Evidence Based Diagnosis of the Dementias
Evidence Based Diagnosis of the Dementias
Validity of criteria for diagnosing su...
Pragmatic definition of dementia

•   Dementia is an acquired global impairment of intellectual functioning
•   Involving ...
Concepts of Screening

• Screening (possible case)       High convenience
  » Eg MMSE
• Case-Finding (probable case)
  » E...
Concepts of Dementia


                                        High convenience
• Symptoms and signs
• Detailed symptoms (...
Clinical Classification of Dementia
Neurodegenerative Disorders
                                                                    Neurodegenerative Disorder...
Primer on Forgotten Neuroanatomy!
Higher Cortical Functions and Association Cortices




  Attending

  Selecting

  Recognizing
                  Associati...
The “Association Cortices” have a distinctive neocortex



Cortical Maps: Brodmann




                                   ...
Introduction to Dementias
Distribution of AD in Different Settings



       AD in the Community   AD within Institutions



                Moderat...
Probability of Institutionalization by Severity


                           1.0
                                         ...
Outcome measures used in Alzheimer’s Disease


                                                               ADAS-Cog
   ...
Dementia Clinical Serie
Primer on Neuropsychology of Memory

                                                              Registration



       ...
Overview of Main Symptoms in Dementias

                  Memory   Language   Visuospatial Attention Behavioural Neurologi...
Alzheimer’s disease
 Auguste D, November 3, 1906
37th Assembly of Southwest German Psychiatrists in Tübingen, Germany
    ...
History of AD

•   1906 Alzheimer presented Auguste D
•   1910 Kraepelin Coined “Alzheimer’s disease” (Psychiatrie: Ein Le...
Gross Pathology - AD
Gross Pathology in Alzheimer’s



          Loss of
           tissue




  Wide Sulci




            Large
          ven...
CT Scan



            Loss of
             tissue




      Wide Sulci



            Large
          ventricles




    ...
CT Scan 2




      Normal Aging       Alzheimer’s Disease
     (coronal section)    (coronal section)
Microscopic Pathology
Neurofibrillary
           Tangles
Neurons have an internal support structure partly
made up of microtubules. A protein ca...
SPECT Scan




       Healthy   AD
What Makes a Diagnosis Correct?
Density of Plaques and Tangles




       Progression of Plaques and
       tangles by region and diagnostic
       accura...
Rate of memory decline increases 5.1 years before dementia diagnosis (Hall et al, 2000)
Healthy Elderly
Mild Cognitive Impairment
Alzheimer’s disease
Clock Drawing - Examples




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



l...
Primer on the Science of Classification
Simple Measures of Accuracy

             Dementia      Dementia
             PRESENT       ABSENT

  Test +ve   True +ve ...
Theory of Diagnostic Tests


                                                                                         Poin...
Ganguli M et al. Detection and Management of Cognitive Impairment in Primary Care: The Steel Valley Seniors Survey. JAGS 5...
MMSE modest sensitivity and
specificity in dementia vs no
dementia.
Data from Cambridge CFAS
Anim als nam ed in 1 m in (m m s>19) - CERAD data set


                   12

                   10
percent of total




...
Classification Systems in Dementia
Dementia in DSMIV

• Short-term memory impairment AND dementia
• At least one of the following:
   » Aphasia - language im...
Dementia in ICD10

• Dementia (memory and thinking)
• Incidious onset > 6months
• Poor function
• Normal consciousness
• E...
Diagnostic criteria & dementia prevalence


                                                Canadian Study of Health and A...
Diagnostic criteria & dementia prevalence
Vascular Dementia
Additional Behavioral Influences
Small and Large Vessel Vascular Supply




Blood vessels in human brain. A plastic emulsi...
Vascular Dementia - SPECT
Diagnosis - Hachinski Scale


                      Item                                     Score

                      ...
MRI Markers of SIVD



   Lacunar
  Infarction




 White Matter
Hyperintensitie
      s
Clinical criteria for VaD

   1.   National Institutes of Neurological Disorders and Stroke-
        Association Internati...
Criteria   Sensitivity %   Specificity %

NINDS-AIREN       20-58           80-97



ADDTC             25-70           64-...
Subtype of VaD

      Macrovasculare thromboembolic (multi-infarct dementia )
      Single strategic strokes
      Multipl...
Multi-infarct dementia (MID)

   • 21.6% of VaD
   • Large and medium vessels
   – Carotid artery atherosclerosis
   – MCA...
Lacunar Stroke

• 33-70 % of VaD
• Lenticulostriate branches (MCA)
  Thalamogeniculate, choroidal and
  thalamoperforator ...
Comparison of                VaD                            AD
     Features
History             Abrupt, stepwise         ...
Fronto-Temporal Dementia (Picks)
Fronto-temporal Dementia
Fronto-temporal Dementia




                                               Semantic Dementia
   Progressive Non-Fluent
  ...
FTD Disease Progression
Lewy Body Dementia + PDD
2005 Consortium Criteria DLB – Important Criteria

•   1. Central feature (essential for a diagnosis of possible or probab...
2005 Consortium Criteria DLB – Less Important Criteria

•   4. Supportive features (commonly present but not proven to hav...
Special Notes on PDD vs LBD
•   DLB should be diagnosed when dementia occurs before or concurrently with
    parkinsonism ...
Gross Pathology in PD
Lewy Body Inclusions

 • Characteristic inclusions in substantia nigra neurons of
   patients with Parkinson’s disease
 • ...
Pathology in Parkinson’s Disease
Pathology in Parkinson’s Disease
Predictive Value of Consensus Criteria



    Author      Cases   DLB    Sens.      Spec.
    Type
       Holmes    80    ...
Lewy Body vs Alzheimer Dementia
Dementia Screening Tests (briefly)
Types of Recognition

• Unassisted Clinical Ability
• Clinician Prompts
   » GDS, CDR
• Patient Complaints / Relatives QQ
...
What Makes for a Good Screening Test?

• Often Examined
     » Rapid training & administration
     » Simple scoring & int...
GP Screening Preferences

• 74% of people consult a GP first after noticing
  symptoms of cognitive decline 3


• 82% of G...
Memory Complaints
Simple Memory Complaints Accuracy?
  Lam et al. Int J Geriatr Psychiatry 2005; 20: 876–882. (n=306)

100



 90           ...
Clinician Accuracy (using GDS)
 HEUN et al IJGP 1998
                Dementia   Dementia
                Present    Absent...
Recognition of “Dementia” by GPs
Using documentation of dementia in the medical notes
                  Dementia         D...
Recognition Rate of Dementia by Severity


100     97%

90


80
                    73%
                                 7...
Predictors of Non-Recognition

• Good Activities of daily living
• Low years since symptoms first started
• Low presence o...
Accuracy of MMSE (n=10,400 x 19)

            Dementia   Dementia
            Present    Absent



 MMSE       2192       ...
MMSE Limitations

• Takes 8-13 minutes. Too long


• Scores are affected by age, ethnicity, language and education


• Lit...
Short Instruments
•   7 minute screen                    •   Mini-Mental State Examination
                               ...
Pre-dementia and MCI (briefly)
Dementia Prognosis




                                                                                       Early Sympto...
Dementia Treatment




                                                                                          Early Sym...
Biochemical Progression of AD-Tau




                Delacourte, Andre. The natural and molecular history of Alzheimer’s ...
tive




                                                                                             tic
                ...
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)
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MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)

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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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MCRPsych09 - Evidence Based Diagnosis of Dementias (Nov09)

  1. 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. 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. 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. 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. 5. Clinical Classification of Dementia
  6. 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. 7. Primer on Forgotten Neuroanatomy!
  8. 8. Higher Cortical Functions and Association Cortices Attending Selecting Recognizing Association cortices = cognition Imitating Remembering
  9. 9. The “Association Cortices” have a distinctive neocortex Cortical Maps: Brodmann Lateral Neocortex ~50 regions Medial Cytoarchitecture = Cell packing density and type
  10. 10. Introduction to Dementias
  11. 11. 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.
  12. 12. 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
  13. 13. 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
  14. 14. Dementia Clinical Serie
  15. 15. 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
  16. 16. 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
  17. 17. 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”
  18. 18. 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
  19. 19. Gross Pathology - AD
  20. 20. Gross Pathology in Alzheimer’s Loss of tissue Wide Sulci Large ventricles 25
  21. 21. CT Scan Loss of tissue Wide Sulci Large ventricles 26
  22. 22. CT Scan 2 Normal Aging Alzheimer’s Disease (coronal section) (coronal section)
  23. 23. Microscopic Pathology
  24. 24. 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.
  25. 25. SPECT Scan Healthy AD
  26. 26. What Makes a Diagnosis Correct?
  27. 27. Density of Plaques and Tangles Progression of Plaques and tangles by region and diagnostic accuracy of p-tau from Mitchell JNNP (2009)
  28. 28. Rate of memory decline increases 5.1 years before dementia diagnosis (Hall et al, 2000)
  29. 29. Healthy Elderly
  30. 30. Mild Cognitive Impairment
  31. 31. Alzheimer’s disease
  32. 32. Clock Drawing - Examples http://www.dementiaguide.com/images/DGI-Ill_5.1-ClockDrawing.jpg ltcif_cog_screen_0809 39
  33. 33. Primer on the Science of Classification
  34. 34. 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
  35. 35. 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
  36. 36. 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)
  37. 37. MMSE modest sensitivity and specificity in dementia vs no dementia. Data from Cambridge CFAS
  38. 38. 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
  39. 39. Classification Systems in Dementia
  40. 40. 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)
  41. 41. Dementia in ICD10 • Dementia (memory and thinking) • Incidious onset > 6months • Poor function • Normal consciousness • Executive dysfunction
  42. 42. 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
  43. 43. Diagnostic criteria & dementia prevalence
  44. 44. Vascular Dementia
  45. 45. 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.
  46. 46. Vascular Dementia - SPECT
  47. 47. 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
  48. 48. MRI Markers of SIVD Lacunar Infarction White Matter Hyperintensitie s
  49. 49. 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)
  50. 50. 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
  51. 51. 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
  52. 52. Multi-infarct dementia (MID) • 21.6% of VaD • Large and medium vessels – Carotid artery atherosclerosis – MCA infarction – watershed infarction – Cardiac emboli
  53. 53. 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
  54. 54. 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 )
  55. 55. Fronto-Temporal Dementia (Picks)
  56. 56. Fronto-temporal Dementia
  57. 57. Fronto-temporal Dementia Semantic Dementia Progressive Non-Fluent Aphasia (PNFA) Social/Executive
  58. 58. FTD Disease Progression
  59. 59. Lewy Body Dementia + PDD
  60. 60. 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
  61. 61. 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
  62. 62. 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
  63. 63. Gross Pathology in PD
  64. 64. 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
  65. 65. Pathology in Parkinson’s Disease
  66. 66. Pathology in Parkinson’s Disease
  67. 67. 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.
  68. 68. Lewy Body vs Alzheimer Dementia
  69. 69. Dementia Screening Tests (briefly)
  70. 70. 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
  71. 71. 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
  72. 72. 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);
  73. 73. Memory Complaints
  74. 74. 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**
  75. 75. 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%
  76. 76. 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%
  77. 77. 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)
  78. 78. 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
  79. 79. 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 =>
  80. 80. 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
  81. 81. 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)
  82. 82. Pre-dementia and MCI (briefly)
  83. 83. 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
  84. 84. 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
  85. 85. Biochemical Progression of AD-Tau Delacourte, Andre. The natural and molecular history of Alzheimer’s disease. J Alzheimer’s Disease 2006;9:1
  86. 86. 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.

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