Showing papers in "Journal of Parkinson's disease in 2016"
TL;DR: Recent findings from in vitro, cell-based assays and in vivo studies are explored describing the potential implications of pS129 in the regulation of α-syn physiological functions, as well as its implication in synucleinopathies pathogenesis and diagnosis.
Abstract: Abnormal accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (LBs) is the neurpathological hallmark of Parkinson's disease (PD) and related synucleinopathies. These inclusions are mainly constituted of a presynaptic protein, α-synuclein (α-syn). Over the past decade, growing amounts of studies reported an aberrant accumulation of phosphorylated α-syn at the residue S129 (pS129) in the brain of patients suffering from PD, as well as in transgenic animal models of synucleinopathies. Whereas only a small fraction of α-syn ( 90%) has been observed within LBs, suggesting that this post-translational modification may play an important role in the regulation of α-syn aggregation, LBs formation and neuronal degeneration. However, whether phosphorylation at S129 suppresses or enhances α-syn aggregation and toxicity in vivo remains a subject of active debate. The answer to this question has important implications for understanding the role of phosphorylation in the pathogenesis of synucleinopathies and determining if targeting kinases or phosphatases could be a viable therapeutic strategy for the treatment of these devastating neurological disorders. In the present review, we explore recent findings from in vitro, cell-based assays and in vivo studies describing the potential implications of pS129 in the regulation of α-syn physiological functions, as well as its implication in synucleinopathies pathogenesis and diagnosis.
235 citations
TL;DR: The evidence that the axonal component of diseased neuronal systems merit more of the authors' attention and the neurobiology of axons is likely to offer many new approaches to protective and restorative therapeutics is reviewed.
Abstract: In spite of tremendous research efforts we have not yet achieved two of our principal therapeutic goals in the treatment of Parkinson's disease (PD), to prevent its onward progression and to provide restoration of systems that have already been damaged by the time of diagnosis. There are many possible reasons for our inability to make progress. One possibility is that our efforts thus far may not have been directed towards the appropriate cellular compartments. Up until now research has been largely focused on the loss of neurons in the disease. Thus, neuroprotection approaches have been largely aimed at blocking mechanisms that lead to destruction of the neuronal cell body. Attempts to provide neurorestoration have been almost entirely focused on replacement of neurons. We herein review the evidence that the axonal component of diseased neuronal systems merit more of our attention. Evidence from imaging studies, from postmortem neurochemical studies, and from genetic animal models suggests that the axons of the dopaminergic system are involved predominantly and early in PD. Since the mechanisms of axonal destruction are distinct from those of neuron cell body degeneration, a focus on axonal neurobiology will offer new opportunities for preventing their degeneration. At present these mechanisms remain largely obscure. However, defining them is likely to offer new opportunities for neuroprotection. In relation to neurorestoration, while it has been classically believed that neurons of the adult central nervous system are incapable of new axon growth, recent evidence shows that this is not true for the dopaminergic projection. In conclusion, the neurobiology of axons is likely to offer many new approaches to protective and restorative therapeutics.
190 citations
TL;DR: This study shows that 150 mg and 300’mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson’s disease, and suggests that it is warranted to evaluate the safety and efficacy of N Pilotinib in larger randomized, double-blind, placebo-controlled trials.
Abstract: Background: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson’s disease dementia or dementia with Lewy bodies.
Objectives: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory.
Methods: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks.
Results: This study shows that 150 mg and 300 mg doses of Nilotinib appear to be safe and tolerated in subjects with advanced Parkinson’s disease. Nilotinib is detectable in the cerebrospinal fluid (CSF) and seems to engage the target Abl. Motor and cognitive outcomes suggest a possible beneficial effect on clinical outcomes. The CSF levels of homovanillic acid are significantly increased between baseline and 24 weeks of treatment. Exploratory CSF biomarkers were measured.
Conclusions: This small proof-of-concept study lacks a placebo group and participants were not homogenous, resulting in baseline differences between and within groups. This limits the interpretations of the biomarker and clinical data, and any conclusions should be drawn cautiously. Nonetheless, the collective observations suggest that it is warranted to evaluate the safety and efficacy of Nilotinib in larger randomized, double-blind, placebo-controlled trials.
187 citations
TL;DR: The results indicate that PA interventions have a positive impact on physical capacities and functional capacities, however, the effect of PA on symptoms of the disease and psychosocial aspects of life are moderate and show more variability.
Abstract: Background: Physical activity (PA) is increasingly advocated as an adjunct intervention for individuals with Parkinson’s disease (PD). However, the specific benefits of PA on the wide variety of impairments observed in patients with PD has yet to be clearly identified.
Objective: Highlight health parameters that are most likely to improve as a result of PA interventions in patients with PD.
Methods: We compiled results obtained from studies examining a PA intervention in patients with PD and who provided statistical analyses of their results. 868 outcome measures were extracted from 106 papers published from 1981 to 2015. The results were classified as having a statistically significant positive effect or no effect. Then, outcome measures were grouped into four main categories and further divided into sub-categories.
Results: Our review shows that PA seems most effective in improving Physical capacities and Physical and cognitive functional capacities. On the other hand, PA seems less efficient at improving Clinical symptoms of PD and Psychosocial aspects of life, with only 50% or less of results reporting positive effects. The impact of PA on Cognitive functions and Depression also appears weaker, but few studies have examined these outcomes.
Discussion: Our results indicate that PA interventions have a positive impact on physical capacities and functional capacities. However, the effect of PA on symptoms of the disease and psychosocial aspects of life are moderate and show more variability. This review also highlights the need for more research on the effects of PA on cognitive functions, depression as well as specific symptoms of PD.
128 citations
TL;DR: The literature supports possible protective and symptomatic effects of vitamin D in PD, however, more observational and interventional studies in humans are needed to confirm and further elucidate the suggested beneficial effect ofitamin D on PD.
Abstract: Background: Although vitamin D may have both protective and symptomatic effects in Parkinson’s disease (PD), the evidence is scarce and not well understood. Also, 25-hydroxyvitamin D (vitamin D) is suggested to play a neuroprotective and neurotrophic role in the brain. Therefore, this review investigates the relationship between vitamin D and PD. Objective: Investigate the evidence for a relationship between vitamin D and PD by summarizing observational and interventional studies in humans, as well as relevant experimental studies. Methods: A systematic search was made in the Medline, Cochrane and Embase databases (from inception to March 2014). All identified titles were independently evaluated by two reviewers. Articles were selected based on the presence of PD-related outcome data. Included were observational studies (including genetic studies) and interventional studies in humans, as well as relevant animal studies. Results: A total of 20 studies (14 observational, 1 interventional and 5 rodent studies) were selected for analysis. Eight observational studies showed that serum 25(OH) D levels tend to be low in PD. One observational study indicated that low serum 25(OH) D may worsen automatic postural responses and one interventional study suggested that vitamin D supplementation can prevent worsening (based on the Hoehn and Yahr rating scale). Studies in rodent models of PD showed a protective effect of vitamin D treatment on dopaminergic neurons in the substantia nigra. Results of genetic studies on the association between vitamin D receptor polymorphisms and the risk of PD were contradictory. Conclusion: The literature supports possible protective and symptomatic effects of vitamin D in PD. However, more observational and interventional studies in humans are needed to confirm and further elucidate the suggested beneficial effect of vitamin D on PD.
79 citations
TL;DR: Submucosa and LTS is present, and when specific staining is defined as being consistent with neuronal morphology, adequately-trained raters may reliably distinguish PD colon from control using suitable IHC methods.
Abstract: BACKGROUND Conflicting results from studies of Lewy-type α-synucleinopathy (LTS) in colonic biopsies of subjects with Parkinson's disease (PD) prompted a two-part multicenter assessment. The first assessment, now published (Acta Neuropathol Commun 4 : 35, 2016), examined archived colonic biopsies and found that none of the tested methods was adequately sensitive or specific. OBJECTIVE As the amount of nervous tissue in typical colonic biopsies may be insufficient, and the clinical diagnosis of PD not completely accurate, the objective of the current study was to use instead full-thickness sections of sigmoid colon from autopsy-proven PD and normal subjects. METHODS Seven different immunohistochemical (IHC) methods were used, employing five different primary antibodies and four different combinations of epitope exposure and signal development protocols. Specific staining was defined as being restricted to morphological features consistent with neuronal elements. Stained slides from each subject were independently categorized as being positive or negative for LTS, and their density semi-quantitatively graded, by four raters blinded to diagnosis. RESULTS Agreement and mean diagnostic performance varied markedly between raters. With the two most accurate raters, 5 methods achieved diagnostic accuracies of 70% or greater; one method had 100% accuracy and 100% inter-rater agreement. The submucosa had the highest prevalence of pathological LTS staining, followed by the muscularis and mucosa. CONCLUSIONS The major conclusion of this study is that, when sufficient submucosa and LTS is present, and when specific staining is defined as being consistent with neuronal morphology, adequately-trained raters may reliably distinguish PD colon from control using suitable IHC methods.
72 citations
TL;DR: The current state-of-art regarding human stem cell-derived dopamine neurons for use in any patient trial is described and the time is ripe for clinical translation of parthenogenetic stem cell technology in Parkinson’s disease is critically assessed.
Abstract: Recent news of an impending clinical cell transplantation trial in Parkinson's disease using parthenogenetic stem cells as a source of donor tissue have raised hopes in the patient community and sparked discussion in the research community. Based on discussions held by a global collaborative initiative on translation of stem cell therapy in Parkinson's disease, we have identified a set of key questions that we believe should be addressed ahead of every clinical stem cell-based transplantation trial in this disorder. In this article, we first provide a short history of cell therapy in Parkinson's disease and briefly describe the current state-of-art regarding human stem cell-derived dopamine neurons for use in any patient trial. With this background information as a foundation, we then discuss each of the key questions in relation to the upcoming therapeutic trial and critically assess if the time is ripe for clinical translation of parthenogenetic stem cell technology in Parkinson's disease.
60 citations
TL;DR: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB and could also be used to verify other biomarkers.
Abstract: Background Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Objective To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders. Methods Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). Results Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. Conclusions These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.
55 citations
TL;DR: An algorithm was developed, which could successfully distinguish been subjects with a resting or postural tremor that involved the wrist whose frequency was greater than 3 Hz, and is proposed as a means of assessing the presence of tremor and its relationship to bradykinesia.
Abstract: Background While tremor in Parkinson's Disease (PD) can be characterised in the consulting room, its relationship to treatment and fluctuations can be clinically helpful. Objective To develop an ambulatory assessment of tremor of PD. Methods Accelerometry data was collected using the Parkinson's KinetiGraph System (PKG, Global Kinetics). An algorithm was developed, which could successfully distinguish been subjects with a resting or postural tremor that involved the wrist whose frequency was greater than 3 Hz. Percent of time that tremor was present (PTT) between 09 : 00 and 18 : 00 was calculated. Results This algorithm was applied to 85 people with PD who had been assessed clinically for the presence and nature of tremor. The Sensitivity and Selectivity of a PTT ≥0.8% was 92.5% and 92.9% in identifying tremor, providing that the tremor was not a fine kinetic and postural tremor or was not in the upper limb. A PTT >1% provide high likely hood of the presence of clinical meaningful tremor. These cut-offs were retested on a second cohort (n = 87) with a similar outcome. The Sensitivity and Selectivity of the combined group was 88.7% and 89.5% respectively. Using the PTT, 50% of 22 newly diagnosed patients had a PTT >1.0%.The PKG's simultaneous bradykinesia scores was used to find a threshold for the emergence of tremor. Tremor produced artefactual increase in the PKG's dyskinesia score in 1% of this sample. Conclusions We propose this as a means of assessing the presence of tremor and its relationship to bradykinesia.
52 citations
TL;DR: Support is provided for the argument that APOE ɛ4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD, which supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer's disease, and tauopathies.
Abstract: Background: Cognitive decline is well recognized in Parkinson’s disease (PD) and a major concern for patients and caregivers. Apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), and microtubule-associated protein tau (MAPT) are of interest related to their contributions to cognitive decline or dementia in PD. Objective: Here, we investigate whether APOE, COMT ,o rMAPT influence the rate of cognitive decline in PD patients. Methods: We relied on 634 PD patients and 879 controls to examine gene-PD susceptibility associations, and nested longitudinal cohort of 246 patients from the case-control study, which followed patients on average 5 years and 7.5 years into disease. We repeatedly assessed cognitive symptom progression with the MMSE and conducted a full neuropsychological battery on a subset of 183 cognitively normal patients. We used repeated-measures regression analyses to assess longitudinal associations between genotypes and cognitive progression scores. Results: The MAPT H1 haplotype was associated with PD susceptibility. APOE 4 carriers (4+) (p = 0.03) and possibly COMT Met/Met (p = 0.06) carriers exhibited faster annual decline on the MMSE. Additionally, APOE 4+ carriers showed faster decline in many of the neuropsychological test scores. No such differences in neuropsychological outcomes were seen for the COMT genotypes. Conclusion: This work supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer’s disease, and tauopathies, especially in the context of cognitive dysfunction in PD. We provide support for the argument that APOE 4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD.
52 citations
TL;DR: It is concluded that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance, so there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value.
Abstract: In contrast to some other neurodegenerative diseases, little is known about ventilatory dysfunction in Parkinson's disease (PD). To assess the spectrum of ventilation disorders in PD, we searched for and reviewed studies of dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders and the response to hypoxemia in PD. Among the studies, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under "off-drug" conditions. Although there are many reports of abnormal spirometry data in PD (mainly related to impairment of the inspiratory muscles), little is known about hypoventilation in PD. We conclude that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance. Hence, there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value.
TL;DR: Individuals with PD show quantitative changes in pressure generation and are able to self-assess aspects of swallowing function in the early and mid-stages of PD, even in the absence of swallowing changes seen on videofluoroscopy.
Abstract: Background
Parkinson disease (PD) has detrimental effects on swallowing function. Treatment options are largely behavioral; thus, patients would benefit from an earlier start to therapy. Early swallowing changes in PD are not well-known, so patients do not typically receive swallowing treatment until later in the progression of PD.
TL;DR: Savinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
Abstract: Background: Studies 016 and SETTLE showed that safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms.
Objective: To evaluate the clinical effects of safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE.
Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of safinamide versus placebo on individual cardinal PD symptoms during ON time.
Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, safinamide improved bradykinesia, rigidity, tremor and gait.
Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
TL;DR: This work reviewed FOG assessment from history taking, questionnaires, lab and home-based measurements and examined how these methods account for presence and severity of FOG, their limits and advantages.
Abstract: BACKGROUND: Freezing of gait (FOG) is a mysterious, complex and debilitating phenomenon in Parkinson's disease. Adequate assessment is a pre-requisite for managing FOG, as well as for assigning participants in FOG research. The episodic nature of FOG, as well as its multiple clinical expressions make its assessment challenging. OBJECTIVE: To highlight the available assessment tools and to provide practical, experience-based recommendations for reliable assessment of FOG. METHODS: We reviewed FOG assessment from history taking, questionnaires, lab and home-based measurements and examined how these methods account for presence and severity of FOG, their limits and advantages. The practicalities for their use in clinical and research practice are highlighted. RESULTS: According to the available assessment tools severity of FOG is marked by one or a combination of multiple clinical expressions including frequency, duration, triggering circumstances, response to levodopa, association with falls and fear of falling, or need for assistance to avoid falls. CONCLUSIONS: To date, a unique methodological tool that encompasses the entire complexity of FOG is lacking. Combining methods should give a better picture of FOG severity, in accordance with the precise clinical or research context. Further development of any future assessment tool requires understanding and thorough analysis of the specific clinical expressions of FOG.
TL;DR: Camptocormia in connection with primary myopathies should be treated according to the underlying illness, and case reports have shown botulinum toxin and DBS of the globus pallidus internus (GPi-DBS) to be effective.
Abstract: Camptocormia is a disabling pathological, non-fixed, forward bending of the trunk. The clinical definition using only the bending angle is insufficient; it should include the subjectively perceived inability to stand upright, occurrence of back pain, typical individual complaints, and need for walking aids and compensatory signs (e.g. back-swept wing sign). Due to the heterogeneous etiologies of camptocormia a broad diagnostic approach is necessary. Camptocormia is most frequently encountered in movement disorders (PD and dystonia) and muscles diseases (myositis and myopathy, mainly facio-scapulo-humeral muscular dystrophy (FSHD)). The main diagnostic aim is to discover the etiology by looking for signs of the underlying disease in the neurological examination, EMG, muscle MRI and possibly biopsy. PD and probably myositic camptocormia can be divided into an acute and a chronic stage according to the duration of camptocormia and the findings in the short time inversion recovery (STIR) and T1 sequences of paravertebral muscle MRI. There is no established treatment of camptocormia resulting from any etiology. Case series suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) is effective in the acute but not the chronic stage of PD camptocormia. In chronic stages with degenerated muscles, treatment options are limited to orthoses, walking aids, physiotherapy and pain therapy. In acute myositic camptocormia an escalation strategy with different immunosuppressive drugs is recommended. In dystonic camptocormia, as in dystonia in general, case reports have shown botulinum toxin and DBS of the globus pallidus internus (GPi-DBS) to be effective. Camptocormia in connection with primary myopathies should be treated according to the underlying illness.
TL;DR: How several aspects of Parkinson’s disease (PD) – known to be correlated with wellbeing and health-related quality of life–could be measured using wearable devices (‘wearables’) is discussed.
Abstract: In this viewpoint, we discuss how several aspects of Parkinson's disease (PD) - known to be correlated with wellbeing and health-related quality of life-could be measured using wearable devices ('wearables'). Moreover, three people with PD (PwP) having exhaustive experience with using such devices write about their personal understanding of wellbeing and health-related quality of life, building a bridge between the true needs defined by PwP and the available methods of data collection. Rapidly evolving new technologies develop wearables that probe function and behaviour in domestic environments of people with chronic conditions such as PD and have the potential to serve their needs. Gathered data can serve to inform patient-driven management changes, enabling greater control by PwP and enhancing likelihood of improvements in wellbeing and health-related quality of life. Data can also be used to quantify wellbeing and health-related quality of life. Additionally these techniques can uncover novel more sensitive and more ecologically valid disease-related endpoints. Active involvement of PwP in data collection and interpretation stands to provide personally and clinically meaningful endpoints and milestones to inform advances in research and relevance of translational efforts in PD.
TL;DR: It is demonstrated that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes and is a unique environment that contains many species of RNA.
Abstract: Background: Parkinson’s disease (PD) is a debilitating neurological disorder for which prognostic and diagnostic biomarkers are lacking. Cerebrospinal fluid (CSF) is an accessible body fluid that comes into direct contact with the central nervous system (CNS) and acts as a nuclease-free repository where RNA transcripts shed by brain tissues can reside for extended periods of time.
Objective: We studied the RNA species present in the CSF of PD patients to identify novel diagnostic biomarkers.
Methods: Small volumes of CSF from 27 PD patients and 30 healthy age- and sex-matched controls were used for RNA extraction followed by next-generation sequencing (RNA-seq) using the Illumina platform. CSF contains a number of fragmented RNA species that were individually sequenced and analyzed. Comparing PD to control subjects, we observed a pool of dysregulated sequencing tags that were further analyzed and validated by quantitative real-time PCR (qRT-PCR).
Results: A total of 201 differentially expressed sequencing tags (DETs), including 92 up-regulated and 109 down-regulated DETs were identified. We validated the following DETs by real time PCR in the patient samples: Dnmt1, Ezh2, CCR3, SSTR5,PTPRC, UBC, NDUFV2, BMP7, SCN9, SCN9 antisense ({"type":"entrez-nucleotide","attrs":{"text":"AC010127.3","term_id":"6139286","term_text":"AC010127.3"}}AC010127.3), and long noncoding RNAs {"type":"entrez-nucleotide","attrs":{"text":"AC079630","term_id":"12643010","term_text":"AC079630"}}AC079630 and UC001lva.4 (close to the LRRK2 gene locus), as potential PD biomarkers.
Conclusions: The CSF is a unique environment that contains many species of RNA. Our work demonstrates that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes.
TL;DR: A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits in Parkinson's disease.
Abstract: Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23rd, 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized.
TL;DR: A custom-designed smartphone application that quantitatively measures hand dexterity can give an indication of a patient's overall motor function and demonstrated satisfactory repeatability and validity when measured against MDS-UPDRS-III.
Abstract: BACKGROUND: Measurement of motor function is critical to the assessment and management of Parkinson's disease. Ambulatory motor assessment has the potential to provide a glimpse of the patient's clinical state beyond the consultation. We custom-designed a smartphone application that quantitatively measures hand dexterity and hypothesized that this can give an indication of a patient's overall motor function. OBJECTIVE: The aims of this study were to (i) validate this smartphone application against MDS-UPDRS motor assessment (MDS-UPDRS-III) and the two-target tapping test; (ii) generate a prediction model for MDS-UPDRS-III; (iii) assess repeatability of our smartphone application and (iv) examine compliance and user-satisfaction of this application. METHODS: 103 patients with Parkinson's disease were recruited from two movement disorders clinics. After initial assessment, a group of patients underwent repeat assessment within two weeks. Patients were invited to use the smartphone application at home over three days, followed by a survey to assess their experience. RESULTS: Significant correlation between key smartphone application test parameters and MDS-UPDRS-III (r = 0.281-0.608, p CONCLUSIONS: Our smartphone application demonstrated satisfactory repeatability and validity when measured against MDS-UPDRS-III. Its performance is acceptable considering our smartphone application measures hand dexterity only. Language: en
TL;DR: It is shown that methods designed to decrease PrP prion infectivity neither effectively remove α-synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency.
Abstract: Background: Preformed α-synuclein fibrils seed the aggregation of soluble α-synuclein in cultured cells and in vivo. This, and other findings, has kindled the idea that α-synuclein fibrils possess prion-like properties.
Objective: As α-synuclein fibrils should not be considered as innocuous, there is a need for decontamination and inactivation procedures for laboratory benches and non-disposable laboratory material.
Methods: We assessed the effectiveness of different procedures designed to disassemble α-synuclein fibrils and reduce their infectivity. We examined different commercially available detergents to remove α-synuclein assemblies adsorbed on materials that are not disposable and that are most found in laboratories (e.g. plastic, glass, aluminum or stainless steel surfaces).
Results: We show that methods designed to decrease PrP prion infectivity neither effectively remove α-synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency. In contrast, both commercial detergents and SDS detached α-synuclein assemblies from contaminated surfaces and disassembled the fibrils.
Conclusions: We describe three cleaning procedures that effectively remove and disassemble α-synuclein seeds. The methods rely on the use of detergents that are compatible with most non-disposable tools in a laboratory. The procedures are easy to implement and significantly decrease any potential risks associated to handling α-synuclein assemblies.
TL;DR: Long-term, open-label treatment with droxidopa for up to 12 months was generally well tolerated and provided durable improvements in nOH signs and symptoms.
Abstract: Background Neurogenic orthostatic hypotension (nOH) is associated with insufficient norepinephrine release in response to postural change. Objective The objective of this study was to evaluate the long-term safety and durability of efficacy of the norepinephrine precursor droxidopa in patients with symptomatic nOH. Methods This multinational study consisted of 3 sequential phases: a 3-month open-label droxidopa treatment phase followed by a 2-week double-blind, placebo-controlled withdrawal phase, and a 9-month open-label extension phase in which all patients received droxidopa. Patients were adults diagnosed with symptomatic nOH associated with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine β-hydroxylase deficiency, or nondiabetic autonomic neuropathy. Efficacy was evaluated using patient- and investigator-reported questionnaire responses and the orthostatic standing test. Safety was assessed through adverse event (AE) reports and vital signs. Results A total of 102 patients received treatment with droxidopa. Initial improvements from baseline in patient-reported nOH symptom severity and impact on daily activities, evaluated using the Orthostatic Hypotension Questionnaire, exceeded 50% and were maintained throughout the 12-month study. Decreased nOH severity was also reflected in clinician and patient ratings on the Clinical Global Impression questionnaire. Standing systolic and diastolic blood pressures were increased from baseline throughout the study with droxidopa treatment. The most frequently reported AEs were falls, urinary tract infection, and headache. There was a low incidence (≤2%) of cardiac AEs (eg, first-degree atrioventricular block, supraventricular extrasystoles). Conclusions Long-term, open-label treatment with droxidopa for up to 12 months was generally well tolerated and provided durable improvements in nOH signs and symptoms.
TL;DR: Singing may benefit the speech of people with PD, although evidence is not unequivocal and further research is required to assess wider benefits including on functional communication, cognitive status, motor function and quality of life.
Abstract: Acknowledgements This study was not supported by any particular grant or funding source. The senior author MSB, an epidemiologist with research experience in PD, wishes to thank clinician authors JB, RAA and SMB for their invaluable contributions. JB is a retired health professional with long-standing experience in community health. RAA and SMB are qualified and practising speech and language therapists and RAA specialises in adult neurological disorders. Additionally, we thank Dr Katherine Deane of the University of East Anglia for expert input regarding the Threats to Validity quality tool, on which she was the lead developer.
TL;DR: This clinical trial aimed at exploring patients' own perceptions of the impact of DBS on their daily living and found it to be consistent with previous studies.
Abstract: Background: Deep brain stimulation (DBS) is an established treatment for Parkinson's disease. However, patients' own perceptions of the impact of DBS on their daily living is not fully explored. Ob ...
TL;DR: Remote monitoring technologies can capture motor features that may be clinically useful in identifying patients who may be candidates for advanced therapy, which could lead to development of automated screening algorithms, improve referral efficiency, and expand access to advanced therapies for patients with advanced PD.
Abstract: Background: Advanced therapies, such as deep brain stimulation and levodopa-carbidopa intestinal gel, can significantly improve quality of life in advanced Parkinson’s disease (PD). However, determining who should be referred for advanced therapy is a challenging problem. Objective: The objective was to determine the impact of remote monitoring using objective, wearable sensors on the advanced therapy referral rate in patients with advanced PD and if sensor data differed in patients who were referred and those who were not. Methods: A retrospective, exploratory, secondary analysis was performed on data collected in a study that followed forty individuals with advanced PD for one year with half receiving standard care and half using motion sensor-based remote monitoring once per month in conjunction with standard care. Advanced therapy referral rates were compared between groups. For the group who underwent remote monitoring, objective motor features representing symptoms, dyskinesias, and fluctuations were examined to determine if objective kinematic features differed between patients who were and were not recommended for advanced therapy. Results: The advanced therapy referral rate was significantly higher for patients when a clinician had access to remote monitoring reports compared to standard care alone (63.6% versus 11.8%, p < 0.01). Bradykinesia severity, bradykinesia fluctuations, and dyskinesia severity differed significantly (p < 10e-8, p < 10e-5, and p < 0.01, respectively) between patients recommended and not recommended for advanced therapy. Conclusions: Remote monitoring technologies can capture motor features that may be clinically useful in identifying patients who may be candidates for advanced therapy. This could lead to development of automated screening algorithms, improve referral efficiency, and expand access to advanced therapies for patients with advanced PD.
TL;DR: Apathy was associated with greater levels of atrophy in the frontal and temporal cortex, and anterior cingulate, as well as overall lower level of cognitive performance, particularly in executive function and memory skills.
Abstract: BACKGROUND: Apathy is one of the most common neuropsychiatric symptoms in Parkinson's disease (PD). Few studies have investigated the cognitive and neuroanatomical correlates of apathy in PD, and those which have done so have not controlled for the presence of other neuropsychiatric comorbidities. OBJECTIVE: To explore the cognitive and neuroanatomical correlates of apathy in PD at a mild disease stage. METHODS: Sixty-five PD patients and 24 healthy controls participated in this study. Patients underwent extensive neuropsychological screening, neuropsychiatric assessment using the Neuropsychiatric Inventory, structural MRI scanning, and neurological examination. A voxel-based multiple regression analysis was used to assess the relationship between grey matter volumes and apathy scores. RESULTS: Higher apathy scores correlated with lower grey matter volume in several brain areas including the left insula, left inferior/middle/medial frontal gyrus, right anterior cingulate, and the left superior temporal gyrus. Significant impairments were found in tests assessing executive functions, and a trend-level significant difference was observed in long term memory tests in patients with apathy, when compared with patients without apathy. CONCLUSIONS: Apathy was associated with greater levels of atrophy in the frontal and temporal cortex, and anterior cingulate, as well as overall lower level of cognitive performance, particularly in executive function and memory skills. Apathy appears to be associated with cognitive impairments in PD, therefore, treatment of this symptom might mitigate its effects on cognitive performance in this clinical population.
TL;DR: This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues.
Abstract: Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (ie different disease stages and/or clinical subtypes), experimental designs (ie cross-sectional vs longitudinal), and image analysis methodologies (ie automatic vs manual segmentation) This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues
TL;DR: The findings suggest that the experience of facial masking is negatively associated with social wellbeing particularly for the CPs, and especially so for the quality of CPs interpersonal relationship with their partner with PD.
Abstract: BACKGROUND Though hypomimia, also called facial masking, is experienced by many people with Parkinson's disease (PD), little is known about how the experience of this motor impairment relates to their own and their care partners' (CP) social life and relationship quality. OBJECTIVE To test if the experience of facial masking relates to social wellbeing in people with PD and their CPs. METHOD Forty individuals with PD and their CPs rated PD's difficulty showing facial expression (facial masking), and completed questionnaires about their own social wellbeing and depression. RESULTS PD-reported and CP-reported facial masking of PD were positively correlated with experience of social rejection in both partners, though this relationship was diminished when controlling for depression. CPs' rating of their partner's facial masking was negatively associated with enjoyment interacting with their partner. This relationship remained when controlling for CP and PD depression. CONCLUSIONS The findings suggest that the experience of facial masking is negatively associated with social wellbeing particularly for the CPs, and especially so for the quality of CPs interpersonal relationship with their partner with PD.
TL;DR: A report in the current issue on clinical and biochemical findings from a safety trial using the cAbl tyrosine kinase inhibitor Nilotinib in a small group of patients with either advanced Parkinson’s disease or Dementia with Lewy Bodies suggests a possible benefit on motor and cognitive outcomes.
Abstract: We discuss a report in the current issue on clinical and biochemical findings from a safety trial using the cAbl tyrosine kinase inhibitor Nilotinib (150 mg or 300 mg given daily for 24 weeks) in a small group of patients with either advanced Parkinson's disease or Dementia with Lewy Bodies. Despite some side effects (one serious), the authors claim that Nilotinib, which is normally used at much higher doses for treating leukemia, is safe and tolerated. Furthermore, they report a possible benefit on motor and cognitive outcomes. We debate the safety of Nilotinib and the reported efficacy signals. We emphasize that due to the small sample size, and lack of a control group, it is impossible to rule out a placebo effect. We briefly discuss a range of aspects surrounding the current and possible future use of this cAbl inhibitor in patients with alpha-synucleinopathy, and what must now be done to obtain definitive information about its safety and efficacy in this population of patients.
TL;DR: This study shows the main impact of mood symptoms and non-motor fluctuations on worsening quality of life in PD.
Abstract: Background Mood symptoms negatively affect quality of life of Parkinson's disease (PD); however little is known about the impact of behavioral disorders such as impulse control disorders, and non-motor fluctuations on quality of life. Objective To assess the impact of mood and behavioral disorders on quality of life in PD. Methods 136 (84% male) PD were included (mean age: 61 ± 8y; mean duration of disease: 8.8 ± 5.4y). Mood symptoms, behavioral disorders and non-motor fluctuations were detected and quantified using the recently validated "Ardouin Scale of Behavior in Parkinson's Disease". Motor symptoms were assessed using UPDRS and quality of life with the "39-item Parkinson's Disease Questionnaire". Results Both motor and non-motor factors significantly affected the quality of life of PD patients. Multivariate regression of the relationship between items of the quality of life questionnaire and the Ardouin Scale showed that alteration of patients' quality of life was strongly correlated with the presence of mood symptoms (such as depression, anxiety ...) and with non-motor fluctuations (especially in the OFF period). A significant correlation was also found between the number of symptoms and their severity, and the quality of life deterioration. Some behavioral disorders (compulsive buying / eating behavior) also negatively affected patient's quality of life to a lesser extent. Alternatively, excess in motivation and hobbyism behaviors had a positive impact on mobility and emotional well-being dimensions respectively of quality of life. Conclusions This study shows the main impact of mood symptoms and non-motor fluctuations on worsening quality of life in PD.
TL;DR: STN-DBS in early PD reduced medication cost over the two-year study period and may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen.
Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson’s disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT).
Objective: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs.
Methods: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS.
Results: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p < 0.05; OR = 0.2; 95% CI: 0.04–0.97).
Conclusions: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD.