bluuebunny/crossref_metadata_2025 huggingface dataset:
Levodopa Fractionation in Parkinson's Disease
Authors: Nyholm Dag , Stepien Victoria
Published: December 2019

Background: Fractionation of daily levodopa dosage is one strategy to manage the almost inevitable development of symptom fluctuations in Parkinson's disease (PD). However, it is not known from the literature how levodopa fractionation is performed in routine clinical practice. Objective: The objective of this study was to capture how anti-parkinsonian medications were used, in particular how the daily dose was fractionated (defined as >4 doses/day). Methods: A pharmacoepidemiological study was undertaken at Uppsala University Hospital. Medical records of PD patients with ≥4 years' disease duration who visited the Neurology Clinic between January and October 2011 were retrospectively reviewed. Times to dose fractionation, to dyskinesias and to hallucinations were calculated using Kaplan-Meier analyses. Results: 175 patients (47% women) were included. Median age at PD onset was 63 years (range 36–83). Median disease duration was 9.0 years. Dose fractionation was used in 85% of patients. The median time to fractionation was 5.0 years. Patients developing dyskinesias had a significantly earlier age at onset than those who did not. Conclusions: Fractionation of levodopa dosage into >4 daily doses was common. It occurred when wearing-off of the levodopa response is expected to present, i.e. after 5 years in 50% of patients. The study highlights the importance of individualizing and frequently adjusting levodopa dosage, already from the initiation of therapy.
α-synuclein Imaging: A Critical Need for Parkinson's Disease Research
Authors: Eberling Jamie L. , Dave Kuldip D. , Frasier Mark A.
Published: December 2019

The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathology over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomography (PET) imaging studies. While this poses a number of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.
Spatiotemporal Parameters of Gait During Treadmill and Overground Walking in Parkinson's Disease
Authors: Bello Olalla , Sánchez José Andrés , Vazquez-Santos Cristina , Fernandez-Del-Olmo Miguel
Published: December 2019

Despite the increasing number of studies that have examined the therapeutic effect of treadmill training programs in Parkinson's disease (PD), there has been little research to evaluate the modifications of gait induced by treadmill walking. We investigated spatiotemporal differences between treadmill and overground walking in patients with PD. PD patients significantly increased their step length and step height; and reduced their cadence, step width and step width variability on the treadmill in comparison with walking overground. PD patients are able to attenuate their short shuffling steps when walking on a treadmill.
Droxidopa in Patients with Neurogenic Orthostatic Hypotension Associated with Parkinson's Disease (NOH306A)
Authors: Hauser Robert A. , Hewitt L. Arthur , Isaacson Stuart
Published: December 2019

Background: Neurogenic orthostatic hypotension (nOH) is common in Parkinson's disease (PD), and represents a failure to generate norepinephrine responses appropriate for postural change. Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an oral norepinephrine prodrug. Objective: Interim analyses of the initial patients enrolled in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of droxidopa for nOH in PD (ClinicalTrials.gov Identifier: NCT01176240). Methods: PD patients with documented nOH underwent ≤2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment (100–600 mg t.i.d.). The primary efficacy measure was change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to Week 8. Key secondary variables included dizziness/lightheadedness score (OHQ item 1) and patient-reported falls. Results: Among 24 droxidopa and 27 placebo recipients, mean OHQ composite-score change at Week 8 was −2.2 versus −2.1 (p = 0.98); in response to this pre-planned futility analysis, the study was temporarily stopped and all data from these patients were considered exploratory. At Week 1, mean dizziness/lightheadedness score change favored droxidopa by 1.5 units (p = 0.24), with subsequent numerical differences favoring droxidopa throughout the observation period, and at Week 1, mean standing systolic blood-pressure change favored droxidopa by 12.5 mmHg (p = 0.04). Compared with placebo, the droxidopa group exhibited an approximately 50% lower rate of reported falls (p = 0.16) and fall-related injuries (post-hoc analysis). Conclusions: This exploratory analysis of a small dataset failed to show benefit of droxidopa, as compared with placebo by the primary endpoint. Nonetheless, there were signals of potential benefit for nOH, including improvement in dizziness/lightheadedness and reduction in falls, meriting evaluation in further trials.
Application of Depression Rating Scales in Patients with Parkinson's Disease with and without Co-Occurring Anxiety
Authors: Calleo Jessica , Williams James R. , Amspoker Amber B. , Swearingen Leah , Hirsch Elaina S. , Anderson Karen , Goldstein Susanne R. , Grill Stephen , Lehmann Susan , Little John T. , Margolis Russell L. , Palanci Justin , Pontone Gregory M. , Weiss Howard , Rabins Peter , Marsh Laura
Published: December 2019

Background: In patients with Parkinson's disease (PD), depressive symptom rating scales facilitate identification of depressive disorders, which are common and disabling. Anxiety disturbances in PD, which lack valid assessment scales, frequently co-occur with PD-depression, are under-recognized, and require different interventions than depressive disorders. Whether high anxiety rates in PD confound depression scale performance or if any depression scales also predict anxiety disturbances is not known. Objective: To test the impact of co-occurring anxiety disorders on psychometric properties of depression rating scales in depressed PD patients and compare disability between PD patients with anxiety, depression, and comorbid anxiety and depressive disorders. Methods: PD subjects (n = 229) completed self-report and clinician-administered depression scales. Receiver operating characteristic curves were developed to estimate psychometric properties of each scale in those with depression alone, anxiety alone, and comorbid depression and anxiety. Between-group differences on all measures were examined. Results: Comorbid anxiety did not affect the psychometric properties of any scale when identifying depressive disorders, but is associated with greater symptom severity and disability. Depression-scale scores were not significantly different between subjects with anxiety disorders only and those without depressive or anxiety diagnoses. Conclusions: Co-occurring anxiety disorders do not impact performance of depression rating scales in depressed PD patients. However, depression rating scales do not adequately identify anxiety disturbances alone or in patients with depression.
Stemming the Hype: What Can We Learn from iPSC Models of Parkinson's Disease and How Can We Learn It?
Authors: Jacobs Benjamin Meir
Published: December 2019

Parkinson's disease (PD) is a prevalent and debilitating neurodegenerative disorder for which there are no available cures. PD pathogenesis is poorly understood because appropriate animal and in vitro models are lacking. The development of induced Pluripotent Stem Cells (iPSCs) has allowed researchers to generate disease-specific dopaminergic neurons in vitro by reprogramming skin cells from patients with the disease. It is hoped that this unprecedented access to PD patients' neurons will yield mechanistic insights into PD pathogenesis, a platform for drug screening, and a means of early diagnosis. In this article I critically evaluate the current usage of iPSCs in PD research. I first outline the iPSC paradigm and emphasise the benefits of this approach for modelling PD. I then ask what we can learn from the iPSC-based studies done to date. I argue that these studies have not been particularly informative when considered as an isolated body of evidence. I suggest that the limitations of this technology can be overcome, and I conclude that iPSCs have the potential to be an extremely useful tool in PD research. However, they will never be a panacea and should continue to be used in concert with other in vitro and animal models.
Brain Volumetric Correlates of Memory in Early Parkinson's Disease
Authors: Ellfolk Ulla , Joutsa Juho , Rinne Juha O. , Parkkola Riitta , Jokinen Pekka , Karrasch Mira
Published: December 2019

Background: Free recall memory deficits are common in Parkinson's disease (PD), even at early stages before mild cognitive impairment or dementia. Their association with brain structural changes has not been established. Objective: We studied local gray matter volumes in relation to different memory tasks in early stage PD. Methods: Magnetic resonance images (MRI) and neuropsychological data were obtained from 28 non-demented, medicated PD patients, and 28 healthy controls. The gray matter segments of T1-weighted MRI images were analyzed using voxel-based morphometry in relation to visual and verbal memory tasks. Measures of immediate free recall, verbal learning, delayed recall and memory consolidation were obtained. A novel measure of incidental memory was included. Results: Patients and controls showed no significant group differences in local gray matter volumes. Voxel-based morphometry analyses revealed that worse performance on an incidental visual memory task was associated with smaller right parietal gray matter volume (Family-wise error corrected P = 0.002). This association was present in the PD group (corrected P = 0.005), but not in controls (corrected P > 0.99). No associations between gray matter volumes and the other memory tasks were found in either group. Conclusions: The results suggest that right parietal cortical gray matter volume is related to free recall memory deficits in early stage PD in conditions not involving an intention to memorize visual items. This preliminary finding needs to be established in further studies utilizing incidental memory tasks in PD.
Interventions that Improve Body and Brain Bioenergetics for Parkinson's Disease Risk Reduction and Therapy
Authors: Mattson Mark P.
Published: December 2019

Studies of Parkinson's disease (PD) patients, animal models and pathogenic actions of genetic mutations that cause familial PD have established that neuronal bioenergetics are compromised with brainstem and midbrain monoaminergic neurons being particularly vulnerable. Peripheral insulin resistance and diabetes in midlife may increase the risk of PD, and diet and lifestyle changes that increase insulin sensitivity (exercise and intermittent energy restriction) can counteract neurodegenerative processes and improve functional outcome in animal models. Insulin sensitizing glucagon-like peptide 1 (GLP-1) analogs are beneficial in animal models of PD, and the results of an initial clinical trial in PD patients are promising. In addition to improving peripheral and brain energy metabolism, exercise, intermittent energy restriction and GLP-1 analogs may bolster neuronal adaptive stress response pathways that enhance neurotrophic signaling, DNA repair, proteostasis and mitochondrial biogenesis.
Dopaminergic Modulation of Arm Swing During Gait Among Parkinson's Disease Patients
Authors: Sterling Nicholas W. , Cusumano Joseph P. , Shaham Noam , Piazza Stephen J. , Liu Guodong , Kong Lan , Du Guangwei , Lewis Mechelle M. , Huang Xuemei
Published: December 2019

Background: Reduced arm swing amplitude, symmetry, and coordination during gait have been reported in Parkinson's disease (PD), but the relationship between dopaminergic depletion and these upper limb gait changes remains unclear. Objective: We aimed to investigate the effects of dopaminergic drugs on arm swing velocity, symmetry, and coordination in PD. Methods: Forearm angular velocity was recorded in 16 PD and 17 control subjects (Controls) during free walking trials. Angular velocity amplitude of each arm, arm swing asymmetry, and maximum cross-correlation were compared between control and PD groups, and between OFF- and ON-medication states among PD subjects. Results: Compared to Controls, PD subjects in the OFF-medication state exhibited lower angular velocity amplitude of the slower- (p = 0.0018), but not faster- (p = 0.2801) swinging arm. In addition, PD subjects demonstrated increased arm swing asymmetry (p = 0.0046) and lower maximum cross-correlation (p = 0.0026). Following dopaminergic treatment, angular velocity amplitude increased in the slower- (p = 0.0182), but not faster- (p = 0.2312) swinging arm among PD subjects. Furthermore, arm swing asymmetry decreased (p = 0.0386), whereas maximum cross-correlation showed no change (p = 0.7436). Pre-drug angular velocity amplitude of the slower-swinging arm was correlated inversely with the change in arm swing asymmetry (R = −0.73824, p = 0.0011). Conclusions: This study provides quantitative evidence that reduced arm swing and symmetry in PD can be modulated by dopaminergic replacement. The lack of modulations of bilateral arm coordination suggests that additional neurotransmitters may also be involved in arm swing changes in PD. Further studies are warranted to investigate the longitudinal trajectory of arm swing dynamics throughout PD progression.
Abnormal Visual Contrast Acuity in Parkinson's Disease
Authors: Lin Tanya P. , Rigby Heather , Adler Jennifer S. , Hentz Joseph G. , Balcer Laura J. , Galetta Steven L. , Devick Steve , Cronin Richard , Adler Charles H.
Published: December 2019

Background: Low-contrast vision is thought to be reduced in Parkinson's disease (PD). This may have a direct impact on quality of life such as driving, using tools, finding objects, and mobility in low-light condition. Low-contrast letter acuity testing has been successful in assessing low-contrast vision in multiple sclerosis. We report the use of a new iPad application to measure low-contrast acuity in patients with PD. Objective: To evaluate low- and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart developed for the Apple iPad. Methods: Thirty-two PD and 71 control subjects were studied. Subjects viewed the Variable Contrast Acuity Chart on an iPad with both eyes open at two distances (40 cm and 2 m) and at high contrast (black and white visual acuity) and 2.5% low contrast. Acuity scores for the two groups were compared. Results: PD patients had significantly lower scores (indicating worse vision) for 2.5% low contrast at both distances and for high contrast at 2 m (p < 0.003) compared to controls. No significant difference was found between the two groups for high contrast at 40 cm (p = 0.12). Conclusions: Parkinson's disease patients have reduced low and high contrast acuity compared to controls. An iPad app, as used in this study, could serve as a quick screening tool to complement more formal testing of patients with PD and other neurologic disorders.
Longitudinal EEG Changes Correlate with Cognitive Measure Deterioration in Parkinson's Disease
Authors: Caviness John N. , Hentz Joseph G. , Belden Christine M. , Shill Holly A. , Driver-Dunckley Erika D. , Sabbagh Marwan N. , Powell Jessica J. , Adler Charles H.
Published: December 2019

Background: QEEG could provide physiological biomarkers for changes over time in Parkinson's disease (PD) cognitive decline if they track with longitudinal neuropsychological performance. Objective: Our aim was to correlate longitudinal changes in frequency domain quantitative electroencephalography (QEEG) measures with change in neuropsychological performance testing in PD. Methods: 71 PD subjects, not demented at baseline, were studied from the Arizona Study of Aging and Neurodegenerative Disorders cohort. Baseline and follow-up digital EEG from PD subjects were analyzed for QEEG measures of background rhythm frequency and global relative power in delta (2.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) bands. Baseline and subsequent evaluation included Mini Mental Status Examination and five other neuropsychological tests that load on cognitive domains known to decline in PD. Pearson coefficient was used to assess correlations. Multiple linear regression modeling was used to assess the effect of variable combinations of QEEG and other measures, including age and PD duration. Results: Changes in delta bandpower showed the highest and most consistent pattern of correlations with longitudinal changes in neuropsychological testing. The highest correlation was between delta bandpower increase and decline in the Rey Auditory-Verbal Learning Test (−0.59:p < 0.001). Delta bandpower was also increased in the incident dementia group compared to non-dementia at followup. Conclusions: 1) Longitudinal change in the QEEG frequency domain measure of delta bandpower correlated best with longitudinal neuropsychological performance change in PD; 2) These results constitute preliminary evidence that delta bandpower may be a suitable biomarker for evaluating PD cognitive deterioration longitudinally.
The Retropulsion Test: A Good Evaluation of Postural Instability in Parkinson's Disease?
Authors: Nonnekes Jorik , Goselink Rianne , Weerdesteyn Vivian , Bloem Bastiaan R.
Published: December 2019

Postural instability is a disabling feature of Parkinson's disease (PD), contributing to recurrent falls and fall-related injuries. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, and is therefore a key component of the neurological examination in PD. Many variants exist, which confuses both clinical practice and research. Here, we evaluate the merits of this test by discussing three common variants: (1) the pull test as described in the MDS-UPDRS scale; (2) using an unexpected shoulder pull, without prior warning; and (3) the push-and-release test. All variants are a quick method to index the degree of postural instability, but the outcome can vary considerably due to variability in test execution and -interpretation. This partially explains why the retropulsion test fails to predict future falls in PD. Another explanation is that falling results from the complex interplay between gait, balance, cognitive decline and environmental factors, and the retropulsion test captures only part of that. We conclude with several recommendations for current clinical practice.
Use of an Online Portal to Facilitate Clinical Trial Recruitment: A Preliminary Analysis of Fox Trial Finder
Authors: Rocker Charlotte , Cappelletti Lily , Marshall Claudia , Meunier Claire C. , Brooks Deborah W. , Sherer Todd , Chowdhury Sohini
Published: December 2019

Background: As in other therapeutic areas, clinical studies in Parkinson's disease (PD) face significant recruitment challenges. However, qualitative surveys suggest that individuals with PD are willing to participate in clinical research. The Michael J. Fox Foundation therefore established Fox Trial Finder in 2011 to facilitate connection between PD research teams and volunteers. Objective: Characterize the research volunteers (with and without PD) registered on Fox Trial Finder as of June 2014, and the published, recruiting studies to identify trends and highlight gaps between research requirements and available volunteers. Methods: Profiles of volunteers with and without PD were analyzed to explore trends in geography, demographics, family history and, for those volunteers with PD, disease progression and treatment history. Clinical study profiles were analyzed to determine study type, phase, sponsor, focus, location and eligibility criteria. The analysis focused on volunteers and studies based in the United States. Results: The database contained 26,261 US-based volunteers, including 19,243 volunteers (73%) with PD and 7,018 (27%) controls without PD. The average time since diagnosis for PD volunteers was 5.7 years and the average age at diagnosis was 58 years. Control volunteers were more likely than volunteers with PD to be female (67% vs. 35%) and to have a family history of PD (49% vs. 12%). Conclusions: Fox Trial Finder's registration history to date demonstrates the high level of willingness among individuals affected by PD to participate in clinical research and provide a significant amount of personal health information to facilitate that participation.
Restorative Effects of Platelet Derived Growth Factor-BB in Rodent Models of Parkinson's Disease
Authors: Zachrisson Olof , Zhao Ming , Andersson Annica , Dannaeus Karin , Häggblad Johan , Isacson Ruben , Nielsen Elisabet , Patrone Cesare , Rönnholm Harriet , Wikstrom Lilian , Delfani Kristofer , McCormack Alison L. , Palmer Theo , Di Monte Donato A. , Hill Michael P. , Janson Lang Ann Marie , Haegerstrand Anders
Published: December 2019

Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with platelet-derived growth factor-BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease.
Productivity and Impact of the Top 100 Cited Parkinson's Disease Investigators since 1985
Authors: Sorensen Aaron A. , Weedon David
Published: December 2019

We have compiled a list of the 100 most cited researchers in Parkinson's disease since 1985 together with H-Indices as a means to assess productivity and impact. Within the total-citations ranking, “broad impact” citations are used as a way of identifying those researchers whose work is cited widely beyond the Parkinson's disease research community. Finally, we present a table of the most cited researchers this decade for a comparison of the two with analysis.
Signs of Degeneration in 12–22-Year Old Grafts of Mesencephalic Dopamine Neurons in Patients with Parkinson's Disease
Authors: Kurowska Zuzanna , Englund Elisabet , Widner Håkan , Lindvall Olle , Li Jia-Yi , Brundin Patrik
Published: December 2019

We demonstrate that grafted human fetal mesencephalic neurons can survive and extend axons for 22 years in the brain of a patient with Parkinson's disease (PD). In this patient, the overall survival and fiber outgrowth of the grafts were, however, relatively poor, which is consistent with the lack of significant clinical graft-induced benefit. We have compared the morphology of neurons in the 22-year old grafts with those in two younger grafts (16- and 12-year old), which were sequentially implanted in another PD patient. In the case with the 22-year-old transplant, a high proportion (up to 38%) of the grafted dopaminergic (pigment-granule containing) neurons do not express tyrosine hydroxylase and dopamine transporter and their perikarya appear atrophic. The proportion of pigmented neurons not expressing these markers is lower in the 12–16 year old grafts. Furthermore, in the 22-year-old graft, 49% of the pigmented neurons display α-synuclein immunoreactivity in the cell body and 1.2% of them contain Lewy bodies. In conclusion, our results show that grafted dopaminergic neurons can survive for more than two decades. However, over time an increasing proportion of grafted neurons exhibit signs of degeneration.
Subthalamic Nucleus Stimulation Increases Brain Derived Neurotrophic Factor in the Nigrostriatal System and Primary Motor Cortex
Authors: Spieles-Engemann Anne L. , Steece-Collier Kathy , Behbehani Michael M. , Collier Timothy J. , Wohlgenant Susan L. , Kemp Christopher J. , Cole-Strauss Allyson , Levine Nathan D. , Gombash Sara E. , Thompson Valerie B. , Lipton Jack W. , Sortwell Caryl E.
Published: December 2019

The mechanisms underlying the effects of long-term deep brain stimulation of the subthalamic nucleus (STN DBS) as a therapy for Parkinson's disease (PD) remain poorly understood. The present study examined whether functionally effective, long-term STN DBS modulates glial cell line-derived neurotrophic factor (GDNF) and/or brain-derived neurotrophic factor (BDNF) in both unlesioned and unilateral 6-hydroxydopamine lesioned rats. Lesioned rats that received two weeks of continuous unilateral STN DBS exhibited significant improvements in parkinsonian motor behaviors in tests of forelimb akinesia and rearing activity. Unilateral STN DBS did not increase GDNF in the nigrostriatal system, primary motor cortex (M1), or hippocampus of unlesioned rats. In contrast, unilateral STN DBS increased BDNF protein 2–3 fold bilaterally in the nigrostriatal system with the location (substantia nigra vs. striatum) dependent upon lesion status. Further, BDNF protein was bilaterally increased in M1 cortex by as much as 2 fold regardless of lesion status. STN DBS did not impact cortical regions that receive less input from the STN. STN DBS also was associated with bilateral increases in BDNF mRNA in the substantia nigra (SN) and internal globus pallidus (GPi). The increase observed in GPi was completely blocked by pretreatment with 5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), suggesting that the activation of N-methyl-D-aspartate (NMDA) receptors was involved in this phenomenon. The upregulation of BDNF associated with long term STN DBS suggest that this therapy may exert pronounced and underappreciated effects on plasticity in the basal ganglia circuitry that may play a role in the symptomatic effects of this therapy as well as support the neuroprotective effect of stimulation documented in this rat model.
Dry Mouth: An Overlooked Autonomic Symptom of Parkinson's Disease
Authors: Cersosimo Maria G. , Raina Gabriela B. , Calandra Cristian R. , Pellene Alejandro , Gutiérrez Cristiam , Micheli Federico E. , Benarroch Eduardo E.
Published: December 2019

There is involvement of salivary glands by α-synuclein pathology in PD. However, the prevalence of dry mouth has not been systematically assessed in these patients. We studied 97 PD patients and 86 controls using a structured questionnaire. Dry mouth was reported by 60.8% of PD patients and 27.9% of controls (p < 0.0001). Dry mouth and drooling coexisted in 30% of cases. Only 12% of patients had reported dry mouth to their physicians. Dry mouth is a frequent but underreported symptom and may be an early manifestation of autonomic involvement in PD.
Use of a Refined Drug Tracer Algorithm to Estimate Prevalence and Incidence of Parkinson's Disease in a Large Israeli Population
Authors: Chillag-Talmor Orly , Giladi Nir , Linn Shai , Gurevich Tanya , El-Ad Baruch , Silverman Barbara , Friedman Nurit , Peretz Chava
Published: December 2019

Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998–2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000–2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75–1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37–1.39) and incidence (RR = 1.45, 95%CI 1.42–1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.
Aberrant Dopamine Transmission and Cognitive Dysfunction in Animal Models of Parkinson's Disease
Authors: Lelos M.J. , Dunnett S.B.
Published: December 2019

Due to the relative success of therapeutic interventions aimed at treating the overt motor symptoms evident in Parkinson's disease (PD), a greater appreciation of the non-motor aspects of the disease has emerged in recent time. Indeed, evidence suggests that impairments in emotional processing, behavioural control and cognitive function may emerge early in the onset of the disease. Decades of experimental research have seen the development of diverse animal models, all of which have aimed to mimic the characteristic features of the disease process including the dopaminergic neural cell loss, the molecular neuropathology and the concomitant behavioural impairments. The following review provides an overview of the use of animal, particularly rodent, models in the quest to obtain a greater understanding of the role of corticostriatal dopamine in cognitive and neuropsychiatric functions. Given the limitations of using the available rodent models of PD, including altered motor and motivational function, it has become necessary to employ a range of techniques to eke out the precise function of this neurotransmitter in corticostriatal function. Combinations of lesion and pharmacological studies have allowed the assessment of dopamine depletion and precise receptor populations in the learning or expression of a range of executive functions, which has gained us considerable insight into the relationship between the neuropathology that occurs in PD and the resulting impairments in cognitive and neuropsychiatric function.
Chronic Subcutaneous Infusion Therapy with Apomorphine in Advanced Parkinson's Disease Compared to Conventional Therapy: A Real Life Study of Non Motor Effect
Authors: Martinez-Martin Pablo , Reddy Prashanth , Antonini Angelo , Henriksen Tove , Katzenschlager Regina , Odin Per , Todorova Antonia , Naidu Yogini , Tluk Susanne , Chandiramani Chandni , Martin Anne , Chaudhuri Kallol Ray
Published: December 2019

Background: Apomorphine infusion therapy remains under-used and there are no comparative studies of motor and non-motor effects of apomorphine infusion. Methods: In this paper we report preliminary results from an ongoing clinical observational “real life” surveillance-based study focused on effects of this therapy on non-motor symptoms and health-related quality of life in a group of patients on apomorphine. Results: Apomorphine infusion led to highly significant improvements in UPDRS 3 (p = 0.0003), UPDRS 4 (p = 0.0003), PDQ-8 (Parkinson's disease questionnaire, p = 0.001) and NMSS total (non motor symptoms scale, p = 0.0003). Furthermore, apomorphine was tolerated in patients with visual hallucinations, illusions and paranoid ideations while significant improvement in specific non-motor symptoms such as hyperhidrosis, nocturia, urgency of micturition, and fatigue was recorded. Levodopa equivalent dose decreased significantly (1077.81 ± 446.26 to 458.75 ± 282.29, p < 0.0001) and a large effect size of intervention was noted. In an untreated group no such improvement was noted. The number needed to treat (NNT) for improvement >1 SEM in the Apo group was calculated and was lower than 2 for >1 SEM improvement of UPDRS 3, NMSS, and PDQ-8 total scores. Conclusions: This pilot observational study suggests that non-motor effects are evident with apomorphine therapy and patients suitable for apomorphine deteriorate in the absence of therapy.
Cardiovascular Autonomic Dysfunction in Animal Models of Parkinson's Disease
Authors: Fleming Sheila M.
Published: December 2019

Cardiovascular autonomic dysfunction is a common non-motor symptom associated with synucleinopathies such as Parkinson's disease (PD). Several recent clinical studies indicate that cardiovascular autonomic impairments including orthostatic hypotension and sympathetic denervation may precede the development of the cardinal motor symptoms in PD, making cardiovascular dysfunction an attractive target for the development of biomarkers for early detection and potential neuroprotective strategies for PD. However, the pathologic mechanisms underlying cardiovascular dysfunction as well as many of the non-motor symptoms in PD remain unknown. This is likely due, in part, to an initial under-appreciation of PD as a systemic disorder as well as limited research in cardiovascular dysfunction in animal models of PD. Here, we highlight studies that have investigated cardiovascular dysfunction in rodent models of PD and the potential usefulness of genetic mouse models of PD for this endeavor.
Molecular Chaperones in Parkinson's Disease – Present and Future
Authors: Ebrahimi-Fakhari Darius , Wahlster Lara , McLean Pamela J.
Published: December 2019

Parkinson's disease, like many other neurodegenerative disorders, is characterized by the progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. The cascade by which the small synaptic protein α-synuclein misfolds to form distinctive protein aggregates, termed Lewy bodies and Lewy neurites, has been the subject of intensive research for more than a decade. Genetic and pathological studies in Parkinson's disease patients as well as experimental studies in disease models have clearly established altered protein metabolism as a key element in the pathogenesis of Parkinson's disease. Alterations in protein metabolism include misfolding and aggregation, post-translational modification and dysfunctional degradation of cytotoxic protein species. Protein folding and re-folding are both mediated by a highly conserved network of molecules, called molecular chaperones and co-chaperones. In addition to the regulatory role in protein folding, molecular chaperone function is intimately associated with pathways of protein degradation, such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway, to effectively remove irreversibly misfolded proteins. Because of the central role of molecular chaperones in maintaining protein homeostasis, we herein review our current knowledge on the involvement of molecular chaperones and co-chaperones in Parkinson's disease. We further discuss the capacity of molecular chaperones to prevent or modulate neurodegeneration, an important concept for future neuroprotective strategies and summarize the current progress in preclinical studies in models of Parkinson's disease and other neurodegenerative disorders. Finally we include a discussion on the future potential of using molecular chaperones as a disease modifying therapy.
Assessing Drug-Induced Dyskinesia in the Clinic, the Laboratory and the Natural Environment of Patients
Authors: Carignan Benoit , Daneault Jean-François , Duval Christian
Published: December 2019

The assessment of drug-induced dyskinesia (DID) in Parkinson's disease represents a formidable challenge for clinicians and researchers alike. The present review describes the current assessment tools used in the clinic, where different scales have been developed for monitoring levels of DID in patients. We also review laboratory tools used to assess the quantity and characteristics of DID. Finally, we review assessment methods currently in development for monitoring DID and voluntary mobility in the natural living environment of patients. Here, we discuss the strengths and weaknesses of these tools as it pertains to their efficacy in assessing the quantity of DID, its characteristics, as well as its impact on the quality of life of patients. Finally, we discuss ongoing challenges and research questions that may guide future development of assessment methods aimed at monitoring DID and its impact on daily lives of patients.
Survival of Human Induced Pluripotent Stem Cell–Derived Midbrain Dopaminergic Neurons in the Brain of a Primate Model of Parkinson's Disease
Authors: Kikuchi Tetsuhiro , Morizane Asuka , Doi Daisuke , Onoe Hirotaka , Hayashi Takuya , Kawasaki Toshiyuki , Saiki Hidemoto , Miyamoto Susumu , Takahashi Jun
Published: December 2019

Before induced pluripotent stem cells (iPSCs) can be used to treat neurologic diseases, human iPSC-derived neural cells must be analyzed in the primate brain. In fact, although mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that are beneficial in rat models of Parkinson's disease (PD), human iPSC-derived neural progenitor cells (NPCs) have not been examined in primate brains. Here, we generated NPCs at different stages of predifferentiation using a feeder-free culture method, and grafted them into the brains of a monkey PD model and NOD-SCID mice. Magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses revealed that NPCs pretreated with Sonic hedgehog and fibroblast growth factor-8 followed by glial cell–derived neurotrophic factor, brain-derived neurotrophic factor, ascorbic acid, and dibutyryl cyclic AMP resulted in smaller grafts than those without these treatments, and survived as DA neurons in a monkey brain as long as six months. Thus, for the first time, we describe a feeder-free neural differentiation method from human iPSCs and an evaluation system that can be used to assess monkey PD models.
Treating Orthostatic Hypotension in Patients with Parkinson's Disease and Atypical Parkinsonism Improves Function
Authors: Hohler Anna D. , Amariei Diana Elena , Katz Douglas I. , DePiero T. Joy , Allen Valerie B. , Boyle Suzanne , Phenix Heidi Alison , DeAngelis Tara Ashley , Geibel Carrie Denise , Smith Karla M. , Saint-Hilaire Marie , Ellis Terry
Published: December 2019

Background: Patients with idiopathic Parkinson's disease (PD) or atypical Parkinsonism (AP) often present with orthostatic hypotension (OH) as a result of the dysautonomia associated with the disease or as a side effect of the dopaminergic medications used to treat it. Our recent study suggested that OH negatively impacts gross motor, balance, and cognitive functions in patients with PD. Objective: To determine if correcting the orthostatic hypotension (OH) of patients with PD or AP improves their gross motor, balance, and cognitive functions. Methods: Forty patients with PD or AP were assessed before and after correcting their OH using a staged approach with a goal of SBP >80 when standing and SBP <180 when laying. Step 1 of treatment included reducing antihypertensive medications, as possible, maintaining hydration with 1500cc/day, decreasing dietary salt, wearing high compression stockings, and keeping the head of bed elevated at 30 degrees when supine. If SBP <80 with standing after step 1, then treatment was started with fludrocortisone and/or midodrine. Results: Patients' OH was managed as part of a rehabilitation program. Tests such as the Motor and Cognitive Functional Independence Measures, Berg Balance Scale, Two Minute Walking test, and the Finger Tapping test showed significant improvements (p < 0.05) in their gross motor, walking, balance and cognitive function with our OH management plan. No significant differences between admission and discharge were found in the Timed Up and Go test. Conclusion: Our data suggest that monitoring and correcting the OH of patients with PD or AP improves their gross motor, balance, and cognitive function.
Cardiovascular Responses During a Submaximal Exercise Test in Patients with Parkinson's Disease
Authors: Speelman Arlène D. , Groothuis Jan T. , van Nimwegen Marlies , van der Scheer Ellis S. , Borm George F. , Bloem Bastiaan R. , Hopman Maria T.E. , Munneke Marten
Published: December 2019

Background: Patients with Parkinson's disease (PD) are physically less active than controls, and autonomic dysfunction may contribute to this sedentary lifestyle. Specifically, an altered cardiovascular response to physical effort may restrict physical activities. Objective: To assess the cardiovascular responses to a submaximal exercise test in PD patients and controls, 546 sedentary PD patients and 29 sedentary healthy controls performed the Åstrand-Rhyming submaximal cycle exercise test. Methods: Average heart rate was used to estimate maximal oxygen consumption (VO2max). Variables that may affect submaximal activity in PD patients, including disease severity, fatigue, and level of physical activity in daily life, were recorded. Results: Fewer PD patients (46%) completed the submaximal exercise test successfully than the controls (86%). The estimated VO2max of patients with a successful test was 34% lower than the controls (p < 0.001). Multivariate regression analyses revealed that higher body weight, lower systolic blood pressure, lower resting heart rate, and lower maximal workload were associated with an increased risk of an inadequate heart rate increase during submaximal exercise (R2 = 27%). PD patients with a successful submaximal exercise test had lower estimated VO2max values than controls. Conclusions: Importantly, half of the PD patients had an inadequate heart rate increase during submaximal exercise, which was likely caused by cardiac sympathetic denervation leading to autonomic dysfunction. PD patients should therefore be screened to identify their limitations in exercise performance. Caution should be applied when prescribing beta blockers, as they might limit physical activities further.
Selective Left, Right and Bilateral Stimulation of Subthalamic Nuclei in Parkinson's Disease: Differential Effects on Motor, Speech and Language Function
Authors: Schulz Geralyn M. , Hosey Lara A. , Bradberry Trent J. , Stager Sheila V. , Lee Li-Ching , Pawha Rajesh , Lyons Kelly E. , Verhagen Metman Leo , Braun Allen R.
Published: December 2019

Deep brain stimulation (DBS) of the subthalamic nucleus improves the motor symptoms of Parkinson's disease, but may produce a worsening of speech and language performance at rates and amplitudes typically selected in clinical practice. The possibility that these dissociated effects might be modulated by selective stimulation of left and right STN has never been systematically investigated. To address this issue, we analyzed motor, speech and language functions of 12 patients implanted with bilateral stimulators configured for optimal motor responses. Behavioral responses were quantified under four stimulator conditions: bilateral DBS, right-only DBS, left-only DBS and no DBS. Under bilateral and left-only DBS conditions, our results exhibited a significant improvement in motor symptoms but worsening of speech and language. These findings contribute to the growing body of literature demonstrating that bilateral STN DBS compromises speech and language function and suggests that these negative effects may be principally due to left-sided stimulation. These findings may have practical clinical consequences, suggesting that clinicians might optimize motor, speech and language functions by carefully adjusting left- and right-sided stimulation parameters.
Difference in MSA Phenotype Distribution between Populations: Genetics or Environment?
Authors: Ozawa Tetsutaro , Revesz Tamas , Paviour Dominic , Lees Andrew J. , Quinn Niall , Tada Mari , Kakita Akiyoshi , Onodera Osamu , Wakabayashi Koichi , Takahashi Hitoshi , Nishizawa Masatoyo , Holton Janice L.
Published: December 2019

The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA-P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations.