Neuroimaging in the prediagnostic phase of Parkinsonphase ... · Neuroimaging in the prediagnostic phase of Parkinsonphase of Parkinsons disease’s disease David J Brooks London,

Neuroimaging in the prediagnostic phase of Parkinson’s diseasephase of Parkinson s disease

David J BrooksLondon, UK

GPSRC CNS 172 0709 RTG 1

PD: nigral pathology

Striatum(basal ganglia)

Substantia nigra

Cortex

Limbic

Midbrain(meso)


Iron measurements using MRI in PD

MRI, magnetic resonance imaging

GPSRC CNS 172 0709 RTG

Michaeli et al. Mov Disord 2007;22:334–40.

MRI, magnetic resonance imaging

3

Diffusion tensor imaging in PD


Chan et al. J Neurol Neurosurg Pyschiatry 2007;78:1383–6.

4

Diffusion tensor imaging in PD

Fractional anisotropy Colour map

Cerebral peduncle


Vaillancourt et al. Neurology 2009;72:1387–94.

5

Altered olfactory bulb diffusion in PD


Personal data.

6

Echogenicity of the substantia nigra

• 92% of cases with clinically

Control

92% of cases with clinically probable PD show midbrain hyperechogenicity – but also 10% of normals and 15% of ET.

• No correlation between disability and midbrain echogenicity in PD.

• No change in echogenicity with

*Parkinson’s di

g g yPD progression.

*disease


Berg et al. J Neurol 2001;248:684–9.

7

Transcranial sonography in PD

Baseline 5 years

Right nigral hyperechogenicity 0.23 ± 0.07 0.23 ± 0.04Left nigral hyperechogenicity 0.25 ± 0.05 0.25 ± 0.04

Hoehn & Yahr stage 1.8 ± 0.6 2.6 ± 0.8UPDRS (I-III) 26.3 ± 11.7 49.2 ± 21.3

Is midbrain hyperechogenicity a trait rather than a state marker for PD?

UPDRS Unified Parkinson’s Disease Rating Scale


Berg et al. Mov Disord 2005;20:383–5.

UPDRS, Unified Parkinson s Disease Rating Scale.

8

Imaging dopamine terminal function

11C-RTI 32DAT

11C-DTBZVMAT2

18F-dopaDDC

123I-ioflupaneDAT

99mTc-TRODATDATDAT VMAT2 DDCDAT DAT

PD


18F-dopa PET: putamen uptake

Unilateral PDUnilateral PDStatistical parametric mapping Ki min -1 0.03

0.02

Preclinical

0 00

0.01 Left Right

Left Right

Clinical

0.00Normal (12) Left hemi-PD (7)

PET positron emission tomography


Personal data.

PET, positron emission tomography.

10

18F-dopa PET: PD progression in twin

Same individual when symptomaticControl

Asymptomaticidentical twin e sy pto at c

5 years laterControl de t ca t

of PD patient




11

18F-dopa uptake in twins of PD patients

0.0115 Identical twins Non-identical twins

0.0095

0.0055

0.0075

0 1 2 3 4 5 6 7 Time (years)

0 1 2 3 4 5 6 7

*0.0035

*

Concordance for dopaminergic nigro striatal dysfunction

At baseline At follow-upIdentical twins 55% 70%Non-identical twins 18% 22%

Concordance for dopaminergic nigro-striatal dysfunction


Piccini et al. Ann Neurol 1999;45:577–82.

12

LRRK2 disease

Control

Patient III-1

LRRK2 leucine rich repeat kinase 2


LRRK2, leucine-rich repeat kinase 2.

13

PET in LRRK2 mutations

C i ith di PD d id f Comparison with sporadic PD and evidence for presymptomatic compensation

• Four clinically affected family members had PET findings similar to sporadic PD, with impaired presynaptic dopaminergic function affecting the putamen more than the caudate.

• Two asymptomatic mutation carriers had abnormal dopamine transporter binding and another two developed such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two also displayed abnormal 11C-DTBZ , g p ybinding.

LRRK2 leucine-rich repeat kinase 2; PET positron emission tomography


Adams et al. Brain 2005;128:2777–85.

LRRK2, leucine-rich repeat kinase 2; PET, positron emission tomography.

14

18F-dopa PET

Control IPD Parkin




15

Parkin heterozygotes

18F-dopa

0.02

p = 0.013

p = 0.009

18F-dopa uptake

Control

0 01

0.015

Parkin carriers (n = 4)

Control

0.005

0.01 Parkin carriers (n = 4)

Controls (n = 14)

Parkin

0

Putamen

Parkin

Caudate


Transcranial sonography (TCS) in parkin carriersparkin carriers

f pat

ients

centa

ge

of

Perc

AsymptomaticPET -ve

AsymptomaticPET +ve

SymptomaticPET +ve

TCS -ve TCS moderately +ve TCS strongly +ve



Walter et al. Mov Disord 2004;19:1445–9.


17

TRODAT SPECT: putamen DAT bindingvs olfactory function in PDvs olfactory function in PD

takeNormal

RO

DA

T u

pt

TR

PD

UPSIT score

DAT, dopamine transporter; SPECT, single photon emission computed tomography; UPSIT University of Pennsylvania Smell Identification Test


Siderowf et al. Neurology 2005;64:1716–20.

UPSIT, University of Pennsylvania Smell Identification Test.

18

Olfactory and dopaminergic dysfunctionin PD relativesin PD relatives

beta-CIT SPECT

Normal

HyposmicPD relative

PD

SPECT single photon emission computed tomography


Berendse et al. Ann Neurol 2001;50:34–41.

SPECT, single photon emission computed tomography.

19

Hyposmia and hippocampal DAT bindingbinding

11C-CFT PET

Normal

40

UP

SIT

-4

PD

DAT dopamine transporter; UPSIT University of Pennsylvania Smell Identification Test

HIPPOCAMPAL DAT


Bohnen et al. Neurosci Lett 2008;447:12–6.

DAT, dopamine transporter; UPSIT, University of Pennsylvania Smell Identification Test.

20

Imaging findings in hyposmia

SPECT, single photon emission computed tomography; TCS, transcranial sonography; UPDRS Unified Parkinson’s Disease Rating Scale


Sommer et al. Mov Disord 2004;19:1196–202.

UPDRS, Unified Parkinson s Disease Rating Scale.

21

18F-dopa uptake in PD patients with REM sleep behaviour disorderREM sleep behaviour disorder

P ti t ith l t PD ( 10)Patients with early-stage PD (n = 10)

r = -0.65 p < 0.05


Hilker et al. Clin Neurol Neurosurg 2003;105:262–9.

22

DAT binding in sleep disorders

FP CIT SPECTFP-CIT SPECT

Contra, striatal IPT binding contralateral to the symptomatic side of the body; DAT, dopamine transporter; Ipsi, striatal IPT binding corresponding to the asymptomatic side of the body; IPT, striatal IPT binding contralateral to the symptomatic side of the body LT, left; RBD, REM sleep behaviour disorder; RT, right; SPECT single photon emission computed tomography


Eisensehr et al. Brain 2000;123:1155–60.

SPECT, single photon emission computed tomography.

23

FP-CIT uptake in RBD

RBD REM sleep behaviour disorder


Stiasny-Kolster et al. Brain 2005;128:126–37.

RBD, REM sleep behaviour disorder.

24

Stages in the evolution of PD-related pathologypathology

Medulla

Olfactory bulb


Braak et al. Cell Tissue Res 2004;318:121–34.

25

MIBG cardiac scintigraphy

Normal

Normallimit

PD

Braune et al. Neurology 1999;53:1020–5. Nagayama et al. J Neurol Neurosurg Psychiatry 2005;76:249–51.


Dementia in PDDementia in PD

GPSRC CNS 000 0709 RTGGPSRC CNS 172 0709 RTG 27

18FDG PET

PD with dementia ControlPD with dementia




28

Decreases in glucose metabolism in PD without dementia detecting using SPMwithout dementia detecting using SPM

PD (n = 12) vs controls (n = 8)( ) ( )

p < 0.05 corrected

SPM statistical parametric mapping


SPM, statistical parametric mapping.

29

Temporal cortical glucose metabolism

Right posterior temporalLeft posterior temporal

10

11

rCMRGlcrCMRGlc

9

10

8

98

9

6

7

6

7

PD patients PD patients

5

Volunteers

5

Volunteers

rCMRGlc regional cerebral metabolic rate for glucose


Hu et al. Brain 2000;123:340–52.

rCMRGlc, regional cerebral metabolic rate for glucose.

30

Amyloid load in PD dementia and diffuse Lewy body disease

11C-PIB PET

diffuse Lewy body disease

Diffuse Lewy body diseaseControl PD with dementia

No significant uptake Increased uptake in 70%


18F-dopa PET cortical decreases in PD

p < 0 001

cingulate

p < 0.001

Prefrontal

motor cortex

Early PD Advanced PD




32

18F-dopa reductions in PD dementia vs PD

Right anterior cingulate

vs PD

Ki/min

.0013

.0014

.0015

.0016

.0017

.0018

Ki/min Left anterior cingulate

.001

.0011

.0012

NC PD PDD

.0013

.0014

.0015

.0016

.0017

.0018

PDD < PD (p < 0.01, corrected)

NC normal controls; PDD PD dementia

.001

.0011

.0012

NC PD PDD


Ito et al. Brain 2002;125:1358–65.

NC, normal controls; PDD, PD dementia.

33

Decreased F-dopa uptake in PD: fatigue vs no fatiguefatigue vs no fatigue

Th k h t d th t thi The speaker has requested that this slide is not shown for copyright reasons

GPSRC CNS 169 0709 RTGGPSRC CNS 172 0709 RTG 34

Acetylcholine esterase imaging

18F-dopa

11C-NM4PA PET

11C-NM4PA

Normal PD PDD

PDD PD dementia; PET positron emission tomography


PDD, PD dementia; PET, positron emission tomography.

Hilker et al. Neurology 2005;65:1716–22

35

Microglial activation in PD

11C-PK11195 PET

Healthy Healthy volunteer

PD patientPD patient


Microglial activation in PD and PD with dementia

Controls (n= 10)11C PK11195 PET

dementia

0.5

0.6 PD (n= 12)

PDD (n= 6)

11C-PK11195 PET

0.3

0.4

0.1

0.2

0A-Cing P-Cing Thalamus Striatum Frontal Temporal Parietal Occipital Cerebellum

PDD PD dementia


PDD, PD dementia.

Personal data.

37

Conclusions

• Structural imaging of the nigra with transcranial sonography • Structural imaging of the nigra with transcranial sonography can detect presymptomatic structural change

• Dopaminergic imaging detects dysfunction in individuals at risk including REM sleep behaviour disorder and hyposmic risk including REM sleep behaviour disorder and hyposmic cases

• Abnormal extrastriatal dopaminergic function can be demonstrated in sleep (midbrain) dementia (frontal) and demonstrated in sleep (midbrain), dementia (frontal) and fatigue (insula)

• Cardiac sympathetic denervation is not a presymptomatic marker of PDmarker of PD

• Loss of cortical glucose metabolism and cholinergic function, and increased inflammation may predict PD dementia


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Neuroimaging in the prediagnostic phase of Parkinsonphase ... · Neuroimaging in the prediagnostic phase of Parkinsonphase of Parkinsons disease’s disease David J Brooks London,