3rd Congress of the European Academy of Neurology

Amsterdam, The Netherlands, June 24 – 27, 2017

Teaching Course 6

MDS-ES/EAN: Neuroimaging in movement disorders - Level 2

Imaging biomarkers for Parkinson’s disease

David J. Brooks London, United Kingdom

Email: david.brooks@imperial.ac.uk

1

1

Imaging biomarkers for Parkinson’s disease

David J Brooks

α-synuclein aggregation

Shah 2014

1

Imaging biomarkers for Parkinson’s disease

David J Brooks

α-synuclein aggregation

Shah 2014

Conflict of interest: David Brooks has worked as a Consultant for GE

Healthcare who own the licence for DatSCAN

2

2

BF227 binding to Lewy bodies and GCIs

Kikuchi 2010BF227 fluorescence α-Syn immunostaining

Kikuchi 2010

Multiple System Atrophy

Alzheimer’s disease

2

BF227 binding to Lewy bodies and GCIs

Kikuchi 2010BF227 fluorescence α-Syn immunostaining

Kikuchi 2010

Multiple System Atrophy

Alzheimer’s disease

3

3

Imaging nigrosome 1

Blazejewska 2013

T2-weighted iron sensitive SWI

7 tesla MRI

Imaging nigrosome 1

Reiter 2015

3 tesla MRI

Susceptibility weighted imaging

3

Imaging nigrosome 1

Blazejewska 2013

T2-weighted iron sensitive SWI

7 tesla MRI

Imaging nigrosome 1

Reiter 2015

3 tesla MRI

Susceptibility weighted imaging

4

4

Cerebral peduncle

Fractional anisotropy

Vaillancourt et al. Neurology 2009;72:1387–84

Diffusion tensor imaging3 tesla MRI

PPMI cohort

DTI changes in de novo PD

Schuff et al. 2016

PPMI database

4

Cerebral peduncle

Fractional anisotropy

Vaillancourt et al. Neurology 2009;72:1387–84

Diffusion tensor imaging3 tesla MRI

PPMI cohort

DTI changes in de novo PD

Schuff et al. 2016

PPMI database

5

5

Free water is increased in Parkinson nigra

Ofori 2015

Free water changes in PD, MSA and PSPPlancetta 2016

5

Free water is increased in Parkinson nigra

Ofori 2015

Free water changes in PD, MSA and PSPPlancetta 2016

6

6

Free water pool progression in PD

Bircui 2017

Magnetisation transfer imaging of neuromelanin

Langley 2015

Loss of substantia nigra signal in PD

6

Free water pool progression in PD

Bircui 2017

Magnetisation transfer imaging of neuromelanin

Langley 2015

Loss of substantia nigra signal in PD

7

7

Reduced melanin volumes in Parkinson’s disease

Langley 2015

Imaging melanin with 18F-AV1451 PET

Controls

PD

Hansen et al. 2016

7

Reduced melanin volumes in Parkinson’s disease

Langley 2015

Imaging melanin with 18F-AV1451 PET

Controls

PD

Hansen et al. 2016

8

8

Transcranial Sonography in clinically uncertain PD

• 60 cases had baseline TCS and were followed up for 12 months in a blinded prospective study

• Nigral hyperechogenicity had a sensitivity of 91%, a specificity of 82%, a positive predictive value of 93%, but a negative predictive value of 78% for detecting iPD.

normal iPD

Gaenslen 2008

Imaging dopamine terminal function

Normal

PD

18F-FP-CIT 123I-FP-CIT 18F-DTBZ 11C-DTBZ 18F-DOPADAT DAT VMAT2 VMAT2 DDC

8

Transcranial Sonography in clinically uncertain PD

• 60 cases had baseline TCS and were followed up for 12 months in a blinded prospective study

• Nigral hyperechogenicity had a sensitivity of 91%, a specificity of 82%, a positive predictive value of 93%, but a negative predictive value of 78% for detecting iPD.

normal iPD

Gaenslen 2008

Imaging dopamine terminal function

Normal

PD

18F-FP-CIT 123I-FP-CIT 18F-DTBZ 11C-DTBZ 18F-DOPADAT DAT VMAT2 VMAT2 DDC

9

9

Striatal DAT vs nigral melanin

• No correlation between striatal DAT binding and nigral melanin• No correlation between disease duration and melanin

FP-CIT

AV1451

Hansen 2016

Nigrostriatal dopaminergic deficiency

Idiopathic PDMultiple system atrophy

Progressive supranuclearpalsy

Corticobasal degenerationLewy body dementia

Spinocerebellar ataxia SCA 2Vascular parkinsonism

No dopaminergic deficiency

Drug-induced parkinsonismPsychogenic parkinsonismDopa responsive dystonia

Essential tremorDystonic tremor

Vascular parkinsonism

DA imaging: diagnostic support

9

Striatal DAT vs nigral melanin

• No correlation between striatal DAT binding and nigral melanin• No correlation between disease duration and melanin

FP-CIT

AV1451

Hansen 2016

Nigrostriatal dopaminergic deficiency

Idiopathic PDMultiple system atrophy

Progressive supranuclearpalsy

Corticobasal degenerationLewy body dementia

Spinocerebellar ataxia SCA 2Vascular parkinsonism

No dopaminergic deficiency

Drug-induced parkinsonismPsychogenic parkinsonismDopa responsive dystonia

Essential tremorDystonic tremor

Vascular parkinsonism

DA imaging: diagnostic support

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10

Discriminating benign tremors from Parkinson’s disease

Essentialtremor

Parkinson’sdisease

18F-dopa 123I-FP-CIT 99mTc-TRODAT

158 PS and 27 ET cases: FP-CIT SPECT had a sensitivity 95% and specificity 93% for differentiating between clinically probable PD and ET patients. Benamer 2000

Essential tremor

0.000

0.004

0.008

0.012

Ki min -1Nor

PD

familial sporadic

Putamen 18F-dopa Ki

essential tremor

Parkinson’sdisease

18F-dopa

10

Discriminating benign tremors from Parkinson’s disease

Essentialtremor

Parkinson’sdisease

18F-dopa 123I-FP-CIT 99mTc-TRODAT

158 PS and 27 ET cases: FP-CIT SPECT had a sensitivity 95% and specificity 93% for differentiating between clinically probable PD and ET patients. Benamer 2000

Essential tremor

0.000

0.004

0.008

0.012

Ki min -1Nor

PD

familial sporadic

Putamen 18F-dopa Ki

essential tremor

Parkinson’sdisease

18F-dopa

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11

Vascular Parkinsonism

Nigral infarct Internal capsule infarct

Courtesy of Per Borghammer

Glucose metabolism in parkinsonian

disorders

PD mild

PD mod

MSA

PSP

CBD

Eckert 2007

MSAPD

11

Vascular Parkinsonism

Nigral infarct Internal capsule infarct

Courtesy of Per Borghammer

Glucose metabolism in parkinsonian

disorders

PD mild

PD mod

MSA

PSP

CBD

Eckert 2007

MSAPD

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12

Baseline DAT binding in PPMIseries of 400 untreated PD

Mean Striatal DAT binding in PD over 4 Years

SB

R

y1 y2 y4B

Ipsilateral

SB

R

y1 y2 y4B

Contralateral

FP-CIT SPECT

2

1

0

0

1

2

12

Baseline DAT binding in PPMIseries of 400 untreated PD

Mean Striatal DAT binding in PD over 4 Years

SB

R

y1 y2 y4B

Ipsilateral

SB

R

y1 y2 y4B

Contralateral

FP-CIT SPECT

2

1

0

0

1

2

13

13

Clinical progression of the PPMI cohort

PD

SWEDD

Controls

• Anti-Parkinson’s therapy had been initiated in 36 (24%) • Therapy withdrawn in 27 - no evidence of deterioration in 25• Final proportion taking anti-Parkinson’s therapy 7.3%

13

Clinical progression of the PPMI cohort

PD

SWEDD

Controls

• Anti-Parkinson’s therapy had been initiated in 36 (24%) • Therapy withdrawn in 27 - no evidence of deterioration in 25• Final proportion taking anti-Parkinson’s therapy 7.3%

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14

SWEDD follow-up

43 of 64 completed 24 mo DAT imaging 5 of 43 now have a visual DAT deficit at follow-up

Abnormal SWEDD

PPMI cohort

DTI findings in SWEDDsPPMI cohort

Schuff - unpublished

14

SWEDD follow-up

43 of 64 completed 24 mo DAT imaging 5 of 43 now have a visual DAT deficit at follow-up

Abnormal SWEDD

PPMI cohort

DTI findings in SWEDDsPPMI cohort

Schuff - unpublished

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15

18F-dopa decreases in PD

Early hemi-PD Advanced PD

Statistical Parametric Mapping

p<0.001

Striatum

Cingulate

Cortical thinning in PD over 18 months

Cortical thinning progresses faster

in PD-MCI than PD

Mak 2015

Cortical thickness correlates with MOCA scores in PD

15

18F-dopa decreases in PD

Early hemi-PD Advanced PD

Statistical Parametric Mapping

p<0.001

Striatum

Cingulate

Cortical thinning in PD over 18 months

Cortical thinning progresses faster

in PD-MCI than PD

Mak 2015

Cortical thickness correlates with MOCA scores in PD

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Resting network connectivity changes in PD-MCI

Decreased dorsal attentionnetwork connectivity withfrontal and insula regions

Increased default modenetwork connectivity withparieto-occipital regions

Baggio 2015

Resting fMRI

Basal Ganglia network

Reduced BG connectivity in PDSzewczyk-Krolikowski 2014

16

Resting network connectivity changes in PD-MCI

Decreased dorsal attentionnetwork connectivity withfrontal and insula regions

Increased default modenetwork connectivity withparieto-occipital regions

Baggio 2015

Resting fMRI

Basal Ganglia network

Reduced BG connectivity in PDSzewczyk-Krolikowski 2014

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17

Amyloid load in Lewy body disease

volu

me

of d

istri

butio

n

11C-PIB PET

Gomperts 2008

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Amyloid load in Lewy body disease

volu

me

of d

istri

butio

n

11C-PIB PET

Gomperts 2008

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18

Microglial activation in Parkinson’s disease

healthy

volunteer

Early

Parkinsons

18

Microglial activation in Parkinson’s disease

healthy

volunteer

Early

Parkinsons

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19

Striatal 11C-PK11195 uptake correlates with disability (UPDRS III scores - p<.001)

posterior putamen

Insular 11C-PK11195 uptake correlates with impaired semantic fluency (p<.01)

insula

11C-PK11195 PET

Inflammation in Parkinson’s disease correlates with disability

Inflammation in PD + dementia11C-PK11195 PET

PDDPD PDD>PD

19

Striatal 11C-PK11195 uptake correlates with disability (UPDRS III scores - p<.001)

posterior putamen

Insular 11C-PK11195 uptake correlates with impaired semantic fluency (p<.01)

insula

11C-PK11195 PET

Inflammation in Parkinson’s disease correlates with disability

Inflammation in PD + dementia11C-PK11195 PET

PDDPD PDD>PD

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Decreased putamen dopamine and increased nigral inflammation in

REM Behaviour Disorder

Putamen

Nigra

Stokholm - submitted

Conclusions• Nigral changes can now be detected with MRI/DTI,

TCS, and PET in Parkinson’s disease

• Imaging DA terminal function detects dopamine

deficient parkinsonism. Normal DA imaging in

uncertain PD has a good prognosis

• PD is associated with cortical thinning and

reduced basal ganglia cortical connectivity

• The presence of amyloid in PD is associated with

rapid cognitive impairment

• Both DTI and FDG PET sensitively discriminate

atypical from typical PD.

20

Decreased putamen dopamine and increased nigral inflammation in

REM Behaviour Disorder

Putamen

Nigra

Stokholm - submitted

Conclusions• Nigral changes can now be detected with MRI/DTI,

TCS, and PET in Parkinson’s disease

• Imaging DA terminal function detects dopamine

deficient parkinsonism. Normal DA imaging in

uncertain PD has a good prognosis

• PD is associated with cortical thinning and

reduced basal ganglia cortical connectivity

• The presence of amyloid in PD is associated with

rapid cognitive impairment

• Both DTI and FDG PET sensitively discriminate

atypical from typical PD.