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

1. Evidence Based Diagnosis of the Dementias
Evidence Based Diagnosis of the Dementias
Validity of criteria for diagnosing subtypes of dementia
Validity of criteria for diagnosing subtypes of dementia
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

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)
2

3. Concepts of Screening
• Screening (possible case) High convenience
» Eg MMSE
• Case-Finding (probable case)
» Eg NINCDS-ADRDA criteria,
• Severity Rating
» Eg ADAS-Cog
• Gold Standard (definite case)
» Pathology => disease High accuracy

4. Concepts of Dementia
High convenience
• Symptoms and signs
• Detailed symptoms (neuropsychology)
• Gross pathology
• In vivo pathology (neuroimaging)
• Microscopic pathology
• Immunochemistry
• Genetics High accuracy

5. Clinical Classification of Dementia

6. Neurodegenerative Disorders
Neurodegenerative Disorders
Intraneuronal Extracellular
Prion Protein Beta-Amyloid
Cytoplasmic/Neuri
Intracellular Creutzfeldt-Jakob disease Alzheimer’s disease
tic
Polyglutamine disorders α-
Ubiquitin disorders
synucleinopathies
Huntington’s disease Motor Neuron Disease Parkinson’s disease
SBMA Motor Neuron Dementia Lewy Body Dementia
Spinocerebellar ataxia 1, 3, 7 Frontotemporal dementia (MND-type) Multiple System Atrophy
dentatorubral-pallidoluysian atrophy
Neuroaxonal dystrophy
Tauopathies
Triplet Band Double Band
Taupathies Taupathies
Triplet-Band Predominanty 4- Predominanty 3-
Tauopathies repeats repeats
Normal Aging Progressive Supranuclear Palsy Pick’s disease
Alzheimer’s disease Corticobasal Degeneration
Down’s Syndrome MSTD, PPND
NPC, PEP, GSS Duke Family 1, 1684
ALS/PDC
Microcellular Classification of Dementia

7. Primer on Forgotten Neuroanatomy!

10. Higher Cortical Functions and Association Cortices
Attending
Selecting
Recognizing
Association cortices = cognition
Imitating
Remembering

11. The “Association Cortices” have a distinctive neocortex
Cortical Maps: Brodmann
Lateral
Neocortex
~50 regions
Medial
Cytoarchitecture = Cell packing density and type

12. Introduction to Dementias

13. Distribution of AD in Different Settings
AD in the Community AD within Institutions
Moderate Moderate
44% 34%
Mild Severe
46% Mild
55%
11%
Severe
10%
CSHA Working Group, CMAJ, 1994.
CSHA Working Group, Can J Aging, 1994.

14. Probability of Institutionalization by Severity
1.0
0.867
0.8
Institutionalization
Probability of
0.6
0.4 0.345
0.2
0.017
0.0
Mild Moderate Severe
(MMSE: 21–30) (MMSE: 11–20) (MMSE: 0–10)
Severity of AD
Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):35

15. Outcome measures used in Alzheimer’s Disease
ADAS-Cog
Cognition Function Alzheimer’s Disease
(ADAS-Cog) (DAD/ADCS- Assessment Scale, Cognitive
ADL) subscale
Global CIBIC-plus
(CIBIC-plus) Clinician Interview-Based
Impression of Change with
Caregiver Input
DAD
Disability Assessment in
Dementia
Behaviour
ADCS-ADL
(NPI) Alzheimer's Disease Co-
Operative Study – Activities of
Daily Living
NPI *
Caregiver burden Neuropsychiatric Inventory
*Contains subscale NPI-D, which measures caregiver distress SCGB
Screen for Caregiver Burden

16. Dementia Clinical Serie

19. Primer on Neuropsychology of Memory
Registration
Memory
Retrieval
Retention
Implicit Declarative
Learning of
Learning of Skills & Automatic Behaviours
Information
Working Memory Short-term Memory Long-term Memory
Retention over Seconds Retention over Minutes Retention over days
Motor Conditioning Priming
Visuospatial Verbal Semantic Memory Episodic Memory
Database of information Narrative Account

20. Overview of Main Symptoms in Dementias
Memory Language Visuospatial Attention Behavioural Neurological
A.D. ++++ ++ ++ ++ + ±
DLB/PDD. ++ + ++++ +++ + ++
FTD - Semantic + ++++ ± + + ±
FTD - Frontal + + ± ++ ++++ ±
FTD - P.N.F.A. ± ++++ ± + + ±
Corticobasal + + +++ ++ ++ +++
PSP. + + + +++ ++ +++
Huntington's + + + +++ ++ +++
20

22. Alzheimer’s disease
Auguste D, November 3, 1906
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”

23. 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

24. Gross Pathology - AD

25. Gross Pathology in Alzheimer’s
Loss of
tissue
Wide Sulci
Large
ventricles
25

26. CT Scan
Loss of
tissue
Wide Sulci
Large
ventricles
26

27. CT Scan 2
Normal Aging Alzheimer’s Disease
(coronal section) (coronal section)

28. Microscopic Pathology

29. Neurofibrillary
Tangles
Neurons have an internal support structure partly
made up of microtubules. A protein called tau
helps stabilize microtubules. In AD, tau changes,
causing microtubules to collapse, and tau
proteins clump together to form neurofibrillary
tangles.

31. SPECT Scan
Healthy AD

32. What Makes a Diagnosis Correct?

34. Density of Plaques and Tangles
Progression of Plaques and
tangles by region and diagnostic
accuracy of p-tau from Mitchell
JNNP (2009)

35. Rate of memory decline increases 5.1 years before dementia diagnosis (Hall et al, 2000)

36. Healthy Elderly

37. Mild Cognitive Impairment

38. Alzheimer’s disease

39. Clock Drawing - Examples
http://www.dementiaguide.com/images/DGI-Ill_5.1-ClockDrawing.jpg
ltcif_cog_screen_0809 39

40. Primer on the Science of Classification

41. Simple Measures of Accuracy
Dementia Dementia
PRESENT ABSENT
Test +ve True +ve False +ve PPV
Test -ve False -Ve True -Ve NPV
Sensitivity Specificity Prevalence

42. Theory of Diagnostic Tests
Point of Partial Rarity?
Number
of Cognitive Impairment
Individuals
Dementia
True ‐ve
True ‐ve
True +ve
True +ve
False ‐ve
False ‐ve False +ve
False +ve
Score on Hypothetical Diagnostic Test Optimum Cut‐off value

43. Ganguli M et al. Detection and Management of Cognitive Impairment in Primary Care: The Steel Valley Seniors Survey. JAGS 52:1668–1675, 2004.
GP Testing by Actual MMSE Score (n=162)

44. MMSE modest sensitivity and
specificity in dementia vs no
dementia.
Data from Cambridge CFAS

45. Anim als nam ed in 1 m in (m m s>19) - CERAD data set
12
10
percent of total
8
6
4
2
0
0 10 20 30 40
num ber of anim als nam ed
Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380

46. Classification Systems in Dementia

47. Dementia in DSMIV
• 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)

48. Dementia in ICD10
• Dementia (memory and thinking)
• Incidious onset > 6months
• Poor function
• Normal consciousness
• Executive dysfunction

50. Diagnostic criteria & dementia prevalence
Canadian Study of Health and Aging (CSHA)
Criteria (n=1879) % of CSHA population
ICD-10 3.1
CAMDEX 4.9
ICD-9 5.0
DSM-IV 13.7
DSM-IIIR 17.3
DSM-III 29.1
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.
50

51. Diagnostic criteria & dementia prevalence

52. Vascular Dementia

53. Additional Behavioral Influences
Small 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.

54. Vascular Dementia - SPECT

55. Diagnosis - Hachinski Scale
Item Score
Sudden onset 2
Stepwise deterioration 1
Fluctuating course 2
Nocturnal confusion 1
Relative preservation of personality 1
Depression 1
Somatic complaints 1
Emotional incontinence 1
History of hypertension 1
History of stroke 2
Evidence of associated atherosclerosis 1
Maximum = 18 Focal neurological symptoms 2
7 : Vascular Focal neurological signs 2
5- 6 : Mixed
< 4 : Alzheimer’s
55

56. MRI Markers of SIVD
Lacunar
Infarction
White Matter
Hyperintensitie
s

57. 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)

61. Criteria Sensitivity % Specificity %
NINDS-AIREN 20-58 80-97
ADDTC 25-70 64-91
DSM-IV 50 84
Hachinski 43 88
ICD-10 20 94

62. 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

63. Multi-infarct dementia (MID)
• 21.6% of VaD
• Large and medium vessels
– Carotid artery atherosclerosis
– MCA infarction
– watershed infarction
– Cardiac emboli

64. 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

65. Comparison of VaD AD
Features
History Abrupt, stepwise Insidous and progression
Risk factors Cerebrovascular risks Family hx, APOE4 allele
Mental status Psychomotor slowing Recent memory
Finding Frontal executive function Visuospatial decline
Memory Retrieval and procedural Worse memory, orientation
memory and recognition
Language Sentence complexity and Naming and comprehension
prosody
Behavioral Apathy, depression, Delusion, poor insight
emotional lability
Neuro exam Focal neuro deficit none
MRI WMLs and stroke Diffuse/ mesial temporal
atrophy
PET/SPECT Patchy, global or frontal Bilateral temporoparietal
(hypometabolism )

66. Fronto-Temporal Dementia (Picks)

67. Fronto-temporal Dementia

68. Fronto-temporal Dementia
Semantic Dementia
Progressive Non-Fluent
Aphasia
(PNFA) Social/Executive

69. FTD Disease Progression

71. Lewy Body Dementia + PDD

72. 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

73. 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

74. 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

76. Gross Pathology in PD

77. Lewy Body Inclusions
• 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

78. Pathology in Parkinson’s Disease

79. Pathology in Parkinson’s Disease

80. Predictive Value of Consensus Criteria
Author Cases DLB Sens. Spec.
Type
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.

81. Lewy Body vs Alzheimer Dementia

83. Dementia Screening Tests (briefly)

84. 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

85. 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, language
UK National Screening Committee (UK-NSC) www.nsc.nhs.uk/whatscreening/whatscreen_ind.htm

86. 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 Psychiatry
2 Bush et al Can Fam Physician. 1997
3 Wilkinson et al (2004);

87. Memory Complaints

88. Simple Memory Complaints Accuracy?
Lam et al. Int J Geriatr Psychiatry 2005; 20: 876–882. (n=306)
100
90 88 87.3
Controls 80.3
80
MCI
73.3 73.2
MCI=>Dementia 70.2
70 68.2 67.6
AD (CDR1)
63.8
60 58
48.5
50
45.1
43.7
41.3
39.4
40
35.1
30.3
30 28
25.5
20
16
10
0
Forgetting w here things are Unable to recall the nam es of Unable to follow and recall Subjective m em ory problem s* Consider ow n m em ory to be
placed good friends* conversation** w orse than others of a sim ilar
age**

89. Clinician Accuracy (using GDS)
HEUN et al IJGP 1998
Dementia Dementia
Present Absent
Clinician 20 8 71% PPV
Yes
Clinician No 37 250 93% NPV
54% (se) 96% (Sp) Prevalence =
10%

90. Recognition of “Dementia” by GPs
Using documentation of dementia in the medical notes
Dementia Dementia
(DSMIV)
ABSENT
Dementia in 54 4 58
notes
PPV 93%
No dementia in 58 1144 1202
notes
NPV 95%
112 1148 1260
Sensitivity Specificity
Prevalence 8%
48% 99.6%

91. Recognition Rate of Dementia by Severity
100 97%
90
80
73%
71%
70 66%
60
50 46%
40
33%
30
20
10
0
Severe Severe Moderate Moderate Mild Mild
Dementia Dementia Dementia Dementia dementia dementia
(CI) (Dementia) (CI) (Dementia) (CI) (dementia)

92. 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 Dementia: Predictors of diagnostic accuracy and the
contribution of diagnostic recommendations
Author(s): van Hout HPJ, Vernooij-Dassen MJFJ,
• milder dementia Hoefnagels WHL, Kuin Y, Stalman WAB, Moons
KGM, Grol RPTM
Source: JOURNAL OF FAMILY PRACTICE 51 (8):
693-699 AUG 2002

93. Accuracy of MMSE (n=10,400 x 19)
Dementia Dementia
Present Absent
MMSE 2192 1005 68% (PPV)
Yes
MMSE 669 6534 90% (NPV)
No
76% (se) 86% (Sp) Prevalence =
10%
ceiling =>

94. 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

95. Short Instruments
• 7 minute screen • Mini-Mental State Examination
(MMSE)
• Short Form, Informant QQ on
Cognitive Decline in the Elderly • Short and Sweet Screening
(short IQCODE) Instrument (SASSI)
• Abbreviated Mental Test (AMT) • Short Test of Mental Status
(STMS)
• Cambridge Cognitive
Examination (CAMCOG) • The 6 Item Cognitive Impairment
Test (6CIT)
• Clock Drawing Test (CDT)
• The General Practitioner
• Memory Impairment Screen
Assessment of Cognition
(MIS)
(GPCOG)
• Mental Alternation Test (MAT)
• The Rowland Universal
• Mini-Cog Dementia Assessment Scale
(RUDAS)
• Time and change Test (T&C)

96. Pre-dementia and MCI (briefly)

98. Dementia Prognosis
Early Symptoms
90%
(Mini-Mental State Examination Score)
(Brain Volume / Intracranial Volume)
Pathological Burden
30
PRE-SYMPTOMATIC
Diagnosis
Diagnosis
85% PRE-CLINICAL
Mild Cognitive Impairment
Death
Death
80% 23
CLINICAL
Mild Dementia
75%
Disease Severity
20
Moderate Dementia
Unmodified Dementia
70%
12
Dementia with Risk Factors
Severe Dementia
T-10 T-5 T0 T+5 T+10
Time in Years Explanation
See text for details
Further Reading: Fox NC, Crum WR, Scahill RI et al. (2001) Lancet 358, 201-205
Imaging of onset and progression of Alzheimer’s disease with voxel compression of serial magnetic resonance images

99. Dementia Treatment
Early Symptoms
90% Pathological Burden
30
((Mini-Mental State Examination Score)
(Brain Volume / Intracranial Volume)
PRE-SYMPTOMATIC
Diagnosis
PRE-CLINICAL
85%
Institutional Care
CLINICAL
Mild Cognitive Impairment
Unmodified 23
80%
Treatment A
Treatment B
Mild Dementia
75%
Care
Treatment C 20
Disease Severity
Care
Moderate Dementia
Care
70%
12
Severe Dementia
T-10 T-5 T T+5 T+10 T+15
0
Time in Years Explanation
See text for details

100. Biochemical Progression of AD-Tau
Delacourte, Andre. The natural and molecular history of Alzheimer’s disease. J Alzheimer’s Disease 2006;9:1

101. tive
tic
olic
r
ra
cula
Etiology
uma
ene
tab
Vas
Deg
Me
Tra
MCI
Clinical classifi cation
Amnestic
MCI
Multiple
Domain
MCI Single
Non-memory
Domain
Heterogeneity of MCI from clinical and etiological perspectives.
Open cells are most common.