Efficacy and safety of high-dose cabergoline in Parkinson's disease

OBJECTIVES: To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias. MATERIALS AND METHODS: Thirty-four PD patients had cabergoline up-titrated and their levodopa (L-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26). RESULTS: Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean L-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious. CONCLUSION: High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for L-dopa.     

Monoamine transporter availability in Parkinson’s disease patients with or without depression

Purpose  Depression is a common symptom in patients suffering from Parkinson’s disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD−D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [¹²³I]FP-CIT. Methods  A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [¹²³I]FP-CIT binding coefficient V₃″ in the striatum, thalamus and midbrain/brainstem regions. Results  PD+D patients had significantly lower V₃″ compared with PD−D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V₃″ than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V₃″ nor midbrain/brainstem V₃″ differed from those in PD−D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318). Conclusion  Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder. The results of this study were partly presented at the Amersham Healthcare User Meeting during the 40^th Annual Meeting of the German Society of Nuclear Medicine 2002 in Freiburg, Germany, and at the 54^th Annual Congress of the Society of Nuclear Medicine 2007 in Washington, DC, USA.     

Possible impact of dopamine SPECT on decision-making for drug treatment in Parkinsonian syndrome

Summary. Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [¹²³I]FP-CIT and dopamine D₂/D₃ receptor SPECT with [¹²³I]IBZM to evaluate whether there is a reduction of DAT and/or D₂/D₃ receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37% of untreated patients were diagnosed as having Parkinson’s disease. 17% of treated patients had additional loss of D₂/D₃ receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38% clinically uncertain cases, SPECT was in concordance with 75% of initial clinical diagnoses. 25% were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS.     

Depression and Parkinson’s disease

Abstract.   Depression occurs in approximately 45% of all patients with Parkinsons disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.     

Switch from selegiline to rasagiline is beneficial in patients with Parkinson’s disease

The objective of this study is to demonstrate that application of rasagiline instead of selegiline with concomitant determination of l-amphetamine and l-methamphetamine in plasma is safe and well tolerated and influences sleep, mood, and motor behavior in patients with Parkinson’s disease on a stable drug therapy. 30 patients, who took 7.5 mg selegiline daily for at least 3 months, were switched to 1 mg rasagiline. Then they were followed over an interval of 4 months. The remaining drug therapy remained stable. This changeover was safe and well tolerated. l-Amphetamine and l-methamphetamine only appeared during selegiline treatment. Motor behavior, motor complications, mood and sleep improved during rasagiline administration. Amphetamine-like derivatives of selegiline could contribute to sleep disturbances, which may be involved in worsening of mood. Motor behavior and motor complications probably became better due to the additional glutamate receptor antagonizing properties of rasagiline in this open label study.     

Effect of neurostimulation on camptocormia in Parkinson's disease depends on symptom duration

Although some reports on neurostimulation are positive, no effective treatment method for camptocormia in Parkinson's disease (PD) is known to date. We aim to identify prognostic factors for a beneficial DBS effect on camptocormia. In an observational cohort study, we investigated 25 idiopathic PD patients, who suffered additionally from camptocormia, and underwent bilateral neurostimulation of the subthalamic nucleus (STN) to improve classical PD symptoms. Using an established questionnaire, we examined deep brain stimulation (DBS) effects on camptocormia in addition to general neurostimulation effects. A beneficial neurostimulation effect on camptocormia was defined as an improvement in the bending angle of a least 50%. In 13 patients, the bending angle of camptocormia improved, in 12 patients it did not. A multifactorial analysis revealed a short duration between onset of camptocormia and start of neurostimulation to be the relevant factor for outcome. All patients with duration of camptocormia up to 1.5 years showed a beneficial effect; patients between 1.5 and ∼3 years showed mixed results, but none with a duration of more than 40 months improved except for 1 patient whose camptocormia was levodopa responsive. The bending angle was not a prognostic factor. Our data indicate that the main prognostic factor for a beneficial DBS effect on camptocormia is its short duration. As an explanation, we suggest that neurostimulation may improve camptocormia only as long as muscle pathology is limited. Our findings may help to elucidate the mode of action of neurostimulation. A prospective study is necessary. © 2015 International Parkinson and Movement Disorder Society     

Effects of subthalamic nucleus stimulation on striatal dopaminergic transmission in patients with Parkinson’s disease within one-year follow-up

The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson's disease (PD), especially with regard to dopaminergic transmission, remain unclear. Therefore, the objective of our study was to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in advanced PD within a one-year follow-up. We used [(123)I]FP-CIT single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) availability and [(123)I]IBZM SPECT to assess dopamine D(2) receptor (D2R) availability (stimulator ON condition).Patients (n=18) showed a tendency towards a better suppression of symptoms after STN-DBS (Unified Parkinson's Disease Rating Scale motor score with medication decreased from 24.1+/-16.1 to 15.4+/-7.45; p=0. 002) while medication was strongly reduced (61% reduction of levodopa equivalent units; p<0. 0001). No changes of striatal [(123)I]FP-CIT binding and an increase of [(123)I]IBZM binding up to 16% (p<0. 05) between pre-surgery and follow-up investigations were noticed. These data show that clinical improvement and reduction of dopaminergic drugs in patients with advanced PD undergoing bilateral STN-DBS are paralleled by stable DAT and recovery of striatal D2R availability 12 months after surgery.     

Dementia in idiopathic Parkinson’s syndrome

Abstract. Approximately 25% of patients with idiopathic Parkinsons disease (IPD) later developdementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.