Journal of Parkinson's Disease - Volume 6, issue 1

Authors: Tagliaferro, Patricia | Burke, Robert E.

Article Type: Review Article

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. Show more

Keywords: Axons, neurodegeneration, autophagy, Wallerian degeneration

DOI: 10.3233/JPD-150769

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 1-15, 2016

Authors: Martin, Ian

Article Type: Review Article

Abstract: Mutations in a number of genes cause rare familial forms of Parkinson’s disease and provide profound insight into potential mechanisms governing disease pathogenesis. Recently, a role for translation and metabolism of mRNA has emerged in the development of various neurodegenerative disorders including Parkinson’s disease (PD). In PD, preliminary evidence supports a role for aberrant translation in the disease process stemming from mutations in several genes. Translation control is central to maintaining organism homeostasis under variable environmental conditions and deregulation of this may predispose to certain stressors. Hypothetically, deregulated translation may be detrimental to neuronal viability in PD through the misexpression …of a subset of transcripts or through the impact of excessive bulk translation on energy consumption and burden on protein homeostatic mechanisms. While compelling preliminary evidence exists to support a role for translation in PD, much more work is required to identify specific mechanisms linking altered translation to the disease process. Show more

DOI: 10.3233/JPD-150738

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 17-27, 2016

Authors: Rimmelzwaan, Lisanne M. | van Schoor, Natasja M. | Lips, Paul | Berendse, Henk W. | Eekhoff, Elisabeth M.W.

Article Type: Review Article

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. Show more

Keywords: Vitamin D, Parkinson’s disease

DOI: 10.3233/JPD-150615

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 29-37, 2016

Authors: Oueslati, Abid

Article Type: Review Article

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 (<4%) is phosphorylated in healthy brains, a dramatic accumulation of pS129 (>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. Show more

Keywords: Phosphorylation, kinases, membrane binding, degradation, subcellular localization, biomarker, toxicity, animal models, cell-based assays

DOI: 10.3233/JPD-160779

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 39-51, 2016

Authors: Molenaar, Joery P. | Wilbers, Joyce | Aerts, Marjolein B. | Leijten, Quinten H. | van Dijk, Jan G. | Esselink, Rianne A. | Bloem, Bastiaan R.

Article Type: Short Communication

Abstract: We present a 75-year-old woman with dementia and parkinsonism who developed severe orthostatic hypotension and eventually died. Autopsy revealed extensive Lewy body formation in the midbrain, limbic system, intermediate spinal cord, and medulla oblongata. Furthermore, a vast amount of Lewy bodies was seen in the paravertebral sympathetic ganglia which likely explained the severe autonomic failure. We speculate that this autonomic failure caused sudden death through dysregulation of respiration or heart rhythm, reminiscent of sudden death in multiple system atrophy (MSA). Clinicians should be aware of this complication in patients presenting with parkinsonism and autonomic dysfunction, and that sudden death may …occur in dementia with Lewy bodies (DLB) as it does in MSA. Show more

Keywords: [28] Dementia with Lewy bodies, [1] autonomic diseases, [172] multiple system atrophy, sudden death

DOI: 10.3233/JPD-150755

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 53-55, 2016

Authors: Barker, Roger A. | Parmar, Malin | Kirkeby, Agnete | Björklund, Anders | Thompson, Lachlan | Brundin, Patrik

Article Type: Article Commentary

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. Show more

DOI: 10.3233/JPD-160798

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 57-63, 2016

Authors: Stamford, Jon | Scheller, Dieter | Jenner, Peter

Article Type: Article Commentary

DOI: 10.3233/JPD-160792

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 65-66, 2016

Authors: Stenberg, Georg

Article Type: Research Article

Abstract: The group Parkinson Inside Out is composed of health professionals and academic researchers who have been diagnosed with Parkinson’s Disease. In our discussions we try to make use of both our inside perspective as patients, and our outside perspective as professionals. In this paper, we apply the two perspectives to the Impulse Control Disorders. These impulsive behaviour patterns are thought to be relatively uncommon side effects of some of the medication used in dopamine replacement therapy. The phenomenon is usually described as relatively rare (<15%), and mainly confined to patients with special vulnerabilities. In contrast, we propose that having some …problems with controlling impulses is a very common experience for patients undergoing dopamine replacement therapy. They result from difficulties in decision making engendered by variations in dopamine accessibility in the reward centre of the brain. Only in a minority do the consequences grow to the damaging proportions of a disorder, but most patients are probably affected to some degree. Seeing, and measuring, decision difficulties as a continuous dimension, rather than as a discrete category, brings increased possibilities for early detection and continuous monitoring. With reliable measures of the propensity for impulsive decision making, it may become possible to both reap the benefits and avoid the dangers of the dopamine agonists. We point to ways of empirically testing our continuity hypothesis. Show more

Keywords: Parkinson’s disease, impulse control disorders, dopamine agonists, impulsivity

DOI: 10.3233/JPD-150770

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 67-75, 2016

Authors: Chu, Yaping | Morfini, Gerardo A. | Kordower, Jeffrey H.

Article Type: Research Article

Abstract: Background: Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and neuronal survival. It is possible that intracellular alpha-synuclein (α -syn) inclusions may be due to, or may cause, down-regulation of ADNP expression. Objective: This study were to determine whether ADNP protein levels are altered in nigral dopaminergic neurons, establish whether ADNP alterations are associated with α -syn accumulation, and evaluate potential correlations between levels of ADNP expression and axonal transport motor proteins in sporadic and experimental Parkinson’s disease (PD). Methods: Twenty human brains from PD (n  = 12) and age-matched controls (n  = 8) and sixteen …rat brains received α -synuclein gene (n  = 8) or empty vector (n  = 8) were analyzed using immunohistochemistry. The number of ADNP labeled nigral neurons were estimated with stereology and the levels of ADNP were determined using densitometry. Results: Compared to age-matched controls, a marked reduction in ADNP protein levels was observed in neuromelanin-containing nigral neurons of PD. Reduced ADNP levels did no relate to the progression of PD symptoms, but instead occurred at early PD stages, before reductions in tyrosine hydroxylase could be detected. Reductions in ADNP were also positively correlated with alterations in axonal transport motor protein. Reductions in ADNP levels were recapitulated in a rat model of PD based on viral over-expression of human wild-type α -synuclein, suggesting that ADNP reductions in PD are a direct result of α -synuclein overexpression. Conclusion: These findings demonstrate that the down-regulation of protein ADNP is an early pathological alteration and may contribute to dopaminergic neurodegeneration in PD. Show more

Keywords: Activity-dependent neuroprotective protein, axonal transport, synucleinopathy, Parkinson’s disease

DOI: 10.3233/JPD-160812

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 77-97, 2016

Authors: Lindqvist, Daniel | Prokopenko, Inga | Londos, Elisabet | Middleton, Lefkos | Hansson, Oskar

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction has been implicated in the pathophysiology of Parkinson’s disease (PD)-related pathologies. Objective: To investigate the role of the Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) variants in PD without dementia (PDND), PD with dementia (PDD) and in Dementia with Lewy bodies (DLB). Methods: 248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included. The rs10524523 locus in the TOMM40 gene (TOMM40 poly-T repeat) is characterized by a variable number of T residues that were classified into three groups based on length; short (S), long (L), …and very long (VL). We tested log-additive genetic model of association with dementia and adjusted for age, sex, and APOE ɛ 4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Aβ 42 and Tau, biomarkers related to Alzheimer’s disease (AD). Results: PDD/DBL status and abnormal CSF AD biomarkers (Aβ 42 and Aβ 42 /Tau ratio) were both associated with the APOE ɛ 4 allele (p  <  0.014) and the L allele of TOMM40 poly-T repeat (p  <  0.008). The VL allele was less frequently observed in the PDD/DLB group (p  = 0.013). In APOE -ɛ 4 adjusted analyses, the relationships between the L and VL alleles and dementia status as well as CSF AD biomarkers were not significant. When adjusting for APOE -ɛ 4, however, there were associations between S carrier status and PDD/DLB (p  = 0.019) and abnormal CSF levels of Aβ 42 /Tau ratio (p  = 0.037) although these were not significant after adjustment for multiple comparisons. Conclusion: Our results do not support the notion that TOMM40 poly-T repeat variants have independent effects on PDD and DLB pathology. This relationship seems to be driven by APOE -ɛ 4. Show more

Keywords: PDD, DLB, TOMM40 , APOE, Parkinson’s disease

DOI: 10.3233/JPD-150693

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 99-108, 2016

Authors: Hossein-nezhad, Arash | Fatemi, Roya Pedram | Ahmad, Rili | Peskind, Elaine R. | Zabetian, Cyrus P. | Hu, Shu-Ching | Shi, Min | Wahlestedt, Claes | Zhang, Jing | Faghihi, Mohammad Ali

Article Type: Research Article

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 (AC010127.3 ), and long noncoding RNAs 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. Show more

Keywords: Parkinson disease, RNA sequencing, cerebrospinal fluid, biomarkers, long noncoding RNA

DOI: 10.3233/JPD-150737

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 109-117, 2016

Authors: Barrett, Matthew J. | Koeppel, Alexander F. | Flanigan, Joseph L. | Turner, Stephen D. | Worrall, Bradford B.

Article Type: Research Article

Abstract: Background: Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. Objective: The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Methods: Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we …selected SNPs for genes associated with AD other than APOE . We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. Results: In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects >  70 years old (OR = 2.3; adjusted p -value = 0.017; n  = 250) but not in PD subjects≤70 years old. Conclusions: Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD. Show more

Keywords: Parkinson disease, mild cognitive impairment, dementia, Alzheimer disease, genetics

DOI: 10.3233/JPD-150706

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 119-124, 2016

Authors: Hacker, Mallory L. | Currie, Amanda D. | Molinari, Anna L. | Turchan, Maxim | Millan, Sarah M. | Heusinkveld, Lauren E. | Roach, Jonathon | Konrad, Peter E. | Davis, Thomas L. | Neimat, Joseph S. | Phibbs, Fenna T. | Hedera, Peter | Byrne, Daniel W. | Charles, David

Article Type: Research Article

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. Show more

Keywords: Parkinson’s disease, deep brain stimulation, subthalamic nucleus, medication cost, cost, cost analysis, health economics

DOI: 10.3233/JPD-150712

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 125-131, 2016

Authors: Lamberti, Valérie M.J. | Pereira, Bruno | Lhommée, Eugénie | Bichon, Amélie | Schmitt, Emmanuelle | Pelissier, Pierre | Kistner, Andrea | Fraix, Valérie | Castrioto, Anna | Esselink, Rianne A. J. | Durif, Frank | Krack, Paul

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson’s disease (PD) and motor complications of dopaminergic treatment. Whether STN-DBS should be considered when PD patients experience neuropsychiatric symptoms is controversial. Lack of systematic behavioral evaluation at baseline hampers the understanding of postoperative neuropsychiatric outcomes. Objective: This study compares the behavioral profile of a surgical population to that in general PD. Methods: Single center data from 234 PD surgical candidates were compared to data from 260 non-demented PD patients consulting in 13 PD expert centers at different stages of disease. The latter were …considered representative of the general PD population. Neuropsychiatric symptoms were assessed using the Ardouin Scale of Behavior in PD, a guided interview quantifying changes in severity of 21 neuropsychiatric symptoms, classified into psychic non-motor fluctuations, hypo- and hyperdopaminergic behaviors. Multivariate analyses were performed to study differences in behavioral items between the two groups. Results: Surgical candidates were younger, had longer disease duration and used significantly higher doses of dopaminergic drugs. After adjustment for covariates, dopaminergic addiction (OR 10.83; p  = 0.002), nocturnal hyperactivity (OR 1.87; p  = 0.04), excessive hobbyism (OR 2.37; p  = 0.008), “excess in motivation” (OR 4.02; p  <  0.001), psychic OFF (2.87; p  <  0.001) and psychic ON (2.10; p  = 0.001) fluctuations were more frequent in the surgical candidates. Depressed mood prevailed in the general PD population (OR 0.53; p  = 0.045). Conclusion: Behavioral complications of dopaminergic treatment are frequent in PD patients candidates for STN-DBS. They cannot be considered as contraindications for STN-DBS but must be taken into account in postoperative management. Show more

Keywords: Parkinson disease, subthalamic nucleus, deep brain stimulation, dopamine, impulse control disorders

DOI: 10.3233/JPD-150698

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 133-142, 2016

Authors: Bousset, Luc | Brundin, Patrik | Böckmann, Anja | Meier, Beat | Melki, Ronald

Article Type: Research Article

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. Show more

Keywords: Alpha synuclein, cleaning procedures, detergent, fibrils, inactivation, Parkinson’s disease, removal

DOI: 10.3233/JPD-150691

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 143-151, 2016

Authors: Beach, Thomas G. | Adler, Charles H. | Serrano, Geidy | Sue, Lucia I. | Walker, D.G. | Dugger, Brittany N. | Shill, Holly A. | Driver-Dunckley, Erika | Caviness, John N. | Intorcia, Anthony | Filon, Jessica | Scott, Sarah | Garcia, Angelica | Hoffman, Brittany | Belden, Christine M. | Davis, Kathryn J. | Sabbagh, Marwan N.

Article Type: Research Article

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. Show more

Keywords: Biopsy, diagnosis, clinical trial, biomarker, pathology, therapy

DOI: 10.3233/JPD-150680

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 153-163, 2016

Authors: Cattaneo, Carlo | Sardina, Marco | Bonizzoni, Ermino

Article Type: Research Article

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. Show more

Keywords: Parkinson’s disease, safinamide, levodopa, MAO-B inhibitor, motor fluctuations, glutamate, adjunct therapy

DOI: 10.3233/JPD-150700

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 165-173, 2016

Authors: Hiorth, Ylva Hivand | Larsen, Jan Petter | Lode, Kirsten | Tysnes, Ole-Bjørn | Godfrey, Alan | Lord, Sue | Rochester, Lynn | Pedersen, Kenn Freddy

Article Type: Research Article

Abstract: Background: A complex relationship exists between motor impairment, physical activity (sedentary behavior, standing and ambulatory activity) and falls in people with Parkinson’s disease (PD). Objective: To explore associations between recent fall history and the ability to retain an active lifestyle as determined by the volume, pattern and variability of physical activity in people with PD. Methods: Forty-eight participants with PD were recruited from the Norwegian ParkWest study. Body posture and ambulatory activity were monitored objectively over 7 days using the activPAL3 TM accelerometer. Clinical assessments included the Hoehn and Yahr stage, Unified Parkinson’s Disease Rating …Scale motor section and Falls Efficacy Scale-International. Structured interviews were performed to obtain information about demographics, fall history last 6 months, mobility and dementia. Results: Participants with a fall history (n  = 20) spent more time sedentary and less time standing than non-falling participants (n  = 28). There were no significant differences regarding pattern or variability of sedentary behavior, standing or ambulatory activity in falling versus non-falling participants. Confidence in being able to get up from floor contributed significantly to time spent in sedentary behavior and ambulatory activity in participants with fall history, whereas motor impairment was significantly associated with time spent in all facets of physical activity for non-falling participants. Conclusions: Fall history in our PD cohort was associated with a more sedentary lifestyle, but not less ambulatory activity. More emphasis on improving the capacity to safely complete activities of daily living and increase confidence in getting up from floor may reduce sedentary behavior in people with PD. Show more

Keywords: Parkinson’s disease, falls, accelerometer, physical activity, sedentary behavior, ambulation

DOI: 10.3233/JPD-150640

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 175-182, 2016

Authors: Rodríguez-Violante, Mayela | de Saráchaga, Adib Jorge | Cervantes-Arriaga, Amin | Millán-Cepeda, Roxanna | Leal-Ortega, Roberto | Estrada-Bellmann, Ingrid | Zuñiga-Ramírez, Carlos

Article Type: Research Article

Abstract: Background: Parkinson’s disease is characterized by motor and non-motor clinical features. The latter may present as pre-motor symptoms several years before the motor onset. Objective: To analyze the association between pre-motor symptoms load and its lead-time in relation to the motor onset and time to diagnosis. Methods: A cross-sectional study was carried including subjects with Parkinson’s disease from five different movement disorders clinics in Mexico. A structured questionnaire was applied to assess the presence of six self-perceived pre-motor symptoms (hyposmia, depression, anxiety, constipation, pain and sleep disorders). Results: Overall frequency of pre-motor symptoms …was 76.2% . Among the most prevalent symptoms were depression (38%), sleep disorders (37%) and anxiety (36.6%). The lead time to motor onset was greater for constipation (9.2±17.89 years) and pain (8.66±13.36 years). Patients with more than two pre-motor symptoms had a later age at motor onset when compared to patients without pre-motor symptoms (52.04±13.11 vs 56.55±12.97 years, p  = 0.037). Late onset patients had a higher frequency of pre-motor symptoms (79% vs 65% in early onset, p  = 0.002) and a higher load (1.75±1.37 vs 1.44±1.38, p  = 0.033) in comparison to those with early onset. Female subjects reported a higher number of pre-motor symptoms (1.91±1.43 versus 1.48±1.29, p ≤0.001). PIGD patients reported a greater frequency of pain (8%) compared to tremor (1%, p  = 0.0064) and bradykinetic-rigid (0.61%, p  = 0.0061). Anxiety lead-time was greater in tremor-dominant (10.83±15.77 years) compared to bradykinetic-rigid patients (3.48±12.56, p  = 0.014). Conclusions: Pre-motor symptoms load is associated to a later motor onset of PD. Pre-motor symptoms are more frequent in subjects with late onset Parkinson’s disease. Female subjects report a higher number of pre-motor symptoms, depression and anxiety being the most common. Show more

Keywords: Parkinson’s disease, pre-motor symptoms, non-motor symptoms, motor onset

DOI: 10.3233/JPD-150705

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 183-190, 2016

Authors: Sorrentino, Pierpaolo | Barbato, Antonio | Del Gaudio, Luigi | Rucco, Rosaria | Varriale, Pasquale | Sibilio, Michelina | Strazzullo, Pasquale | Sorrentino, Giuseppe | Agosti, Valeria

Article Type: Research Article

Abstract: Type 1 Gaucher’s disease (GD1) is traditionally regarded as “non-neurological”. Spatiotemporal and kinematic analysis of gait was carried on thirteen GD1 patients and thirteen healthy controls. We identified a previously unknown subclinical reduction of amplitude of movements in GD1. Articular excursion of ankle, knee and hip was reduced during the swing phase of gait (p  <  0.0001). Furthermore, the excursion of the knee appeared also significantly more asymmetric in GD1 patients (p  = 0.02). Correction for age, BMI and basal walking speed did not modify the significance. Accordingly to the recent observations that GD1 predisposes to Parkinson’s disease, the impaired and …asymmetric gait kinematics that we observed might be interpreted as a form of extrapyramidal involvement. Show more

Keywords: Gaucher’s disease, gait analysis, joint excursion, extrapyramidal system, Parkinson disease, parkinsonism

DOI: 10.3233/JPD-150660

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 191-195, 2016

Authors: Jones, Corinne A. | Ciucci, Michelle R.

Article Type: Research Article

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. Objective: We used predictive modeling to determine what quantitative swallowing variables best differentiate individuals with early to mid-stage PD from healthy controls. Methods: Participants included twenty-six individuals with early to mid-stage PD and 26 healthy, age- and sex-matched controls. Swallowing was evaluated by simultaneous high-resolution manometry and …videofluoroscopy as well as the Sydney Swallow Questionnaire (SSQ). Binomial logistic regression was performed on 4 sets of data: 1) high-resolution manometry only; 2) videofluoroscopy only; 3) SSQ only; and 4) all data combined. Results: A model from a combined data set had the highest accuracy in differentiating individuals with PD from controls. The model included maximum pressure in the velopharynx (soft palate), pressure variability in the velopharynx, and the SSQ item concerning difficulty with swallowing saliva. No significant models could be generated using the videofluoroscopy data. Conclusions: 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. A multimodal approach for the assessment of swallowing may be more accurate for determining subtle swallowing changes that occur in the early stages of PD. Show more

Keywords: Parkinson disease, deglutition, high-resolution manometry, videofluoroscopy

DOI: 10.3233/JPD-150687

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 197-208, 2016

Authors: Murakami, Hidetomo | Momma, Yutaro | Nohara, Tetsuhito | Mori, Yukiko | Futamura, Akinori | Sugita, Toshihisa | Ishigaki, Seiichiro | Katoh, Hirotaka | Kezuka, Machiko | Ono, Kenjiro | Miller, Michael W. | Kawamura, Mitsuru

Article Type: Research Article

Abstract: Background: Dopaminergic drugs, the gold standard for motor symptoms, are known to affect cognitive function in Parkinson’s disease (PD) patients. Objective: We compared the effects of dopaminergic treatment on motor and cognitive function in drug-naïve patients. Methods: Dopaminergic medication (levodopa, dopamine agonist, selegiline) was given to 27 drug-naïve PD patients and increased to a dose optimal for improved motor symptoms. Patients were tested prior to, and 4–7 months after, drug initiation. Motor function was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). Cognitive function was assessed using both the Japanese version of the Montreal …Cognitive Assessment (MoCA-J) and the Neurobehavioral Cognitive Status Examination (COGNISTAT-J). Improvements from baseline for both motor and cognitive assessment were compared. Results: Mean score of all motor assessments (UPDRS total score of Parts II and III, and sub-scores of tremor, rigidity, bradykinesia, gait, and postural instability) and certain cognitive assessments (MoCA-J total score and subscore of delayed recall) significantly improved with dopaminergic medication. Gait score improvement showed significant positive correlation with improvement in MoCA-J language domain and in language-comprehension subtests of COGNISTAT-J using Spearman’s correlation coefficients. Furthermore, multiple regression analysis showed gait score improvement significantly correlated with improvements in the subtests of language-comprehension in COGNISTAT-J. Conclusion: There is correlated improvement in both gait and language function in de novo PD patients in response to dopaminergic drugs. Gait and language dysfunction in these patients may share a common pathophysiology linked to dopamine deficits. Show more

Keywords: Parkinson’s disease, cognition, executive function, language, verbal fluency disorders, working memory, gait

DOI: 10.3233/JPD-150702

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 209-217, 2016

Authors: Martens, Heidi | Van Nuffelen, Gwen | Wouters, Kristien | De Bodt, Marc

Article Type: Research Article

Abstract: Background: Mapping adequacy of receptive prosodic abilities in speakers with hypokinetic dysarthria due to Parkinson’s disease (PD) is useful, because therapy of disturbed production of prosody relies on adequate reception of prosody. There is evidence for a deficit of reception of emotional prosody in PD. Objective: The present study aims at presenting a comprehensive picture of the reception of various communicative functions of prosody in hypokinetic dysarthria due to PD. Methods: We assessed perception (using a discrimination task) and comprehension (using an identification task) of five communicative functions of Dutch prosody (lexical stress, boundary marking, …focus, sentence mode, and emotional prosody) in a group of adults with hypokinetic dysarthria due to PD (n  = 22) and a gender and age matched group of unimpaired adults (n  = 22). We also investigated the relationship between age and global test score, and the effect of perception and comprehension subtest sequence on the global test score. Results: Between groups, no significant differences in receptive prosodic abilities were found. Within both groups, the comprehension subtest was significantly more difficult than the perception subtest, and there was a significant negative correlation between age and global test score. No subtest sequence effect could be demonstrated. Conclusions: Considering that the older speakers with hypokinetic dysarthria due to PD had receptive prosodic skills inferior to those of the younger speakers, notwithstanding apparently intact cognition and hearing, the findings suggest that age is a factor to be reckoned with in prosody assessment and management in this population. Show more

Keywords: Parkinson’s disease, dysarthria, speech, perception, comprehension

DOI: 10.3233/JPD-150678

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 219-229, 2016

Authors: Jacobs, Marie L. | Dauvilliers, Yves | St. Louis, Erik K. | McCarter, Stuart J. | Romenets, Silvia Rios | Pelletier, Amélie | Cherif, Mahmoud | Gagnon, Jean-François | Postuma, Ronald B.

Article Type: Research Article

Abstract: Background: Numerous large-scale studies have found diverse risk factors for Parkinson’s disease (PD), including caffeine non-use, non-smoking, head injury, pesticide exposure, and family history. These studies assessed risk factors for PD overall; however, PD is a heterogeneous condition. One of the strongest identifiers of prognosis and disease subtype is the co-occurrence of rapid eye movement sleep behavior disorder (RBD). In previous studies, idiopathic RBD was associated with a different risk factor profile from PD and dementia with Lewy bodies, suggesting that the PD-RBD subtype may also have a different risk factor profile. Objective: To define risk …factors for PD in patients with or without associated RBD. Methods: In a questionnaire, we assessed risk factors for PD, including demographic, medical, environmental, and lifestyle variables of 189 PD patients with or without associated polysomnography-confirmed RBD. The risk profile of patients with vs. without RBD was assessed with logistic regression, adjusting for age, sex, and disease duration. Results: PD-RBD patients were more likely to have been a welder (OR = 3.11 (1.05–9.223), and to have been regular smokers (OR = 1.96 (1.04–3.68)). There were no differences in use of caffeine or alcohol, other occupations, pesticide exposure, rural living, or well water use. Patients with RBD had a higher prevalence of the combined family history of both dementia and parkinsonism (13.3% vs. 5.5% , OR = 3.28 (1.07–10.0). Conclusion: The RBD-specific subtype of PD may also have a different risk factor profile. Show more

Keywords: Parkinson’s disease, REM sleep behavior disorder, risk factors

DOI: 10.3233/JPD-150725

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 231-237, 2016

Authors: Canesi, Margherita | Rusconi, Maria Luisa | Moroni, Federica | Ranghetti, Alessandra | Cereda, Emanuele | Pezzoli, Gianni

Article Type: Research Article

Abstract: Background: An increase in artistic-like production in Parkinson’s disease (PD) has been associated with compulsive and repetitive behaviours after the introduction of dopaminergic treatment (DT). Recent data suggest that it could be due to the emergence of artistic-like skills triggered by DT. Objective: In order to evaluate whether artistic production and creative thinking are influenced by DT or linked to artistic-like skills, we characterize creativity features in PD and healthy controls (HC) including professional artists. Methods: Three groups of PD out-patients were included consecutively: professional artists (PD-A), patients with (PD-C) and without artistic-like production (PD-NC). …Twenty-four gender and age-matched HC were included: professional artists (HC-A) and non-artists (HC-NC). All patients were evaluated by means of a) a battery of neuropsychological tests and a semi-structured interview; b) the Abbreviated Torrance Test for Adults (ATTA) for creative thinking; c) the Minnesota Impulsive Disorders Interview (mMIDI) and a screening for impulse control disorders (ICDs) for compulsive behaviour. Results: ATTA total score was significantly higher in HC-A and PD-A than in the other groups. Although PD-NC showed the lowest ATTA total score the difference vs HC-NC was not significant. ATTA scores were not significantly correlated with DT dosage and duration. mMIDI tests were positive only in PD. There were no differences in ICDs among PD groups. Conclusions: Our results do not support a relationship between DT and the emergence of artistic creativity. We believe that DT may increase the drive to create and that further studies in “on” and “off” medication are needed to clarify this issue. Show more

Keywords: Creativity, professional artists, dopaminergic therapy, impulse control disorders, Parkinson phenotype

DOI: 10.3233/JPD-150681

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 239-246, 2016

Authors: Bhattacharjee, Sandipan | Goldstone, Lisa | Warholak, Terri

Article Type: Research Article

Abstract: Background: Elderly individuals with Parkinson’s disease (PD) generally suffer from more than one psychiatric comorbidity, which necessitates the use of concurrent psychotropic medications. To the best of the author’s knowledge there are no nationally representative estimates of psychotropic polypharmacy among elderly individuals with PD in the United States (US). Objective: Therefore, the primary objective of this study was to examine the prevalence, patterns and predictors of psychotropic polypharmacy among elderly individuals with PD in the (US). Methods: A retrospective, cross-sectional study design with 2004 National Nursing Home Survey (NNHS) and 2007 National Home and Hospice …Care Survey (NHHCS) data was used. The analytic sample included elderly (age ≥65 years) individuals with PD. Antidepressants, antipsychotics, sedative/hypnotics, and anti-anxiety medications constituted the psychotropic medication classes. Concurrent use of two or more psychotropic medications was classified as psychotropic polypharmacy. Results: Approximately 93,648 and 37,439 elderly individuals with PD resided in nursing homes and home health settings respectively. Among elderly nursing home residents with PD, the nationally representative prevalence of psychotropic polypharmacy was 26.28%, whereas, it was 21.36% in the home health setting. Use of antidepressant medications constituted the majority of the psychotropic medication use among both nursing home (48.91%) and home health (40.98%) residents with PD. Multiple logistic regression analyses revealed that specific comorbidities were significantly associated with psychotropic polypharmacy among elderly nursing home residents with PD. Conclusions: These findings underscore the importance of evidence-based prescribing when psychotropic medications are used in elderly individuals with PD to reduce unnecessary polypharmacy. Show more

Keywords: Parkinson’s disease, nursing homes, home health Care, psychotropic drugs, elderly

DOI: 10.3233/JPD-150646

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 247-255, 2016

Authors: Weintraut, Rita | Karádi, Kázmér | Lucza, Tivadar | Kovács, Márton | Makkos, Attila | Janszky, József | Kovács, Norbert

Article Type: Research Article

Abstract: Background: Apathy is a syndrome characterized primarily by lack of motivation which may be associated with cognitive, affective and behavioral changes. Although the Lille Apathy Scale (LARS) has been extensively utilized in PD for detecting apathy and testing the effectiveness of specific therapeutic interventions, the highly variable cut-off values (between –11 and –22 points) ensures the applicability of the LARS degree of difficulty as a superb screening tool. Objective: The aim of this study is to determine more reliable threshold values based on the neuropsychiatric status of patients. Methods: Depression was assessed utilizing the Montgomery-Asberg …Depression Rating Scale and neurocognitive status by Addenbrooke’s Cognitive Examination. The presence of apathy was assessed by the proposed diagnostic criteria of Drijgers et al, and graded by both LARS and the ‘Apathy’ item of MDS-UPDRS. Results: Based on multivariate regression analysis, we revealed the neurocognitive status, severity of depression, and also gender while applying dosage of dopamine agonists to determine the degree of patient apathy. Based on whether or not depression and neurocognitive disorders were indeed present, we established four different threshold values for the LARS: patients with normal cognition and without depression: –22.5; patients with normal cognition and with depression: –18.5; patients with NCD and without depression: –19.5; patients with NCD and with depression: –14.5. Conclusions: The LARS and the ‘Apathy’ item of MDS-UPDRS were confirmed to be potentially operational, beneficial and easy-to-assess instruments for detecting apathy syndrome in PD. However, there is no universal threshold value for the LARS suitable in all types of Parkinson’s patients. Show more

Keywords: Apathy, scale, threshold value, Parkinson’s disease, validation

DOI: 10.3233/JPD-150726

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 257-265, 2016

Authors: Rieu, Isabelle | Houeto, Jean Luc | Pereira, Bruno | De Chazeron, Ingrid | Bichon, Amélie | Chéreau, Isabelle | Ulla, Miguel | Brefel-Courbon, Christine | Ory-Magne, Fabienne | Dujardin, Kathy | Tison, François | Krack, Paul | Durif, Franck

Article Type: Research Article

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. Show more

Keywords: Parkinson’s disease, quality of life, impulse control disorders, mood disorders

DOI: 10.3233/JPD-150747

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 267-277, 2016