AD
AS
-Co
g m
ean
ch
ang
e f
rom
bas
elin
e
6–12 mg/day Exelon® 1–4 mg/day Exelon® Placebo
All patients receive Exelon®
*
*** ********
* ****
Long-Term Effects of Exelon® on Cognition Over 52 Weeks in Patients With More Advanced
Disease )GDS 5(
Department of Neurology
Cholinomimetic Treatment in Alzheimer’s Disease
Department of Neurology
Cholinergic Treatment in AD
Department of Neurology
Cholinergic Drugs
MMSE
TimeStart Tx 6 mo
AChEI Effect
No Tx
2 yr
Department of Neurology
The A.B.C. of Alzheimer’s Disease Treatment
Improvement in 3 key domainsImprovement in 3 key domains
AAActivity of Activity of Daily livingDaily living
BBBehaviorBehavior
CCCognitionCognition
Department of Neurology
Department of Neurology
Item Mild Moderate Moderately severe
Ability to handle money
Ability to tell time
Time spent on hobbies
Participation in family finances
Reduced forgetfulness
Time rearranging objects
Ability to dress properly
Ability to use phone
Confusion in different settings
Proper eating manners
Messina et al., 2000
Significant improvement for Exelon® 6–12mg/day vs placebo. Pooled OC data
AD
ADL showing 10% Improvement Following Exelon® Treatment
Department of Neurology
The A.B.C. of Alzheimer’s Disease Treatment
Improvement in 3 key domainsImprovement in 3 key domains
AAActivity of Activity of Daily livingDaily living
BBBehaviorBehavior
CCCognitionCognition
Department of Neurology
Amyloid Production and Aggregation
Neurotransmitter Deficits
Cognitive and behavioral disturbances
Nerve Cell Death
Psychotropic Agents
• Anti-Psychotics• Anti-Agitation Agents
– Barbiturates– Anti-Epileptics
• Anti-Depressants
Department of Neurology
Ag
itat
ion
Irri
tab
ilit
y
An
xiet
y
Ab
err.
mo
tor
beh
avio
ur
Ap
ath
y
Dep
ress
ion
Del
usi
on
Dis
inh
ibit
ion
Hal
luci
nat
ion
s
Eu
ph
ori
a
Nig
ht-
tim
eb
ehav
iou
r
Ap
pet
ite
**
*
**
**
**
*
***
NP
I-N
HM
ean
ch
ang
e fr
om
bas
elin
e –4.0
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0
Cummings et al., 2000*p<0.05 vs baseline; **p<0.001 vs baselineStudy B452, OC analysis
Imp
rove
men
t
Effects of Exelon® on Behaviour Following 26 Weeks of Treatment
Department of Neurology
• Financial and Legal Consulting
• Care-giver Support Group
• Alzheimer’s Disease
Association
• Day Care Programs
• Home Care Programs
Alzheimer’s Disease –
Non-Pharmacological Therapy
Department of Neurology
תודה רבה
Department of Neurology
Glutamate Hypothesis of Cognitive Deficit
Neuronal damage/lossNeuronal damage/lossfollowing chronic insultfollowing chronic insult
Abnormal glutamatergic activity leads to Abnormal glutamatergic activity leads to sustained low-level activation of NMDA receptorssustained low-level activation of NMDA receptors
Cognitive deficitCognitive deficit
Source: Danysz W, et al. Neurotoxicity Res. 2000;2:85-87. Orgogozo JM, et al. Stroke. 2002;33:1834-1839.
Department of Neurology
Antiglutamatergic treatment in Antiglutamatergic treatment in Alzheimer’s DiseaseAlzheimer’s Disease
MEMAMTINE
Department of Neurology
ffect of Memantine on ADL Function: ADCS-ADLsev
Tariot et al 2004
Memantine
Placebo
*p<0.05
* * Imp
rov
em
en
tW
ors
en
ing
*
*
n=198
n=197
n=198
n=195
n=190
n=182
n=185
n=170
n=181
n=163
n=172
n=152
*
*
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
0 4 8 12 16 20 24
Week
AD
CS
-AD
Lse
v s
co
re
dif
fere
nc
e (±
SE
M)
Department of Neurology
Brain Cholinergic System
Department of Neurology
The Cholinergic Deficit Theory
Amyloid Production and Aggregation
Neurotransmitter Deficits
Cognitive and behavioral disturbances
Nerve Cell Death
Septum and DBB
Basal nucleus
Department of Neurology
Revised Petersen Criteria )2004(
Department of Neurology
Apolipoprotein E and Alzheimer’s Disease
Department of Neurology
COGNITIVE REHABILITATION IN EARLY-STAGE DEMENTIA: Linda Clare, University College London
• Aims to increase orientation and improve cognitive and behavioural functioning through cognition-based activities, social interaction and discussion, combined with use of cues and prompts to assist in remembering• Mainly offered in group format • Usually targets people with early-stage dementia• Cochrane review - 6 RCTs. Significant improvements in cognition, though not in all studies; weaker evidence for positive impact on behaviour.
Department of Neurology
Aging, AAMI )ARCD(, MCI, and AD
Department of Neurology
Preventive treatments currently under investigation
Inhibitors of GSK3 (e.g. Lithium, Valporate)
Vitamin E and antioxidants (supported by clinical studies)
Metalchelators (e.g. Clioquinol gives positive effects in clinical trials)
Antiinflammatory agents (ADAPT – Cox2, Propentofyline )
Cholesterol metabolism modifiers (e.g. Statins; variable results)
Ginkgo biloba (GEM, very weak, if any effect)
Neurotrophic factors
Department of Neurology
Davis et al 2001
5 weeks of individual, weekly sessions plus home practice
Face-name associations; spaced retrieval for personal info; peg task; attention
Significant improvement in face-name association learning and personal info cf placebo
De Vreese et al 1998
Twice weekly indiv sessions for 12 weeks plus home practice
Cognitive training
CT + AChEI > CT alone > AChEI alone > placebo on ADAS-Cog
Quayhagen et al 1995, 2000
One hour per day of practice directed by caregiver, 6 days per week, for 8 or 12 weeks
Memory, conversational fluency, problem-solving - tasks related to daily life
Significant improvement on Dementia Rating Scale and tests of memory, verbal fluency and problem-solving
Heiss et al 1993
Two sessions per week for 24 weeks
Computerised cognitive training
CT = social support placebo
Cognitive training in early-stage dementia: RCTs
Department of Neurology
Symptomatic Trials in MCI
Agent Endpoint No Duration Result
Donepezil
Vit E
NYU DPR
270 6 mo No
Saegis 742- GABA
Hopkins VLT
110 2 mo No
Piracetam Co.C.Bat 675 12 mo No
Ampakin 160 4 w ?
Department of Neurology
Prevention Trials in MCI
Agent Endpoint No Duration Result
Donepezil
Vit E
ADCS-MCI
AD 769 3 Y Pos-12m
Neg 36 m
Rofecoxib
PRAISE
AD 1453 4 Y Neg, Placebo
Rivastigmine
InDEx
AD 1018 4 Y Neg
Galantamine AD 995 2 Y Neg
Galantamine AD 1052 2Y Neg
Department of Neurology
2002- Human clinical study was stopped due to side 2002- Human clinical study was stopped due to side effects !!effects !!
Department of Neurology
Prevalence of four major types of dementia
AD
VaD
DLB
FLD
Other60%
5%5%
15%
15%
Pure DLB 3%FLD
Other
DLB with AD, 12%
Mixed VaD and AD, 10%
Pure VaD 5%
Department of Neurology
Brain Areas involved in Alzheimer’s Disease
Department of Neurology
הקשר בין רמות כולסטרול ומחלת אלצהיימר
-טיפול בתרופות מורידות כולסטרול )סטטיניםסימוביל, ליפידל( מוריד שכיחות של מחלת
אלצהיימר טיפול בתרופות מורידות כולסטרול בחיות הוריד
את כמות החלבונים הפתולוגיים במוח החולים
Department of Neurology
שכיחות של ירידה קוגניטיבית עם עלית הגיל
65-74 75-84 85+0
20
40
60
80
100 severe moderate mild
Age Group (years)
% o
f pop
ulat
ion
Department of Neurology
הקשר בין נטילת אסטרוגנים ומחלת אלצהיימר
שכיחות מחלת אלצהיימר גבוהה בנשים כמעט מאשר בגברים2פי
עבודות ראשונות טענו שנטילת תחליפיאסטרוגן מורידה את השכיחות של מחלת
אלצהיימר לאחרונה פורסם שנטילת אסטרוגן דוקא
מגבירה הסיכון למחלת אלצהיימר כמו למחלות כלי דם ולסרטן
Department of Neurology
הקשר בין השכלה ומחלת אלצהיימר
0
5
10
15
20
25
30
Per
cent
age
of A
D p
ati e
nts
יסודית
תיכונית
על תיכונית
Department of Neurology
מחקר הנזירות
Department of Neurology
EDr. David Snowdon, University of Dr. David Snowdon, University of KentuckyKentucky1986- Today1986- Today
מחקר הנזירות
Department of Neurology
פעילות מוחית למניעת מחלת אלצהיימר
מספר רב של עבודות ברחבי העולם הראו שהשתתפות בפעילות מוחיתכגון:
קרי אה–משחקי קלפים וקופסא–
נגינה–
ריקוד–
היתה בקורלציה עם ירידה בשכיחות של מחלת אלצהיימרהיתה בקורלציה עם הקטנה בירידה בזיכרון באנשים בריאים
"Use it or lose it" "Use it or lose it"
Department of Neurology
הקשר בין מחלות לב ומחלת אלצהיימרמה שגרוע ללב - גרוע למוח
מחלת כלי דם כליליים–יתר לחץ דם–סכרת–כולסטרול גבוה–עישון–אלכוהול בכמות גדולה–הומוציסטאין גבוה )חסר חומצה פולית(–
Department of Neurology
הקשר בין חבלות ראש ומחלת אלצהיימר
הנתונים אינם מוחלטים ברוב העבודות אכן יש קשר בין היסטוריה של
חבלת ראש בעיקר אם היה איבוד הכרה ממושך לבין עליה בשכיחות מחלת אלצהיימר
נבדק גם בנפגעי ראש בפעולות צבאיות- חיילים משוחררים מוייטנאם
Department of Neurology
הקשר בין תרופות נוגדות דלקת ומחלת אלצהיימר
NSAIDתרופות נוגדות דלקת מסוג חולים הסובלים מכאבי פרקים
ירידה בשכיחות של מחלת אלצהיימר
Department of Neurology
MCIסוגי Amnestic Alzheimer’s DiseaseAmnestic Alzheimer’s Disease
Multiple Domain Alzheimer’s DiseaseMultiple Domain Alzheimer’s Disease
Vascular DementiaVascular Dementia
Normal AgingNormal Aging Single non-memory FTDSingle non-memory FTD
Domain DLBDDomain DLBD
PPAPPA
Alzheimer’s Disease Alzheimer’s Disease
Department of Neurology
Hachinski’s Score in Vascular Dementia
Abrupt onset of dementia 2 Stepwise deterioration 1 Somatic complaints 1 Emotional incontinence 1 Hypertension )past or present( 1 History of stroke 2 Focal neurological symptoms 2 Focal neurological signs 2
Total Score > 4 Vascular Dementia
Department of Neurology
fMRI in Alzheimer’s Disease