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)

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

Concepts of Dementia

• Symptoms and signs

• Detailed symptoms (neuropsychology)

• Gross pathology

• In vivo pathology (neuroimaging)

• Microscopic pathology

• Immunochemistry

• Genetics High accuracy

High convenience

Clinical Classification of Dementia

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

Primer on Forgotten Neuroanatomy!

Higher Cortical Functions and Association Cortices

Attending

Selecting

Recognizing

Imitating

Remembering

Association cortices = cognition

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

Introduction to Dementias

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%

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

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

Dementia Clinical Serie

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

20

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

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

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

Gross Pathology - AD

25

Large ventricles

Wide Sulci

Loss of tissue

Gross Pathology in Alzheimer’s

26

Loss of tissue

Wide Sulci

Large ventricles

CT Scan

CT Scan 2

Normal Aging(coronal section)

Alzheimer’s Disease

(coronal section)

Microscopic Pathology

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.

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)

Healthy Elderly

Mild Cognitive Impairment

Alzheimer’s disease

39ltcif_cog_screen_0809

Clock Drawing - Examples

http://www.dementiaguide.com/images/DGI-Ill_5.1-ClockDrawing.jpg

Primer on the Science of Classification

PrevalenceSpecificitySensitivity

NPVTrue -VeFalse -VeTest -ve

PPVFalse +veTrue +veTest +ve

Dementia

ABSENT

Dementia

PRESENT

Simple Measures of Accuracy

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

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

Focal neurological symptoms 2Focal neurological signs 2

Maximum = 187 : Vascular 5- 6 : Mixed < 4 : Alzheimer’s

Diagnosis - Hachinski Scale

MRI Markers of SIVD

LacunarInfarction

White MatterHyperintensitie

s

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)

9420ICD-10

8843Hachinski

8450DSM-IV

64-9125-70ADDTC

80-9720-58NINDS-AIREN

Specificity %Sensitivity %Criteria

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

• 21.6% of VaD

• Large and medium vessels

– Carotid artery atherosclerosis

– MCA infarction

– watershed infarction

– Cardiac emboli

Multi-infarct dementia (MID)

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

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

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

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

Lewy Body vs Alzheimer Dementia

Dementia Screening Tests (briefly)

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

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

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);

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.