Ruolo dell’imaging nella diagnosi

differenziale delle demenze

parkinsoniane

ROBERTO CERAVOLO

Department of Clinical and Experimental Medicine,

University of Pisa

Department of Neuroscience

Azienda Ospedaliero-Universitaria Pisana

Frontotemporal

Dementia

Parkinson’s

Disease with

dementia

Lewy body Dementia

Coticobasal

Degeneration Progressive

supranuclear

Palsy

Alzheimer’s

Disease

Lewy Bodies

ßAmyloid

Tau Protein

Subcortical involvement

Cortical involvement

Arch Neurol 2009 Portet et al.

12% 18% 22%

Disease progression

DLB vs AD: Clinical implications

• Improvement of DLB parkinsonism with

L-Dopa

• >> responsiveness to AChE inhibitors in

DLB

• Extreme neuroleptic sensitivity in DLB

• Different progression and prognosis

Which clinical feature (among visual hallucinations, extrapyramidal symptoms

and visuospatial dysfunction) does better predict autoptic diagnosis of DLB in

early-stage 23 patient with autoptic diagnosis of DLB

94 patient with autoptic diagnosis of AD

Visual hallucinations are the best positive predictor for the

differential diagnosis between DLB and AD in an early phase

?

DAT

11C-RTI 32 18F-CFT 18F-FP-CIT 18F-FECNT 123I-beta CIT 123I-FP-CIT 123I-altropane 99mTc-TroDAT

PET

SPECT

11C-DTBZ PET Aromatic

Amino acid

decarboxylase

18F- dopa

18F- dopamine

Functional imaging

DOPAMINERGIC SYSTEM

Movement Disorders 2009

Lancet Neurology, 2007

SPECT diagnosis vs clinical diagnosis SPECIFICITY : 90.4 - SENSITIVITY : 77.7 Clinical diagnosis vs neuropathological diagnosis

SPECIFICITY : 92.0 - SENSITIVITY : 49.0

Lancet Neurology, 2007

Ceravolo et al, 2004

PD DLB AD

20 15 13

All with parkinsonism

A multicentre, randomised, open label, comparative

Phase 4 trial to assess changes in dementia diagnostic

category and diagnostic confidence after DaTSCAN

imaging in subjects with an uncertain diagnosis of

Dementia with Lewy bodies (possible DLB)

A. Padovani1, F. Inglis2, M. Rainer3, A. Lladó4, R. Ehret5, R. Ceravolo6, E. Moreno7, G. Amer Ferrer8, Z. Walker9,10, DaTSCAN DLB Study Group 1) Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy, 2) Glasgow Memory Clinic Ltd, Glasgow, UK, 3) Centre for mental health in old age, Vienna, Austria, 4) Neurology Service, Hospital Clinic i Universitari, Barcelona, Spain, 5) Neurologie Berlin, Berlin, Germany, 6) Università di Pisa, Pisa, Italy, 7) Medical Affairs, GE Healthcare, Madrid, 8) Hospital Universitari Son Espases Palma de Mallorca, Spain, 9) University College London, London, 10)North Essex Partnership NHS Foundation Trust, Epping, UK

• 6 Countries involved

(UK, FR, GE, AU, IT,

SP)

• 23 Centres initiated – 21

actively recruiting

• 192 Patients enrolled and

187 randomized

• 170 Full analysis set (114

DaTSCAN – 56 Control)

DLB core and suggestive features at

baseline

DaTSCAN vs Control group

33%

23% 25%

21%

0%

25%

29%

34%

13%

0% 0%

5%

10%

15%

20%

25%

30%

35%

40%

Fluctuations Visual Hallucinations

Parkinsonism REM Neuroleptic Sensitivity

DaTSCAN n=114

Control n=56

Primary endpoint

Percentage of change in diagnostic

category

61%

71%

4%

16%

0%

10%

20%

30%

40%

50%

60%

70%

80%

week 8 week 24

DaTSCAN n=114

Control n=56

P<.0001 P<.0001

Percentage of change by diagnostic

category

28%

39% 33% 34%

28% 33%

4%

96%

0% 7%

82%

9%

0%

20%

40%

60%

80%

100%

120%

non-DLB Possible DLB

Probable DLB

non-DLB Possible DLB

Probable DLB

Perc

enta

ge o

f subje

cts

DaTSCAN

Control

Week 8 Week 24

Missing values at week 24 - DaTSCAN 5 subjects - Control 1 subject

Change in diagnostic confidence

51,0

68,5 72,6

48,2 49,9 55,7

0

10

20

30

40

50

60

70

80

90

100

Baseline week 8 week 24

DaTSCAN

Control

18/05/2013 Investigator Meeting 16

Visual Analogue Scale P<0.001 P<0.001

Dementia with Lewy bodies:

a comparison of clinical diagnosis, FP-CIT single photon emission computed

tomography imaging and autopsy

Walker et al, JNNP 2007

FP-CIT SPECT significantly changed the accuracy of

diagnosis of DLB

SS O’Sullivan, DJ Burn, JL Holton, AJ Lees

2011

4/36 (10%) FP-CIT SPECT normal

Neuropsycological testing CBStot CBSN, n=4 CBSP, n=32 Cut-off values

MMSE 22.7 (5.0) 19.5 (6.9) 23.1 (4.7) 24

Frontal Assessment Battery 9.6 (3.7) 8.7 (3.0) 9.7 (3.9) 13.4

Attentional Matrices 27.1 (11.3) 21.9 (9.3) 27.8 (11.4) 30

Digit Span 4.1 (1.0) 4.5 (0.4) 4.1 (1.1) 3.5

Story recall 8.1 (3.6) 6.2 (1.9) 8.4 (3.7) 4.5

Corsi Block Tapping Test 3.3 (1.0) 2.6 (0.9) 3.4 (1.0) 3.5

Category Verbal Fluency 20.8 (9.3) 18.3 (5.1) 21.1 (9.8) 24

Phonemic Verbal Fluency 14.9 (7.2) 13.2 (4.1) 15.1 (7.5) 16

Neuropsychiatric Inventory 12.7 (8.2) 15.2 (3.4) 12.3 (8.7) n.a.

No differences in clinical and

neuropsychological presentation between

patients with positive and negative SPECT

CBSn FOLLOW-UP

Case 2

Case 1

Park Related Disord 2013

J Mol Neurosci 2011

Name FDTP 17T/MAPT FTDP-17U/PRGN FDT-3/CHMP2B FTD link crom 9 C9ORF72

Inheritance AD (full penetrance) AD AD (low penetrance)

Mean age onset

50 60 57 45

Men disease duration

7 7 10 7

Common clinical presentation : EARLY

Behavioural change, personality

change, Parkinsonism,

language

Behavioural change, personality change, CBS,

Parkinsonism, language

Behavioural change, personality change, language

Behavioural change, personality change, MND

LATE Pyramidal, visuospatial Piramidal, dyshasia

Parkinsonism Parkinsonism, visuospatial

Levodopa responsiveness

Temporarily effective Not beneficial Unk Unk

Morgan et al, JNNP 2013

FP-CIT SPECT FTD (22) DLB (10) AD (9) p value

Normal/ abnormal 8/4 1/9 8/1 0.001

% abnormal 33.3% 90% 11.1%

Visual inspective analysis

Morgan et al, JNNP 2013

FP-CIT SPECT FTD (12) DLB (10) AD (9) p value

Normal/ abnormal 8/4 1/9 8/1 0.001

% abnormal 33.3% 90% 11.1%

Visual inspective analysis

?

DLB vs PDD

COGNITIVE DYSFUNCTION •Deficits in attention and memory

•Apathy

•Visuospatial dysfunction

•Fluctuating cognition

•Aberrant behavior

•Confusion

•Delusions

•Hallucinations

•Delirium

Within the first 12

months after the

onset of

parkinsonism

Later than 1 year

in patients fulfilling

criteria for PD

DLB

PDD

1 YEAR RULE

DLB vs PD

Neurology 2004

lower uptake in the caudate in DLB patients

than in PD patients

?

DLB n 30 PDD n 30

MMSE 16 17

Age 77 75

Duration 3 aa 9 aa

UPDRS 39 42

2009 Parkinsonism and Related Disorders 2009

No differences in flow and DAT density

between PDD and DLB

DLB vs PDD

n.s.

Colloby et al.

Tracer uptake was associated with nigral

dopaminergic neuronal density, but not with

a-synuclein , tau or amyloid b burden

degeneration

Pathology

Dysfunction

Degeneration

PET amiloide: [11C] PiB-PET, Florbetapir F18 Tau scan: 18F-T807 PET, 18F-THK523 PET BF227 α-synuclein/Lewy bodies

PET metabolica: 18F-FDG PET

PET colinergica: [11C]4-MPB, N-[11C]-MPA

MRI, UHF MRI

fMRI

DWI/DTI

FP-CIT SPECT 18F Dopa PET

SPECT di Flusso: Tc-99m HM-PAO, Tc-99m ECD

[15O]H2O PET

Evolution of molecular imaging

PET-FDG : FTD

Hellwig et al, 2012 PSP

Hellwig et al, 2012 CBD

degeneration

Pathology

Dysfunction

Degeneration

PET amiloide: [11C] PiB-PET, Florbetapir F18 Tau scan: 18F-T807 PET, 18F-THK523 PET BF227 α-synuclein/Lewy bodies

PET metabolica: 18F-FDG PET

PET colinergica: [11C]4-MPB, N-[11C]-MPA

MRI, UHF MRI

fMRI

DWI/DTI

FP-CIT SPECT 18F Dopa PET

SPECT di Flusso: Tc-99m HM-PAO, Tc-99m ECD

[15O]H2O PET

Evolution of molecular imaging

Williams Lancet Neurol 2009

TAU Alfa-Sinuclein

PSP-CBS-FTD PD-PDD-DLB

Fodeo tavoletti, 2011 BRAIN

Tau-imaging

Neuron 2013

[11C]PBB3, was applied in a clinical PET study, and showed robust signal in the AD hippocampus wherein tau pathology. [11C]PBB3-PET data were also consistent with the spreading of tau pathology with AD progression. Furthermore, increased [11C]PBB3 signals were found in a corticobasal syndrome patient negative for [11C]PIB-PET.

Williams Lancet Neurol 2009

TAU Alfa-Sinuclein

PSP-CBS-FTD PD-PDD-DLB AD-park

Amyloid

Patologia nella DLB

Huang and Halliday Translational Neurodegeneration 2013

Corpo di Lewy in un neurone dopaminergico (eosifilina)

Corpo di Lewy in un neurone neocorticale (ɑ-sinucleina)

Corpo di Lewy immaturo in un neurone neocorticale e astrocita stellato (ɑ-sinucleina)

Corpo di Lewy in un neurone temporale (ɑ-sinucleina)

Placche di ß-amiloide

PET Amyloid Tracers

18F-Flutemetamol

11C-PiB 18F-Florbetaben

Florbetapir F 18

«34 autopsy cases conforming to the standard neuropathologic criteria of Parkinson disease were sex- and age-matched with controls who had died of infarct or trauma. Nineteen (56%) of the Parkinson cases had shown some degree of dementia.

All brains were reviewed for changes compatible with Alzheimer disease, and available clinical data were retrospectively reviewed. Plaques, neurofibrillary tangles, granulovacuolar degeneration, and cortical cell loss were present in all but one of the parkinsonian brains; these pathologic changes were present in fewer controls and to a lesser degree. The higher incidence of dementia in patients with Parkinson disease may be explained by the simultaneous presence of Alzheimer disease»

Dementia in Parkinson disease: a neuropathologic study

Hakim AM, Mathieson G. Neurology 1979

«36 patients with autopsy-demonstrated idiopathic Parkinson disease (PD) were reviewed

Nine (31%) of the 29 patients with adequate clinical data had severe dementia and 7 (24%) had mild dementia. The cerebral cortex showed senile plaques and fibrillary tangles in 15 of the 36 patients (42%). These changes were found in all 9 patients with severe dementia, in 3 of the 7 with mild dementia, and in 3 of the 13 patients with normal mental status. The prevalence of pathologically established Alzheimer changes and dementia among the patients with PD (33%) was over six times that found in an age-matched population (5.1%). Survival after the onset of PD with Alzheimer disease was shorter than in PD without Alzheimer disease.»

Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations.

Boller F et al, Ann Neurology 1980

Alzheimer’s disease

Amyloid load in PDD and DLB

Control

70% increased uptake

DLB

PD/PDD

11C-PIB PET

Courtesy of N.Pavese

Author year

PIB+/ DLB

PIB+/ PDD

PIB+/ PD

PIB+/ PDMCI

note

Maetzler 2008 - 2/10 - - PDD 20% +

Edison 2008 11/13 2/12 0/10 - PDD 16% +, DLB 84% +

Gomperts 2008

7/8 7/7 7/11 - PDD 100% +, DLB 87% +, PD 63% +…46% of healthy controls PIB +

Maetzler 2009 4/9 4/12 - - PDD 30% +, DLB 45% +

Foster 2010 2/6 4/15 1/8 1/9 PDD 26% +, DLB 30%+

Burack 2010 - 2/3 (AP)

- - PDD 60% +

Compta 2010 - 4/4 7/11 - PDD 100% +, 1/3 of healthy controls: positive Tracer FDDNP

Petrou 2012 - - 6/40 - PD 15% +

Gomperts 2012

18 12 29 14 PIB Uptake higher in DLB than PD, PD-MCI e PDD. PDD=HC

Amyloid imaging in PDD and DLB: not so clear

Author year

PIB+/ DLB

PIB+/ PDD

PIB+/ PD

PIB+/ PDMCI

note

Maetzler 2008 - 2/10 - - PDD 20% +

Edison 2008 11/13 2/12 0/10 - PDD 16% +, DLB 84% +

Gomperts 2008

7/8 7/7 7/11 - PDD 100% +, DLB 87% +, PD 63% +…46% of healthy controls PIB +

Maetzler 2009 4/9 4/12 - - PDD 30% +, DLB 45% +

Foster 2010 2/6 4/15 1/8 1/9 PDD 26% +, DLB 30%+

Burack 2010 - 2/3 (AP)

- - PDD 60% +

Compta 2010 - 4/4 7/11 - PDD 100% +, 1/3 of healthy controls: positive Tracer FDDNP

Petrou 2012 - - 6/40 - PD 15% +

Gomperts 18 12 29 14 PIB Uptake higher in DLB than PD, PD-MCI

Amyloid imaging in PDD and DLB: not so clear

Petrou et al, 2012 Neurology

40 pts PD, 6 PIB + (2 MCI, 4 PDD)

Elevated cerebral A-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. …

Neocortical PiB binding correlated robustly with measures of cognitive impairment

…

Gomperts et al, 2013

1. Both higher PiB retention and a diagnosis of PD-MCI predicted greater hazard of conversion to a more severe diagnosis.

2. Baseline PiB retention predicted worsening in executive function over time.

CLB/LN pathology is the most significant correlate of dementia in PD.

AD pathology was abundant in a subset of patients, and may modify the clinical phenotype (onset time after motor symptoms).

Pathologic Accumulation of α-Synuclein and Aβ in Parkinson Disease Patients With Dementia

Kotzbauer 2012, Arch Neurol

Neuropathologic substrates of Parkinson disease dementia

Irwin 2012, Ann Neurol

Silver stain:

neuritic plaques (beta

amyloid)

Neurofibrillary

Tangles (TAU)

Compta et al, Brain 2011

Lewy body inclusions

A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson’s disease Cortical amyloid-b and age at disease onset seem to determine the rate to dementia.

Relationship between neuropathology and timing of dementia across the PDD–DLB spectrum

Pure synucleinopathies PDD with minimal co-morbid AD neuropathology

Mixed pathology diagnoses PDD plus AD and DLB plus AD

differing clinical and genetic phenotypes?

shorter time to dementia and shorter disease duration

long PD-to-dementia onset interval

Irwin et al, Nat Rev Neur sept 2013