BRAIN IMAGING OF MOVEMENT DISORDERS George P Gerasimou MD, PhD Clinical Director NuclMed Clinical Institute of Nuclear Medicine AHEPA University Hospital Thessaloniki, Macedonia, Greece.

Ο Μέγας Αλέξανδρος-Alexander the Great, the Great Hellinas (=Greek), the one and only Great in History.

INTRODUCTION 

Degenerative Parkinsonism, with Parkinson’s disease (PD) being the major representative, affects as many as 2% of all adults over the age of sixty five and most commonly presents with rest tremor, although the presence of bradykinesia on neurological examination is a sine qua non for its clinical confirmation. de Rijck MC et al Neurology 2000.

CLINICAL EVALUATION (I) 

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Skilled clinicians use a number of clinical features to distinguish among the parkinsonisms and other neurodegenerative disorders. Operationally, the diagnosis of PD requires the identification of 2 out of 3 cardinal symptoms (tremor, bent posture, dyskinesia) and a response to L-DOPA treatment. Studies suggest the accuracy of clinical diagnosis is poor, especially in new onset pts. Adler CH 1999 Gelb DJ 1999

CLINICAL EVALUATION (II) 

Up to one third of pts, initially evaluated as degenerative parkinsonism by general neurologists, were incorrect when examined by autopsy.

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One quarter of the population would not derive any benefit from antiparkinsonian medication.

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In a district PD Clinic, a time of 1.6+1.5 years and 1.8+2.9 years was needed on average to reach the diagnosis of iPD and Parkinsonian Syndromes other than iPD. The need to shorten this period is obvious.

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Anatomical imaging modalities (CT-MRI) are useful to exclude conditions, like MS and cerebral infarcts, but cannot identify a true presynaptic PS. Meara et al Age and Aging 1999 McMahon DG et al 1999 Morrish PK et al 2003.

CLINICAL EVALUATION (III) 

In routine clinical practice a tendency towards overdiagnosis and subsequent ‘‘overtreatment’’ of non-PD patients with anti-Parkinson medication exists.

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In a European multicenter study, when compared with the video gold standard diagnosis after 3 years, PD was erroneously diagnosed clinically in 53.6% of patients on entry. Jennings DL et al Arch Neurol 2004.

NEUROTRANSMITTERS   

Receptors for transporters occur in extremely low concentrations (10-13-10-9 moles/tissue ml). Radiolabelled ligands bind with high affinity to receptors or transporters for various neurotransmitters. Thanks to γ-photons emitted by the radioactive label, NM techniques offer the opportunity of imaging these receptors/ transmitters in vivo, which no other technique is able to do.

Brain Imaging in Clinical Practice  Clinical

Radiology -Instrumentation induces signal changes and detects the effects  Nuclear Medicine  Instrumentation detects the signal  The radioligand is the source of the signal

Functional Specificity is characteristic of Brain Emission Tomography

Left: Substantia nigra from a normal (top) and PD brain (bottom). Center: Cross-section of substantia nigra. Right: A Lewy body. These proteinaceous inclusions are the pathologic hallmark of PD.

WHAT IS DaT 

Ioflupane (I-123-N-ω-fluoropropyl-2β-

carbomethoxy–3β–(4-iodophenyl) nortropane-DaTSCAN), is a cocaine analogue, tagged to dopamine transporter.  Introduction of I-123 in combination with replacement of esteric bond with a carbon one, is increasing its stability and binding of the radioligand with dopamine transporter at the level of the striatum.

I-123-DATSCAN IN ESSENTIAL TREMOR AND PARKINSONISM.

Patients Abnormal scan Normal scan Total

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Sensitivity Specificity PPV NPV

PS 154 4 158

ET 0 27 27

Total 154 31 185

154/158 (97.5%) - 150/158(94.9%) 27/27 (100%) - 25/27 (92.6%) 154/154 (100%) - 150/152(98.7%) 27/31 (87.1%) -25/33 (75.8%)

The I-123-FP-CIT Study Group Writing Committee, Movem.Disord 2000,15:503-10.

DaTSCAN - SPECT images 

Striatum: dorsal and ventrical  Caudate nucleus: caudate accumbens plus main part of the caudate nucleus.  Putamen: anterior and posterior putamen

Healthy Volunteer male age 56

Essential Tremor male age 67

Parkinson’s Disease male age 55 Hoehn & Yahr I

Striatum Caudate Putamen

3

Specific:nonspecific uptake ratio 2

1

0 Essential Healthy Volunteers Tremor

Parkinsonism

THE CLINICAL IMPACT 

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In 36% of patients with presynaptic PS and 54% with nonpresynaptic PS, imaging results were not consistent with the initial diagnosis. Initial diagnosis was changed after SPECT study in 52% of the patients: -42% with an initial diagnosis of presynaptic PS -54% with a diagnosis of non-presynaptic PS. In a series of 125 individuals with MD, change of initial clinical diagnosis accordingly to DaTSCAN SPET data has been made to 33.6% of pts -25.6% from degenerative parkinsonism to essential tremor -8% from essential tremor to degenerative parkinsonism). In addition, in pts with an established DP diagnosis, clinical management has been re-evaluated to 20% of them. Catafau A, Tolosa E Movement Disorders, 2004 Gerasimou G et al Eur J Nucl Med Molec Imaging, 2007

CLINICAL ASPECTS 

1) Why do some patients who probably meet diagnostic criteria for PD have normal scans?

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2) Is functional imaging able to pre-diagnose PD?

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3) Why clinical measures of disease progression are not well correlated with imaging measures of progression?

CLINICAL PROBLEMS 

Several clinical and postmortem studies in healthy individuals reported an age-dependent decline of dopamine transporters in the putamen and nucleus caudate (3–7% per decade).

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In PD patients, however, striatal 123I-FP-CIT–SPECT binding seems not to be correlated with aging, however decline is clearly visualized and quantified. Booij J et al J Nucl Med Elsing EG et al J Invest Medicine.

CLINICAL PROBLEMS 

If imaging has low sensitivity, then the annual 6 to 13% loss of uptake known to occur in PD over time wouldn’t have transformed many of the initial normal scans to abnormal upon repeat testing.

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Observations suggest that low sensitivity is not the explanation for normal baseline scans among the majority of SWEDD cases.

CLINICAL PROBLEMS 

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Potential sources of error in DaT reporting are level of contrast and bkg substraction, technical artifacts and medicaton effects (?). Consideration of reduction of DaT binding with natural ageing (5.5% per decade). Varrone A et al. Eur J nucl Med Mol imaging 2013.

CLINICALLY UNCERTAIN PARKINSONIAN SYNDROMES (CUPS) 

The 2-year follow-up of the CUPS study, which aimed to validate the results of DaTSCAN imaging and to ascertain whether a second scan could minimize any residual diagnostic uncertainty among those with an inconclusive diagnosis.

Tolosa E et al. Mov Disorders 2007.

CLINICALLY UNCERTAIN PARKINSONIAN SYNDROMES (CUPS) 

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At follow-up, clinical diagnosis agreed with initial DaTSCAN SPECT results in 90% of pts in whom a specific diagnosis was established. A second SPECT scan was performed if clinical diagnosis at follow-up differed to that suggested by the initial scan (n = 8) or was inconclusive (n = 8). Follow-up DaTSCAN SPECT helped to establish a diagnosis in 7 of 8 patients (87.5%) with a previously inconclusive diagnosis. DaTSCAN imaging shows a high rate of agreement with clinical diagnosis after 2-years follow-up.

CLINICAL PROBLEMS-SWEDDS  

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DaTSCAN in selected pts? In early diagnosed PD, a normal PET scan was reported in a large number of pts, with a second one being normal at a 2 years followup. Again, in SWEDDS, a normal baseline SPECT scan, had no worsening at 40 weeks follow-up. Furthermore, withdrawal of antiparkinsonian drugs in those pts was successful. Finally, comparison of data support the hypothesis that the vast majority of pts with SWEDDS do not have PD. Barrett M Neurology 2011 Whone AL et al Annals Neurol 2003 Fahn S et al New Engl J Med 2004 Silveira-Moriyama M et al J Neurol Neurosurg & Psychiatry 2009.

CLINICAL ASPECTS-ANSWERS? 

It seems that there is a rapid degeneration of the DAT in PD pts, between stages I and II, as well as between II and III. This degeneration seems to start at the level of the putamen, sparing at the latest stages of the disease the CN.

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Estimation of asymmetry index.

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More widespread cell loss in the substantia nigra of the patients with the a-synuclein mutation. Gerasimou G et al Eur J Nucl Med Mol Imag 2003,30: S307 Itti E et al Nucl Med Communications 2009: 513-18 Antotnini A et al Nucl Med Communications 2009: 93-94 Bonstanjiopoulou S et al Hell J Nucl Med 2008: 157-159

CORRELATION OF PD AND ET. 

Only 2/32 pts (6%) with ET presented finally typical PD-like pattern of Ioflupane (DaTSCAN) uptake loss to the striatum and its parts (Isaias I et al Nucl Med Commun 2008: 349-53).

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No link seems to exist between PD and ET (Gerasimou G et al Annals of Nucl Med 2012).

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It is noticeable that in both studies, higher uptake values of the radiopharmaceutical to the striatum and its parts have been mentioned in normal volunteers compared to individuals characterized as ET.

RIGHT STRIATUM

LEFT STRIATUM 3,5

3,5 3

3

2,5

2,5

2

2

1,5

1,5

1 0,5

NV

1

NV

ET

0,5

ET

0

0 0

20

40

60

80

0

100

20

40

AGE

4 3,5 3 2,5 2 1,5 1 0,5 0

NV ET 0

20

40

80

100

RIGHT CAUDATE NUCLEUS

LEFT CAUDATE NUCLEUS 4 3,5 3 2,5 2 1,5 1 0,5 0

60 AGE

60

80

NV ET 0

100

20

40

60

80

100

80

100

AGE

AGE

RIGHT PUTAMEN

LEFT PUTAMEN

3

3,5

2,5

3 2,5

2

2

1,5

1,5

1

1

NV

0,5

NV

0,5

ET

ET

0

0 0

20

40

60 AGE

80

100

0

20

40

60 AGE

SPECT or PET in early cases of PD?

CLINICAL PROBLEMS 

The symptomatic threshold and the onset of motor signs to be at 50 to 64% loss of dopamine transporters (DAT) in the putamen.

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An abnormal study is available, when about 40-50% of DAT has been degenerated.

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In early PD, dopamine transporter mRNA expression is downregulated as a possible measure to compensatorily increase striatal dopamine levels. Thus, 123I-FP-CIT–SPECT might be more sensitive in the early or preclinical detection of PD than fluorodopa PET. Booij J et al Synapse 2001

CLINICAL PROBLEMS 

A study of olfactory function in 361 first-degree relatives of patients with Parkinson’s disease identified 40 individuals with strictly defined hyposmia.

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These clinically asymptomatic individuals, as well as 38 normosmic controls, were followed up with clinical examination and dopamine-transporter (DAT) SPECT imaging over 2 years, when 10% of the hyposmic patients with reduced DAT binding at baseline developed clinical Parkinson’s disease.

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The remaining hyposmic people showed a significantly increased decline of DAT binding during follow-up compared with none of the normosmic controls. Ponsen MM et al Ann Neurol 2004.

PREVENTIVE-PROTECTIVE TREATMENT IN PD. 1) Symptomatic: pharmacological strategies, restoring the dopamine deficiency-induced balance at the level of the striatum neuronal output structures. 2) Restorative: grafting fetal dopaminergic stem cells genetic manipulated cells pallidotomy or deep brain stimulation of the subthalamic nucleus 3) Neuroprotective treatment:interferes with the regional oxidative stress supposely underlying PD. Wolters EC, Berendse HW. New Tools in the Diagnosis of Parkinsonism, Acad.Pharmac.Productions,2001.

DEEP BRAIN STIMULATION 

Selected pts.  Improvement up to 73% 5 yrs post implantation.  Reduction of drug intake up to 58%.  Improvement of dyskinesia in 67%.

Brain 2007.

rCBF-SPECT in Dementia with Lewy bodies and AD 

Temporoparietal hypoperfusion on rCBF-SPECT is common to both AD and DLB. Occipital hypoperfusion is more frequently seen in DLB.

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Although not diagnostically specific in individual cases, occipital hypoperfusion on rCBF-SPECT should raise suspicion that DLB may be the cause of dementia, prompting careful search for other features of the disorder.

Lobotesis K et al Neurology 2000, 56: 643-49.

KJ, 67 y old male; no previous psychiatric history; onset at 55 y; persistent visual hallucinations; tremor; rigidity and akinesia H &Y=3.0; MMSE=unable; CAMCOG=unable; CDR=3.0 DaTSCANTM CN and putamen demonstrated; low background R CN=5.79 R AP=4.92 R PP=3.66

L CN=5.72 L AP=5.04 L PP=4.28

Neuropathological diagnosis: Alzheimer’s disease; neuritic plaques neurofibrilliary tangles; no Lewy bodies; no nigral degeneration

LW, 84 y old male; FH of PD and AD; no past psychiatric history; acute confusional state; vis. hallucin; no tremor; falls; fluctuation H&Y=1.0; UPDRS=2.0; MMSE=18; CAMCOG=76 DaTSCANTM

CN demonstrated bilaterally; putamen left > right; high background R CN=3.55 R AP=2.57 R PP=2.18

L CN=3.49 L AP=3.02 L PP=2.45

Neuropathological diagnosis:

Dementia with Lewy bodies; Cerad 4a; Braake stage 2; CLB score 8; severe nigral degeneration.

CLINICAL ASPECTS 

DaTSCAN cannot differentiate between DLB and Parkinson’s disease dementia as they share the same underlying LB pathology.  It has been postulated that these two entities may represent ends of the same clinical spectrum, with an arbitrary dividing line between cases in which dementia develops within 1 year of onset of clinical parkinsonism, classified as DLB, and cases in which dementia develops later, classified as Parkinson’s disease dementia.

CLINICAL ASPECTS 

The pooled sensitivity was somewhat lower (86.5%) owing to a substantial proportion of false negative scans.

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The explanation given for false negatives is that they may include cases of early-stage disease in which LB pathology is already present in the cerebral cortex but does not affect dopaminergic function and DaTSCAN imaging. Such patterns of neocortical predominant LB pathology, not penetrating the midbrain, have previously been reported in pathological studies that showed a non-uniform regional LB pattern within DLB brains.

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Another explanatory factor for false negative scans could be the inaccuracy of clinical diagnosis, against which DaTSCAN is usually validated. Colloby S et al Eur J Nucl Med Molec Imaging 2004.

Dopaminergic synapse

I-123-Ioflupane (DaTSCAN) Pre-synaptic dopamine transporter ligands

I-123-IBZM

Post-synaptic D2 dopamine receptor ligands

ß-CIT IPT TRODAT-1

Epidepride Raclopride

N Eng J Med 1996; 335: 128-9

Alan I. Leshner, PhD

IPS

Parkinson‘s disease

Template: normal controls

Characteristic findings in dopamine D2 receptor studies Binding: normal or increased (upregulation) asymmetry putamen higher Results: correspond to positive apomorphine test long term dopam. therapy Pitfalls: age dependency pretreated pts

Non-IPS

Multiple system atrophy

Characteristic findings in dopamine D2 receptor studies Binding: decreased (degeneration) no/less accent. asymmetry Results: correspond to negative apomorphine test long term dopam. therapy

Template: normal controls

Pitfalls: age dependency pretreated pts normal in early stages

A novel computer-assisted image analysis of [123I]β-CIT SPECT images improves the diagnostic accuracy of parkinsonian disorders. Eur J Nucl Med Mol Imaging 2011; 38:702-10.

Tc-99m-HMPAO SPECT IN PARKINSONPLUS SYNDROMES  

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1) iPD-normal pattern 2) MSA: frontal ? cerebellum striatum 3) PSP: prefrontal anterior cingulate gyrus caudates thalami brain stem 4) CBD: striatum temporo-parietal unilateral www.glimpsproject.com

DRUG INTERFERENCE IN IBZM-SPECT STUDY     

Neuroleptics-Antipsychotics: Chlorpromazine, Flufenazine, Zuclopentixol, Benperidol, Haloperidol. Dopamine agonists: Apomorphine, Bromocryptine, Lisuride, Pergolide. Availability of endogenous dopamine: Cocain, Amphetamine. Calcium overload blockers: Cinnarizine, Flunarizine. Anti-emetics with central action: Metoclopramide, Alizapride.

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