MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
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Transcript of MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
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Alex Mitchell www.psycho-oncology.info
Department of Cancer & Molecular Medicine, Leicester Royal Infirmary
Department of Liaison Psychiatry, Leicester General Hospital
MRCPsych Leicester Nov 2009
Evidence Based Diagnosis of the DementiasValidity of criteria for diagnosing subtypes of dementia
Evidence Based Diagnosis of the DementiasValidity of criteria for diagnosing subtypes of dementia
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Pragmatic definition of dementia
• Dementia is an acquired global impairment of intellectual functioning
• Involving memory, language, thinking, and perception
• Associated with disability
• Usually is progressive and irreversible
• Current Treatments make a modest difference to the disease course
• Dementia is a syndrome with many underlying diseases
• Some diseases may yet not be adequately described
• Dementia is preceded by mild cognitive impairment (which may not come to medical attention)
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Concepts of Screening
• Screening (possible case)» Eg MMSE
• Case-Finding (probable case)» Eg NINCDS-ADRDA criteria,
• Severity Rating
» Eg ADAS-Cog
• Gold Standard (definite case)» Pathology => disease High accuracy
High convenience
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Concepts of Dementia
• Symptoms and signs
• Detailed symptoms (neuropsychology)
• Gross pathology
• In vivo pathology (neuroimaging)
• Microscopic pathology
• Immunochemistry
• Genetics High accuracy
High convenience
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Clinical Classification of Dementia
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Neurodegenerative DisordersNeurodegenerative Disorders
α-synucleinopathies
Parkinson’s disease
Lewy Body Dementia
Multiple System Atrophy
Ubiquitin disorders
Motor Neuron Disease
Motor Neuron Dementia
Frontotemporal dementia (MND-type)
Neuroaxonal dystrophy
Polyglutamine disorders
Huntington’s disease
SBMA
Spinocerebellar ataxia 1, 3, 7
dentatorubral-pallidoluysian atrophy
Intraneuronal Extracellular
Intracellular
Tauopathies
Triplet-Band Tauopathies
Normal Aging
Alzheimer’s disease
Down’s Syndrome
NPC, PEP, GSS
ALS/PDC
Predominanty 4-repeats
Progressive Supranuclear Palsy
Corticobasal Degeneration
MSTD, PPND
Duke Family 1, 1684
Predominanty 3-repeats
Pick’s disease
Prion Protein
Creutzfeldt-Jakob disease
Double Band Taupathies
Cytoplasmic/Neuritic
Triplet Band Taupathies
Beta-Amyloid
Alzheimer’s disease
Microcellular Classification of Dementia
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Primer on Forgotten Neuroanatomy!
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Higher Cortical Functions and Association Cortices
Attending
Selecting
Recognizing
Imitating
Remembering
Association cortices = cognition
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The “Association Cortices” have a distinctive neocortex
Cortical Maps: Brodmann
Lateral
Medial
Cytoarchitecture = Cell packing density and type
~50 regions
Ne oc or te x
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Introduction to Dementias
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Distribution of AD in Different Settings
CSHA Working Group, CMAJ, 1994.CSHA Working Group, Can J Aging, 1994.
AD in the Community
Severe10%
Mild46%
Moderate44%
AD within Institutions
Severe55%Mild
11%
Moderate34%
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Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):35
Prob
abili
ty o
f In
stitu
tiona
lizat
ion
0.0
0.2
0.4
0.6
0.8
1.0
Mild(MMSE: 21–30)
Moderate(MMSE: 11–20)
Severe(MMSE: 0–10)
Severity of AD
0.017
0.345
0.867
Probability of Institutionalization by Severity
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Outcome measures used in Alzheimer’s Disease
Caregiver burdenCaregiver burden
Function(DAD/ADCS-
ADL)
Cognition(ADAS-Cog)
Behaviour(NPI)
Global(CIBIC-plus)
ADAS-Cog Alzheimer’s Disease Assessment Scale, Cognitive subscale
CIBIC-plus Clinician Interview-Based Impression of Change with Caregiver Input
DAD Disability Assessment in Dementia
ADCS-ADL Alzheimer's Disease Co-
Operative Study – Activities of Daily Living
NPI *Neuropsychiatric Inventory
SCGBScreen for Caregiver Burden
*Contains subscale NPI-D, which measures caregiver distress
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Dementia Clinical Serie
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Primer on Neuropsychology of Memory
DeclarativeLearning of Information
ImplicitLearning of Skills & Automatic Behaviours
Motor Conditioning Priming
Working MemoryRetention over Seconds
Long-term MemoryRetention over days
Semantic MemoryDatabase of information
Episodic MemoryNarrative Account
Visuospatial
Memory
Registration
Retention
Retrieval
Short-term MemoryRetention over Minutes
Verbal
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A.D.
DLB/PDD.
FTD - Semantic
FTD - Frontal
FTD - P.N.F.A.
Corticobasal
PSP.
Huntington's
Memory Language Visuospatial Attention Behavioural Neurological
++++ ++ ++ ++ + ±++ + ++++ +++ + +++ ++++ ± + + ±+ + ± ++ ++++ ±± ++++ ± + + ±+ + +++ ++ ++ ++++ + + +++ ++ ++++ + + +++ ++ +++
Overview of Main Symptoms in Dementias
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Alzheimer’s disease
37th Assembly of Southwest German Psychiatrists in Tübingen, Germany“atrophied brain; numerous ganglia cells have disappeared” “remarkable changes in neurofibrils”“millet-seed lesions, characterized by the deposits of a peculiar substance spread over entire cerebral cortex”“we clearly have a distinct disease process”
Auguste D, November 3, 1906
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History of AD
• 1906 Alzheimer presented Auguste D• 1910 Kraepelin Coined “Alzheimer’s disease” (Psychiatrie: Ein Lehrbuch fur Studierende und
Ärzte, Leipzig)• 1960 Electron microscopic studies in the 1960s by M Kidd and R Terry (with H Wisniewski, M
Shelanski, B Ghetti, K Iqbal, D Dickson, etc.) revealed the ultrastructural features of AD• 1968 Tomlinson, Blessed and Roth (1968, 1970) showed that the brains of healthy and
demented older adults differ and that most demented persons have AD• 1976 Cholinergic deficit (ChAT) in AD brains (Davies and Maloney, 1976; Bowen et al.,
1976• 1991 APP mutation causing dominantly inherited AD (Goate et al., 1991)
• 1991 Concept of mild cognitive impairment, or MCI (Flicker et al)• 1992 Presenilin 1 (St George-Hyslop et al., 1992)• 1993 ApoE identified as the major susceptibility gene for AD (Strittmatter et al., 1993)
• 1993 Tacrine approved
• 1995 Presenilin 2 (Rogaev et al., 1995) mutations identified• 1996 Donepezil approved
• 2001 Galantamine approved
• 2003 memantine approved
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Gross Pathology - AD
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Large ventricles
Wide Sulci
Loss of tissue
Gross Pathology in Alzheimer’s
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Loss of tissue
Wide Sulci
Large ventricles
CT Scan
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CT Scan 2
Normal Aging(coronal section)
Alzheimer’s Disease
(coronal section)
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Microscopic Pathology
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Neurofibrillary Tangles
Neurons have an internal support structure partly made up of microtubules. A protein called tauhelps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tauproteins clump together to form neurofibrillary tangles.
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SPECT Scan
Healthy AD
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What Makes a Diagnosis Correct?
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Density of Plaques and Tangles
Progression of Plaques and tangles by region and diagnostic accuracy of p-tau from Mitchell JNNP (2009)
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Rate of memory decline increases 5.1 years before dementia diagnosis (Hall et al, 2000)
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Healthy Elderly
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Mild Cognitive Impairment
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Alzheimer’s disease
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39ltcif_cog_screen_0809
Clock Drawing - Examples
http://www.dementiaguide.com/images/DGI-Ill_5.1-ClockDrawing.jpg
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Primer on the Science of Classification
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PrevalenceSpecificitySensitivity
NPVTrue -VeFalse -VeTest -ve
PPVFalse +veTrue +veTest +ve
Dementia
ABSENT
Dementia
PRESENT
Simple Measures of Accuracy
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Theory of Diagnostic Tests
Cognitive Impairment
Dementia
Number ofIndividuals
Optimum Cut‐off value
False +veFalse +veFalse ‐veFalse ‐ve
True ‐veTrue ‐ve
True +veTrue +ve
Point of Partial Rarity?
Score on Hypothetical Diagnostic Test
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GP Testing by Actual MMSE Score (n=162)Ganguli M et al. Detection and Management of Cognitive Impairment in Primary Care: The Steel Valley Seniors Survey. JAGS 52:1668–1675, 2004.
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MMSE modest sensitivity and specificity in dementia vs no dementia.Data from Cambridge CFAS
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Animals named in 1 min (mms>19) - CERAD data set
0
2
4
6
8
10
12
0 10 20 30 40
number of animals named
perc
ent o
f tot
al
Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380
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Classification Systems in Dementia
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• Short-term memory impairment AND dementia
• At least one of the following:
» Aphasia - language impairments
» Apraxia - motor memory impairments
» Agnosia - sensory memory impairments
» Abstract thinking / Exec. fn impairments
• Impairment in social and/or occupational function
• Not explainable by another disorder (such as delirium)
Dementia in DSMIV
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Dementia in ICD10
• Dementia (memory and thinking)
• Incidious onset > 6months
• Poor function
• Normal consciousness
• Executive dysfunction
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29.1DSM-III
17.3DSM-IIIR
13.7DSM-IV
5.0ICD-9
4.9CAMDEX
3.1ICD-10
% of CSHA populationCriteria (n=1879)Canadian Study of Health and Aging (CSHA)
Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. NEJM 1997 337(23):1667-74.
Diagnostic criteria & dementia prevalence
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Diagnostic criteria & dementia prevalence
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Vascular Dementia
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Small and Large Vessel Vascular SupplySmall and Large Vessel Vascular Supply
Blood vessels in human brain. A plastic emulsion was injected into brain vessels and brain tissue was dissolved. Zlokovic & Apuzzo: Neurosurgery 43(4):877-878, 1998.
Additional Behavioral Influences
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Vascular Dementia - SPECT
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Item Score
Sudden onset 2Stepwise deterioration 1Fluctuating course 2Nocturnal confusion 1Relative preservation of personality 1Depression 1Somatic complaints 1Emotional incontinence 1History of hypertension 1History of stroke 2Evidence of associated atherosclerosis 1
Focal neurological symptoms 2Focal neurological signs 2
Maximum = 187 : Vascular 5- 6 : Mixed < 4 : Alzheimer’s
Diagnosis - Hachinski Scale
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MRI Markers of SIVD
LacunarInfarction
White MatterHyperintensitie
s
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Clinical criteria for VaD
1. National Institutes of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN)
2. State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC)
3. Diagnostic and Statistical Manual of Mental Disorders. 4th
edition (DSM-IV)
4. Hachinski Ischemic scale
5. International Classification of Disease-10 (ICD-10)
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9420ICD-10
8843Hachinski
8450DSM-IV
64-9125-70ADDTC
80-9720-58NINDS-AIREN
Specificity %Sensitivity %Criteria
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Subtype of VaD
Macrovasculare thromboembolic (multi-infarct dementia )
Single strategic strokes
Multiple subcortical lacunar strokes ( lacunar state )
Extensive WMLs or Binswanger’s disease
Mixture of type 1,2,3,and 4 esp. lacunar-Binswanger
Postischemic dementia
Hemorrhagic dementia
Genetic cerebrovascular disease
Vascular-Alzheimer dementia
Vasculitides and other miscellaneous causes
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• 21.6% of VaD
• Large and medium vessels
– Carotid artery atherosclerosis
– MCA infarction
– watershed infarction
– Cardiac emboli
Multi-infarct dementia (MID)
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Lacunar Stroke
• 33-70 % of VaD
• Lenticulostriate branches (MCA) Thalamogeniculate, choroidal and thalamoperforator branches (PCA, Pcom)
• Frontal white matter 34.8%
• Basal ganglia 34.2%
• Pons 8%
• > 10-15 infarctions of deep structures
• 10 cm3 or 0.5% of intracranial volume
• >1/4 white matter
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Bilateral temporoparietalPatchy, global or frontalPET/SPECT
(hypometabolism )
Diffuse/ mesial temporal atrophy
WMLs and strokeMRI
noneFocal neuro deficitNeuro exam
Delusion, poor insightApathy, depression, emotional lability
Behavioral
Naming and comprehensionSentence complexity and prosody
Language
Worse memory, orientation and recognition
Retrieval and procedural memory
Memory
Visuospatial decline Frontal executive functionFinding
Recent memoryPsychomotor slowingMental status
Family hx, APOE4 alleleCerebrovascular risksRisk factors
Insidous and progressionAbrupt, stepwiseHistory
ADVaDComparison of Features
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Fronto-Temporal Dementia (Picks)
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Fronto-temporal Dementia
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Fronto-temporal Dementia
Progressive Non-Fluent Aphasia
(PNFA) Social/Executive
Semantic Dementia
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FTD Disease Progression
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Lewy Body Dementia + PDD
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2005 Consortium Criteria DLB – Important Criteria
• 1. Central feature (essential for a diagnosis of possible or probable DLB)• Dementia (progressive cognitive decline of sufficient magnitude to interfere with normal social or
occupational function)
• Prominent or persistent memory impairment• Deficits on tests of attention, executive function, and visuospatial ability may be
especially prominent.• 2. Core features (two core features are sufficient for a diagnosis of probable
DLB, one for possible DLB)• Fluctuating cognition with pronounced variations in attention and alertness• Recurrent visual hallucinations • Spontaneous features of parkinsonism• 3. Suggestive features (If one or more of these is present in the presence of one or
more core features, a diagnosis of probable DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone.)
• REM sleep behavior disorder• Severe neuroleptic sensitivity• Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET
imaging
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2005 Consortium Criteria DLB – Less Important Criteria
• 4. Supportive features (commonly present but not proven to have diagnostic specificity)
• Repeated falls and syncope• Transient, unexplained loss of consciousness• Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary incontinence• Hallucinations in other modalities• Systematized delusions• Depression• Relative preservation of medial temporal lobe structures on CT/MRI scan• Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity• Abnormal (low uptake) MIBG myocardial scintigraphy• Prominent slow wave activity on EEG with temporal lobe transient sharp waves• 5. A diagnosis of DLB is less likely• In the presence of cerebrovascular disease evident as focal neurologic signs or on
brain imaging• In the presence of any other physical illness or brain disorder sufficient to account in
part or in total for the clinical picture• If parkinsonism only appears for the first time at a stage of severe dementia
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Special Notes on PDD vs LBD
• DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term Parkinson
• disease dementia (PDD) should be used to describe dementia that occurs in the context of well-established Parkinson disease. In a practice setting the term that is most appropriate to the clinical situation should be used and generic terms such as LB disease are often helpful. In research studies in which distinction needs to be made between DLB and PDD, the existing 1-year rule between the
• onset of dementia and parkinsonism DLB continues to be recommended. Adoption of other time periods will simply confound data
• pooling or comparison between studies. In other research settings that may include clinicopathologic studies and clinical
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Gross Pathology in PD
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• Characteristic inclusions in substantia nigra neurons of patients with Parkinson’s disease
• Immunoreactive for neurofilaments, ubiquitin and alpha-synuclein, but not tau (NFT are tau and ubiquitin positive)
• In substantia nigra it is cytoplasmic, round, eosinophilic with clear halo
• In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistry
Lewy Body Inclusions
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Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
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Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
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Predictive Value of Consensus Criteria
Holmes 80 2 0.22 1.00 Prosp.Luis 56 23 0.65 0.90 Retro.Litvan 105 14 0.57 0.87 Retro McKeith 50 29 0.83 0.91 Prosp.Papka 40 19 0.43 xxx Retro McShane 102 9 0.58 0.89 Props.Mega 18 6 0.40 1.00 Retro.
Author Cases DLB Sens. Spec.Type
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Lewy Body vs Alzheimer Dementia
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Dementia Screening Tests (briefly)
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Types of Recognition
• Unassisted Clinical Ability
• Clinician Prompts» GDS, CDR
• Patient Complaints / Relatives QQ» Subjective Memory Complaints (SMC)
• Simple (Bedside) Single Item Cognitive Tests» Verbal fluency, Name & Address, Orientation
• Short Batteries» MMSE
• Long Batteries» CAMCOG
• Criterion Standard
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What Makes for a Good Screening Test?
• Often Examined» Rapid training & administration
» Simple scoring & interpretation
» Good rule-out accuracy, ideally good rule-in accuracy also
• Rarely Examined» High patient acceptance
» Multiple validation samples & settings
» Superiority to unassisted recognition
» Minimal bias => education, languageUK National Screening Committee (UK-NSC) www.nsc.nhs.uk/whatscreening/whatscreen_ind.htm
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GP Screening Preferences
• 74% of people consult a GP first after noticing symptoms of cognitive decline 3
• 82% of GPs say screening for dementia is worthwhile» but 24% routinely screen (GPs)
» 39% psychiatrists use the MMSE1
• 93% would use a brief effective tool2
1 Gilbody, House Sheldon (2002) Br J Psychiatry2 Bush et al Can Fam Physician. 19973 Wilkinson et al (2004);
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Memory Complaints
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Simple Memory Complaints Accuracy?
63.8
25.5
35.1
70.2
16
68.2
39.4
48.5
80.3
30.3
73.3
41.3
58
88
28
73.2
45.1
67.6
87.3
43.7
0
10
20
30
40
50
60
70
80
90
100
Forgetting where things areplaced
Unable to recall the names ofgood friends*
Unable to follow and recallconversation**
Subjective memory problems* Consider own memory to beworse than others of a similar
age**
ControlsMCIMCI=>DementiaAD (CDR1)
Lam et al. Int J Geriatr Psychiatry 2005; 20: 876–882. (n=306)
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Clinician Accuracy (using GDS)
Prevalence = 10%
96% (Sp)54% (se)
93% NPV25037Clinician No
71% PPV820Clinician Yes
Dementia
Absent
Dementia
Present
HEUN et al IJGP 1998
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Recognition of “Dementia” by GPs
12601148112
1202114458No dementia in notes
58454Dementia in notes
Dementia
ABSENT
Dementia (DSMIV)
Sensitivity48%
PPV 93%
Specificity99.6%
NPV 95%
Prevalence 8%
Using documentation of dementia in the medical notes
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Recognition Rate of Dementia by Severity
97%
73% 71%
46%
66%
33%
0
10
20
30
40
50
60
70
80
90
100
SevereDementia
(CI)
SevereDementia
(Dementia)
ModerateDementia
(CI)
ModerateDementia
(Dementia)
Milddementia
(CI)
Milddementia
(dementia)
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Predictors of Non-Recognition
• Good Activities of daily living
• Low years since symptoms first started
• Low presence of somatic comorbidity [Van Hout, 2002]
• male lived at home
• Coped better
• more depression
• milder dementiaDementia: Predictors of diagnostic accuracy and the contribution of diagnostic recommendations Author(s): van Hout HPJ, Vernooij-Dassen MJFJ, Hoefnagels WHL, Kuin Y, Stalman WAB, Moons KGM, Grol RPTM Source: JOURNAL OF FAMILY PRACTICE 51 (8): 693-699 AUG 2002
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Accuracy of MMSE (n=10,400 x 19)
Prevalence = 10%
86% (Sp)76% (se)
90% (NPV)6534669MMSE
No
68% (PPV)10052192MMSE
Yes
Dementia
Absent
Dementia
Present
ceiling =>
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MMSE Limitations
• Takes 8-13 minutes. Too long
• Scores are affected by age, ethnicity, language and education
• Little executive or memory
• Some GPs find it difficult to interpret
• Patients acceptability not the best
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Short Instruments
• 7 minute screen
• Short Form, Informant QQ on Cognitive Decline in the Elderly (short IQCODE)
• Abbreviated Mental Test (AMT)
• Cambridge Cognitive Examination (CAMCOG)
• Clock Drawing Test (CDT)
• Memory Impairment Screen (MIS)
• Mental Alternation Test (MAT)
• Mini-Cog
• Mini-Mental State Examination (MMSE)
• Short and Sweet Screening Instrument (SASSI)
• Short Test of Mental Status (STMS)
• The 6 Item Cognitive Impairment Test (6CIT)
• The General Practitioner Assessment of Cognition (GPCOG)
• The Rowland Universal Dementia Assessment Scale (RUDAS)
• Time and change Test (T&C)
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Pre-dementia and MCI (briefly)
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Dementia Prognosis
PRE-SYMPTOMATIC
PRE-CLINICAL
CLINICAL
Pathological Burden
Earl
y Sy
mpt
oms
Dia
gnos
is
Dis
ease
Sev
erit
y
Time in Years
T0T-5 T+10T-10 T+5
Dea
th
(Bra
in V
olu
me
/ In
trac
ran
ial V
olu
me)
80%
85%
90%
75%
70%
Further Reading: Fox NC, Crum WR, Scahill RI et al. (2001) Lancet 358, 201-205Imaging of onset and progression of Alzheimer’s disease with voxel compression of serial magnetic resonance images
Severe Dementia
Moderate Dementia
Mild Dementia
Mild Cognitive Impairment
23
30
20
12
(Min
i-M
enta
l Sta
te E
xam
inat
ion
Sco
re)
Dia
gnos
is
Dea
th
Unmodified Dementia
Dementia with Risk Factors
ExplanationSee text for details
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Dementia Treatment
PRE-SYMPTOMATICPRE-CLINICAL
CLINICAL
Severe Dementia
Moderate Dementia
Mild Dementia
Earl
y Sy
mpt
oms
Dia
gnos
is
Dis
ease
Sev
erit
y
Time in Years
T0
T-5 T+10T-10 T+5
Mild Cognitive Impairment
Car
e
(Bra
in V
olu
me
/ In
trac
ran
ial V
olu
me)
80%
85%
90%
75%
70%
Inst
itu
tion
al C
are
23
30
20
12
((M
ini-
Men
tal S
tate
Exa
min
atio
n S
core
)
T+15
Treatment B
Treatment A
Treatment C
Unmodified
Car
e
Car
e
ExplanationSee text for details
Pathological Burden
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Biochemical Progression of AD-Tau
Delacourte, Andre. The natural and molecular history of Alzheimer’s disease. J Alzheimer’s Disease 2006;9:1
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Clin
ical
cla
ssifi
catio
nC
linic
al c
lass
ifica
tion
EtiologyEtiology
MCIAmnestic
MCIMultipleDomain
MCI SingleNon-memoryDomain
Deg
ener
ativ
e
Vas
cula
r
Met
abol
ic
Trau
mat
ic
Heterogeneity of MCI from clinical and etiological perspectives.Open cells are most common.