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Patients with Parkinson's disease (PD) experience a range of non-motor symptoms, including constipation and other gastrointestinal problems. These symptoms are sometimes present in the prodromal disease phase. An improved understanding of the underlying pathophysiology is needed considering that PD has been hypothesized to originate in the gut. Delayed gastric emptying time (GET) is often listed as a prevalent gastrointestinal symptom in PD, but the true prevalence is controversial. The aim of this short review was to investigate if GET in PD is dependent on the applied measuring methodology. A systemic search of Pubmed identified 15 relevant studies, including six using gold standard method gastric scintigraphy and nine using 13C-octanoate breath tests. Overall, gastric scintigraphy studies showed a non-significant GET delay (standardized mean difference (SMD) 0.42) in PD patients. After exclusion of one outlier study, GET was significantly increased (SMD 0.59). In contrast, highly significant GET delay (SMD 1.70) was seen in breath test studies. A limitation of the meta-analyses was reuse of the same control group in some studies. In summary, the marked GET delay observed in breath test studies is not confirmed by gold standard gastric scintigraphy studies. This discrepancy can perhaps be explained by breath test being an indirect GET measure, depending not only on mechanic stomach emptying but also intestinal absorption and liver metabolism. Thus, multi-modality studies under standardized conditions are needed to elucidate the prevalence and severity of gastric dysmotility in PD, along with contributions from other factors including intestinal absorption and permeability. [ABSTRACT FROM AUTHOR]

Abstract: Background: Stiff person spectrum disorders (SPSD) are a group of rare conditions clinically characterized by stiffness, spasms, and heightened stimulus sensitivity. They also share a spectrum of antibodies. Methods: We reviewed the literature and our own experience with the aim of providing a practical approach to the treatment of SPSD. Results: Because of the rarity of SPSD, there is little evidence to guide treatment decisions. The treatment of SPSD is based on the triad of symptomatic treatment, immunotherapy, and tumor treatment where appropriate. Moreover, the management involves continuous and appropriate monitoring of the symptoms of the disease, its autoimmune associations, and potential treatment side effects. Conclusions: Here we delineated a pragmatic treatment approach to SPSD, based on our experience and existing literature. We also highlighted how our understanding of neuronal antibodies and their implications reflects on management considerations. [ABSTRACT FROM AUTHOR]

By following this stepwise approach, you can confidently incorporate newer agents into your armamentarium with little or no consultation with subspecialists. [ABSTRACT FROM AUTHOR]

Purpose: An elemental diet (ED) can suppress inflammation in patients with Crohn's disease (CD); however, adherence to this diet is difficult. We examined the correlation between ED adherence and the postoperative recurrence of CD. Methods: The subjects of this study were 38 patients who underwent intestinal resection with anastomosis. We defined ED adherence as consuming the average daily ED dose (≥900 kcal/day) for 2 years after surgery. Patients who did not adhere to the ED were allocated to the non-ED group. We diagnosed symptomatic recurrence using the CD activity index and endoscopic recurrence using the Rutgeerts' score. Results: The ED and non-ED groups comprised 21 and 17 patients, respectively, with ED adherence of 55.3% (21/38). At the initial endoscopy, symptomatic and endoscopic recurrence rates were 4.8 and 14.3%, respectively, in the ED group, and 23.5 and 41.2%, respectively, in the non-ED group ( P = 0.152 and P = 0.078, respectively). The overall symptomatic recurrence-free duration was significantly longer than the endoscopic recurrence-free duration ( P = 0.022). Symptomatic and endoscopic recurrence-free durations were longer in the ED group than in the non-ED group ( P = 0.003 and P = 0.021, respectively), and ED adherence was a prognostic factor for endoscopic recurrence (HR = 2.777, 95% CI = 1.036-8.767, P = 0.042). Conclusion: Maintaining ED adherence for 2 years after surgery improved the symptomatic and endoscopic recurrence-free durations. [ABSTRACT FROM AUTHOR]

Background Rifaximin has been proposed as an alternative treatment for specific cases of Clostridium difficile infection (CDI) and intestinal decontamination. Rifaximin-resistant C. difficile has occasionally been reported. Antibiotic susceptibility testing relies on anaerobic agar dilution (reference method), which is cumbersome and not routinely used. There is no commercial test for detection of resistance to rifaximin. Objectives To assess resistance to rifaximin by C. difficile and to evaluate the correlation between the results of the rifampicin E-test and susceptibility to rifaximin. Methods We compared the in vitro susceptibility of clinical CDI isolates to rifaximin over a 6-month period using the agar dilution method with susceptibility to rifampicin using the E-test. All isolates were characterized using PCR-ribotyping. Clinical data were recorded prospectively. Results We recovered 276 consecutive C. difficile isolates and found that 32.2% of episodes were caused by rifaximin-resistant strains. The MICs for rifaximin ranged from <0.0009–256 mg/L, with a geometric mean (GM) of 0.256 mg/L, an MIC 50/90 of 0.015/>256 mg/L. Rifaximin and rifampicin MICs were comparable, and all strains classed as resistant by agar dilution were correctly classified as resistant by E-test. The most common ribotypes were 001 (37.2%), 078/126 (14.3%), and 014 (12.0%). Ribotype 001 exhibited the highest MICs for rifaximin. Conclusions Resistance to rifaximin was common; resistance rates were higher in ribotype 001 strains. Susceptibility to rifaximin determined by agar dilution correlated with susceptibility to rifampicin determined using the E-test, including rifaximin-resistant strains. Our results suggest that the rifampicin E-test is a valid method for the prediction of rifaximin-resistant C. difficile . [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases represent a large group of neurological disorders with heterogeneous clinical and pathological profiles. The majority of current therapeutic strategies provide temporary symptomatic relief but do not target the underlying disease pathobiology and thus do not affect disease progression. G protein-coupled receptors (GPCRs) are among the most successful targets for therapeutic development of central nervous system (CNS) disorders. Many current clinical therapeutic agents act by targeting this class of receptors and downstream signaling pathways. Here, we review evidence that perturbation of GPCR function contributes to the pathophysiology of various neurodegenerative diseases, including Alzheimer’s disease, Frontotemporal dementia, Vascular dementia, Parkinson’s disease, and Huntington’s disease. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is characterized by the progressive degeneration of the dopaminergic neurons in the substantia nigra (SN) region. Acteoside has displayed multiple biological functions. Its potential role against PD and the underlying signaling mechanisms are largely unknown. Here, we showed that oral administration of acteoside significantly attenuated parkinsonism symptoms in rotenone-induced PD rats. Further, acteoside inhibited rotenone-induced α-synuclein, caspase-3 upregulation and microtubule-associated protein 2 (MAP2) downregulation in PD rats. The molecular docking and molecular dynamics (MD) simulation results indicated that acteoside may directly bind to and inhibit caspase-3. Acteoside formed hydrogen bonds with at least six residues of caspase-3: ThrA177, SerA178, GlyA238, SerB339, ArgB341 and TrpB348. In addition, a pi-pi interaction was formed between acteoside and caspase-3’s HisA237, which might further stabilize the complex. MD simulation results demonstrated that the binding affinity of the caspase-3-acteoside complex was higher than that of caspase-3 and its native ligand inhibitor. Together, we show that acteoside binds to caspase-3 and exerts neuroprotection in the rotenone rat model of PD. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the five year clinical and radiographic outcome of unilateral open-door laminoplasty with alternative levels centerpiece mini-plate fixation for cervical compressive myelopathy.Methods: From August 2009 to June 2010, 56 patients with cervical compressive myelopathy underwent unilateral open-door laminoplasty with alternative levels centerpiece mini-plate fixation with a mean age of 64.8 years. Clinical results were investigated including Japanese Orthopedic Association (JOA) scores, Neck Dysfunction Index (NDI), occurrences of complications and neurological deterioration. Radiographic results including cervical alignments, cervical range of motion (ROM), spinal canal enlargement and spinal cord decompression were assessed on X-ray, three-dimensional CT and MRI.Results: The mean follow-up period was 59.2 months (range 53∼64 months), and all patients achieved osseous fusion at hinge side at an average of 6.8 months after operation. The average cost from admission to discharge is $9817.9. Compared to previous all-level fixation, the cost decreased nearly 40 %. During the follow-up, all patients showed a significant improvement in the JOA score and NDI score. A 23.2 % incidence of axial neck pain were also observed; Significant enlargement of the spinal canal and spinal cord drift was achieved and well maintained, overall cervical ROM decreased by 27.1 % (mean 12.9° loss) at the final follow-up and cervical lordosis decreased slightly in all patients without statistic difference. No instrumentation failure or lamina reclosure was observed in our study. Comparing mini-plate segments and suture segments, the mean AP diameter and Pavlov's ratio at the final follow-up showed no statistic difference, only open angle at the final follow-up showed significant decrease.Conclusions: Unilateral open-door laminoplasty with alternative levels centerpiece mini-plate fixation is a safe, effective and economical surgical method for cervical compressive myelopathy and the five year result is satisfactory. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the outcome of symptomatic lumbar degenerative disease treated with topping-off technique (Coflex(™) combined with fusion) and compare two-segment fusion at mid-long term follow-up; and find out whether the topping-off technique can reduce the rate of adjacent segment degeneration (ASD) after fusion.Methods: One hundred and fifty-four consecutive patients who received topping-off surgery (76 patients) and two-segment fusion surgery (88 patients) from March 2009 to March 2012 were studied. All patients included in the analysis had a minimum of three years of follow-up. Radiographic and clinical outcomes between the two groups were compared. A logistic regression analysis was used to analyze risk factors for developing radiographic ASD.Results: Significant differences in clinical outcomes were observed between these two groups at three post-operative years (all, p < 0.05). Compared with the fusion group, the topping-off group showed preserved mobility at the Coflex(™) level (p = 0.000), which is associated with less blood loss (p = 0.000), shorter duration of surgery (p = 0.000) and lower incidence of ASD (Chi-square test, rate topping-off vs fusion = 13.2 vs 26.1 %, p = 0.039). There were no differences in complications between the two groups.Conclusion: Mid-long term follow-up efficacy and safety between topping-off and fusion were similar, while topping-off reduced the rate of ASD. Under strict indications, topping-off surgery is an acceptable alternative to fusion surgery for the treatment of two-segment lumbar disease. [ABSTRACT FROM AUTHOR]

Introduction: The UPDRS-IV represents the most common screening tool to assess motor fluctuations in patients with PD despite the lack of a clinimetric validation.Objectives: We evaluated sensitivity and specificity of UPDRS-IV using a 12-h waking-day motor assessment as the gold standard.Methods: We consecutively enrolled PD patients who underwent a 12-h waking-day motor assessment in the study. Patients were clinically evaluated every 2 h for 12 h using the UPDRS-III. Motor scores were reported as a line graph and six blinded raters classified patients as having or not having motor fluctuations. The UPDRS-IV was used in order to assess the presence of predictable and unpredictable motor fluctuations according to items 36-38.Results: Sixty two PD patients were enrolled in the study. According to the raters' evaluations, 39 (62.9%) were classified as having motor fluctuations, while according to the UPDRS-IV 47 (75.8%) presented a motor fluctuation giving a sensitivity of 87.2% (95%CI 72.6-95.7) and a specificity of 43.5% (95%CI 23.2-65.5).Conclusion: Our study results confirm the high level of sensitivity with a lower level of specificity of UPDRS-IV to screen motor fluctuations in PD patients. [ABSTRACT FROM AUTHOR]

Background: Operative treatment is the standard for severely displaced proximal humerus fractures, but functional impairment can persist. Retaining of the implant can be a reason and in other fracture situations has proved to ameliorate patient satisfaction. The aim of this study was to analyse the functional outcome after locking plate removal in proximal humerus fractures. Methods: In a two-year period, all symptomatic patients with plate osteosynthesis for proximal humerus fracture and hardware removal were retrospectively evaluated clinically and radiologically pre- and post-implant removal. Evaluation included Constant score, height of plate position and possible impingement, as well as intraoperative complications. Results: Twenty patients met the inclusion criteria. The mean age was 56 ± 12 years. The plates were placed 6.9 ± 3 mm distal to the greater tubercle. The operation was performed in 35 ± 10 min and no intraoperative complications were reported. The Constant score improved significantly after implant removal from 71 to 76 (p = 0.008). Conclusion: Symptomatic patients after locked plate osteosynthesis for proximal humerus fractures showed statistically significant improvement of the Constant score after implant removal. [ABSTRACT FROM AUTHOR]

The aim of this work was to report on 7 patients presenting a distinctive form of multimodal (tactile and visual) hallucinations for which the term 'string hallucinations' is proposed. Having observed a patient interacting with imaginary strips of skin in his hands at our movement disorders unit, we prospectively studied PD patients and caregivers over a 6-month period using a semistructured interview addressed to this particular phenomenon. Demographic characteristics as well as cognitive and motor function were assessed. A total of 7 of 164 PD patients (4.3%) observed during the study period had string hallucinations. One patient was cognitively intact and the other 6 had some degree of cognitive impairment. Common to the phenomenology of the hallucinations was the unpleasant feeling and vision of threads emerging from the subjects' hands. Patients interacted with these 'threads,' trying to remove them from their hands. Our study identifies a previously undescribed type of hallucinations in PD, characterized by a complex pattern of multimodal tactile and visual hallucinations. [ABSTRACT FROM AUTHOR]

Background Postural instability ( PI) and falls, major causes of morbidity in patients with PD, are often overlooked. DBS is a mainstay therapy for Parkinson's disease ( PD) and has been purported to both worsen and improve PI. An effective PI evaluation that can predict fall risk in patients with PD presenting for DBS is needed. Methods Forty-nine consecutive patients with PD were enrolled. Self-reported falls were the gold standard. Tests evaluated were the Berg Balance Scale ( BBS), Timed-Up-and-Go ( TUG), Pull Test, and Biodex Balance System Sway Index on firm ( SI- FIRM) and soft ( SI- SOFT) surfaces. Results The best single tests for fall risk were the BBS and SI- FIRM, each with sensitivities of 79% and specificities of 60% and 65%, respectively. When the evaluation was combined into a composite measure requiring four positive tests out of five, the sensitivity was 72% and specificity was 80%. Conclusions A simple, efficient outpatient physical therapy assessment is effective in diagnosing fall risk in patients with PD. [ABSTRACT FROM AUTHOR]

Background and Methods To investigate the possible efficacy of an elastic abdominal binder to control orthostatic hypotension ( OH) associated with Parkinson's disease ( PD), 15 patients with PD and OH were enrolled in a single-blind crossover study with elastic abdominal versus placebo binder on two different days, separated by a 1-day interval, followed by a 4-week open-label follow-up. Results Intervention significantly reduced blood pressure fall upon tilting. The mean difference (standard deviation; 95% confidence intervals) between abdominal binder versus placebo was +10 mm Hg (10.2; +3.5, +16.5; P = 0.006). No significant effect on supine mean blood pressure values was observed compared to placebo ( P = 0.3). Symptoms of OH decreased significantly during follow-up ( P = 0.003), as assessed by means of the Orthostatic Hypotension Questionnaire. Conclusions Our findings suggest that elastic abdominal binders may be a simple complementary tool to alleviate OH in PD. [ABSTRACT FROM AUTHOR]

Background Waking up from sleep more than once to pass urine, known as nocturia, is an important nonmotor symptom in Parkinson's disease ( PD). Very little is known about the cause for nocturia. The aim of this work was to evaluate lower urinary tract ( LUT) symptoms in patients with PD reporting nocturia using standardized validated questionnaires and bladder diaries and to assess the impact of nocturia on quality of life and sleep. Methods Twenty-three consecutive patients with PD (17 males, 6 females; mean age: 68.5 years; range, 50-85) referred to a specialist uro-neurology clinic reporting nocturia according to the International Continence Society definition were included. Patients measured their daily fluid intake, urinary output per void, and recorded these with the timing of voids on a 3-day bladder diary. Standardized questionnaires were used to assess LUT symptoms (Urinary Symptom Profile, International Prostate Symptom Score, and Qualiveen Short Form) and sleep quality (Parkinson's Disease Sleep Scale). Results Mean duration of PD was 10.1 years, and mean severity on H & Y scale was 3.0 (range, 1.0-5.0). Median duration of LUT symptoms was 6.0 years. Mean night-time urinary frequency was 3.5 (range, 1.0-7.3), and mean nocturnal maximum voided volume was 242 mL. Mean Nocturnal Polyuria Index ( NPi) was 0.4 (range, 0.13-0.75), and 13 patients (56.5%) had nocturnal polyuria ( NPi > 0.33). Patients with nocturnal polyuria reported more-severe LUT symptoms that impacted quality of life and sleep. Conclusions In this preliminary study, nocturnal polyuria seems to be common in patients with PD reporting nocturia and appears to affect quality of life and sleep, though this was not statistically significant. The bladder diary is an essential tool in the assessment of nocturia in patients with PD. [ABSTRACT FROM AUTHOR]

Protease-resistant, misfolded isoforms (PrP Sc ) of a normal cellular prion protein (PrP C ) in the bodily fluids, including blood, urine, and saliva, are expected to be useful diagnostic markers of prion diseases, and nonhuman primate models are suited for performing valid diagnostic tests for human Creutzfeldt-Jakob disease (CJD). We developed an effective amplification method for PrP Sc derived from macaques infected with the atypical L-type bovine spongiform encephalopathy ( l -BSE) prion by using mouse brain homogenate as a substrate in the presence of polyanions and l -arginine ethylester. This method was highly sensitive and detected PrP Sc in infected brain homogenate diluted up to 10 10 by sequential amplification. This method in combination with PrP Sc precipitation by sodium phosphotungstic acid is capable of amplifying very small amounts of PrP Sc contained in the cerebrospinal fluid (CSF), saliva, urine, and plasma of macaques that have been intracerebrally inoculated with the l -BSE prion. Furthermore, PrP Sc was detectable in the saliva or urine samples as well as CSF samples obtained at the preclinical phases of the disease. Thus, our novel method may be useful for furthering the understanding of bodily fluid leakage of PrP Sc in nonhuman primate models. [ABSTRACT FROM AUTHOR]

Context The optimal management of nonfunctioning pituitary adenomas presenting without symptomatic mass effect remains uncertain. The objective of this study was to elucidate the natural history of nonfunctioning pituitary adenomas managed conservatively. Design Volumetric evaluation of tumour growth in serial pituitary MRI scans by a single observer and retrospective review of changes in pituitary function. Patients Patients with nonfunctioning pituitary adenomas who underwent at least 2 serial pituitary MRI scans over ≥6 months between 2003 and 2013 prior to any intervention. Measurements Primary end-point was a ≥20% increase in volume or surgery. Secondary end-points were rate of pituitary dysfunction and pituitary apoplexy. Results Fifty nonfunctioning pituitary adenomas (23 macroadenomas and 27 microadenomas, mean age 49, range 17-85 years) were identified. Mean follow-up was 36 months (range 6-79). An increase in volume occurred in macroadenomas ( P < 0·01) but not in microadenomas ( P = 0·44). A ≥20% increase in volume occurred in nine of 23 macroadenomas compared with two of 27 microadenomas ( P < 0·05). Five macroadenomas (one with new visual field defect) and one microadenoma proceeded to surgery ( P = 0·08). Hormone deficiency was present in four of 24 macroadenomas vs 0 of 27 microadenomas ( P < 0·05) at baseline, while new hormone deficiency developed in only two macroadenomas during follow-up. Pituitary apoplexy occurred in one microadenoma. A growth rate of >10 mm3/month assessed at approximately 2 years of follow-up among the macroadenoma group was highly predictive (sensitivity and specificity of 90%) of a ≥20% increase in volume or surgery. Conclusions Nonfunctioning pituitary macroadenomas have a greater tendency to grow and require surgical intervention while microadenomas rarely progress. [ABSTRACT FROM AUTHOR]

There is a general consensus relating to the multidimensional aspects of fatigue in people with multiple sclerosis (PwMS), however, the exact impact of this symptom on gait is not fully understood. Our primary aim was to examine the relationship between definite parameters of gait with self-reported symptomatic fatigue in PwMS according to their level of neurological impairment. Spatio-temporal parameters of gait were studied using an electronic walkway. The Multiple Sclerosis Walking Scale (MSWS-12) questionnaire, a patient-rated measure of walking ability was collected. The Modified Fatigue Impact Scale (MFIS) questionnaire was used to determine the level of symptomatic fatigue. One hundred and one PwMS (61 women) were included in the study analysis. Subjects were divided into mild and moderate neurological impaired groups. Fatigue was correlated with 5 (out of 14) spatiotemporal parameters. However, correlation scores were all <0.35, thus considered as weak correlations. In the mild group, the double support period was the only variable positively correlated to fatigue (Spearman's rho=0.28, P=0.05). In the moderate group, step and stride length were solely negatively correlated to fatigue (Spearman's rho=0.32, P=0.03). In contrast to the definite gait parameters, the MSWS-12 self-questionnaire was moderately positively correlated to the level of fatigue. Scores for the total, mild and moderate groups were 0.54, 0.57 and 0.51; P<0.01, respectively. The present results indicate that modifications in spatio-temporal parameters of gait are not closely related to symptomatic fatigue in PwMS. On the contrary, the self-reported MSWS-12 questionnaire is predisposed to level of fatigue in PwMS. [ABSTRACT FROM AUTHOR]

Problem and pathological gamblers demonstrate high levels of depression, which may be related to coping styles, reactive emotional states, and/or genetics (Potenza et al., Arch Gen Psychiat 62(9):1015-1021, 2005; Getty et al., J Gambl Stud 16(4):377-391, 2000). Although depression impacts treatment outcomes (Morefield et al., Int J Men Healt Addict 12(3):367-379, 2013), research regarding depression among gamblers in residential treatment is particularly limited. This study attempts to address this deficit by examining the course of depressive symptoms among clients at a residential gambling program in the Western United States. Forty-four adults were administered a weekly measure of depression (Beck Depression Inventory-II, BDI-II) for eight consecutive weeks. Levels of depression were classified into three groups based on standard scoring criteria for the BDI-II: no/minimal, mild/moderate, and severe depression. Results from a mixed-model analysis indicated a main effect for group and time, as well as an interaction between group and time. Examination of the slopes for the rate of change for the three depression groups indicated no change in the non-depressed group and a decrease in depression scores over time for both the mild/moderate and severely depressed groups. The slopes for the two symptomatic depression groups were not significantly different, indicating a similar rate of change. We speculate that reductions in depression symptoms may be related to feelings of self-efficacy, environmental containment/stabilization, and therapeutic effects of treatment. These results help to illuminate the role of significant processes in residential treatment, including initial stabilization, insight, self-efficacy, and termination. [ABSTRACT FROM AUTHOR]

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers. [ABSTRACT FROM AUTHOR]

Background: There is a growing interest in the objective assessment of health related outcomes using technology providing quality measurements to be applied not only in daily clinical practice, but also in scientific research. Differences in the understandings of the condition and the terminology used between people with Parkinson's (PwPs), clinicians and technical developers may influence the progress of a participatory design process. Objective: This paper reports on a participatory design process to achieve a consensus among PwPs, clinicians and technologists over the selection of a set of symptomatic domains to be continuously assessed, in order to provide results relevant to both PwPs and clinicians. Methods: The methods used were a Web based user survey, end-user focus groups, ranking by combined methods, a Delphi process performed among clinicians and scientists, and prioritization of the results in a concertation workshop for PwPs, clinicians and technologists. Results: The following symptomatic domains were commonly agreed by PwPs and clinicians to be of central importance in a system of continuous assessment: hypokinesia/bradykinesia, tremor, sway, gait, sleep and cognition. This list satisfied both the needs of the PwPs and the concerns of the clinicians regarding the means of advancing new strategies in assessment and interventions in PD. Conclusions: A participatory design strategy allowed the definition of a consensual list of symptomatic domains. Both the strategy and the achieved results may be of relevance for similar interdisciplinary approaches in the field of PD using a participatory design involving patients, clinicians and technologists. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), like many common age-related conditions, has been recognized to have a substantial genetic component. Multiple lines of evidence suggest that Leucine-rich repeat kinase 2 (LRRK2) is a crucial factor to understanding the etiology of PD. LRRK2 is a large, widely expressed, multi-domain and multifunctional protein. LRRK2 mutations are the major cause to inherited and sporadic PD. In this review, we discuss the pathology and clinical features which show diversity and variability of LRRK2-associated PD. In addition, we do a thorough literature review and provide theoretical data for gene counseling. Further, we present the evidence linking LRRK2 to various possible pathogenic mechanism of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system. Based on the above work, we investigate activities both within GTPase and outside enzymatic regions in order to obtain a potential therapeutic approach to solve the LRRK2 problem. [ABSTRACT FROM AUTHOR]

Background Persistent negative symptoms are an important area of clinical research. However, there is limited consensus on how to define positive and negative symptom severity thresholds for inclusion in clinical trials. From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset we evaluated the performance of varying baseline negative and positive symptom thresholds on baseline symptom severity, change from baseline, and negative symptom variance attributable to positive symptom change. Methods In CATIE, we first identified the group of subjects lacking an exacerbation prior to study enrollment. Six subsets with varying baseline positive and negative symptom thresholds were then identified. Baseline characteristics were summarized; negative and positive symptom change from baseline through month 3 was calculated both as crude change and change adjusted for corresponding baseline scores. Sensitivity analyses and correlations were calculated to assess the extent to which negative symptom variance was attributable to positive symptom change. Results More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline. Unadjusted negative symptom change was greater with more restrictive criteria; when adjusted for baseline severity the magnitude of change was comparable across subsets. The amount of variance in negative symptom change attributed to positive symptom change was also comparable across subsets. Conclusions The use of restrictive positive and negative symptom thresholds yields a marked decrease in eligible sample size with no clear improvement in adjusted negative symptom change or amount of variance associated with positive symptom change. [ABSTRACT FROM AUTHOR]

Introduction The aim of this study was to evaluate the consistency of 'probable RBD' diagnosis with the RBD screening questionnaire ( RBDSQ) assessed 2 years apart in a population-based study. Methods Probable RBD was assessed by RBDSQ in 2008 and in 2010 in the Bruneck Study Cohort, with participants aged ≥60 years. Results A total of 437 participants completed the RBDSQ in 2008 and 2010. There were 29 (6.6%) and 23 (5.3%) participants with probable RBD in 2008 and in 2010, respectively. Only eight (1.8%) screened positive on both occasions. RBDSQ values 2 years apart showed low correlation with each other (Spearman rank coefficient r = 0.348, P < 0.001) and low agreement (intraclass correlation coefficient 0.388, P < 0.001). Conclusions We found low agreement between the two assessments. Possible explanations are the fluctuation of untreated RBD expression and the poor utility of the RBDSQ to detect RBD in the general population. Until further PSG validation of the RBDSQ in population-based studies, investigators must be aware of the inherent uncertainty of questionnaire-based RBD diagnosis. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates patients with symptomatic Morgagni Hernia (MH) who underwent emergency surgery. Topics discussed include patients being diagnosed with chest X-rays and contrast enhanced thoracoabdominal computed tomography (CT),p patients being treated via transabdominal approach and mesh hernia repair; and need for immediate treatment of MH especially when the patient is symptomatic.

IMPORTANCE Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. OBJECTIVE To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. EVIDENCE REVIEW References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. RESULTS Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. CONCLUSIONS AND RELEVANCE Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established. [ABSTRACT FROM AUTHOR]

Background Stenosis of the internal carotid artery has been associated with cognitive impairment and decline. However, studies testing the effect of carotid revascularisation on cognition have had conflicting results. This may in part be explained by variation in the flow territory of the carotid artery. In 12 to 36% of the patients, the posterior cerebral artery is mainly or exclusively supplied by the internal carotid artery via a foetal-type posterior cerebral artery. In these patients, ipsilateral carotid artery stenosis is likely to result in a larger area with hypoperfusion than in case of a normal posterior cerebral artery. Patients with a foetal-type posterior cerebral artery could therefore benefit more from revascularisation. We compared the effects of carotid revascularisation on cognition between patients with a foetal-type and those with a normal posterior cerebral artery. Methods Patients with symptomatic internal carotid artery stenosis ⩾ 50%, enrolled in the International Carotid Stenting Study (ICSS) at a single centre, underwent detailed neuropsychological examinations before and 6 months after revascularisation. Cognitive test results were standardized into z-scores, from which a cognitive sumscore was calculated. The primary outcome was the change in cognitive sumscore between baseline and follow-up. Changes in cognitive sumscore were compared between patients with an ipsilateral foetal-type and those with a normal posterior cerebral artery, as assessed with CT or MR angiography. Results Of 145 patients enrolled in ICSS at the centre during the study period, 98 had both angiography at baseline and neuropsychological examination at baseline and at 6-months follow-up. The cognitive sum score decreased by 0.28 (95% confidence interval, 0.10 to 0.45) in 13 patients with an ipsilateral foetal-type posterior cerebral artery and by 0.07 (95% CI, 0.002 to 0.15) in 85 patients with a normal posterior cerebral artery (mean difference, - 0.20; 95% CI, -0.40 to -0.01). This did not change essentially after adjustment for baseline factors. Conclusion An ipsilateral foetal-type posterior cerebral artery appears to increase cognitive decline after carotid revascularisation. Our findings have to be reproduced in an independent study before further implications can be made. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare the short‐term clinical outcome of patients with acute cerebral ischemia and mild symptoms receiving rt‐PA with that of patients with acute cerebral ischemia and mild symptoms not treated with rt‐PA, and to investigate the frequency of symptomatic intracranial hemorrhage (sICH) in these patients. Materials and methods: All patients with confirmed ischemic stroke/TIA and mild symptoms were included. Mild symptoms were defined as NIHSS score ≤5 on admission. Functional outcome was assessed with modified Rankin Scale (mRS) at day 7 or at earlier discharge. Excellent outcome was defined as mRS = 0. sICH was defined according to both NINDS and ECASS III criteria. Results: Of 2753 patients with confirmed ischemic stroke/TIA admitted between February 2006 and February 2013, 966 (35.3%) were excluded because of having admission NIHSS >5. A total of 1791 patients presented with mild symptoms on admission (NIHSS ≤5), of which 158 (8.8%) patients received rt‐PA. Treatment with rt‐PA and early admission were independently associated with excellent outcome. Higher NIHSS score on admission and prior ischemic stroke were independently associated with poor outcome. Three (1.9%) sICH were diagnosed in rt‐PA‐treated patients and one (0.1%) in patients not receiving rt‐PA. Conclusions: This study highlights the efficacy of rt‐PA in patients with acute cerebral ischemia presenting with mild symptoms and confirms the low‐risk profile of this treatment. [ABSTRACT FROM AUTHOR]

Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis. [ABSTRACT FROM AUTHOR]

Aim Difficult-to-treat epilepsies and attention-deficit-hyperactivity disorder ( ADHD) often co-occur. Because of concerns about the use of stimulants in children with this comorbidity, the impact of ADHD treatment on seizure frequency and severity is not known. This pilot study evaluated the safety and efficacy of methylphenidate in this population. Method After a 3 month period in which antiepileptic drugs were adjusted, 22 patients recruited from a specialist outpatient clinic for severe epilepsy (16 males, six females; mean age 11y 2mo, SD 3y 2mo) received methylphenidate for 3 months in an open label, non-controlled trial; four with generalized or multifocal (symptomatic/cryptogenic) epilepsy, one with generalized (idiopathic) epilepsy, 17 with partial (symptomatic/cryptogenic) epilepsy; five with partial seizures only, 17 with primarily or secondarily generalized seizures). Epilepsy, ADHD symptoms, and side effects were assessed using the Swanson, Nolan, and Pelham Questionnaire, the Child Behavior Checklist, the Hague Seizure Severity Scale, and the Side Effects Rating Scale. Results Methylphenidate significantly improved ADHD. After 3 months of treatment, 73% of patients no longer had clinically significant symptoms. Methylphenidate also reduced seizure severity (9-point median decrease on the Hague Seizure Severity Scale). Seizure frequency increased in four out of 22 patients, but only one patient withdrew from the study for this reason. Most patients experienced no major side effects. Interpretation These data are among the first showing that low doses of methylphenidate are safe and effective to treat ADHD symptoms in patients with difficult-to-treat epilepsies. Randomized controlled trials are needed to replicate the findings. [ABSTRACT FROM AUTHOR]

Abstract: The term “ventricular preexcitation” or “preexcitation” refers to the presence of a delta wave and short PR interval on electrocardiogram (ECG) during normal sinus rhythm. The Wolff–Parkinson–White (WPW) syndrome refers to preexcitation during sinus rhythm, in association with episodes of supraventricular tachycardia (SVT). The delta wave represents extra-nodal conduction via an accessory connection located along the atrioventricular groove or the septal region, and this substrate can support atrioventricular reentrant tachycardia. Patients with Wolff–Parkinson–White syndrome may experience symptoms of palpitations, dizziness, syncope, or sudden cardiac arrest related to supraventricular tachycardia; infants may present with congestive heart failure. Catastrophic symptoms such as cardiac arrest or sudden death may be triggered from atrial fibrillation with rapid antegrade conduction to the ventricle via the accessory connection, resulting in ventricular fibrillation [1–4]; this risk is likely higher in patients in the first three decades of life [4,5]. Sudden cardiac arrest as the initial symptom may be more common in younger patients [2,4,6]; for this reason, appropriate evaluation and management of the young patient with preexcitation is essential. [Copyright &y& Elsevier]

Summary: Study aim: We describe a new neuronavigation-guided technique to target the posterior-superior insula (PSI) using a cooled-double-cone coil for deep cortical stimulation. Introduction: Despite the analgesic effects brought about by repetitive transcranial magnetic stimulation (TMS) to the primary motor and prefrontal cortices, a significant proportion of patients remain symptomatic. This encouraged the search for new targets that may provide stronger pain relief. There is growing evidence that the posterior insula is implicated in the integration of painful stimuli in different pain syndromes and in homeostatic thermal integration. Methods: The primary motor cortex representation of the lower leg was used to calculate the motor threshold and thus, estimate the intensity of PSI stimulation. Results: Seven healthy volunteers were stimulated at 10Hz to the right PSI and showed subjective changes in cold perception. The technique was safe and well tolerated. Conclusions: The right posterior-superior insula is worth being considered in future studies as a possible target for rTMS stimulation in chronic pain patients. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson''s disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET (18F-DOPA Ki and 11C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features. [Copyright &y& Elsevier]

Background: Steroid-responsive encephalopathies can be considered vasculitic or non-vasculitic. Clinicopathological studies of non-vasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid-responsive presentation in life. Objective: To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy. Design, methods, and patients: A clinicopathological case series of four patients (two women, ages 54–71 years) with steroid-responsive encephalopathy followed at this institution until the time of death. Results: Clinical features were suggestive of Creutzfeld–Jakob disease (CJD), dementia with Lewy bodies (DLB), and parkinsonism, but pathological examination revealed only Alzheimer's disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studies. Alzheimer's disease was not diagnosed in life due to the atypical clinical features, lack of hippocampal atrophy on brain imaging, and a dramatic symptomatic response to steroids. Conclusions: Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer's disease-related pathology at autopsy, and can be consistent with the clinical diagnoses of parkinsonism, DLB, or CJD disease in life. [ABSTRACT FROM AUTHOR]

Background: Clinical prediction rules do not incorporate real-time incidence data to adjust estimates of disease risk in symptomatic patients. Objective: To measure the value of integrating local incidence data into a clinical decision rule for diagnosing group A streptococcal (GAS) pharyngitis in patients aged 15 years or older. Design: Retrospective analysis of clinical and biosurveillance predictors of GAS pharyngitis. Setting: Large U.S.-based retail health chain. Patients: 82 062 patient visits for pharyngitis. Measurements: Accuracy of the Centor score was compared with that of a biosurveillance-responsive score, which was essentially an adjusted Centor score based on real-time GAS pharyngitis information from the 14 days before a patient's visit: the recent local proportion positive (RLPP). Results: Increased RLPP correlated with the likelihood of GAS pharyngitis (r2 = 0.79; P < 0.001). Local incidence data enhanced diagnostic models. For example, when the RLPP was greater than 0.30, managing patients with Centor scores of 1 as if the scores were 2 would identify 62 537 previously missed patients annually while misclassifying 18 446 patients without GAS pharyngitis. Decreasing the score of patients with Centor values of 3 by 1 point for an RLPP less than 0.20 would spare unnecessary antibiotics for 166 616 patients while missing 18 812 true-positive cases. Limitations: Analyses were conducted retrospectively. Real-time regional data on GAS pharyngitis are generally not yet available to clinicians. Conclusion: Incorporating live biosurveillance data into clinical guidelines for GAS pharyngitis and other communicable diseases should be considered for reducing missed cases when the contemporaneous incidence is elevated and for sparing unnecessary antibiotics when the contemporaneous incidence is low. Delivering epidemiologic data to the point of care will enable the use of real-time pretest probabilities in medical decision making. [ABSTRACT FROM AUTHOR]

PurposeTo investigate whether psychophysical, morphological, and/or optical characteristics of symptomatic non-advanced cataract are complementary to, or more appropriate than, visual acuity (VA) for the purposes of recording visual data that reflect subjective visual difficulty in patients with cataract that exhibit relative sparing of high contrast acuity (0.4 logarithm of minimal angle of resolution (logMAR) scale or better).MethodsEighty-two patients with symptomatic non-advanced cataract and no other ocular pathology were asked to complete a validated questionnaire, and to perform a series of visual function assessments including: corrected distance VA (CDVA); photopic and mesopic contrast sensitivity; photopic and mesopic glare disability (GD); reading acuity and reading speed; stereoacuity; and retinal sensitivity. Optical and morphological characteristics of the cataract were evaluated by lens optical density and by the Lens Opacities Classification System III, respectively. Correlations between questionnaire score and each of these measures were calculated.ResultsStatistically significant negative correlations were observed between the Rasch-scaled questionnaire score and mesopic GD (at 3 and 6 cycles per degree (cpd); r=−0.396 (P<0.01) and −0.451 (P<0.05), respectively) and between the Rasch-scaled questionnaire score and photopic GD (at 3 and 6 cpd; r=−0.328 (P<0.01) and −0.440 (P<0.01), respectively).ConclusionSymptomatic non-advanced cataract, in the presence of good CDVA, is associated with measurable subjective visual difficulty, best reflected in a decrease in mesopic and photopic GD (at medium spatial frequencies). CDVA does not reflect the patient's visual dissatisfaction in such cases. [ABSTRACT FROM AUTHOR]

The article offers information on a medicine research carried out on independent and joint effects of the MAPT and SNCA genes in Parkinson disease (PD). Independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease were studied. The association between PD and both SNCA SNPs and the H1 MAPT haplotype was confirmed and it was also seen that the joint action of variants in these 2 loci is consistent.

Ergoline derivative 9,10-Didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate (LEK8829), possesses dopamirte (DA) D1 agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways. These unique dual effects have suggested that LEK-8829 could effectively restore previously imbalanced functional linkage between D1 and D2 receptors under schizophrenic conditions in which, LEK-8829 could improve both the negative and positive symptoms of schizophrenia. As dopamine D1 receptor agonist, LEK-8829 may also be beneficial in relieving the motor symptoms of parkinsonism, alone, or when co-administered with antiparkinsonic dopamine D2 agonists, such as ergoline derivative bromocriptine. Moreover, antiparkinsonic potential of LEK-8829 may be particularly useful when the treatment of parkinsonism with D2 agonist drugs is complicated by psychosis. Antiparkinsonic properties of LEK-8829 also suggest a lower propensity of the drug for the induction of extrapyramidal syndrome in the treatment of schizophrenia. Furthermore, by blocking dopamine D2 receptors, LEK-8829 could block the incentive for drug-seeking and drug-craving while by stimulating dopamine D1 receptors it could mediate drug reward and gratification. This implies that LEK-8829 could also attenuate the relapse of psychostimulant drug-addiction, while not being addictive by itself. We conclude that agents with LEK-8829-like dual actions toward dopamine receptors, may represent a new and potent drug class for the treatment parkinsonism, schizophrenia and drug-addiction. [ABSTRACT FROM AUTHOR]

Mesencephalic-diencephalic dopaminergic neurons control locomotor activity and emotion and are affected in neurodegenerative and psychiatric diseases. The homeoprotein Otx2 is restricted to ventral tegmental area (VTA) neurons that are prevalently complementary to those expressing Girk2 and glycosylated active form of the dopamine transporter (Dat). High levels of glycosylated Dat mark neurons with efficient dopamine uptake and pronounced vulnerability to Parkinsonian degeneration. We found that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of dorsal-lateral VTA, such as Girk2 and Dat expression. Otx2 limited the number of VTA neurons with efficient dopamine uptake and conferred resistance to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Ectopic Otx2 expression also provided neurons of the substantia nigra with efficient neuroprotection to MPTP. These findings indicate that Otx2 is required to specify neuron subtype identity in VTA and may antagonize vulnerability to the Parkinsonian toxin MPTP. [ABSTRACT FROM AUTHOR]

Background: As Parkinson's disease (PD) progresses, patients and their families experience substantial health and economic burdens. Because motor fluctuations (also called 'off-time') are linked to poor quality of life and higher healthcare costs, minimizing off-time is an effective strategy for reducing costs associated with PD. Objective: To assess the cost utility of rasagiline or entacapone as adjunctive therapies to levodopa versus levodopa/carbidopa/entacapone (LCE) versus standard levodopa monotherapy in patients with advanced PD and motor fluctuations in the US. Methods: A 2-year stochastic Markov model was utilized to examine the cost effectiveness of treatments of advanced PD. The model assumed that patients transition health status every 4 months. Transition probabilities, including uncertainties, were estimated from clinical trial data. Medical costs, daily drug costs and utility weights were obtained from published literature. Results: Over 2 years, all therapy options showed greater effectiveness than levodopa alone. Rasagiline+levodopa and LCE were cost saving from a payor perspective, while entacapone+levodopa was cost saving from a societal perspective. Mean benefits over 2 years were 0.12 (90% credibility interval [CI] 0.07, 0.18) additional quality-adjusted life-years (QALYs) for rasagiline+levodopa, entacapone+levodopa and LCE, 5.08 (90% CI 3.87, 6.28) additional months with ≤25% off-time for rasagiline+levodopa and 4.85 (90% CI 3.63, 6.06) additional months with ≤25% off-time for entacapone+levodopa and LCE versus levodopa alone. Conclusion: From a payor perspective, rasagiline+levodopa and LCE were dominant therapies over levodopa monotherapy, while entacapone + levodopa was effective at a higher cost. With no additional cost over a 2-year period, rasagiline+levodopa presents a valuable alternative to entacapone+ levodopa, LCE and levodopa monotherapy in the treatment of advanced PD patients, Results from this cost-utility model and prior adjunctive clinical data provide ongoing support for the adjunctive use of rasagiline in advanced PD patients with motor fluctuations. [ABSTRACT FROM AUTHOR]

Abstract: Adenosine A2A receptor (A2AR) antagonists are being investigated as promising treatment strategy for Parkinson''s disease (PD). To test whether A2AR antagonists are beneficial in early PD stages we used MitoPark mice, a genetic model with gradual degeneration of DA cells. Daily treatment of young MitoPark mice for eight weeks with the A2AR antagonist MSX-3 prevented the reduction of spontaneous locomotor activity observed in saline or L-DOPA treated animals. Chronic A2AR antagonist treatment neither induced desensitization of receptors nor accumulation of the drug in brain tissue. Despite beneficial effects on behavior, which are not improved upon addition of a low dose of L-DOPA, the characteristic decline of dopamine levels was not changed. Our results indicate that effective dosing with A2AR antagonists should be tested as monotherapy in early PD, and serves to remind us that positive behavioral effects of such treatment need not be reflected in rescue of striatal dopamine levels. [Copyright &y& Elsevier]

Abstract: Although acupuncture has been widely and routinely used in healthcare in the USA, its use has been based more on empirical observation than on scientific knowledge. Therefore, there is a great need for better understanding the underlying mechanism(s) of action. A great body of evidence supports that nonhuman primates are a candidate for studying human diseases. However, the use of nonhuman primates in neurophysiological, neuroimaging and neurochemical studies is extremely challenging, especially under fully conscious, alert conditions. In the present study, we developed a protocol for safely performing acupuncture, electroacupuncture (EA) and electromyography (EMG) in both normal nonhuman primates and animals with parkinsonian-like symptoms. Four normal and four hemiparkinsonian middle-aged rhesus monkeys were extensively trained, behaviorally monitored, and received both EA and EMG for several months. The results demonstrated that (1) all rhesus monkeys used in the study could be trained for procedures including EA and EMG; (2) all animals tolerated the procedures involving needle/electrode insertion; (3) EA procedures used in the study did not adversely alter the animal''s locomotor activities; rather, MPTP-treated animals showed a significant improvement in movement speed; and (4) EMG detected significant differences in muscle activity between the arms with and without MPTP-induced rigidity. Our results support that rhesus monkeys can be used as an experimental animal model to study EA and that EMG has the potential to be used to objectively assess the effects of antiparkinsonian therapies. The results also indicate that animals, especially those with parkinsonian-like symptoms, could benefit from long-term EA stimulations. [Copyright &y& Elsevier]

In this study, we wished to test, using magnetic resonance imaging and voxel-based morphometry (VBM), whether specific cortical and subcortical patterns of brain grey (GM) and white matter (WM) tissue loss can be detected in patients with Richardson’s syndrome (PSP-RS) and progressive supranuclear palsy-parkinsonism (PSP-P), and possibly account for their clinical heterogeneity. Twenty patients with PSP, classified as PSP-RS (10 patients) or PSP-P (10 patients), and 24 healthy controls were studied. The Statistical Parametric Mapping (SPM5) and the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra method were used to perform a VBM analysis. Compared with controls, both patient groups showed GM loss in the central midbrain, cerebellar lobes, caudate nuclei, frontotemporal cortices and right hippocampus. WM loss was detected in both conditions in the midbrain, left superior cerebellar peduncle, internal capsulae, and left premotor and bilateral prefrontal regions. Compared with PSP-P, patients with PSP-RS showed additional regions of GM loss in the midbrain, left cerebellar lobe and dentate nuclei. PSP-RS was also associated with a more severe WM loss in the midbrain, internal capsulae, and orbitofrontal, prefrontal and precentral/premotor regions, bilaterally. Patients with PSP-P showed a more pronounced GM loss only in the frontal cortex, bilaterally. This study shows that, albeit the overall pattern of brain atrophy associated with PSP appears remarkably consistent across the spectrum of clinical features recorded in life, major anatomical differences between these two conditions do exist. Such a different topographical distribution of tissue damage may account for the clinical differences between PSP-RS and PSP-P. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) consists of loss of pigmented dopamine-secreting neurons in the pars compacta of the midbrain substantia nigra. These neurons project to the striatum (putamen and caudate nucleus) and their loss leads to alterations in the activity of the neural circuits that regulate movement. In a simplified model, two dopamine pathways are involved: the direct pathway, which is mediated through facilitation of the D1 receptors, and the indirect pathway through D2 receptors (inhibitory). Positron emission tomography (PET) tracers to image the presynaptic sites of the dopaminergic system include 6-[18F]FDOPA and 6-[18F]FMT, [11C]dihydrotetrabenazine, [11C]nomifensine and various radiolabelled cocaine derivatives. Postsynaptically, for the dopamine D1 subtype the most commonly used ligands are [11C]SCH 23390 or [11C]NNC 112 and for the D2 subtype [11C]raclopride, [11C]MNPA and [18F]DMFP. PET is a sensitive and specific non-invasive molecular imaging technique that may be helpful for evaluation of PD and its differential diagnosis from other parkinsonian syndromes. [ABSTRACT FROM AUTHOR]

Abstract: Western blot has been used to study the time-course effect of the two most popular parkinsonian neurotoxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, i.p.) and 6-hydroxydopamine (6-OHDA, intra-substantia nigra), on the expression of several regulators of G-protein signaling (RGS2, 4 and 9) in striatum in rodents. During the few days after MPTP challenge, there was a decline (as expected) in tyrosine hydroxylase expression in the mouse striatum that was accompanied by a decline in RGS9 protein; the latter was specific and did not extend to RGS2 or RGS4 which were resistant to the MPTP challenge. Much the same pattern was observed in rats after 6-OHDA challenge, again, specific to RGS9, although the effect takes a few weeks, rather than a few days, to develop. These results may be helpful for the understanding of molecular mechanism underlying Parkinson''s disease (PD) and RGS9 might involve in the striatal function associated with PD. [Copyright &y& Elsevier]

The current therapy of Alzheimer’s disease is primarily symptomatic. Drugs which aim to modify the course of the disease are currently being developed and tested in clinical trials. Given the complex and partly unknown pathogenesis of the disease, failure of such forms of therapy has to be taken into account. Clinical epidemiology suggests a possible neuroprotective effect of statins and non-steroidal anti-inflammatory drugs, however, the molecular basis of these effects has to be further unraveled. Therapies that modify the course of Alzheimer’s disease are only likely to be effective years if not decades before the disease becomes clinically apparent. Thus, the therapy of risk factors including arterial hypertension and obesity in midlife as well as a Mediterranean diet currently provides the highest chance of modifying the course of the disease. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Multiple system atrophy (MSA) is a progressive neurodegenerative disorder divided into a parkinsonian (MSA-P) and a cerebellar variant. The purpose of this study was to assess regional brain atrophy and iron content using Voxel-based morphometry (VBM) and Voxel-based relaxometry (VBR) respectively, in MSA-P. METHODS Using biological parametric mapping the effect of brain atrophy was evaluated in T2 relaxation time (T2) measurements by applying analysis of covariance (ANCOVA) and correlation analysis to the VBM and VBR data. Eleven patients with MSA-P (aged 61.9 ± 11.7 years, disease duration 5.42 ± 2.5 years) and 11 controls were studied. RESULTS In comparison to the controls the patients showed decreased gray matter in the putamen, the caudate nuclei, the thalami, the anterior cerebellar lobes, and the cerebral cortex, and white matter atrophy in the pons, midbrain, and peduncles. VBR analysis showed prolonged T2 in various cortical regions. On ANCOVA, when controlling for gray and white matter volume, these regions of prolonged T2 were shrunk. Negative correlation was demonstrated between T2 and gray and white matter volume. CONCLUSIONS Diffuse brain atrophy, mainly in the motor circuitry is observed in MSA-P. Normalization for atrophy should always be performed in T2 measurements. [ABSTRACT FROM AUTHOR]