Atbin Djamshidian

Exenatide and the treatment of patients with Parkinson’s disease

UNLABELLED BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinsons disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD. TRIAL REGISTRATION Clinicaltrials.gov NCT01174810. FUNDING Cure Parkinsons Trust.

Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinsons disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinsons disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinsons disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinsons disease groups following L-dopa challenge with neutral cues. The group with Parkinsons disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinsons disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions.

Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease

BACKGROUND Data from an open label randomised controlled trial have suggested possible advantages on both motor and non-motor measures in patients with Parkinsons disease following 12 months exposure to exenatide. OBJECTIVE Continued follow up of these same patients was performed to investigate whether these possible advantages persisted in the prolonged absence of this medication. METHODS All participants from an open label, randomised controlled trial of exenatide as a treatment for Parkinsons disease, were invited for a further follow up assessment at the UCL Institute of Neurology. This visit included all 20 individuals who had previously completed twelve months exposure to exenatide 10ug bd and the 24 individuals who had acted as randomised controls. Motor severity of PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the MDS-UPDRS, together with several non-motor tests. This assessment was thus 24 months after their original baseline visit, i.e. 12 months after cessation of exenatide. RESULTS Compared to the control group of patients, patients previously exposed to exenatide had an advantage of 5.6 points (95% CI, 2.2-9.0; p = 0.002) using blinded video rating of the MDS-UPDRS part 3 motor subscale. There was also a difference of 5.3 points; (95% CI, 9.3-1.4; p = 0.006) between the 2 groups on the Mattis Dementia Rating scale. CONCLUSIONS While these data must still not be interpreted as evidence of neuroprotection, they nevertheless provide strong encouragement for the further study of this drug as a potential disease modifying agent in Parkinsons disease.

Risk and learning in impulsive and nonimpulsive patients with Parkinson's disease.

Relatively little is known about the interaction between behavioral changes, medication, and cognitive function in Parkinsons disease (PD). We examined working memory, learning and risk aversion in PD patients with and without impulsive or compulsive behavior (ICB) and compared the results with those in a group of age‐matched control subjects. Parkinson patients with PD+ICB had poorer working memory performance than either controls or PD patients without ICB. PD+ICB patients also showed decreased learning from negative feedback and increased learning from positive feedback in off compared with on dopaminergic medication. This interaction between medication status and learning was the opposite of that found in the PD patients without a diagnosis of ICB. Finally, the PD group showed increased risk preference on medication relative to controls, and the subgroup of PD+ICB patients with pathological gambling were overall more risk prone than the PD group. Thus, medication status and an impulsive behavioral diagnosis differentially affect several behaviors in PD.

A novel mutation in the VCP gene (G157R) in a German family with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia.

Mutations in the valosin‐containing protein (VCP) are known to cause autosomal‐dominant inclusion‐body myopathy with Pagets disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N‐terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD. Muscle Nerve 39: 389–391, 2009

Decision making, impulsivity, and addictions: do Parkinson's disease patients jump to conclusions?

Links between impulsive‐compulsive behaviors (ICBs) in treated Parkinsons disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age‐matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions.

Stroop test performance in impulsive and non impulsive patients with Parkinson's disease.

Impulsive personalities are considered to have a general impairment in cognitive flexibility and cortical inhibition. To examine this hypothesis we used a trial by trial Stroop task in impulsive and non impulsive patients with Parkinsons disease (PD) and recorded errors and reaction times (RT). We tested 28 impulsive PD (PD+ICB) and 24 non impulsive PD (PD-ICB) patients prior to and after dopaminergic medication. These results were compared with 24 age matched normal controls. We found an increased error rate in all PD patients prior to their usual medication which resolved after medication. Furthermore patients on medication showed enhanced cognitive flexibility and shorter RT. There was no difference between non impulsive and impulsive PD patients. This suggests that the impulsive behaviours may not affect response inhibition tasks and the response inhibition required in the Stroop test does not engage the same processes that differentiate impulsive and non-impulsive PD patients, which likely involve mesolimbic dopamine.

Probable RBD and association with neurodegenerative disease markers: A population‐based study

The prevalence of rapid eye movement sleep behavior disorder (RBD) and its association with markers of neurodegeneration in the general population are poorly defined.

Pathological gambling in Parkinson's disease--a review of the literature.

The prevalence of pathological gambling is 3.4% to 6% in treated Parkinsons disease, which is higher than the background population rate. In this review we discuss current evidence to indicate that dopamine agonists are much more likely to trigger this behavior than either L‐dopa or selective monoamine oxidase B inhibitor monotherapy. New insights from recent behavioral and functional imaging studies and possible treatment approaches are also covered. A PubMed literature search using the terms “gambling” and “Parkinsons disease,” “impulse control disorder,” “impulsive compulsive behaviour,” “dopamine agonist,” of individual dopamine agonists, and of ongoing drug trials, using http://www.clinicaltrials.gov, was carried out for the period up to January 2011.

Excessive hoarding in Parkinson's disease†

Hoarding is seen in several psychiatric conditions, but has not been specifically assessed in Parkinsons disease (PD). This study investigates hoarding tendency amongst patients with PD, and its association with impulsive‐compulsive spectrum behaviors (ICBs). We compare clinical features, measures of hoarding, impulse buying, self‐control, obsessive‐compulsive symptoms, depression, and anxiety in 39 patients with PD with ICBs (PD + ICB), 61 patients with PD without ICBs (PD − ICB), and 50 healthy controls. A much higher proportion of PD + ICB (27.8%) than PD − ICB (3.5%) were hoarders (P = 0.001). 6% of healthy controls were hoarders. Compulsive shoppers scored higher than other varieties of ICB on excessive acquisition measures. Hoarding correlated positively with impulsive buying, obsessive‐compulsive symptoms, PD duration, and negatively with self‐control measures. Using multivariate regression analyzes, the presence of ICBs and measures of impulsive buying were the only variables independently associated with hoarding in PD. The association of hoarding with other ICBs and low trait impulse control suggests that excessive hoarding is related to the spectrum of impulsive behaviors in PD.