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  • Novita’ cliniche e medico-nucleari nella demenza con corpi di Lewy

    Pietro Tiraboschi Pesaro, 27 settembre 2012

  • Dementia With Lewy Bodies — DLB

    • 15% to 20% of all dementia in the elderly

    • Onset ~75 years (50-83)

    • Duration ~5.5 years (

  • A brief history of Lewy bodies and dementia

    1912: Lewy observes Lewy bodies (LB) in patients with paralysis agitans

    Girl Running on a Balcony Giacomo Balla 1912 Galleria Civica d'Arte Moderna Milan, Italy

    Ian McKeith, Milan, November 18, 2006

    http://tvm.tigtail.org/TIG/S_View/TVM/B/European/a.%20pre%20WW%20I/Italian-Greek/balla/M/balla_girl_running_on_balcony.1912.jpg

  • A brief history of Lewy bodies and dementia

    1961: Okazaki links LB to dementia, hallucinations and rigidity

    1961 Lambretta Li125, Series 2. Innocenti, Milan, Italy

    Ian McKeith, Milan, November 18, 2006

    http://images.google.co.uk/imgres?imgurl=http://www.maxmatic.com/Graphics/li125s2.jpg&imgrefurl=http://www.maxmatic.com/scooters.htm&h=402&w=600&sz=46&hl=en&start=5&tbnid=bSiURozQNVtD5M:&tbnh=90&tbnw=135&prev=/images?q=milan+italy+1961&svnum=10&h

  • A brief history of Lewy bodies and dementia

    1976 Kosaka reports case series in Japan with dementia, delusions, hallucinations, +/- EPMS - associated with diffuse Lewy body disease +/- AD pathology

    Ian McKeith, Milan, November 18, 2006

  • A brief history of Lewy bodies and dementia

    • 1980s – Multiple Nomenclatures

     Diffuse cortical LB disease -Gibb 1987

     AD with PD changes - Ditter 1987

     AD with incidental LB - Joachim 1988

     Diffuse Lewy Body Disease – Kosaka 1990

     LB variant of AD - Hansen 1990

     Senile dementia of LB type - Perry 1990

    • 1996 - The First Report of the International Consortium on Dementia with Lewy bodies (DLB)

  • Neuropathologic antecedents of DLB

    SDLT Perry

    J Neurol Sci ‘90

    LBV Hansen

    Neurology ‘90

    (D)LBD Kosaka

    J Neurol ’90

    Lewy bodies

    Diffuse

    Diffuse

    1. Brainstem 2. Limbic 3. Neocortical

    Neuritic Plaques

    Present

    Present

    1. Present (common form)

    2. Absent (pure form)

    Neocortical Tangles Occasional Occasional Occasional

  • Neuropathology of dementia with Lewy bodies (DLB) Consensus Criteria, McKeith et al., Neurology ‘96

    • Requisite for diagnosis  Lewy bodies

    • Typically associated findings (not necessary for diagnosis):  Lewy neurites

     Plaques, all subtypes

     Tangles, usually confined to midtemporal lobe (Braak ≤ IV)

     Regional neuron loss and gliosis  Substantia nigra (SN), locus coeruleus (LC), nucleus basalis of Meynert (nbM)

     Spongiform vacuolization of neuropil

     Neurochemical abnormalities and neurotransmitter deficits

  • Clinical diagnosis of Dementia with Lewy bodies (DLB): Consortium on DLB criteria (1996)

    • Main Clinical Features

    • Cognitive decline with at least 2 of the following:

    • Fluctuations (cognitive function and level of consciousness) • Hallucinations (usually visual and well-formed) • Spontaneous extrapyramidal signs

    • Other common signs and symptoms (supportive):

    • Repeated falls • Syncope • Transient loss of consciousness • Sleep disturbances including REM sleep behavior • Delusions • Hallucinations in other modalities • Neuroleptic sensitivity • Myoclonus • Autonomic Dysfunction

  • 1996 Consensus Diagnostic Criteria for “probable DLB”: validation studies

    0.95 1.00

    0.83 0.31

    50 26

    Prospective: McKeith, Neurology ’00 Lopez, Arch Neurol ’02

    1.00 0.87 1.00 0.90 0.84

    0.40 0.57 0.22 0.65 0.61

    18 105 80 56 18

    Retrospective:

    Mega, Neurology ’96 Litvan, Arch Neurol ’98 Holmes, Br J Psychiatry ’99 Luis, Int J Geriatr Psychiatry ’99 Verghese, Neurology ’99

    Specificity Sensitivity N Study

    The presence of  2 core features is strongly predictive of cortical LB pathology,

    BUT few patients with dementia and LB pathology show > 1 core clinical feature.

    As a result, DLB is under-recognized

  • Braak stage cohorts and clinical features Merdes et al., Neurology 2003;60:1586-1590

    0.12

    2.46

    23 (35)

    4 (17)

    27 (30)

    Neither

    0.04

    4.29

    14 (21)

    10 (44)

    24 (27)

    Both

    0.51

    0.42

    35 (53)

    14 (61)

    49 (55)

    EPS

    0.008

    7.14

    22 (33)

    15 (65)

    37 (42)

    Visual Hallucinations

    P X2 Braak high 3- 6 n = 66

    Braak low 0 – 2

    n = 24

    Total n = 90

    Features

  • Braak stage and clinical diagnostic accuracy Merdes et al., Neurology 2003;60:1586-1590

    46 (51)

    40 (61)

    6 (25)

    Clinical Diagnosis of AD

    44 (49)

    26 (39)

    18 (75)

    Clinical Diagnosis of DLB

    Total n = 90

    Braak high 3- 6 n = 66

    Braak low 0 - 2 n = 24

    Diagnosis

  • Individual Braak stage and diagnostic accuracy Merdes et al., Neurology 2003;60:1586-1590

    11

    73% 27% 6

    23 15

    65% 60%

    35% 40%

    4 5

    10 14

    40% 43%

    60% 57%

    2 3

    1 12

    17%

    100% 83%

    0 1

    N Clinical diagnosis of AD

    n = 44

    Clinical diagnosis of DLB

    n = 42

    Braak stage

  • Neuropathological features of DLB

    Report of 3rd Consortium Meeting (Neurology 2005)

    Alzheimer Type Pathology

    NIA-Reagan Low

    NIA-Reagan Intermediate

    NIA-Reagan High

    (Braak stage 0- II)

    (Braak stage III-IV) (Braak stage V-VI)

    Brainstem Predominant

    Low Low Low

    Limbic (transitional)

    High Intermediate Low

    Diffuse Neocortical

    High High Intermediate

    Le w

    y B

    o d

    y Ty

    p e

    P at

    h o

    lo gy

    Relation of AD- and LB-pathology to DLB clinical phenotype

  • What best predicts LBD in early-stage dementia? Demographics of patient groups

    DLB

    (n = 23) AD

    (n = 94) p

    Age at 1st presentation 73.7 ± 4.8 74.8 ± 8.4 0.5

    Age at onset 70.2 ± 6.1 70.1 ± 8.0 0.9

    Age at death 79.6 ± 5.8 81.3 ± 8.0 0.3

    Gender (% female) 43 48 0.6

    Education 14.7 ± 2.8 14.4 ± 3.3 0.7

    DRS at 1st presentation 123.6 ± 8.0 125.7 ± 7.9 0.3

    MMSE at 1st presentation 24.0 ± 4.2 25.0 ± 2.7 0.2

    Tiraboschi et al., Brain 2006

  • What best predicts LBD in early-stage dementia? Frequency of clinical features

    DLB (n = 23)

    AD (n = 94) p

    Visual hallucinations 5 (22) 1 (1) 0.001

    Extrapyramidal signs 6 (26) 15 (16) 0.3

    Visuospatial impairment on DRS – Construction 17 (74) 42 (45) 0.011

    Visuospatial impairment on MMSE pentagon copy 7 (30) 15 (16) 0.1

    Tiraboschi et al., Brain 2006

  • What best predicts LBD in early-stage dementia? Sensitivity, specificity, predictive values of clinical variables for

    distinguishing DLB from AD

    Sens Spec PPV NPV OR (95% CI)

    Visual Hallucinations

    0.22 0.99 0.83 0.84 25.8

    (2.8 – 234.6)

    Extrapyramidal signs

    0.26 0.82 0.26 0.82 1.6

    (0.5 – 4.7)

    Visuospatial deficit on DRS-C

    0.74 0.55 0.29 0.90 3.5

    (1.3 – 9.7)

    Visuospatial deficit on MMSE

    0.30 0.84 0.32 0.83 2.3 (0.8 - 3.6)

    Tiraboschi et al., Brain 2006

  • 1) A new pathological algorithm which accounts for the modifying influence of Alzheimer pathology upon the clinical presentation

    2) Better methods of identifying core features are described

    3) Addition of 3 new clinical features “suggestive” of DLB

    - Severe neuroleptic sensitivity

    - REM Sleep Behaviour Disorder

    - Reduced striatal dopamine transporter on functional imaging

    4) Further clarification of features “supportive” of a DLB diagnosis

    Clinical and pathological criteria for DLB have been revised in the light of new information obtained since 1995 McKeith et al., Neurology 2005;65:1863-1872

    “Lewy AND dementia refs: 279 from 1986-1995, 2152 from 1996-2005

  • Assessing Cognitive Fluctuation in DLB

    The Clinician Assessment of Fluctuation (Walker, Br J Psych 2000)

    a. Does he/she ever have spontaneous impaired alertness and concentration (ie, appear drowsy but awake, look dazed, unaware of what’s up around)? Have thes