Donald G. Grosset

Correlation of Parkinson's disease severity and duration with 123I-FP-CIT SPECT striatal uptake

The variability in clinical features and the masking effects of drug therapy in Parkinsons disease (PD) can affect clinical assessment of disease severity. The aim of this study was to assess the imaging of dopamine transporters using 123I‐FP‐CIT SPECT and its correlation with disease staging, severity, and duration. Differences between the clinical severity of the onset and non‐onset side and the corresponding striatal uptake ratios were also examined. Forty‐one patients with PD (nine unilateral, 32 bilateral clinical features) were studied. Clinical severity was determined by using the Unified Parkinsons Disease Rating Score (UPDRS). Unilateral UPDRS was calculated from unilateral arm and leg resting and action tremor, rigidity, finger taps, hand movements, alternating movements, and leg agility. 123I‐FP‐CIT striatal uptake was expressed as the ratio of specific:nonspecific (SP:NS) uptake for defined brain areas. Patients with PD who had unilateral symptoms showed a significant difference between the ipsilateral and contralateral SP:NS ratios in both the caudate and putamen, but there was a considerable overlap between between the two sides. This result was repeated in patients with bilateral symptoms and there was overlap of SP:NS ratios between the two groups. For the whole group of patients with PD, striatum, caudate, and putamen SP:NS ratios correlated with disease severity assessed by UPDRS and duration of disease. The SP:NS ratios correlated with the bradykinesia subscore but not with rigidity or tremor subscore. In conclusion, this study provides further evidence that the SP:NS ratio is a robust measure of disease severity correlating with duration of PD. However, variability in uptake values suggest that factors other than nigrostriatal degeneration may contribute to disease severity. Correlation with bradykinesia but not with tremor may indicate an origin for tremor outwith the dopamine transporter system. 123I‐FP‐CIT SPECT offers significant potential in defining the nigrostriatal changes in PD.

Role of dopamine transporter imaging in routine clinical practice

Functional imaging of the dopamine transporter (DAT) defines integrity of the dopaminergic system and has its main clinical application in patients with mild, incomplete, or uncertain parkinsonism. Imaging with specific single positron emission computerised tomography ligands for DAT (FP‐CIT, β‐CIT, IPT, TRODAT) provides a marker for presynaptic neuronal degeneration. Striatal uptake correlates with disease severity, in particular bradykinesia and rigidity, and monitoring of progression assists in clinical trials of potential neuroprotective drugs. DAT imaging is abnormal in idiopathic Parkinsons disease, multiple system atrophy and progressive supranuclear palsy and does not distinguish between these disorders. Dopamine loss is seen even in the earliest clinical presentations of true parkinsonism; a normal scan suggests an alternative diagnosis such as essential tremor, vascular parkinsonism (unless there is focal basal ganglia infarction), drug‐induced parkinsonism, or psychogenic parkinsonism. Congruence between working clinical diagnosis and DAT imaging increases over time in favour of baseline DAT imaging results. Additional applications are characterising dementia with parkinsonian features (abnormal results in dementia with Lewy bodies, normal in Alzheimers disease); and differentiating juvenile‐onset Parkinsons disease (abnormal DAT) from dopa‐responsive dystonia (normal DAT).

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study

Dopamine agonists are used as initial treatment in patients with Parkinsons disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long‐term studies, allowing “rescue” therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide‐versus‐L‐dopa‐monotherapy‐and‐positron‐emission‐tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa “rescue” medication. This multicenter, double‐blind, randomized, 3‐year trial compared pergolide monotherapy (n = 148) with levodopa monotherapy (n = 146) in dopamine‐naive patients with early PD (Hoehn and Yahr stage 1–2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinsons Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Role of DAT-SPECT in the diagnostic work up of Parkinsonism

The diagnosis of idiopathic Parkinsons disease (PD) can be achieved with high degrees of accuracy in cases with full expression of classical clinical features. However, diagnostic uncertainty remains in early disease with subtle or ambiguous signs. Functional imaging has been suggested to increase the diagnostic yield in parkinsonian syndromes with uncertain clinical classification. Loss of striatal dopamine nerve terminal function, a hallmark of neurodegenerative Parkinsonism, is strongly related to decreases of dopamine transporter (DAT) density, which can be measured by single photon emission computed tomography (SPECT). The use of DAT‐SPECT facilitates the differential diagnosis in patients with isolated tremor symptoms not fulfilling PD or essential tremor criteria, drug‐induced, psychogenic and vascular Parkinsonism as well as dementia when associated with Parkinsonism. This review addresses the value of DAT‐SPECT in early differential diagnosis, and its potential as a screening tool for subjects at risk of developing PD as well as issues around the assessment of disease progression.

Problematic gambling on dopamine agonists: Not such a rarity.

Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinsons disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti‐Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect.

Suboptimal medication adherence in Parkinson's disease.

Patients take less medication than prescribed in many disease areas but evidence for suboptimal therapy adherence in Parkinsons disease (PD) is limited. A single‐center observational study of antiparkinsonian medication was undertaken using electronic monitoring (MEMS; Aardex, Zug, Switzerland) over 3 months. Of 68 patients approached, 6 declined and 8 dropped out, leaving 54 patients (taking 117 preparations) with available data. Poorer compliance was associated significantly with younger age, with taking more antiparkinsonian tablets per day, with higher depression scores, and with poorer quality of life. Of the 54 evaluable patients, 11 (20%) had average total compliance of under 80% (underusers) and 43 (80%) had average total compliance of over 80% (satisfactory adherence). Underusers had median total compliance of 65% (interquartile range, 37–74) versus 98% (interquartile range, 93–102) in the satisfactory adherence group. Timing compliance (number of doses taken in the correct time interval) was poor in both underusers (median, 11%; interquartile range, 2–20) and those with satisfactory adherence (median, 25%; interquartile range, 11–73). In conclusion, poorer compliance is associated with younger age, depression, and more tablets per day, and one‐fifth of PD patients underuse medication. Consideration of drug therapy adherence has implications in the management of PD.

Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT

Overdiagnosis of Parkinsons disease (PD) is suggested by specialist review of community diagnosis, and in postmortem studies. In specialist centers 4 to 15% of patients entered into clinical trials as early PD do not have functional imaging support for a PD diagnosis. In a European multicenter, prospective, longitudinal study, we compared clinical diagnosis with functional SPECT imaging using [123I]FP‐CIT (DaTSCAN™, GE Healthcare). Repeat observations were performed over 3 years in patients with tremor and/or parkinsonism in whom there was initial diagnostic uncertainty between degenerative parkinsonism and nondegenerative tremor disorders. Video‐recording of clinical features was scored independently of functional imaging results by two blinded clinicians at 36 months (= gold standard clinical diagnosis). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The main endpoint was the sensitivity and specificity of SPECT imaging at baseline compared with the gold standard. In 99 patients completing the three serial assessments, on‐site clinical diagnosis overdiagnosed degenerative parkinsonism at baseline in diagnostically uncertain cases compared with the gold standard clinical diagnosis (at 36 months), the latter giving a sensitivity of 93% and specificity of 46%. The corresponding baseline [123I]FP‐CIT SPECT results showed a mean sensitivity of 78% and a specificity of 97%. Inter‐reader agreement for rating scans as normal or abnormal was high (Cohens

Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: Part 1. Baseline and 3-month observations

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A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson’s disease left untreated at diagnosis

= 0.94–0.97).

Adherence to Antiparkinson medication in a Multicenter European study

To record prospectively, from early presentation, the clinical features of parkinsonism and tremor disorders, in relation to evidence of dopaminergic deficit shown with [123I]‐FP‐CIT (DaTSCAN, Amersham Health) single photon emission computerised tomography (SPECT). Clinical signs were recorded in 62 patients, of whom 24 failed standard Parkinsons disease (PD) and essential tremor criteria, and 38 fulfilled UK Brain Bank step 1 PD criteria. Striatal radioligand uptake was graded visually as normal or abnormal, and specific:nonspecific ratios were calculated. Bradykinesia and rigidity showed significant overall association with abnormal scans (P ≤ 0.003), but rest tremor did not (P = NS). In the 24 patients not fulfilling specific criteria (mean age 63 [SD 9] years, disease duration 3 [SD 4] years), 10 (42%) had abnormal visual SPECT assessment and 14 (58%) had normal scans. Of 38 patients with early PD by clinical criteria (mean age 60 [SD 9] years, disease duration 3 [SD 1.7] years), 33 (87%) were visually abnormal. Baseline clinical diagnosis corresponded with SPECT imaging results in 51 of 62 cases (82%), which increased to 56 of 62 cases (90%) with amendment of seven clinical diagnoses at 3 months (blind to SPECT results). Akinetic–rigid cardinal diagnostic features of parkinsonism associate well with dopaminergic deficit in patients with early and mild clinical features. When these clinical features are uncertain, or the patient fails clinical diagnostic criteria, testing for dopaminergic deficit with [123I]‐FP‐CIT SPECT may assist the diagnostic process.