Diagnostic testing and neuroimaging

Dopaminergic challenge tests

♦ Levodopa and apomorphine challenge tests may help to determine whether a patient is responsive to dopaminergic therapy (40).

♦ Levodopa challenge: score the patient before and 60 min after a single high dose of levodopa (e.g. 250 mg). (Levodopa is given in the usual way in conjunction with a dopa-decarboxylase inhibitor, as Sinemet (co-careldopa) or Madopar (co-beneldopa), in a standard-release formulation).

♦ Apomorphine challenge: score the patient before and 20 minutes after sequential doses of subcutaneous apomorphine (e.g. 1 mg, 3 mg, 5 mg, but stopping once benefit or side-effects emerge).

40 Dopaminergic challenge testing. Motor score responses to dopaminergic challenge tests - apomorphine and single high-dose levodopa - are shown.

Pretreatment with an antinauseant (e.g. domperi-done) reduces nausea and hypotension side-effects, and this is especially important for apomorphine. Pretreatment is less important when testing a patient who is already taking antiparkinson medication, as they have more tolerance to side-effects (challenge testing in this situation is to check an uncertain therapy response).

A positive response is declared when the reduction in motor score is 20% or more (sometimes a target of 30% is set). Low pretreat-ment scores in early PD (due to mild clinical features) make determination of improvement difficult so that challenge testing is better avoided when the baseline motor score is less than 10. Other parameters have been used, e.g. walking speed.

1 mg subcutaneous apomorphine

1 mg subcutaneous apomorphine

Sequential doses given if initial doses ineffective

3 mg subcutaneous apomorphine

Pretreat with antinauseant, e.g. domperidone 20 mg tid for 3 days

Sequential doses given if initial doses ineffective

3 mg subcutaneous apomorphine

Pretreat with antinauseant, e.g. domperidone 20 mg tid for 3 days

>20% reduction indicates positive response

>20% reduction indicates positive response

5 mg subcutaneous apomorphine

Time (minutes)

41 Dopamine activity. MRI scanning at the level of the brainstem (a) and through the caudate and putamen (b—d); matching FP-CIT SPECT dopamine transporter activity (e—h). There is some activity at the substantia nigra level (e) but the

Some patients do not show a response to a challenge test but do show a response to longer-term oral therapy. For this reason, challenge tests cannot be used to declare a patient unresponsive to dopaminergic medication. Challenge tests have a limited role in routine clinical practice, but may be part of a research protocol. They are occasionally helpful in a diagnostically difficult patient. If a challenge test is planned in a patient who has yet to start treatment, and in whom the initial oral treatment choice would be a dopamine agonist (DA) rather than levodopa, then apomorphine is the preferred challenge test. This is because levodopa may 'prime' the patient for the earlier development of dyskinesia. Assessing the response to apomorphine is part of initiating this treatment, for intermittent use for sudden 'off periods (see Chapter 8).

Olfactory testing

Olfaction (sense of smell) is impaired in PD (see Chapter 2).

Smell testing is best performed using standardized methods, e.g. University of Pennsylvania Smell Identification Test (UPSIT) or Sniffin' sticks. Impaired olfaction correlates with functional neu-roimaging abnormalities in early PD. Twin studies suggest that olfactory abnormalities occur <7 years before the onset of PD.

Structural neuroimaging

The basal ganglia and substantia nigra are well visualized on MRI and can be matched to areas of dopamine activity on functional imaging (41). Although structural imaging is quite often performed in patients with suspected idiopathic PD, it is usually normal, and may therefore be reserved for patients more likely to show abnormalities.

41 Dopamine activity. MRI scanning at the level of the brainstem (a) and through the caudate and putamen (b—d); matching FP-CIT SPECT dopamine transporter activity (e—h). There is some activity at the substantia nigra level (e) but the greatest activity is through the middle of the striatum (f-g). Figures courtesy of Dr Jim Patterson, Glasgow.

1 Substantia nigra 3 Putamen

2 Head of caudate 4 Body of caudate

Incidental abnormalities may be seen, such as basal ganglia calcification (42). Structural neuroimaging may assist in diagnosis in some patients with dual pathology, e.g. PD plus cerebrovascular disease (suggested clinically, for example, by prominence of walking and balance problems).

42 Basal ganglia calcification.This was an incidental finding in a patient with idiopathic PD.

43 Posterior fossa atrophy and the 'hot cross bun' sign.

Normal brainstem and basal cistern size (a). Increase in basal cistern size (circled area) in a patient with MSA (b). In another patient with MSA (c), brainstem atrophy gives a distinctive appearance, referred to as the 'hot cross bun' sign, based on a traditional English bun appearance (inset).

Structural neuroimaging may be indicated if: O Tremor is acute in onset (suggesting a vascular cause). O Features remain unilateral (since PD should become bilateral). O There are features unusual for PD (e.g. early gait ataxia, incontinence, or frontal features suggesting hydrocephalus). O Lower -body involvement is prominent (especially with vascular disease at other body sites or risk factors for vascular disease, e.g. hypertension).

O There is a poor response to antiparkinson therapy (in association with some of the above features). Structural neuroimaging may show localized abnormalities on MRI in cases of degenerative parkinsonism other than idiopathic PD (although none of these techniques reliably distinguishes Parkinson-plus from PD at an early stage), e.g.: O Midbrain atrophy in MSA (which sometimes results in a brainstem appearance called the 'hot cross bun' sign) (43). O A hyperintense putaminal rim in MSA (this may be seen in normal patients using high-field (3-Tesla) scanning, but is absent on the fluid-attenuated inversion recovery (FLAIR) sequence).

44 MRI scans showing Hallevorden-Spatz disease.

Increased iron deposition in the putamen in a case of pantothenate kinase-associated neurodegeneration (also called Hallervorden-Spatz disease and sometimes referred to as neurodegeneration with brain iron accumulation).The scan on the left (a) shows normal basal ganglia structures and appear-ance.The scan on the right (b) shows increased signal bilaterally in the putamen (arrows) caused by iron deposition.

45 MRI scan showing cerebrovascular disease.There is evidence of small vessel cerebrovascular disease at multiple sites, including the typical periventricular location (a, b, arrowed). FP-CIT SPECT was nomal (c) and the patient's parkinsonism, which was principally axial and lower body, showed a poor response to levodopa.

O Morphometric changes in Wilson's disease (i.e. reductions from normal in the diameter and other measurements of brainstem size).

O Abnormal iron deposition in the putamen (44) in the rare syndrome of pantothenate kinase-associated neurodegeneration (Hallevorden-Spatz disease).

Structural brain causes of parkinsonism

♦ Cerebrovascular disease:

O Ischaemic changes in a periventricular pattern (subcortical white matter), relating to small vessel disease (e.g. hypertension, diabetes) (45).

O Diffuse cerebral white matter lesions mainly frontally are reported in one series.

O Small basal ganglia infarcts may cause acute onset tremor or parkinsonism; cases of sub-clinical PD might be unmasked by acute ischaemic damage.

O The classical clinical pattern of lower-body parkinsonism has been attributed to ischaemic disruption of pathways between primary and supplementary motor cortex and the basal ganglia and cerebellum.

O Diffuse white matter lesions may initially cause an isolated gait disorder without other parkinsonian features.

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46 Focal basal ganglia abnormalities.

FP-CIT SPECT (a) showing reduced caudate dopamine activity (arrow) and matching CT brain (b) showing infarction in the caudate at the same site.The patient did not have any clinical features of tremor or parkinsonism. Figure courtesy of Dr Jim Patterson, Glasgow.

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47 Damage to the substantia nigra. MRI showing unilateral vascular lesion (prior haemorrhage) in the substantia nigra (arrowed, a, b).The patient had left-sided tremor and parkinsonism, which responded to levodopa. Presynaptic dopamine activity was absent (c, arrow), while postsynaptic activity was increased through upregulation (not shown). Figure courtesy of Dr Jim Patterson, Glasgow.

O As well as causing lower-body parkinsonism, vascular damage may cause a clinical picture very like idiopathic PD, PSP, or corticobasal degeneration. O Vascular lesions may cause focal basal ganglia abnormalities without causing parkinsonism (46). O Lesions within the substantia nigra, or affecting the nigrostriatal pathway, can affect dopamine activity within the striatum, resulting in parkinsonism (47). ♦ Arteriovenous malformation or cavernoma (48), typically in basal ganglia.

48 Arteriovenous malformation.

Left-sided arteriovenous malformation (circled) in a patient presenting with clinical features suggesting early right-sided hemiparkinsonism.The patient was managed conservatively and did not progress to bilateral involvement.

49 Hydrocephalus.This patient had parkinsonism with predominant gait ataxia.Ventricular enlargement is obvious both on MRI (a) and CT (b). FP-CIT SPECT showed normal dopamine activity (c) but also gave a hint of the hydrocephalus (dotted area with absence of even background tracer uptake). The patient improved on ventricular decompression. FP-CIT scan courtesy of Dr Jim Patterson, Glasgow.

49 Hydrocephalus.This patient had parkinsonism with predominant gait ataxia.Ventricular enlargement is obvious both on MRI (a) and CT (b). FP-CIT SPECT showed normal dopamine activity (c) but also gave a hint of the hydrocephalus (dotted area with absence of even background tracer uptake). The patient improved on ventricular decompression. FP-CIT scan courtesy of Dr Jim Patterson, Glasgow.

O Obstructive (relieved by ventriculostomy or drainage).

O Normal-pressure hydrocephalus - enlarged ventricles disproportionate to any cortical atrophy.

Functional neuroimaging

PET and SPECT can identify pre- and postsynaptic components of the dopaminergic system in PD and other types of degenerative parkinsonism (50, 51).

There is some geographical variation in availability of these tests.

The cost of such scans may not be reimbursed in healthcare schemes.

Such testing is not required for uncomplicated cases with typical features. Research evaluation of other systems is of interest:

O Serotonin (5-hydroxytryptamine or 5-HT) in relation to tremor. O Cholinergic systems in relation to dementia.

Mechanisms in functional neuroimaging

18F-dopa (or i8-fluoro-dopa): O Is a marker of presynaptic dopamine activity. O Is taken up in the presynaptic neurone and converted to 18F-dopamine by decarboxylation.

O Requires omission of antiparkinson medication before the scan (for 12 hours). O Underestimates the true degree of dopaminergic loss, due to upregulation (i.e. increased turnover within the presynaptic neurone, to compensate for dopamine deficiency). Dopamine transporter ligands. Several isotopes function as markers of dopamine transporter activity (i.e. re-uptake of dopamine from the synaptic cleft into the presynaptic neurone) (50b).

O Dopamine transporter studies overestimate the true degree of dopaminergic loss, due to downregulation (i.e. less dopamine transporter activity than normal, to preserve active dopamine in the synaptic cleft). Dopamine transporter ligands are cocaine analogues but do not have psychotropic effects: O FP-CIT (DaTSCAN, GE Healthcare) is licensed in Europe to aid diagnosis in cases of clinical uncertainty between benign tremor disorders and PD. O Beta-CIT, IPT, and TRODAT-1 are similar ligands used mainly in research. FP-CIT, Beta-CIT, IPT and TRODAT-1 are all used primarily in SPECT studies; studies of the dopamine transporter with PET have used, e.g. 18F-CFT and 11C-WIN.

♦ Uptake in regions of interest is usually compared to a reference area such as the cerebellum to calculate an uptake ratio (for SPECT studies; in PET there is no need to calculate a ratio to a reference range as absolute values are measured).

♦ Direct comparisons between studies using different ligands, or using different scanning equipment, are difficult; typical normal uptake ratios of 2.3 for FP-CIT compare to 5.5 for Beta-CIT and 2 for TRODAT.

♦ Test-retest reliability affects interpretation of repeat scans in individual patients:

O It is 7% for FP-CIT in normal subjects and PD patients.

O It is between 13 and 17% for Beta-CIT.

There is no requirement to stop levodopa, DA, or monoamine oxidase B inhibitor (MAOB-I) therapy before presynaptic SPECT scanning. O Interaction studies show negligible if any effect on scan results comparing drug-naive patients at baseline to patients on antiparkinson therapy for up to 10 weeks. O Repeat scanning after drug withdrawal also shows no effect of short-term drug treatment on presynaptic activity (levodopa up to ting ging

Amphetamine and sympathomimetic agents osticeuro should be stopped 4 weeks before scanning; ^ -o o c some such agents are present in nasal Da decongestants.

Dopamine transporter

Dopamine

Presynaptic neurone degenerates in PD

Synaptic cleft

Synaptic cleft

Dopamine

Presynaptic neurone degenerates in PD

Dopamine transporter activity is downregulated in PD so FP-CIT studies underestimate residual neurones

I8F-dopamine ^ jt I8F-

neurones

Labelled dopamine transporter

I8F-dopamine ^ jt I8F-

Dopamine synthesis is upregulated in PD, so l8F-dopa studies overestimate residual neurones

Dopamine synthesis is upregulated in PD, so l8F-dopa studies overestimate residual neurones

Presynaptic neurone

Degenerates in # idiopathic PD

Degenerates in # Parkinson-plus disorders

Site of metabolism of # levodopa

Turnover of levodopa • and dopamine is regulated in PD

Postsynaptic neurone

# Available for antiparkinson therapy benefit

# Pre- and post-synaptic degeneration = limited therapy benefit in Parkinson-plus disorders

# Blockade by anti-psychotics/ anti-emetics may unmask early PD or cause reversible parkinsonism

# Dopamine agonists act at various receptor sites

50 PET and SPECT in PD. Dopamine is synthesized in the presynaptic neurone and released into the synaptic cleft, with extracellular dopamine being reabsorbed via transporter proteins (a).l8F-dopa is a PET marker for dopamine synthesis, while dopamine transporters are isotope-labelled by FP-CIT Beta-CITTRODAT etc., to trace activity (b). Although there is evidence of compensatory mechanisms, such effects are minor relative to the loss of neurones even in early PD.

51 Neurone abnormalities. Differentiating features increase synaptic versus postsynaptic dopamine neurones in parkinson-ism.The characteristics of abnormalities occurring in the presynaptic and postsynaptic neurones in PD and Parkinson-plus disorders as well as drug effects are shown.

Patients presenting with possible PD

Presynaptic dopamine imaging as a diagnostic and research tool in PD

Imaging findings need to be considered separately for:

O Patients presenting with possible PD (i.e. already symptomatic), who may later have repeat scans (in research studies). O Relatives of patients with PD, who may be identified as having early (preclinical) PD.

Patients presenting with possible PD

At first presentation with PD there is usually at least 30% reduction from normal in presynaptic dopamine activity on PET or SPECT. O This is consistent with the degree of substantia nigra cell loss in early PD seen in postmortem studies. Initial changes are often bilateral but more marked in the putamen contralateral to symptom onset (suggesting 'presymptomatic' loss in the initially clinically unaffected side)(52b). O Progressive loss occurs in putamen then caudate and eventually low activity is almost symmetrical (52c). O PET studies of the dopamine transporter showed putamen reduction to 42% of normal controls, and caudate reduction to 76% of normal controls, at around 2 years' duration of symptoms. O Presynaptic dopamine deficiency occurs in a number of other degenerative disorders which feature parkinsonism (53).

The pattern of loss differs from normal ageing, where neuronal loss occurs evenly in different brain areas.

Clinical severity of bradykinesia and rigidity correlates with presynaptic dopaminergic activity (but tremor severity does not correlate). There is an overall correlation of scan results with H&Y scoring of PD patients. Clinical severity in relation to the degree of dopaminergic loss is less in patients with the PARK 2 (Parkin) variant of PD, compared to other PD patients (54).

52 Presynaptic dopamine imaging.

(a) The comma-shaped caudate and putamen on FP-CIT SPECT (DaTSCAN) are shown.This pattern is seen in healthy individuals and patients with ET

(b) A reduction in the left more than right putamen (arrow) but bilaterally abnormal with reduced caudate activity. This patient had 2 years' symptoms and greater clinical involvement on the right side of the body matching the more marked putamen loss on the left side.

(c) An advanced case: virtually no activity in either putamen. Caudate activity is bilaterally reduced, particularly on the patient's right side (arrow). Some asymmetry may persist clinically throughout the patient's life and matches the dopamine levels seen on functional dopaminergic brain imaging.

Normal

Abnormal

e \

• %

Essential tremor

Idiopathic PD

Drug-induced parkinsonism

Multiple system atrophy

Vascular parkinsonism

(except if there are focal infarcts)

Progressive supranuclear palsy Corticobasal degeneration

Dystonic tremor (including dopa-responsive dystonia)

Psychogenic parkinsonism

Wilson's disease Spinocerebellar ataxia type 3

Alzheimer's disease

Distinguishing idiopathic PD from MSA, PSP, and other forms of degenerative parkinsonism has proved difficult.

O Higher degrees of asymmetry in dopaminergic activity are more likely in PD than MSA or PSP (which matches the clinical pattern of asymmetry in these disorders, i.e. PD is more likely to present with asymmetry, and remain more troublesome for one body side than the other).

O Mapping techniques for scan readings offer the potential to distinguish these disorders, since striatal loss tends to be more uniform, for example, in MSA than in PD (the putamen:caudate ratio has been used in this setting but more sophisticated techniques are probably required).

53 Differentiating parkinsonian and tremor disorders.

The left panel shows conditions in which normal presynaptic dopamine imaging occurs.The right panel shows conditions in which abnormal presynaptic dopamine imaging occurs.

54 Dopamine activity and the rate of change.There is evidence of a varying rate of dopamine loss as the disease progresses. Patients with parkin-positive PD show a somewhat different pattern to those with sporadic PD: younger age of onset, lower dopamine activity at presentation, but subsequently a slower decline.This is one source of variability in comparing clinical to imaging findings in PD.

Preclinical

(3-5 years) May be preceded by medulla and olfaction loss o

Preclinical

(3-5 years) May be preceded by medulla and olfaction loss o

Parfc/n.posit(Ve pD

Early clinical Younger onset age and lower dopamine activity than sporadic PD

Later stages

Rate of dopamine loss lower than in sporadic PD; definite plateau

Advanced

Plateau in dopamine activity; nonmotor features dominate clinically

Parfc/n.posit(Ve pD

Advanced

Plateau in dopamine activity; nonmotor features dominate clinically

Early clinical Younger onset age and lower dopamine activity than sporadic PD

Later stages

Rate of dopamine loss lower than in sporadic PD; definite plateau

Time

Postsynaptic dopamine imaging in parkinsonism

Progression rates in PD

♦ Annual loss occurs at around 8% (FP-CIT) and 6-11% (Beta-CIT) in PD (compared to an age-related change of 0.3-1% per annum).

♦ Annual progression at 4.7% (of normal mean) occurs on repeat 18F-dopa PET studies (which suggests a 5-year duration for preclinical PD). O The rate of putamen loss may be higher than that of caudate loss (more than double in one study) but differences arise from calculation techniques and study timings. The rate of change may be faster around the time of clinical presentation than later during the disease course.

O A 'reverse exponential' rate of loss may occur at disease onset. O Later progression rates are more stable. O Progression rates were steady for up to 7 years' disease duration when comparing scans at 0, 2, and 3 years (0 = study entry, not disease onset). O Selection bias - including less severely affected patients in later studies - may influence these observations.

♦ The test-retest variability of these techniques indicates that progression rates are not reliable for individual patients, but require group studies.

♦ Continued dopaminergic loss has been shown to occur after subthalamic stimulation (18F-dopa PET study in 30 patients before and 16 months after deep brain surgery; conducted to determine whether such surgery might be neuroprotective).

Relatives of patients with PD

♦ Heterozygotes for Parkin (which is related to the PARK2 genetic type of PD, see Chapter 1) have reduced dopaminergic activity (18F-dopa PET study in asymptomatic first-degree relatives of familial or isolated cases). Subtle parkinsonian clinical features, insufficient to fulfil Brain Bank criteria, were found in a subset of cases. Similar features occur in relatives of PARK6 patients.

♦ Relatives of PD patients who have a reduced sense of smell and/or abnormal transcranial ultrasound signals from the basal ganglia, show reduced dopamine activity on SPECT scanning.

♦ 18F-dopa PET uptake is reduced in monozygotic twins (75% concordance) to a greater extent than in dizygotic twins (22% concordance), supporting a role for genetics in developing PD.

♦ Functional imaging of the postsynaptic dopamine system is possible using SPECT (ligands include IBZM, 55) and PET (ligands include C11-raclo-pride).

♦ The postsynaptic neurones remain intact in idiopathic PD. Imaging of this area (e.g. ligands binding to the D2 receptor) therefore give a normal result (or a marginal increase from normal activity caused by upregulation in response to reduced presynaptic dopamine availability).

♦ Drugs which are antagonists at D2 receptors cause reduced uptake of the imaging ligand (i.e. the ligand has reduced binding to the receptor which is already occupied by the offending drug). This is the mechanism for most drugs which induce parkinsonism (e.g. neuroleptic agents).

♦ Parkinsonism occurs when D2 receptor occupancy by the drug is around 60-70%.

♦ Blockade by a drug at the D2 receptor may 'unmask' a very early case of idiopathic PD (see 33).

O This occurs through blockade at a second neuronal site of dopaminergic transmission. O Prolonged occupancy of D2 receptors, weeks or months after stopping the offending drug, has been shown.

♦ Abnormal D2 scans also occur in Parkinson-plus disorders.

O This occurs because the neuronal degeneration affects not only the presynaptic system (which is also affected in idiopathic PD, as described above) but also the postsynaptic system.

O In earlier stage Parkinson-plus disorders, the D2 SPECT results are often within the normal range or intermediate, preventing definitive radiological diagnosis. O More correctly, the D2 SPECT results indicate the likelihood of a treatment response to dopaminergic therapy (at the time of the scan).

O Interpreting the postsynaptic scan assumes that dopamine-blocking drugs were not present at the time of the scan.

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