dementia vs delirium acad of med, 21st april
TRANSCRIPT
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Dr Yau Weng KeongGeriatric Unit, Department of Medicine
Hospital Kuala Lumpur
Dementia VsDelirium
http://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://reginanuzzo.com/wp-content/digitalbrain_01.jpg&imgrefurl=http://reginanuzzo.com/%3Ftag%3Dalzheimers&usg=__CAMuf1VKbk6QHBY2UWM9waKoFqs=&h=1063&w=876&sz=225&hl=en&start=8&tbnid=BDPXuiJy6DUYzM:&tbnh=150&tbnw=124&prev=/images%3Fq%3Dalois%2Balzheimer%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://www.affordable-home-care.com/images/AloisAlzheimer.jpg&imgrefurl=http://www.affordable-home-care.com/alzheimers.html&usg=__qF8x2NxMk90torrb_y2n_CbjCYI=&h=241&w=200&sz=14&hl=en&start=7&tbnid=lSE0QpcMrjOZXM:&tbnh=110&tbnw=91&prev=/images%3Fq%3Dalois%2Balzheimer%26gbv%3D2%26hl%3Den -
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
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World is Ageing!
DEMOGRAPHIC
TIME BOMB
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How common is dementia?
Age group(years)
Meta-analyses
Jorm et al, 1987 Hofman et al, 1991 Ritchie et al, 1992 Ritchie & Kildea,1995
6064 0.7 1.0 0.9
6569 1.4 1.4 1.6 1.5
7074 2.8 4.1 2.8 3.5
7579 5.6 5.7 4.9 6.8
8084 10.5 13.0 8.7 13.6
8589 20.8 21.6 15.5 22.3
9094 38.6 32.2 24.5 31.5
9599 34.7 36.7 44.5
Prevalence rates (%) of dementia in people aged 60 years ofage and older as assessed in four meta-analyses
Jorm et al 1987; Hofman et al 1991; Ritchie et al 1992; Ritchie & Kildea 1995
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Prevalence of dementia andcognitive impairment in Malaysia
There have been few prevalence studies of dementia in Malaysia.
Community
Authors Cognitive Impairment Dementia
Krishnaswamy et al, 1997 6%
Fadhilah et al, 1996 6%
Sherina et al, 2004 24%
Aizan et al, 2003 14.4%
Long Tern Care
Hasanah et al, 1996 45%Al-Jawad et al, 2008 36.5%
National Health and Morbidity Survey (NMHS-III, 2006) - 19.5%
(aged 70-74 years) mental health problems
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Alzheimers disease -Estimated impact on US businesses
Itemizing the Impact
Caregivers
Caregiver absenteeismProductivity lossReplacement of caregivers who leaveContinuing insurance for workers on leave,
fees to temp agencies, and Employee Assistance Programs
Caregiving Total
Medical Care and Medical Research
Business share of healthcare costs
Business share of research on Alzheimers
Medical Total
Total
In Billions (U.S.$)
7.8913.223.59
1.33
26.03
7.090.05
7.14
$33.17
Adapted from Koppel R, Dept. Sociology, Univ. Pennsylvania (1998)
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Prevalence and Treatment Rates
0
200
400
600
800
1000
12001400
1600
1800
2000
Mild Moderate Severe
NumberofPatients
(thousands)
Prevalence1
Diagnosed2
Treated with AChEI3
Sources: 1. Hebert LE, Scherr PA, Bienias J, et al. Arch Neurol. 2003;60:1119-1122.2. Datamonitor AD Treatment Algorithms. 2002.3. Market Measures. 2003.
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AD is Under-diagnosed Early Alzheimers disease is subtle, the diagnosis continues to
be missed
it is easy for family members to avoid the problem and compensate forthe patient
physicians tend to miss the initial signs and symptoms
Less than half of AD patients are diagnosed
Estimates are that 25% to 50% of cases remain undiagnosed Diagnoses are missed at all levels of severity: mild, moderate, severe
Undiagnosed AD patients often face avoidable social, financial,and medical problems
Early diagnosis and appropriate intervention may lessendisease burden
No definitive laboratory test for diagnosing AD exist
Evans DA. Milbank Quarterly. 1990; 68:267-289
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
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No Disease,No Symptoms Early BrainChanges,No Symptoms
Mild MemoryLoss Mild, Moderateand SevereImpairment
MildCognitive
Impairment
Pre-symptomatic
ADNormal AD
Disease ProgressionDisease Progression
Multiple cognitive deficits
Amnesia (Memory loss)
Aphasia (language disturbance)
Apraxia (impaired ability to carry outmotor activities despite intact motorfunction)
Agnosia (failure to recognize or identifyobjects despite intact sensory function)
Executive function disturbance (e.g.,planning, organizing, sequencing,abstracting)
These lead to functional decline
Definition of the dementia synd
American Psychiatric Association: Diagnostic and Statistical Manual ofMental Disorders, 4th edn. Washington DC: APA, 1994
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Inability to choose properclothing to wear
Inability to putOn clothings
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Requiring assistance in
cleanliness in toileting
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8 years average. Range 2-20 years
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Peak Frequency of Behavioral Symptoms asAlzheimers Disease Progresses
Agitation
Diurnalrhythm
IrritabilityWandering
Aggression
Hallucinations
Moodchange
Socially unacc.
Delusions
Sexually inappr.AccusatorySuicidal
ideation
Paranoia
Depression
100
80
60
40
20
040 30 20 10 0 10 20 30
Months Before/After Diagnosis
Prevalence(%o
fpatients)
Anxiety
Socialwithdrawal
Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081.
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AD: a progressive CNS disorderimpairingpatients ability to function
INCREASED SEVERITY INCREASED BURDEN
Stage 7 very severe
Stage 6 severe
Stage 6 severe
Stage 5 mod severe
Stage 4 moderate
Stage 3 mild
Stage 2 very mild
Stage 1 appears normal
Years after onset
0 5 10 15 20
Loss of speech, locomotion,consciousness; death
Full-time care needed;institutionalised
Can no longer care for self;incontinent, depressed
Can no longer manage personal affairs;agitated, care needed
Family and friends notice problems
Normal
No noticeable cognitive decline
Mild function deficitforgetful
Definitions from the Global Deterioration Scale Reisberg B et al., 1982
P i f t i t i l d ti
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Lovestone & Gauthier 2000
BURDEN
Progression of symptoms in typical dementia
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
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Steps in diagnosing dementia
History
Physical examination
Cognitive tests
Perform brief cognitive tests
Neuropsychological testsNon-cognitive tests
Assessment of BPSD
Assessment of ADL
Screening co-morbid condition
Establishing diagnoses
Assessing severity and progression
Neuroimaging
EEG
Biomarkers
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Course of Aging, MCI and AD
AAMI / ARCD
MCI
Clinical AD
Time (Years)
CognitiveDec
line
BrainADBrain
AgingMild
Moderate
ModeratelySevere
Severe
(Ferris, 4/03)
Brain Aging
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Differential Diagnosis of Dementia
5% 10% 65% 5% 7% 8%
Dementia with Lewy bodiesParkinsons disease
Diffuse Lewy body diseaseLewy body variant of AD
Vasculardementias and AD
Other dementiasFrontal lobe dementiaCreutzfeldt-Jakob diseaseCorticobasal degenerationProgressive supranuclear palsyMany others
AD and dementia
with Lewy bodies
Vascular dementiasMulti-infarct dementiaBinswangers disease
AD
Small GW, et al . JAMA. 1997;278:1363-1371; American Psychiatric Association. Am J Psychiatry.1997;154(suppl):1-39; Morris JC. Clin Geriatr Med. 1994;10:257-276.
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Differential Diagnosis
Alzheimers disease
Lewy body
dementia
cEPS,
Visual
hallucination
Frontotemporal
dementia
Behaviour,
Language
Vascular
dementia
Stroke,
Focal signs
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Regional distribution of atrophy in thecommon dementias
Alzheimers disease predominantly parietal and temporal
Frontotemporal dementia predominantly frontal and temporal
Dementia with Lewy bodies as for AD, but with additional subcortical pathology
Vascular dementia vascular distribution
Executivefunctions
Praxia
PerceptuospatialfunctionMemory
Language
Functional regionsFTDAD
Differential Diagnosis:
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Differential Diagnosis:Top Ten
(commonly used mnemonic device: AVDEMENTIA)
1. Alzheimer Disease (pure ~40%, +mixed~70%, ? dLbd)
2. Vascular Disease, MID (5-20%)
3. Drugs, Depression, Delirium
4. Ethanol (5-15%)
5. Medical /Metabolic Systems6. Endocrine (thyroid, diabetes), Ears,
Eyes, Environ.
7. Neurologic (other primary degenerations,fronto-temporal
- Consider diffuse Lewy body dementia,
Parkinson component)
8. Tumor, Toxin, Trauma
9. Infection, Idiopathic, Immunologic
10. Amnesia, Autoimmune, Apnea, AAMI
Adapted from Yesavage, 1979
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Co Morbidity issues
Multiple medical problems
Cumulative effect
Poly pharmacy
Acute illnesses
Under assessment and treatment
..added to dementia in the equation
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DEMENTIACOMORBIDITIES
Cognitive
impairments
Poor reporting of co-morbidities
Under- or late diagnosis of comorbid conditions
Worsening of overall health status
Atypical presentation
Excess morbidity
worsening
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Chronic Disease Model of AD
Diffuse plaques
Neuritic plaques, NFTs,
neuron and synapse loss
Cognitive impairment
Functional loss
Preclinical phase Clinical phase
Death
Diagnosis
Onset of symptomsGenetic & environmentalfactors
Antecedent biomarkers
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Dementia in local services
UMMCMemory
clinic(Geriatric)
HospSeremban
Memoryclinic(Geriatric)
Hosp JohorBahru
Memoryclinic(GeriatricPsych)
Hosp Kajang(Geriatric
psych)
AD 64% 63% 60% 62%
VaD 17% 29 % 24% 25%
Mixed (AD-
VaD)
17% 8 % 15% 15%
Otherdementias
2%
Database: Yau WK et al, Chin A-V,Yusoff S, Vengadasalam
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Diagnostic Thresholds for Dementia
Course of Dementia
CognitiveAbili
ties
Threshold 1
Threshold 2
Threshold 3
Very Mild or
MCI
Mild
Moderate
-Severe
Dementia results from progressive neuronal deterioration, fromminimal to extensive. Conventional diagnosis draws a line in
its course, labeling one side as demented and the other not.
Max Markah
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Max Markahpesakit
5 Orientasi Masa Tahun, bulan, hari, tarikh, waktu (+/- 1 jam)
5 Orientasi Tempat: Negara, Negeri, Bandar,Tempat (hospital/rumah), bilik(wad/klinik)
3 Pendaftaran:Saya akan menguji ingatan awak. Sila dengar dengan teliti,tiga objek yang saya akan baca, iaitu, oren, kunci dan sikat. Sila sebutsemula tiga objek tadi. Ingat betul-betul, kerana saya akan bertanyakemudian.
5 Perhatian dan Pengiraan (sila guna salah satu kaedah)
M-MMSE-7: Sila tolak 7 dari 100 dan teruskan.M-MMSE -3: Atau, tolak 3 dari 20 dan teruskan.
M-MMSE-S: Atau, ejakan perkataan DUNIA dari belakang ke depan.
3 Ingat Kembali
Sila sebut kembali 3 objek yang telah disebut tadi.
2 Penamaan
Namakan benda ini. (Pensel dan Jam Tangan)
1 Ulangan Sebutkan Tidak mungkin dan cukup mustahil3 Arahan tiga peringkat: Ambil kertas dengan tangan kanan, lipat setengah
dan letakkan atas lantai/meja.
1 Pembacaan: Baca dan lakukan ..TUTUP MATA ANDA
1 Penulisan: Tulis satu ayat yang lengkap.
1 Penyalinan
Jumlah
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Clock Drawing Test (CDT)
12
6
39
1
2
4
57
8
10
11
.
10 minutes past 11
Closed circle = 1
All 12 numbers present = 1
12 numbers in correct = 1position
Handsin correct = 1position ___
4
Low score indicates impairment.Cut-off score is subjective & arbitrary.Clinical judgment must be applied.
Nolan KA 1994
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Malay Mini Mental StateExamination
M-MMSE-7(n=300)
M-MMSE-3(n=160)
M-MMSE-S(n=145)
Optimal cut-off 21/ 22 18/19 17/ 18
Sensitivity 88.5 97.1 97.7
Specificity 75.3 90.0 93.3
PPV 53.7 57.6 62.5
NPV 95.5 99.2 100.0AUC 0.9 1.0 1.0
Cut off values and accuracy of the different versions of the Malay MMSE
Ibrahim et al, 2009
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Diagnosing Alzheimers disease
8090% accuracy
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems
Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
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Mechanism of cognitive impairment
2 mechanism:
Acetycholine
deficits
NMDA receptorantagonist
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Reduces severity of cognitive symptoms
Improved Quality of Life
Decreased caregiver burden
Above - For Mild to Severe disease
Stabilisepts symptoms for a period of 1-3 years
but without modifying progression of thedisease
Ezio Giacobini and Robert E becker, One Hundred Years after the Discovery of Alzheimers
Disease. A Turning Point for Therapy? Journal of Alzheimers Disease 12 (2007) 37-52 IOS Press
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T t t O t i
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Treatment Outcomes in
Alzheimers Disease
Time
Functionalab
ility
Slowing of diseaseprogressionTreatment
Symptomaticbenefit
Maintenanceof function
Cure
Natural Progression
(Ferris, 8/03)
Cli i l Di P i
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Clinical Disease Progression
Years From Diagnosis
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8 9
MMSES
core
Mild SevereModerateCognitiveSymptoms
Diagnosis
Loss of FunctionalIndependence
Behavioral Problems
Nursing Home Placement
Death
Reprinted from Clinical Diagnosis and Management of Alzheimers Disease, H Feldman and S Gracon;Alzheimers Disease: symptomatic drugs under development, pages 239-259, copyright 1996, with permissionfrom Elsevier.
AntidepressantCHEi
CHEiMemantine
CHEi+/-Memantine
Atypical Antipsychotics
CHEi+/-MemantineAtypical Antipsychotics
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Dementia CPG 2nd
Ed
Mdm LKM mom of senior radiographer
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Mdm LKM, mom of senior radiographerin Hosp Seremban
1stnotice memory problem in 1995, forgotten her
medications, content of conversation s over phone andthings around her. Still driving and MMSE 26/27
2001Hiding things (family found rotten buns), forgottento lock door.
2002. Worst. Agnosia, lost way home, cantcommunicate with others well. Manages ADL but
stopped IADL. Treated with Rivastigmine.
Till 2009 - on and off UTI, incontinence. Daughter comefor medications. Cant do MMSE. Hardly talk. Admitted in2009, stormy progress. DNR discussed. Needed RTfeeding. Bedridden mostly. Bedsore dressed by
daughter. Had stopped talking all together. August 2009 started memantine. RT off. Become more
chatty. Ask maid to move aside as she want to watchTV, started walking back again with 2 and bed soresettled.
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H Cayton, N Graham, J Warner, Alzheimers at your fingertips, 1997
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Barbara Sherman, Dementia with dignity. A Handbook for Carers, Revised Ed1994
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Amyloid Generation
Neuritic Plaque
NFT Excitotoxicity Oxidation
Cell
Death
Cholinergic Deficit
Inflammation
Cummings 2004
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Disease-Modifying Strategies
APP A
Neurondeath
-secretase
-secretase
inflammationoxidative stress
excitotoxicitydirect toxicity
secretasemodulators
immunotherapy
amyloid binders
anti-inflammatoriesantioxidantsneuroprotectants
Primary Prevention Trials in AD
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Study Agent Enrollmentcriteria
Noenrolled
Duration Currentlyactive
Outcomemeasures
Result
ADAPTNaprosynCelecoxib
Cognitivelyscreened, >70, 1stdegree relativewith AD
2496enrolled
7-10yrs Tx stopped ConversionStudyto dementia andcognitive decline
No result yet
Neg - 2008
GEM Gingko Bilobaextract
Asymptomatic,>75
5000 5-7 yrs Active Inc of dementiaor cognitivedecline
No result yet
Neg - 2009
HERS Estrogen andmedroxyprogesterone
Asymptomaticwomen, mean age67
1063 4.2 yrs Completed Cognitive test 1 test improved
HeartProtectionStudy
Vit E, C, and betacarotene
Asymptomaticwith CVS rsikfactors, age 40-80years
20536 5 yrs Completed TICS andincidentdementia
No differencebtwn tx and untxarm
HeartProtectionStudy
Simvastatin Asymptomaticwith CVS rsik
factors, age 40-80years
20536 5 yrs Completed TICS andincident
dementia
No differencebtwn tx and untx
arm
PREADVISE Selinium, Vit E Asymp men, >60yrs
10,400 12 yrs Completed Incidentdementia andcognitive tests
No result yetMaybe in 2012 /2013
Sano M, Current Concept in the Prevention of AD, Cns spectrum 2003:8: 846-853
y
Primary Prevention Trials in AD Cont ..
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Study Agent Enrollmentcriteria
Noenrolled
Duration Currentlyactive
Outcomemeasures
Result
WHI-PERT Estrogen nmedroxyprogest.
Women
withoutdementia,ages 65-80
4532 4 yrs completed Incident
dementia, MCIand 3MS score
Treated
subjects hadelevated riskof dementiaand worse3MS score
WHI-ERT Estrogen. Womenwithoutdementia,
ages 65-80
2497 5 yrs completed Incidentdementia, MCIand 3MS score
Treatedsubjects hadelevated risk
of compositeMCI/dementiaand worse3MS score
GUIDAGE Gingko Bilobaextract
Subjectivememorycomplaints,>70
2600 4 yrs Ongoing Incidentdementia
Not yetavailable
PHS-II Vit E, Folate, betacarotene
Asymptomatic, >65 yrs
10, 000 9yrs Ongoing TelephonecognitiveTesting
Not yetavailable
Sano M, Current Concept in the Prevention of AD, Cns spectrum 2003:8: 846-853
CONNECTION trial, MC RCT,
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, ,phase 3, of almost 600 patientswith AD, result negative, after 6months of treatment.- mac 2010
CONCERT trial, a 12-month studytesting latrepirdine in patients withmild-to-moderate AD who are
taking donepezil;
CONTACT and CONSTELLATIONtrials, 6-month trials of latrepirdine
in patients with moderate-to-severe AD also taking donepeziland memantine, respectively.
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The etiology of Alzheimer's disease remains elusive, althoughconsiderable progress has been made in understanding its biochemicaland genetic mechanisms.
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems
Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
100 years of AD major milestone
http://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DGhttp://images.google.com.my/imgres?imgurl=http://www.topnews.in/health/files/eldermen.jpg&imgrefurl=http://www.topnews.in/health/folate-deficiency-may-triple-dementia-risk-elderly-people-2938&usg=__XyRMKjkCcEtI9stFw7FQFUtiAb8=&h=567&w=378&sz=107&hl=en&start=9&tbnid=K61BBRJya2ESuM:&tbnh=134&tbnw=89&prev=/images%3Fq%3Delderly%2Bpeople%26gbv%3D2%26hl%3Den%26sa%3DG -
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100 years of AD- major milestone
Slides fr Professor Roy Jones Director Research Institute for Care of Elderly,Bath presented at the 11th InternationalGeneva/Springfield Symposium on Advances in Alzheimer Therapy March 24 27, 2010Geneva
Presenile dementiaRareYoung onset
Separation of SenileDementia fr VaD andDepression
1950s 1960s
Presenile Dementia= Senile Dementia=ADStructures of tangles and plagues determinedNeuritis plagues contains amyloid protein
Cholinergichypothesis of AD
AD recognised asmajor health issue
1970s
Tacrine trials amyloid sequenced
Role of NFTs and tau
Age of geneticsAPP, presenilin 1 and 2 mutationAPOE4 E4 susceptibility
Amyloid cascade hypothesis of AD
CHEIs approved
Role of glutamate approved
Memantine approved
1980s 1990s /2000s
THE FUTURE
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THE FUTURE1. Better detection
- GPs, public
2. Better diagnosis- biomarkers- imaging amyloid and
tangles
3. Disease prevention / delay
4. Disease cure?
- eg vaccination
5. Better support
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http://clinicaltrials.gov/ct2/results?term=DEMENTIA
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm
http://www.alzforum.org/dis/tre/drc/default.asp
Ongoing NIA-Funded AD/MCI Prevention and TreatmentClinical Trials as of November 2009
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm -
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Trial Name Principal
Investigator
Intervention Population
CardiovascularACCORD-MIND (Action to ControlCardiovascular Risk inDiabetes/Memory in Diabetes)*
Lenore Launer Intensive glucose, bloodpressure, and lipidmanagement
People ages 40-79 with type2 diabetes mellitus
Effects of Simvastatin on CSF AD
Biomarkers
Cynthia Carlsson Simvastatin People ages 45-65 at high
risk of AD (family history,APOE 4)
ESPRIT (Evaluating Simvastatins
Potential Role in Therapy)Cynthia Carlsson Simvastatin People ages 35-69 at high
risk of AD (family history)
SPRINT-MIND (Systolic BloodPressure Intervention Trial-MIND)*
Lawrence Fine Blood pressure loweringto
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Trial Name PrincipalInvestigator
Intervention Population
Hormones
lzheimers Disease:Potential Benefit ofIsoflavones
Carey Gleason Novasoy (soyisoflavonesphytoestrogens)
People with AD
ELITE (Early versus LateIntervention with Estradiol)
Howard Hodis 17-estradiol Healthy early (less than 6years) or late (10 years +)menopausal women
KEEPS-CA (Kronos Early
Estrogen Prevention Study -Cognitive and AffectiveStudy)*
Sanjay Asthana Oral conjugated
equine estrogen (CEEor Premarin)and
transdermal 17-estradiol (tE2)
Healthy perimenopausal
women ages 42-58
Raloxifene for Women withAlzheimer's Disease
VictorHenderson
Raloxifene (selectiveestrogen receptor
modulator or SERM)
Older women with AD
SMART (Somatotrophics,Memory, and AgingResearch Trial)
Michael Vitiello Growth hormonereleasing hormone(GHRH)
People with MCI andhealthy older adults ages55-80
TestosteroneSupplementation in Men withMCI
MoniqueCherrier
Testosterone Older men with MCI andlow testosterone
Page last updated Jan 12, 2010
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm
Ongoing NIA-FundedAD/MCI Prevention and Treatment ClinicalTrials as of November 2009 Cont
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm -
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Other Interventions
AAV-NGF Gene Delivery inAlzheimers Disease
Paul Aisen Nerve growth factor(NGF) gene delivery
People with AD
fMRI Activation in MildCognitive Impairment
MichelaGallagher
Levetiracetam People with MCI
GAP (GammaglobulinAlzheimers Partnership) NormanRelkin Immune globulinintravenous (IVIg),
passiveimmunization
People with AD
Study on Thalidomide asBACE1 Inhibitor in
Alzheimers Disease
Yong Shen Thalidomide People with AD
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm
Trials, as of November 2009 Cont
AD treatment 2010 and Beyond
http://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htmhttp://www.nia.nih.gov/Alzheimers/Publications/ADProgress2008/rapid/ongoing1.htm -
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AD treatment 2010 and Beyond2010
ACHEIs, Memantine, Combination
Other cognitive enhancers (Dimebon?, 5HT6, H3)
Improved and Early Diagnosis
Patient segmentation(genetics)
Disease modifying therapies
Community-wide preventive initiatives (diet, exercise)
2020
Slides fr Professor Roy Jones Director Research Institute for Care of Elderly,Bath presented at the 11th InternationalGeneva/Springfield Symposium on Advances in Alzheimer Therapy March 24 27, 2010Geneva
Overlap between Alzheimers
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Probable Possible Possible ProbableMixed
disease and vascular dementia
VaD
Stroke/TIAHypertension
DiabetesHypercholesterolemia
Heart disease
AD
Amyloid plaquesGenetic factors
Neurofibrillary tangles
MixedAD/CVD
Amyloid plaquesGenetic factors
Neurofibrillary tangles
Stroke/TIAHypertensionDiabetes
HypercholesterolemiaHeart disease
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S115-123.
Cholinergic deficit
Hypertension
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Hypertension
A systematic review & meta-analysis of 4studies:
non-sig: RR =0.8, 95%CI 0.6 - 1.0
Hypertension in the Very Elderly TrialCognitive Function Assessment (HYVET-COG) Non-sig: HR 09, 95%CI 07 - 11
These data -combined in meta-analysis withother placebo-controlled trials of a/HPT rx , favoured treatment(HR 09, 95%CI 08 to10, p=0045).[46]Level I, fair
http://images.google.com.my/imgres?imgurl=http://www.gothypertension.com/images/hypertension-mercury.jpg&imgrefurl=http://www.gothypertension.com/hypertension/&usg=__tCOVERRaSJ-UVPLy0riwzAUQyS8=&h=328&w=246&sz=22&hl=en&start=17&tbnid=iPnwJKG9lyJPQM:&tbnh=118&tbnw=89&prev=/images%3Fq%3Dhypertension%26gbv%3D2%26hl%3Den -
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Recommendation
Hypertension, occurring at mid-life (40-60 years)is a risk factor for dementia and should beappropriately treated. (Grade A)
Hypertension in the VeryElderly Trial Cognitive
Function Assessment(HYVET-COG)
Diabetes
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Swedish HTA report - evidence linkingdiabetesmod strong.[47] Level 1, good
A recent meta-analysis of 15 prospectivecohort studiesdiabetes was associated with a 47%
increased risk for all dementia,39% for Alzheimers dementia,
>2-fold risk for vascular dementia,(community dwelling )
Diabetes mellitus is a modifiable risk factor for thedevelopment of dementia and shouldbeappropriately treated. (Grade C)
Lifestyle Risk Factors
http://images.google.com.my/imgres?imgurl=http://www.just-diagnosed-diabetes-mellitus.com/images/Spoonfull_of_Sugar_and_Diabetes_500x320.jpg&imgrefurl=http://www.just-diagnosed-diabetes-mellitus.com/what-is-diabetes.html&usg=__tIZ2U9WOo55Xqw4chLmty-GhgbI=&h=332&w=500&sz=31&hl=en&start=57&tbnid=y91FyR_Uk3sDuM:&tbnh=86&tbnw=130&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://novarider.com/wp-content/uploads/2009/04/diabetes.jpg&imgrefurl=http://novarider.com/2009/04/diabetes-cause-eye-diseases/&usg=__byTDBIUaN3lFMQu8M30Bpq6-dt0=&h=320&w=480&sz=25&hl=en&start=14&tbnid=TDMYA_0mn0c3UM:&tbnh=86&tbnw=129&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://www.geneplanet.com/_files/51/sladkorna_bolezen_tipa_2.jpg&imgrefurl=http://www.geneplanet.com/have_your_dna_analyzed/what_you_can_learn_from_dna_analysis/potential_diseases/type_ii_diabetes_mellitus&usg=__E2fQebCXEvTHbISLdG2JKsLUidE=&h=300&w=400&sz=161&hl=en&start=55&tbnid=mo6XUQRxmaCRDM:&tbnh=93&tbnw=124&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://www.just-diagnosed-diabetes-mellitus.com/images/Spoonfull_of_Sugar_and_Diabetes_500x320.jpg&imgrefurl=http://www.just-diagnosed-diabetes-mellitus.com/what-is-diabetes.html&usg=__tIZ2U9WOo55Xqw4chLmty-GhgbI=&h=332&w=500&sz=31&hl=en&start=57&tbnid=y91FyR_Uk3sDuM:&tbnh=86&tbnw=130&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D40http://images.google.com.my/imgres?imgurl=http://novarider.com/wp-content/uploads/2009/04/diabetes.jpg&imgrefurl=http://novarider.com/2009/04/diabetes-cause-eye-diseases/&usg=__byTDBIUaN3lFMQu8M30Bpq6-dt0=&h=320&w=480&sz=25&hl=en&start=14&tbnid=TDMYA_0mn0c3UM:&tbnh=86&tbnw=129&prev=/images%3Fq%3Ddiabetes%2Bmellitus%26gbv%3D2%26hl%3Den -
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Lifestyle Risk Factors
Smoking
Alcohol
Obesity
Head Injury
Exercise
Education / Mental stimulation
Social network
LEARNING AND LON
GEVITY OF THE BRAINNUNS d
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The Nun Study is a longitudinal study of aging and Alzheimer'sdisease funded by the National Institute on Aging.
678 American members of the School Sisters of Notre Damereligious congregation who are 75 to 106 years of age.
Study
http://www.mc.uky.edu/nunnet/ Snowdon et al. JAMA 1997; 277: 813-7
Subcortical infarctionImportance of educationImportance of moodHead size
ALCOHOL & DEMENTIA
http://www.mc.uky.edu/nunnet/http://www.mc.uky.edu/nunnet/ -
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ALCOHOL & DEMENTIA
Several studies - light to moderate
alcohol consumption assoc.with a lower risk of DementiaAND AD
Rotterdam study1 - 45% < risk ofany dementia in those whodrink 1-3 drinks / day, comparedto non drinkers
1. Ruitenberg et al. Lancet 2002; 359:281-6
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Obesity
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Obesity Several prospective studies found an association
between raised body mass index in mid life and
an increased risk of dementia and AD. A systematic review of 4 cohort (n=22,861) F/U
20 years = significant risk. [59]Level II-2, fair
A meta-analysis of 7 prospective studiesfoundmoderate association
Obesity and incident AD was 1.8 (95% CI1.0 to 3.3)
Obesity and VaD was 1.7(95% CI 0.5 to 6.3)[60] Level II-2, good
Recommendation
Obesity is a modifiable risk factor andmaintenance of normal body mass index isrecommended. (Grade C)
PHYSICAL ACTIVITY
http://images.google.com.my/imgres?imgurl=http://no-bullfitness.com/wp-content/uploads/2009/08/obesity_lifespan-287x300.jpg&imgrefurl=http://www.no-bullfitness.com/&usg=__96cgoDbRXC2fw-JDtuu_3xjdk58=&h=300&w=287&sz=19&hl=en&start=17&tbnid=vJW7_6p2K9GHzM:&tbnh=116&tbnw=111&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26hl%3Denhttp://images.google.com.my/imgres?imgurl=http://going-well.com/wp/wp-content/uploads/2009/09/childhood-obesity-television-fast-food.jpg&imgrefurl=http://going-well.com/category/weight-loss/&usg=__izSmNHxsf3iI9wU6pmXY85O9coE=&h=276&w=460&sz=35&hl=en&start=38&tbnid=dMO1G7WnHrJrzM:&tbnh=77&tbnw=128&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D20http://images.google.com.my/imgres?imgurl=http://image3.examiner.com/images/blog/wysiwyg/image/obesity3(1).jpg&imgrefurl=http://www.examiner.com/x-12596-Milwaukee-Health-Examiner~y2009m7d23-Obesity-statistics-reveal-glaring-health-disparities-among-minorities&usg=__lo_NISgTPFOcsVye2zEbfEaLYKk=&h=288&w=400&sz=20&hl=en&start=31&tbnid=0FrtNET96-KTcM:&tbnh=89&tbnw=124&prev=/images%3Fq%3Dobesity%2Bpictures%26gbv%3D2%26ndsp%3D20%26hl%3Den%26sa%3DN%26start%3D20 -
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0
5
10
15
20
25
1 2 3 4
ACTIVITY QUARTILE
1. Yaffe et al. Arch Intern Med 2001; 161:1703-8
NEW
COGNITIVE
IMPAIRMENT
(%)
Women Who Walk project15,925 woman over age 65
no cognitive impairment at baselinefollow up 6-8 years
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Will C h f ll i
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems
Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
Acute Delirium
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Acute Delirium
Confused
Restless
Pulled outCBD
The older patient with
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The older patient withdelirium :
Associated with
longer hospital stays,increased mortality
hospitalized patients with delirium : 22 - 76percent, [2]
1-year mortality rate : 35 - 40 percent. [3]
2. Am J Psychiatry 1999;156:Suppl:1-203. Moran Aust J Hosp Pharm 2001;31:35-40
http://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htmhttp://../xToDo0601/Delirium%202006/060510/MDJN%20NEJM/current%20concept%20delirium%20in%20older%20person%20inouye.htm -
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quiet patientnon-demanding
good patient
Last cubicle
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Classification-
Lipowski1. Hyperactive-hyperalert
(agitated)
Hypervigilance,agitationHyperactivityHallucinations
Vs
schizophrenia
3. Mixed delirium
2. Hypoactive-hypoalert(somnolent)
lethargic & quietoverlooked in busy wardrespond appropriately
monosyllable answerswithdrawn,
drift off to sleepVS
DepressionUncooperative
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JAGS MARCH 2006VOL.54,NO.3 DELIRIUM SUBTYPES IN THE CRITICALLY ILL 481
J Am Geriatr Soc 54:479
484, 2006.
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FSLee Geriatrics HKL May06 89
Delirium in the Hospitalised ElderlyJuli A Moran, Michael I Dorevitch Aust J Hosp Pharm 2001; 31: 35-40.
3. Inouye SK. The dilemma of delirium: clinical and research controversies regardingdiagnosis and evaluation of delirium in hospitalized elderly medicalpatients. Am J Med 1994; 97: 278-88.
Number of precipitating
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u be o p ec p tat gfactors
Interaction
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FSLee Geriatrics HKL May06
Mx of delirium in hospital
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Mx of delirium in hospital
Prevention
Early diagnosis
Search and treat precipitating factors
Supportive measures, if necessary -medication
Delirium in the Hospitalised Elderly Juli A Moran, Michael IDorevitch Aust J Hosp Pharm 2001; 31: 35-40
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Detection
Lewis and colleagues11
N= 385 patients,prevalence of 10% - CAM.detection rate of delirium by ED
physicians based on chart review -17%.
11. Lewis LM, Am J Emerg Med 1995; 3:142-5.
CAM (Confusion
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CAM(ConfusionAssessment Method)
1. Acute change & fluctuation in mentalstatus and behavior
AND2. InattentionAND EITHER
3. Disorganized thinking
OR4. Altered consciousness
Inouye SK et al. Ann Intern Med 1990;113:941-948.
UTI
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For rehab
Multicomponent Mx of Delirium Symptoms
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www.health.vic.gov.au/acute-agedcare
Features Delirium Alzheimer's diseaseOnset Acute or subacute onset (hours or
days)
Insidious (usually several years)
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days)
Frequent and rapid fluctuations
(hours)
Slow changes (months)
Rapid functional decline Relatively slow functional declineConscious level Attention markedly reduced Attention reduced only in severely
affected patients
Arousal increased or decreased Arousal usually normal
Psychotic
symptoms
Delusions (if present) fleeting Delusions (if present) often
consistent
Hallucinations common often visual Hallucinations infrequent, visual,
and auditory
Motor features Abnormal movements such as
tremor or myoclonus common
Abnormal movements often
absent
Psychomotor activity increased or
decreased
Psychomotor activity usually
normalUnderlying
physical illness
Symptoms and signs usually present Symptoms absent
Day and night
rhythm
Often disturbed with a marked
increase in symptoms during the
night
No clear day and night rhythm.
Symptoms are more consistent
Prevention
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1. Cognitive impairment
2. Sleep deprivation
3. Immobility
4. Visual impairment
5. Hearing impairment
6. Dehydration
Prevention
Delirium: Summary :
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99
Delirium: Summary :
Delirium is under diagnosed.
Hypoactive deliriumMore difficult to diagnose
Poorer outcome
Management :Early Diagnosis
Multifactorial approach
Prevention
Will Cover the followings
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Will Cover the followings
Introduction to dementia
The spectrum of cognitive dysfunction
Evaluation of memory problems
Management
Non-pharmacological management
Pharmacological management
Whats in the future for dementia
What about Delirium
Conclusion
C l i 1
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Conclusion 1
Normal changes =more forgetful & slower to learn
MCI Mild Cognitive Impairment no functionaldecline
Some eventually develop dementia
Dementia =Chronic thinking problems in > 2 areas
Vascular dementia - covers the whole spectrum ofcerebrovascular disease and cognition
DLB sits on the interface between AD, delirium and
Parkinsons disease FTD dementia without the dementia, revealing how the
frontal lobes govern personality and theory of mind
Delirium =Rapid changes in thinking & alertness Seek cause and treat urgently
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Two elderly ladies had been friends for many decades. Overthe years they had shared all kinds of activities andadventures. Lately, their activities had been limited tomeeting a few times a week to play cards.One day they were playing cards when one looked at the
other and said, "Now don't get mad at me....I know we'vebeen friends for a long time.....but I just can't think of yourname! I've thought and thought, but I can't remember it.Please tell me what your name is." Her friend glared at her.
For at least three minutes she just stared and glared at her.
Finally she said, "How soon do you need to know?"
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Conclusion 2
AD is an expensive illness in human and economic
terms for patients, their caregivers, and society.
Diagnosis is often not made, especially in earlyand mild AD; clinical nihilism can interfere with
initiating or sustaining treatment.
Cholinesterase inhibitors and NMDA receptor
antagonists attenuate symptomatic decline
Early treatment pays off; delaying treatment has
long-term consequences.
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Therapeutic Strategies
Pathogenesis
Symptoms
Disease
Induction Genetic/hereditary
Latency Traumatisms Vascular risk factors
Detection
PrimaryPrevention ?Vaccine ?Estrogen ?Ginkgo
SecondaryPrevention(Mild cognitive
Impairment) ?Antioxydants ?Anti-inflammatories ?Neurotrophic factors ?Estrogens ?Others
SymptomaticTreatment Cholinergic replacement
therapy
Vascular Prevention
Mind your Mind
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Mind your brain cognitive stimulation
Mind your body exercise Mind your head protect head
Mind your habits smoking
Mind your health check BP, cholesterol
Mind your diet antioxidant, polyphenol
Mind your social activities - engagement
Prof Henry Brodaty; Dementia: Can it be prevented?
Alzheimers Australia: Position Paper 6 August 2005
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