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 (<1-20)

• Male predominance (1.2-3.0)

• Core features 2/3 = “probable DLB” 1/3 = “possible DLB”

Fluctuating cognitive impairment ~80%

Persistent visual hallucinations ~70%

Extrapyramidal features ~75%

McKeith et al. Neurology. 1996;47:1113-1124.

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

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

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

Lew

y B

od

y Ty

pe

Pat

ho

logy

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 these episodes occurred within the last month?

b. Has the level of confusion experienced by the patient tended to vary a lot recently from day to day or week to week? Has it become worse then improved for a while, ie been up and down?

If a positive rating is present (positive answer to ≥ 1 of prior questions), a severity rating based on fluctuation frequency and duration is made

Frequency Duration

1 = one per month 0 = seconds

2 = monthly – weekly 1 = ≤ 5 minutes

3 = weekly - daily 2 = 5 minutes – 1 hour

4 = ≥ daily 3 = ≥ 1 hour

4 = ≥ 1 day

Walker MP et al., Neurology 2000

Assessing Cognitive Fluctuation in DLB

• Mayo Fluctuations Questionnaire

Most carers report fluctuations

DLB 87% AD 73%

• 4 items distinguish DLB and AD

Daytime drowsiness and lethargy

Daytime sleep >2 hours

Staring into space for long periods

Episodes of disorganized speech

3 or 4 features in 63% DLB, 12% AD, 0.5% controls

• Melbourne Fluctuation Scales

Most carers report fluctuations

DLB 77% AD 67%

Yes/no items unhelpful

Qualitative differences can distinguish between fluctuations in DLB and AD

Examples of “worst and best period of function” discriminated

DLB 89% correct

AD 94% correct

Bradshaw et al. JNNP. 2004;75:382-387 Ferman et al. Neurology. 2004;62:181-187

9% RBD 71%

AD DLB

37%

14% VH EPS

10%

RBD

25%

1% 13% 62% with VH 89% with EPS

72% with RBD

Fluctuations were not included in the DLB diagnosis for this study in an effort to avoid the circularity of defining a patient group based on the construct of interest.”

Ferman et al. Neurology 2004;62:181-187

“The DLB diagnosis required the presence of dementia plus visual hallucinations (VH) and/or extrapyramidal signs (EPS).

REM Sleep Behaviour Disorder

• Rapid eye movement sleep behaviour disorder (RBD) is characterised by loss of normal skeletal muscle atonia during REM sleep with prominent motor activity and dreaming

• Patients appear to “act out in their dreams”

• RBD may start in 4th – 6th decades and later progress to PD or DLB

Nature 2006

Synthesis

Dopamine

Vesicle

presynaptic

post- synaptic

Receptors

Reuptake- Site

D 1- like

D 2- like

Active pre-synaptic dopamine transporter site

FP-CIT binding at pre-synaptic dopamine

transporter site

Caudate

Putamen

Occipital

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Differentiation of DLB from AD using a dopaminergic presynaptic ligand [FP-CIT]

NC PD

AD DLB

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Radioactivity ratios in the caudate nucleus for patients with DLB, AD, PD, and healthy controls. Means and 95% confidence intervals are shown.

Radioactivity ratios in the anterior putamen for patients with DLB, AD, PD, and healthy controls. Means and 95% confidence intervals are shown.

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Radioactivity ratios in the posterior putamen for patients with DLB, AD, PD, and healthy controls. Means and 95% confidence intervals are shown.

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Differentiation of DLB from AD using a dopaminergic presynaptic ligand [FP-CIT]

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Differentiation of DLB from AD using a dopaminergic presynaptic ligand [FP-CIT]

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

Differentiation of DLB from AD using a dopaminergic presynaptic ligand [FP-CIT]

Walker, Z et al. J Neurol Neurosurg Psychiatry 2002;73:134-140

O'Brien, J. T. et al. Arch Neurol 2004;61:919-925.

Iodine I 123-radiolabeled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)-N-(3-fluoropropyl) nortropane with SPECT images

NC AD

DLB PD PDD

O'Brien, J. T. et al. Arch Neurol 2004;61:919-925.

Differentiating DLB from AD using a dopaminergic presynaptic ligand

Sensitivity and specificity of FP-CIT SPECT imaging to Dementia with Lewy bodies

Walker et al., JNNP 2007

Walker et al., JNNP 2007

*

Walker et al., JNNP 2007

Are presynaptic dopamine markers really unchanged in AD?

Scatter plot showing individual[11C][beta]-CFT uptake values in patients with AD (n = 12; mean MMSE = 16; mean UPDRS-III score = 10) and age-matched healthy control subjects (n = 6) in the putamen and caudate nucleus. Rinne: Neurology 1998;50:152.

p=0.002 p=0.002

A PET image demonstrating a reduction in the uptake of the dopamine reuptake ligand [11C][beta]-CFT in both the putamen and caudate nucleus in an Alzheimer compared to a control subject. Rinne: Neurology 1998;50:152.

Are presynaptic dopamine markers really unchanged in AD?

Are presynaptic dopamine markers really unchanged in AD?

• Ligands for the dopamine reuptake system measure the reuptake of dopamine from the synaptic cleft into the presynaptic terminals. Binding declines with age in both the putamen and the caudate nucleus

• In Rinne et al.’s study, clinical diagnoses of AD were not pathologically confirmed. However, apart from mild parkinsonism, none of the patients had delusions, hallucinations, syncope, transient loss of consciousness, or repeated falls nor was the cognitive state fluctuating

• In Rinne et al.’s study, [11C] beta-CFT uptake in putamen and caudate nucleus was decreased by 20% compared to control subjects. This reduction was inversely associated with the UPDRS score (the greater EPS severity, the lower the uptake)

Striatal dopaminergic markers in DLB, PD, and AD

Piggott, Brain 1999

25 DLB, 14 PD, 17 AD, 20 NC

• Mazindol binding to striatal dopamine uptake sites in DLB and in PD, but unchanged in AD, compared to NC

• Raclopride binding to D2 postsynaptic receptors in DLB but in PDα and unchanged in AD compared to NC

• Striatal dopamine concentration and nigral cell density in DLB and in PD, but unchanged in AD, compared to NC

Murray, Ann Neurol 1995

11 PD, 18 AD, 12 AD/P+, 16 NC

• AD: Mazindol binding to striatal dopamine uptake sites in PD , but unchanged in AD

• AD/P+: Mazindol binding to dopamine uptake sites in rostral putamen and caudate, despite no evidence of nigral degeneration (no LBs, no change in D2 autoreceptors or tyrosine hydroxylase)

• PD: binding to dopamine uptake sites with nigral degeneration (cell loss, LBs in surviving neurons, tyrosine hydroxylase and D2 autoreceptors)

α May explain poor l-dopa response and marked neuroleptic sensitivity

A personal view….

① Decreased binding/EPS +

Not incompatible with AD or other dementias (VaD, CBD, PSP, FTD-17, CJD). In the absence of visual hallucinations, REM behavior disorder or fluctuations, a diagnosis of DLB may be questionable

② Decreased binding/EPS −

in the presence of at least another core feature or REM behavior disorder a diagnosis of DLB is the first option

③ Normal binding/EPS +

consider AD or other dementias (VaD, NPH)

④ Normal binding/EPS −

in the presence of other core features, do not exclude DLB. Isolated cases with cortical LB pathology, in the absence of brainstem LB pathology, have been reported

Yoshita, M et al. J Neurol Neurosurg Psychiatry 2001;71:583-588

A clinical role for myocardial [123I] MIBG scintigraphy in the distinction between AD and DLB

Yoshita, M et al. J Neurol Neurosurg Psychiatry 2001;71:583-588

Planar cardiac imaging of [123I]metaiodobenzyl guanidine ([123I]MIBG) in a patient with AD (A, early; B, delayed), and with DLB (C, early; D, delayed)

Individual values for heart to mediastinum (H/M) ratio of iodine - 123 metaiodobenzylguanidine (123I-MIBG) uptake and cardiac MIBG washout rate. The dashed lines indicate the mean values in 10 normal controls. Significant reductions in early (A) and delayed (B) H/M ratios and increased washout were observed in both the DLB/P+ and the DLB/P- group.

Value of 123I-MIBG radioactivity in differentiating DLB from AD

Yoshita et al., 2006

AD (n = 42, mean MMSE = 20); DLB/P+ (n = 30, mean MMSE = 18.7); DLB/P- (n = 7; mean MMSE = 19.9); NC (n =10; mean MMSE = 29.6)

Value of 123I-MIBG radioactivity in differentiating DLB from AD

Yoshita et al., 2006

Imaging markers as supportive features for

DLB

Occipital Hypoperfusion Sens 65% Spec for DLB 64% Lobotesis et al, 2001

Absence of MTA Sens 40% Spec for DLB 100% Barber et al, 1999

MIBG scintigraphy

Sens 100% Spec for DLB 100% Yoshita et al, 2006