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 Dementias Validity of criteria for diagnosing subtypes of dementia
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MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
This is a presentation on the science behind diagnosis of dementias (inc alzheimer's, FTD, lewy body). The take home message is that our clinical accuracy is modest. Includes images from several sources. Delivered to MRCPsych Leicester 2009
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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
2
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)
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
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)
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.
SPECT Scan
Healthy AD
What Makes a Diagnosis Correct?
Density of Plaques and Tangles
Progression of Plaques and tangles by region and diagnostic accuracy of p-tau from Mitchell JNNP (2009)
Rate of memory decline increases 5.1 years before dementia diagnosis (Hall et al, 2000)
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.
MMSE modest sensitivity and specificity in dementia vs no dementia.Data from Cambridge CFAS
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
Classification Systems in Dementia
• 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
Dementia in ICD10
• Dementia (memory and thinking)
• Incidious onset > 6months
• Poor function
• Normal consciousness
• Executive dysfunction
50
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
Diagnostic criteria & dementia prevalence
Vascular Dementia
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
Vascular Dementia - SPECT
55
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
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)
Family hx, APOE4 alleleCerebrovascular risksRisk factors
Insidous and progressionAbrupt, stepwiseHistory
ADVaDComparison of Features
Fronto-Temporal Dementia (Picks)
Fronto-temporal Dementia
Fronto-temporal Dementia
Progressive Non-Fluent Aphasia
(PNFA) Social/Executive
Semantic Dementia
FTD Disease Progression
Lewy Body Dementia + PDD
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
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
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
Gross Pathology in PD
• 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
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
• 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);
Memory Complaints
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)
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
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
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)
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
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 =>
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
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)
Pre-dementia and MCI (briefly)
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
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
Biochemical Progression of AD-Tau
Delacourte, Andre. The natural and molecular history of Alzheimer’s disease. J Alzheimer’s Disease 2006;9:1
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.