Search

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease. [ABSTRACT FROM AUTHOR]

Dopamine dysregulation syndrome (DDS) is a relatively recently described iatrogenic disturbance that may complicate long-term symptomatic therapy of Parkinson's disease. Patients with DDS develop an addictive pattern of dopamine replacement therapy (DRT) use, administering doses in excess of those required to control their motor symptoms. The prevalence of DDS in patients attending specialist Parkinson's disease centres is 3-4%. Amongst the behavioural disturbances associated with DDS are punding, which is a complex stereotyped behaviour, and impulse control disorders (ICDs), such as pathological gambling, hypersexuality, compulsive shopping and compulsive eating. We review the risk factors and potential mechanisms for the development of DDS, including personality traits, potential genetic influences and Parkinson's disease-related cognitive deficits. Impulsive personality traits are prominent in patients developing DDS, and have been previously associated with the development of substance dependence. Candidate genes affecting the dopamine 'D(2)-like' receptor family have been associated with impulsive personality traits in addition to drug and nondrug addictions. Impaired decision making is implicated in addictive behaviours, and decision-making abilities can be influenced by dopaminergic medications. In Parkinson's disease, disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex following dopamine depletion may predispose to DDS. The role of DRT in DDS is discussed, with particular reference to models of addiction, suggesting that compulsive drug use is due to progressive neuroadaptations in dopamine projections to the accumbens-related circuitry. Evidence for neuroadaptations and sensitization occurring in DDS include enhanced levodopa-induced ventral striatal dopamine release. Levodopa is still considered the most potent trigger for DDS in Parkinson's disease, but subcutaneous apomorphine and oral dopamine agonists may also be responsible. In the management of DDS, further research is needed to identify at-risk groups, thereby facilitating more effective early intervention. Therefore, an increased awareness of the syndrome amongst treating physicians is vital. Medication reduction strategies are employed, particularly with regard to avoiding rapidly acting 'booster' DRT formulations. Psychosocial treatments, including cognitive-behavioural therapy, have been beneficial in treating substance use disorders and ICDs in non-Parkinson's disease patients, but there are currently no published trials of psychological interventions in DDS. Further studies are also required to identify factors that can predict those patients with DDS or ICDs who will derive benefit from surgical interventions such as deep brain stimulation. [ABSTRACT FROM AUTHOR]

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA. Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined. On the basis of early symptoms, we subdivided cases with PSP into 'Richardson's syndrome' (RS) and 'PSP-parkinsonism' (PSP-P). Cases of MSA were subdivided according to the presence or absence of early autonomic failure. Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P. Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset. Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA. In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P. In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival. We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival. [ABSTRACT FROM AUTHOR]

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 Parkinson's 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. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work.

Background: Little is known about the cognitive and neuropsychiatric profile associated with punding and hobbyism in Parkinson's disease (PD)., Objective: To compare the clinical and neuropsychological features of PD patients with punding and hobbyism to PD controls., Methods: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used as a screening tool, and a structured interview was used to diagnose punding/hobbyism. Clinical and neuropsychological assessment was conducted with validated questionnaires/scales., Results: Twenty-one patients with PD and punding (PD + pu) were compared to 26 with hobbyism (PD + h) and 25 PD controls. PD + pu patients showed higher levels of anxiety, non-motor symptoms and motor symptoms, and lower Frontal Assessment Battery scores. The PD + h group exhibited similar levels of anxiety and motor fluctuations to the PD + pu group., Conclusion: PD + pu showed increased anxiety and frontal lobe dysfunction, similar to PD + h. Hobbyism could be a prodromal phase with increased risk of leading to punding., Competing Interests: This article presents independent research supported by the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility at the University College London (UCL) Institute of Neurology and UCLH‐National Hospital for Neurology and Neurosurgery, London, UK. We thank the Reta Lila Weston Institute of Neurological Studies for the support received during this research project. P.B.is supported by a grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazilian National Council for Scientific and Technological Development)., (© 2021 International Parkinson and Movement Disorder Society.)

Impulse control disorders (ICDs) and related impulsive and compulsive behaviors (together called ICBs) have been increasingly recognized in the context of Parkinson's disease (PD) and treatment. The International Parkinson's and Movement Disorder Society commissioned a task force to assess available clinical screening instruments and rating scales, including their clinimetric properties, make recommendations regarding their utility, and suggest future directions in scale development and validation. The literature was systematically searched for scales measuring a range of reported ICBs in PD. A scale was designated "recommended" if the scale had been employed in PD studies, been used beyond the group that developed it, and had adequate clinimetric data published for PD. Numerous diagnostic screening tools and severity rating scales were identified for a range of ICBs, including compulsive medication use, punding/hobbyism, walkabout, pathological gambling, hypersexuality, compulsive or binge eating, compulsive buying, reckless driving, compulsive exercise, pyromania, trichotillomania, hoarding, kleptomania, intermittent explosive disorder, and internet addiction. For screening across the range of ICBs (except compulsive medication use), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP) and QUIP-Rating Scale (QUIP-RS) are recommended, and for severity rating across the range of ICBs the QUIP-RS and the Ardouin Scale of Behavior in Parkinson's Disease are recommended. The Scale for Outcomes in Parkinson's Disease-Psychiatric Complications is recommended for rating of hypersexuality and the compulsive behaviors gambling/shopping. Further testing of established scales against gold standard diagnostic criteria is urgently required for all other individual ICBs in PD. © 2019 International Parkinson and Movement Disorder Society © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Introduction Dopamine transporter scans are increasingly being used in the diagnosis of clinically undefined Parkinsonism. Aims To assess the indications for imaging usage and its impact on future clinical management. Methods Retrospective review of scans ordered and their corresponding results over a five-year period. A chart review was carried out on a cohort of scans to assess changes in clinical management. Results One hundred and eighty scans (69% of total) were reported as showing evidence of dopaminergic deficit. A chart review in 81 patients showed a change in clinical management in 53 patients (65%). Scans were ordered inappropriately in 34 patients (13%). Discussion 123I-FP-CIT SPECT scans are being more frequently ordered and if used correctly can alter clinical management. Increased education on indications for use is required to reduce waste of resources and risk to patients., Competing Interests: The authors of this manuscript have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Background: Palliative care is recommended for non-malignant illnesses, including Parkinson's disease. However, past research with healthcare workers highlights unmet palliative needs in this population and referral rates to Specialist Palliative Care are low. Some healthcare workers perceive a 'fear' in their patients about introducing palliative care. However, less is known about the views of people with Parkinson's disease and their carers about palliative care., Aim: (1) To explore the palliative care and related issues most affecting people with Parkinson's disease and their families and (2) to examine perceptions about/understanding of palliative care., Design: This was a qualitative study; semi-structured interviews were conducted, transcribed and analysed using thematic analysis., Setting/participants: A total of 31 people participated, both people with Parkinson's disease ( n = 19) and carers ( n = 12), across three Movement Disorder Clinics in the Republic of Ireland., Results: People with Parkinson's disease and their carers were unfamiliar with the term palliative care. When informed of the role of palliative care, most felt that they would benefit from this input. People with Parkinson's disease and carers experienced a high illness burden and wanted extra support. Crises requiring Specialist Palliative Care involvement may occur at diagnosis and later, with advancing illness. Participants wanted more information about palliative care and especially further supports to address their psychosocial needs., Conclusion: A holistic palliative care approach could address the complex physical and psychosocial symptoms experienced by people with Parkinson's disease and their carers, and people with Parkinson's disease and their carers are open to palliative care. Further research needs to explore how palliative care can be introduced into the routine care for people with Parkinson's disease.

Impulsive-compulsive behaviours are common, quality of life affecting consequences of dopamine replacement therapy which are well recognized in patients with idiopathic Parkinson's disease. Details of the occurrence and nature of these disorders in the atypical parkinsonian neurodegenerative disorders, and in non-Parkinson's patients prescribed dopaminergic stimulation for other disease processes, are slowly emerging. Here we review what is known about the phenomenology, epidemiology and risk factors for impulsive-compulsive behaviours in Parkinson's disease and in other, less well studied, patient groups. By analyzing the available published data, this review identifies potential clues as to the underlying neurobiological mechanism of these disorders, and further identifies critical gaps yet to be addressed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS)., Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed., Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10 -6 , including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA., Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps., (© 2016 American Academy of Neurology.)

Background: Jumping to conclusions due to impulsivity has been shown to be a sensitive marker for dopamine dysregulation and addictive behaviour patterns in treated patients with Parkinson's disease (PD). It is unknown whether drug naïve PD patients, who have never received dopaminergic therapy also have deficits in information sampling., Methods: Twenty five de novo PD patients and twenty matched healthy controls were recruited and tested on the beads task, which is a validated information sampling task to assess reflection impulsivity and a temporal discounting questionnaire., Results: Patients gathered significantly less information and made more irrational choices than matched controls. There was, however, no group difference on the temporal discounting questionnaire., Conclusions: Poor information sampling and irrational decision making may be an inherent component of the neuropsychological deficit in Parkinson's disease. These findings suggest that underlying impulsivity detected by a metric task is common in de novo PD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Evidence from clinical and pathological studies suggests a role for both alpha-synuclein and amyloid-beta in the pathophysiology of dementia associated with PD. Recent work demonstrated improvement in memory and reduced amyloid-beta burden in transgenic murine Alzheimer's models given subcutaneous apomorphine. The aim of this work was to determine whether antemortem exposure to apomorphine was associated with lower levels of amyloid-beta in brain tissue in a clinicopathological study of PD., Methods: The case notes of donors with pathologically proven PD who had (n = 36) and had not received apomorphine (n = 35) during life for motor complications were reviewed to determine presence or absence of cognitive impairment. The four groups were well matched for disease duration, age at death, sex, and apolipoprotein E4 genotype. The severity of amyloid-beta mature/diffuse plaque load, tau pathology, and alpha-synuclein pathology were all established. Cerebral amyloid angiopathy was determined based on a four-tier grading system., Results: Within the cognitively normal cases, significantly reduced amyloid-beta deposition was present in those with antemortem apomorphine exposure; this finding was not replicated in those with cognitive impairment plus previous apomorphine use. In the apomorphine cognitively normal group only, a significant negative association was observed between maximum apomorphine dose received and amyloid-beta burden. Early and maximum doses of apomorphine plus apolipoprotein genotype and sex were significant predictors of total plaque load in an explanatory model., Conclusion: This exploratory study suggests that apomorphine may have a modifying effect on amyloid deposition in nondemented PD cases and thus may represent a potential therapy to reduce cognitive impairment in PD. © 2015 Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Background: An integrated palliative care approach is recommended in all life-limiting diseases, including Parkinson's disease (PD). However research shows that people with PD have unmet palliative care needs. The study aimed to explore multidisciplinary healthcare workers' (HCWs) views on palliative care for people with PD, identifying perceived barriers and facilitators., Methods: A qualitative design was used; data was analysed using Thematic Analysis. Semi-structured interviews were conducted with 30 HCWs, working either with people with PD or in a palliative care setting in Ireland., Results: A number of perceived barriers were evident helping to account for the previously reported unmet palliative care needs in PD. A lack of education about PD and palliative care meant that HCWs were unsure of the appropriateness of referral, and patients and carers weren't equipped with information to seek palliative care. A lack of communication between PD and palliative care specialists was seen to impede collaboration between the disciplines. Uncertainty about the timing of palliative care meant that it was often not introduced until a crisis point, despite the recognised need for early planning due to increased prevalence of dementia., Conclusions: Most HCWs recognised a need for palliative care for people with PD; however several barriers to implementing a palliative care approach in this population need to be addressed. Implications for clinical practice and policy include the need for an integrated model of care, and education for all HCWs, patients, carers, and the public on both the nature of advanced PD, and the potential of palliative care in support of patients and their family members.

The first step in screening for potential Wilson disease is serum ceruloplasmin testing, whereby a level of less than 0.2g/L is suggestive of the disease. We aimed to determine what proportion of an Irish population had a low ceruloplasmin level, whether low measurements were appropriately followed-up and what were the clinical outcomes. We conducted a retrospective review of all serum ceruloplasmin measurements between August 2003 and October 2009 in a large tertiary referral centre in Southern Ireland. Clinical data, serum ceruloplasmin, liver function tests, urinary copper and liver biopsy reports were all recorded where available. 1573 patients had a serum ceruloplasmin measurement during the 7-year study period. 96 patients (6.1%) had a ceruloplasmin level < 0.2g/L and of these only 3 patients had Wilson disease. There was only 1 new diagnosis. Only 27 patients (28.1%) had some form of confirmatory testing performed. In our centre's experience, the positive predictive value of a significantly low ceruloplasmin level is 11.1% (95% CI 2.91-30.3%). In practice a low serum ceruloplasmin measurement is often not followed by appropriate confirmatory testing. Measuring serum ceruloplasmin as a singular diagnostic test for Wilson disease or as part of the battery of unselected liver screening tests is inappropriate and low-yield.

Impulse control disorders (ICDs) occur in a subset of patients with Parkinson's disease (PD) who are receiving dopamine replacement therapy. In this study, we aimed to investigate structural abnormalities within the mesocortical and limbic cortices and subcortical structures in PD patients with ICDs. We studied 18 PD patients with ICDs, 18 PD patients without ICDs and a group of 24 age and sex-matched healthy controls. Cortical thickness (CTh) and subcortical nuclei volume analyses were carried out using the automated surface-based analysis package FreeSurfer (version 5.3.0). We found significant differences in MRI measures between the three groups. There was volume loss in the nucleus accumbens of both PD patients with ICDs and without ICDs compared to the control group. In addition, PD patients with ICDs showed significant atrophy in caudate, hippocampus and amygdala compared to the group of healthy controls. PD patients with ICDs had significant increased cortical thickness in rostral anterior cingulate cortex and frontal pole compared to PD patients without ICDs. Cortical thickness in rostral anterior cingulate and frontal pole was increased in PD patients with ICDs compared to the control group, but the differences failed to reach corrected levels of statistical significance. PD patients with ICDs showed increased cortical thickness in medial prefrontal regions. We speculate that these findings reflect either a pre-existing neural trait vulnerability to impulsivity or the expression of a maladaptive synaptic plasticity under non-physiological dopaminergic stimulation.

Introduction: Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks., Methods: With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected., Results: Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions., Conclusions: The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

There is increasing awareness that the medications used to treat the motor symptoms of Parkinson's disease (PD) contribute to the development of behavioral addictions, which have been clinically defined as impulsive-compulsive behaviors (ICBs). These features include pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, excessive hobbyism or punding, and the excessive use of dopaminergic medication. ICBs frequently have devastating effects on the social and occupational function of the affected individuals as well as their families. Although ICBs are an important clinical problem in PD, the number of studies in which these symptoms have been modeled in rodents is still limited. This may depend on uncertainties regarding, on one hand, the pathophysiology of these behaviors and, on the other hand, the experimental paradigms with which similar features can be induced in rodents. To help compose these uncertainties, we will here review the characteristics of ICBs in PD patients and then describe behavioral methods to approximate them in rodents. We will discuss both the challenges and the possibilities of applying these methods to animals with PD-like lesions, and review the recent progress made to this end. We will finally highlight important questions deserving further investigation. Rodent models having both face validity and construct validity to parkinsonian ICBs will be essential to further pathophysiological and therapeutic studies into this important area., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Impulse control disorders (ICDs) are reported in Parkinson's disease (PD) in association with dopaminergic treatment. Approximately 25 % of patients with ICDs have multiple co-occurring ICDs (i.e. more than one diagnosed ICD). The extent to which dopaminergic neurotransmission in PD patients with multiple ICDs differs from those with only one diagnosed ICD is unknown. The aims of this study are: (1) to investigate dopamine neurotransmission in PD patients diagnosed with multiple ICDs, single ICDs and non-ICD controls in response to reward-related visual cues using positron emission tomography with (11)C-raclopride. (2) to compare clinical features of the above three groups. PD individuals with mulitple ICDs (n = 10), single ICD (n = 7) and no ICDs (n = 9) were recruited and underwent two positron emission tomography (PET) scans with (11)C-raclopride: one where they viewed neutral visual cues and the other where they viewed a range of visual cues related to different rewards. Individuals with both multiple ICDs and single ICDs showed significantly greater ventral striatal dopamine release compared to non-ICD PD individuals in response to reward cues, but the two ICD groups did not differ from each other in the extent of dopamine release. Subjects with multiple ICDs were, however, significantly more depressed, and had higher levels of impulsive sensation-seeking compared to subjects with single ICDs and without ICDs. This is the first study to compare dopamine neurotransmission using PET neuroimaging in PD subjects with multiple vs. single ICDs. Our results suggest that striatal dopamine neurotransmission is not directly related to the co-occurrence of ICDs in PD, potentially implicating non-dopaminergic mechanisms linked to depression; and suggest that physicians should be vigilant in managing depression in PD patients with ICDs.

Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P < 0.0001) and the dopamine transporter (P < 0.0001) in the striatum, and dopaminergic neurons (P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls (P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD., (© 2015 International Parkinson and Movement Disorder Society.)

The aim of this study was to investigate the knowledge, attitudes, and previous training of Irish health care workers (HCWs) in palliative care in end-stage Parkinson's disease (PD). A survey was distributed to HCWs, including neurologists, geriatricians, general practitioners, nurses, and allied health professionals, in acute and community settings in the Republic of Ireland. Three-hundred and six surveys were returned (32% average response rate). Most HCWs (90%) believed that people with PD have palliative care needs; however, 76% of HCWs also said that these needs are "never" or only "sometimes" met. These unmet needs are reflected in relatively few people with PD being referred to specialist palliative care; 48% of hospital consultants had referred no patients in the previous 6 months, and just 7% had referred more than 10. Just 8% of the HCWs surveyed reported having any training on the palliative care aspects of PD, and 97% expressed an interest in receiving further education. Respondents wanted all topics pertinent to palliative care in PD covered, and many felt that they also needed further information on PD in general. People with PD are seen to have palliative care needs; however, the findings suggest that these needs are not being met. There is a discrepancy between best practice recommendations for palliative care in PD and the beliefs and practices of HCWs. Further education in palliative care in PD is needed to ensure better quality of care for people with PD.

Impulsive choice and poor information sampling have been found to be key behavioural mechanisms linked to impulse control disorders (ICDs) in Parkinson's disease (PD). Perceptual decision-making is intimately related to information sampling. Therefore, we wanted to determine whether dopaminergic medication or ICDs influence perceptual decision-making in PD. All participants performed two tasks. One was a simple reaction time task, where subjects needed to respond as quickly as possible. The second was a perceptual decision-making task, in which participants had to estimate whether a stimulus contained either more red or more blue pixels. We tested three groups of patients, one treated with levodopa monotherapy, one additionally treated with dopamine agonists, and a third group had ICDs. Results were compared to healthy controls. We found that all patients made more errors than controls. Further, patients with ICDs responded fastest on the reaction time task and also in incorrect trials on the perceptual decision-making task. Similarly, patients with dopamine agonists responded faster than those on levodopa monotherapy and controls. Our results demonstrate that all patients have deficits in perceptual decision-making. However, patients treated with dopamine agonists closely resembled patients with ICDs., (© The Author(s) 2014.)

The aim of this study was to assess the neuropsychological behavior of Parkinson's disease (PD) patients with addictive behaviors. Characteristically, these patients have younger onset of PD, higher novelty-seeking personality traits, jump to conclusions, and often make irrational choices. We assessed whether PD patients with and without addictive behaviors have deficits in a sequential sampling task, often called the secretary problem. In this task, participants needed to pick the best out of multiple offers. Critically, once participants rejected a deal, this option became unavailable. Thus, decisions needed to be balanced not to stop too soon or sample for too long and miss the best deal. We tested 13 PD patients with and 13 patients without addictive behaviors. Results were compared to healthy volunteers. We found that all patients declined fewer options before committing to a deal. There was, however, no difference between the two patient groups. Furthermore, there was no difference in overall choice rank between patients and controls. These results suggest that, compared to controls, PD patients gather less evidence before committing to an offer, but have no deficits in recognizing the best deal out of many options, regardless of whether or not they have addictive behaviors.

Background: Problematic Internet use (PIU) has been associated with impulse control disorders (ICDs), and postulated to share characteristics of a behavioral addiction with both impulsive and compulsive features. However, Internet use has not been previously systematically studied in Parkinson's disease., Aim: We explore Internet use in PD patients with and without ICDs and matched healthy controls. We hypothesize that the PD-ICD patients will spend more time on the Internet, accessing websites related to their ICDs, compared with PD patients without ICDs and healthy volunteers., Methods: Our study is the first to systematically explore problematic Internet use in patients with PD, with and without ICDs. Twenty-nine PD patients with ICDs, twenty PD patients without ICDs and nineteen healthy controls were recruited. All participants endorsed using the Internet for non-essential purposes. They underwent a semi-structured interview and completed questionnaires including the Yale-Brown Obsessive Compulsive Scale adapted for Internet use (Y-BOCS-Internet)., Results: PD-ICD patients scored significantly higher on the Y-BOCS-Internet than the PD-control and HV groups (PD-ICD: 13.69; PD-control: 5.42; HV: 4.70; p < 0.0001). Compared to PD controls and HV groups, the PD-ICD group spent more time on the Internet (p = 0.0001), described significantly more effort to resist Internet use (p = 0.0002), thoughts about Internet use (p < 0.0001) and its interference with their life functioning (p = 0.0025)., Discussion: Our results suggest that PD patients with ICDs have a relative increased tendency towards excessive Internet use compared to those without ICDs and healthy controls. Clinicians should actively screen for excessive Internet use in patients with ICDs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Impulsive-compulsive behaviors (ICBs) in Parkinson's disease (PD) are a common and devastating side effect of dopamine replacement therapy. In this review we describe the phenomenology, prevalence, and risk factors of patients with PD. Results of behavioral studies assessing the neuropsychological profile of patients with PD emphasize that the ICBs, which are behavioral addictions, are not hedonically motivated. Rather, other factors such as the inability to cope with uncertainty may be triggering ICBs. New insights from functional imaging studies, strengthening the incentive salience hypothesis, are discussed, and therapeutic guidelines for the management of ICBs in PD are given.

Background: It has been suggested that all patients with Parkinson's disease (PD) who undergo functional neurosurgery have difficulties in slowing down in high conflict tasks. However, it is unclear whether concomitant dopaminergic medication is responsible for this impairment., Objective: To assess perceptual decision making in PD patients with bilateral deep brain stimulation., Methods: We tested 27 PD patients with bilateral deep brain stimulation on a task in which participants had to filter task relevant information from background noise. Thirteen patients were treated with Levodopa monotherapy and 14 patients were treated with Levodopa in combination with a dopamine agonist. RESULTS were compared to healthy matched controls., Results: We found that all PD patients who were treated with a dopamine agonist made faster decisions than controls and PD patients who were not exposed to a dopamine agonist. Further, all patients made more errors than controls, but there was no difference between the two patient groups., Conclusions: Our results suggest that dopamine agonist therapy rather than deep brain stimulation is likely responsible for the inability to slow down in high conflict situations in PD. These results further strengthen the need to reduce dopamine agonists in PD patients undergoing functional neurosurgery in order to prevent them making inadvisable decisions.

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence., Objective: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID., Methods: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course., Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025)., Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation., (Copyright © 2013 S. Karger AG, Basel.)

Objectives: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP., Methods: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21)., Results: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm., Conclusions: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

A subset of patients with Parkinson's disease (PD) develops behavioral addictions, which may be due to their dopamine replacement therapy. Recently, several groups have been comparing PD patients with and without behavioral addictions on tasks that are thought to measure aspects of impulsivity. Several of these experiments, including information sampling, a bias toward novel stimuli and temporal discounting, have shown differences between PD patients with and without behavioral addictions. We have developed a unifying theoretical framework that allows us to model behavior in all three of these tasks. By exploring the performance of the patient groups on the three tasks with a single framework, we can ask questions about common mechanisms that underlie all three. Our results suggest that the effects seen in all three tasks can be accounted for by uncertainty about the ability to map future actions into rewards. More specifically, the modeling is consistent with the hypothesis that the group with behavioral addictions behaves as if they cannot use information provided within the experimental context to improve future reward guided actions. Future studies will be necessary to more firmly establish (or refute) this hypothesis. We discuss this result in light of what is known about the pathology that underlies the behavioral addictions in the PD patients.

Aims: To examine a syndrome of chronic manganism that occurs in drug addicts in eastern Europe who use intravenous methcathinone (ephedrone) contaminated with potassium permanganate. In many cases the basal ganglia, especially the globus pallidus and the putamen, are damaged irreversibly. Routine neuropsychological assessment has revealed no cognitive deficits, despite widespread abnormalities on brain imaging studies and severe extrapyramidal motor handicap on clinical examination., Design: Case-control study., Setting: Ephedrone patients and patients with opioid dependence were recruited from Lviv, Ukraine., Participants: We tested 15 patients with ephedrone-induced toxicity, 13 opiate-dependent patients who were receiving opioid replacement therapy and 18 matched healthy volunteers., Measurements: The 'beads task', an information-gathering task to assess reflection impulsivity, was used and feedback learning, working memory and risk-taking were also assessed., Findings: Opiate-dependent patients differed from controls on three of four tasks, whereas ephedrone patients differed from controls on only one task. More specifically, both patient groups were more impulsive and made more irrational choices on the beads task than controls (P < 0.001). However, ephedrone patients had no deficits in working memory (P > 0.1) or risk-taking (P > 0.1) compared with controls. Opioid-dependent patients had significantly worse working memory (P < 0.001) and were significantly more risk-prone than controls (P = 0.002)., Conclusions: Ephedrone patients may have similar deficits in information-gathering and decision-making to opiate-dependent patients, with preservation of working memory and risk-taking. This may reflect specific damage to anterior cingulate- basal ganglia loops., (© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.)

The classical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) is rapid progressive dementia often associated with myoclonus and ataxia followed by death in less than a year from diagnosis. The few patients in the literature who presented with parkinsonism and who were suspected to have progressive supranuclear palsy (PSP) all ran a malignant course and most of them died within 3 years of diagnosis. We screened the Queen Square Brain Bank database and, among 213 patients with a clinical diagnosis of PSP, we found ten patients with 3 years or less disease duration, including one patient with CJD pathology. We report this patient and review other similar cases from the literature. Ten additional cases with similar presentation were identified in the literature. The mean disease duration was 24.2 months. The classical clinical, radiological and laboratory findings for sCJD were absent in the majority of these cases. Clinical presentation of these patients consists of: early falls, prominent dementia, early vertical supranuclear gaze palsy and symmetric akinetic syndrome. In the patients who were subtyped at post-mortem, all four represented the MM2 subtype of sCJD. A rapidly progressive course of PSP with early falls, cognitive impairments and vertical supranuclear gaze palsy should raise suspicion of underlying sCJD pathology regardless of absence of supportive findings on ancillary tests. This case and the literature support the notion that biochemical properties of the prion protein can influence the clinical presentation of sCJD.