Clinical Utility of GBA Genotyping Prior to Deep Brain Stimulation: A Narrative Review.

SummaryBackgroundSurgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease.MethodsThe PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222.Findings366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment.InterpretationAt 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted.FundingUK Medical Research Council, Parkinson's UK, and UK Department of Health.

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkinson's disease (PD). The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinctive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and functional evaluation of related diseases. PD is one of the most common neurodegenerative disorders in the elderly. It is characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta. Throughout the course of disease, the most obvious symptoms are movement-related, such as resting tremor, muscle rigidity, hypokinesia and postural instability (Worth, 2013). Currently, a definite diagnosis of PD is made by clinical evaluation with at least 2 years of follow-up (Hughes et al., 2002; Bhidayasiri and Reichmann, 2013), due to the overlap of motor symptoms between early PD and atypical parkinsonism including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). However, this classic diagnostic criterion does not benefit the early diagnosis of disease. The prognostic outcome and treatment option are substantially different between PD and atypical parkinsonism. Thus it is critical to develop biomarkers for earlier and more accurate diagnosis of PD. Generally, appropriate diagnostic biomarker for PD ought to cover several key characteristics: (i) minimal invasiveness to detect the biomarker in easily accessible body tissue or fluids, (ii) excellent sensitivity to explore the patients with PD, (iii) high specificity to prevent false-positive results in PD-free individuals, and (iv) robustness against potential affecting factors. A PD-related spatial covariance pattern (PDRP) with quantifiable expression on 18F-FDG PET imaging has been gradually detected using a spatial covariance method during the last two decades and it has been demonstrated to be the right diagnostic biomarker for PD (Eidelberg et al., 1994). PDRP has proven not only to be effective in early discrimination of PD from atypical parkinsonian disorders, but also to be able to assess the disease progression and treatment response. Thus it is considered as a multifunctional biomarker. In this review, we aim to provide an overview of the development in pattern-based biomarker for PD.

Parkinson's Disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor (such as resting tremor, hypokinesia, postural instability) and non-motor symptoms (such as neuropsychiatric decline and autonomic dysfunction). Since its introduction in the late 1980s, deep brain stimulation (DBS) has revolutionized the treatment of PD. Initially used in patients' with advanced PD with either medically refractory motor symptoms or medication intolerance, DBS typically provides excellent improvement in motor symptoms. Indications for DBS have continued to expand, with demonstrated efficacy in early PD and essential tremor, and promising preliminary results in the treatment of epilepsy, psychiatric disease, and depression. Advancements in DBS hardware, programming, neuroimaging, and surgical techniques have led to progressive improvement in efficacy and safety profiles. Thanks to ongoing research into remote programming, adaptive DBS, new targets, and alternative interventions, such as transcranial magnetic stimulation, the opportunities for further improvements in DBS and neuromodulation are bright.

Increased Stroke Risk in Patients with Parkinson's Disease with LRRK2 Mutations.

Objective:To provide a comprehensive review and evaluation of the literature pertaining to the psychiatric sequelae of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson’s disease (PD).Methods:A structured search of the EMBASE, PsychINFO and MEDLINE databases was performed on articles published since the first use of STN DBS in 1993 for PD until March 2007. Non-human studies were excluded, along with studies reporting on unilateral DBS and studies reporting on the use of STN DBS for indications other than idiopathic PD. Ninety-seven articles were selected for inclusion in the review.Results:Patients with advanced PD have a high rate of psychiatric morbidity. STN DBS has been shown to be an effective treatment for the control of motor symptoms in advanced PD. Neurobehavioural side-effects are, however, relatively common following STN DBS. Side-effects include impaired executive function and verbal fluency, depression, hypomania, apathy, postoperative delirium, anxiety disorders and psychotic symptoms, especially hallucinations. The alteration in dopaminergic medication following surgery as well as the direct effect of STN stimulation both appear to contribute to the short-term and long-term postoperative psychiatric complications. Methodological issues that limit the applicability of the current literature in this field are highlighted.Conclusions:STN DBS is an effective treatment for the motor symptoms of advanced PD. However, further research is needed to assess the extent to which STN DBS contributes to or exacerbates psychiatric morbidity over and above that associated with advanced PD. Careful neuropsychiatric evaluation and monitoring are required in this patient group.

Apomorphine infusion for improving sleep in Parkinson's disease

Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of nonlevodopa responsive motor and nonmotor symptoms. The management of advanced stage Parkinson's disease can be complex. This review summarizes the currently available treatment strategies for addressing advanced Parkinson's disease. We will discuss the latest pharmacological strategies (e.g., inhibitors of dopamine-metabolizing enzymes, dopamine agonists, and extended release dopamine formulations) for addressing motor dysfunction. We will summarize the risks and benefits of current invasive treatments. Finally, we will address the current evidence supporting the treatment of nonmotor symptoms in the advanced Parkinson's disease patient. We will conclude by detailing the potential nonpharmacological and multidisciplinary approaches for advanced stage Parkinson's disease. The optimization of levodopa is, in most cases, the most powerful therapeutic option available; however, medication optimization requires an advanced understanding of Parkinson's disease. Failure of conventional pharmacotherapy should precipitate a discussion of the potential risks and benefits of more invasive treatments. Currently, there are no comparative studies of invasive treatment. Among the invasive treatments, deep brain stimulation has the largest amount of existing evidence, but also has the highest individual per patient risk. Nonmotor symptoms will affect quality of life more than the motor Parkinson's disease symptoms, and these nonmotor symptoms should be aggressively treated. Many advanced Parkinson's disease patients will likely benefit from multi and interdisciplinary Parkinson's disease teams with multiple professionals collaborating to develop a collective and tailored strategy for an individual patient.

Advances in GBA-associated Parkinson's disease – Pathology, presentation and therapies

Deep brain stimulation in the subthalamic nucleus is an effective and safe surgical procedure that has been shown to reduce the motor dysfunction of patients with advanced Parkinson's disease. Bilateral subthalamic nucleus deep brain stimulation, however, has been associated with declines in cognitive and cognitive-motor functioning. It has been hypothesized that spread of current to nonmotor areas of the subthalamic nucleus may be responsible for declines in cognitive and cognitive-motor functioning. The aim of this study was to assess the cognitive-motor performance in advanced Parkinson's disease patients with subthalamic nucleus deep brain stimulation parameters determined clinically (Clinical) to settings derived from a patient-specific computational model (Model). Data were collected from 10 patients with advanced Parkinson's disease bilaterally implanted with subthalamic nucleus deep brain stimulation systems. These patients were assessed off medication and under three deep brain stimulation conditions: Off, Clinical or Model based stimulation. Clinical stimulation parameters had been determined based on clinical evaluations and were stable for at least 6 months prior to study participation. Model-based parameters were selected to minimize the spread of current to nonmotor portions of the subthalamic nucleus using Cicerone Deep Brain Stimulation software. For each stimulation condition, participants performed a working memory (n-back task) and motor task (force tracking) under single- and dual-task settings. During the dual-task, participants performed the n-back and force-tracking tasks simultaneously. Clinical and Model parameters were equally effective in improving the Unified Parkinson's disease Rating Scale III scores relative to Off deep brain stimulation scores. Single-task working memory declines, in the 2-back condition, were significantly less under Model compared with Clinical deep brain stimulation settings. Under dual-task conditions, force tracking was significantly better with Model compared with Clinical deep brain stimulation. In addition to better overall cognitive-motor performance associated with Model parameters, the amount of power consumed was on average less than half that used with the Clinical settings. These results indicate that the cognitive and cognitive-motor declines associated with bilateral subthalamic nucleus deep brain stimulation may be reversed, without compromising motor benefits, by using model-based stimulation parameters that minimize current spread into nonmotor regions of the subthalamic nucleus.

Neuropsychiatric characteristics of GBA-associated Parkinson disease

Glucocerebrosidase (GBA) gene has been proved to be a risk factor for the development of Parkinson's disease (PD). However, the gender effect in the prevalence of GBA-associated PD (GBA-PD) is still controversial. And there is no conclusion whether the age at onset (AAO) of PD is different between carriers and non-carriers of GBA. To clarify the association between gender and AAO in GBA-PD, we conducted a systematic review and meta-analysis. PubMed, Web of Science, and Embase were retrieved to obtain potentially related studies. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association between gender and GBA-PD. And the weighted mean difference (WMD) with 95% CIs was employed to assess the difference of AAO between carriers and non-carriers of GBA. A total of twenty-eight studies involving 16,488 PD patients were included in this meta-analysis. The results showed the prevalence of female patients was higher in GBA-PD [OR: 1.19, (95% CI, 1.07-1.32), P = 0.001]. Meanwhile, GBA carriers had younger age at PD onset than GBA non-carriers [WMD: 2.87, (95% CI, 2.48-3.27), P < 0.001]. Results of subgroup analysis showed the prevalence of women in GBA-PD was higher than men in North American and European PD patients, while the gender difference was not significant in other areas around the world, suggesting an ethnic specificity of gender effect for GBA-PD. Our results indicate the higher female prevalence with ethnic specificity and younger AAO of GBA carriers in GBA-PD.

Deep brain stimulation for advanced Parkinson's disease

This article is a report of an exploration of the lived experience of being a spouse to a person living with advanced Parkinson's disease, before and during the first year of deep brain stimulation. Parkinson's disease is a chronic progressive neurodegenerative disease. It has a profound impact on the everyday life for patients and spouses. Deep brain stimulation is offered with the aim of reducing symptoms of Parkinson's disease. The treatment is known to improve quality of life for patients, but little is known of how spouses experience life following their partners' treatment. A longitudinal interview study with a hermeneutic phenomenological approach. Ten spouses were included in the study. Data were gathered in 2007-2008, through qualitative in-depth interviews with spouses once before and three times during the first year of their partners' treatment with Deep Brain Stimulation. Data collection and data analysis were influenced by the hermeneutic phenomenological methodology of van Manen. The uniting theme 'Solidarity - the base for joined responsibility and concern' was the foundation for the relationship between spouses and their partners. Before treatment, the theme 'Living in partnership' was dominant. After treatment two dichotomous courses were described 'A sense of freedom embracing life' and 'The challenge of changes and constraint'. Spouses are deeply involved in their partners' illness and their experience of life is highly affected by their partners' illness, both before and after deep brain stimulation. The relationship is founded on solidarity and responsibility, which emphasizes spouses' need to be informed and involved in the process following Deep Brain Stimulation.

Deep brain stimulation (DBS) is a surgical procedure that has been shown effective in improving the cardinal motor signs of advanced Parkinson's disease, however, declines in cognitive function have been associated with bilateral subthalamic nucleus (STN) DBS. Despite the fact that most activities of daily living clearly have motor and cognitive components performed simultaneously, postoperative assessments of cognitive and motor function occur, in general, in isolation of one another. The primary aim of this study was to determine the effects of unilateral and bilateral STN DBS on upper extremity motor function and cognitive performance under single- and dual-task conditions in advanced Parkinson's disease patients. Data were collected from eight advanced Parkinson's disease patients between the ages of 48 and 70 years (mean 56.5) who had bilaterally placed STN stimulators. Stimulation parameters for DBS devices were optimized clinically and were stable for at least 6 months prior to study participation. Data were collected while patients were Off anti-parkinsonian medications under three stimulation conditions: Off stimulation, unilateral DBS and bilateral DBS. In each stimulation condition patients performed a cognitive (n-back task) and motor (force tracking) task under single- and dual-task conditions. During dual-task conditions, patients performed the n-back and force-maintenance task simultaneously. Under relatively simple dual-task conditions there were no differences in cognitive or motor performance under unilateral and bilateral stimulation. As dual-task complexity increased, cognitive and motor performance was significantly worse with bilateral compared with unilateral stimulation. In the most complex dual-task condition (i.e. 2-back + force tracking), bilateral stimulation resulted in a level of motor performance that was similar to the Off stimulation condition. Significant declines in cognitive and motor function under modest dual-task conditions with bilateral but not with unilateral STN DBS suggest that unilateral procedures may be an alternative to bilateral DBS for some patients, in particular, those with asymmetric symptomology. From a clinical perspective, these results underscore the need to assess cognitive and motor function simultaneously during DBS programming as these conditions may better reflect the context in which daily activities are performed.