bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping Cortical Atrophy in Parkinson's Disease Patients with Dementia
Authors: Hwang Kristy S. , Beyer Mona K. , Green Amity E. , Chung Christine , Thompson Paul M. , Janvin Carmen , Larsen Jan P. , Aarsland Dag , Apostolova Liana G.
Published: December 2019

Background: Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established. Methods: We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01. Results: PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left pcorrected = 0.06, right pcorrected = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right pcorrected = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%. Conclusion: Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia.
mTOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats
Authors: Decressac Mickael , Björklund Anders
Published: December 2019

The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients.
Guided Self-Help for the Management of Worry in Parkinson's Disease: A Pilot Study
Authors: Lawson Rachael A. , Millar David , Brown Richard G. , Burn David J.
Published: December 2019

Background: Anxiety disorder and anxiety symptomatology are common in Parkinson's disease (PD), with up to 25% patients experiencing significant worry. There is no systematic evidence base for the management of anxiety or anxiety related symptoms such as worry in PD. Objectives: To investigate whether cognitive therapy, delivered as bibliotherapy, is an effective intervention for worry in PD. Methods: 54 participants were randomly allocated to a guided reading group and a control group. The guided reading group were given a CBT based self-help resource called What? Me Worry!?! to work through over eight weeks, with telephone support at two week intervals. Controls were given information about worry only, and one phone call. Measures of worry, intolerance of uncertainty, metacognitions and health status were taken at baseline and after 3 months. Results: Analysable data were obtained for 15 controls and 17 from the guided reading group. Worry and intolerance of uncertainty were significantly reduced in the guided reading group. However, no significant differences were found for the follow up measures between the groups. Conclusions: Bibliotherapy has the potential to be useful and cost effective as a management strategy for the treatment of worry in people with PD.
The α7 nAChR Agonist PNU-282987 Reduces Inflammation and MPTP-Induced Nigral Dopaminergic Cell Loss in Mice
Authors: Stuckenholz Vanessa , Bacher Michael , Balzer-Geldsetzer Monika , Alvarez-Fischer Daniel , Oertel Wolfgang H. , Dodel Richard C. , Noelker Carmen
Published: December 2019

Background: Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons and an accompanying neuroinflammatory process in the substantia nigra (SN). The cholinergic anti-inflammatory signalling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. A major component of this pathway is the α7 nicotinic acetylcholine receptor (α7 nACh receptor), which is expressed on immune cells such as microglia. Objective: To determine the role of this cholinergic anti-inflammatory signalling pathway, we investigated the effects of the selective α7 nACh agonist PNU-282987 and of the non-competitive nACh antagonist mecamylamine on microglia-induced neuroinflammation and toxin-induced degeneration of dopaminergic neurons in a mouse model of PD. Methods: PNU-282987, mecamylamine or placebo administration was started one day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57Bl/6 mice were injected intraperitoneally four times at 2 h intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or seven days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis. Results: Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion. Unexpectedly, mecamylamine lowered neuroinflammation as well, though it did not show a neuroprotective potential at the nigral level. Conclusions: Our results demonstrate the therapeutic potential of the selective α7 nicotinic acetylcholine agonist PNU-282987 in attenuating neuroinflammation and toxin-induced loss of dopaminergic neurons in the acute MPTP mouse model of PD.
LRRK2: Cause, Risk, and Mechanism
Authors: Paisán-Ruiz Coro , Lewis Patrick A. , Singleton Andrew B.
Published: December 2019

In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last.
Role of Serum Cholesterol in Parkinson's Disease: A Meta-Analysis of Evidence
Authors: Gudala Kapil , Bansal Dipika , Muthyala Harini
Published: December 2019

Background: Results from several epidemiological studies found a potential role of cholesterol metabolism in Parkinson's disease (PD) pathogenesis. Further several studies assessed relation between dietary intake of cholesterol and risk of PD, although these studies showed varied results but give a clue of association between serum cholesterol and PD. Objective: We therefore examined the association between serum cholesterol and risk of PD. Methods: PubMed database and bibliographies of retrieved articles were searched for observational studies (published up to January 2013) investigating the relationship between serum cholesterol and PD. Pooled risk ratio (RR) was calculated using random-effects model. Subgroup, sensitivity analysis and publication bias were also done. Results: Eight relevant studies were identified, consisting of 4 each case-control and cohort studies involving a total of 246,112 subjects including 5,488 PD cases. Because of significant heterogeneity (pheterogeneity < 0.001, I2 = 70.34%) was observed, a random-effects model was chosen over a fixed-effects model. A combined analysis of 8 studies found no significant association between serum cholesterol and risk of PD (RR 0.87, 95% CI 0.67–1.13; p = 0.41). Conclusions: We observed no probable association between serum cholesterol and risk of PD.
Locomotor Velocity and Striatal Adaptive Gene Expression Changes of the Direct and Indirect Pathways in Parkinsonian Rats
Authors: Capper-Loup Christine , Kaelin-Lang Alain
Published: December 2019

Background: In Parkinson's disease (PD), bradykinesia, or slowness of movement, only appears after a large striatal dopamine depletion. Compensatory mechanisms probably play a role in this delayed appearance of symptoms. Objective: Our hypothesis is that the striatal direct and indirect pathways participate in these compensatory mechanisms. Methods: We used the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD and control animals. Four weeks after the lesion, the spontaneous locomotor activity of the rats was measured and then the animals were killed and their brain extracted. We quantified the mRNA expression of markers of the striatal direct and indirect pathways as well as the nigral expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) mRNA. We also carried out an immunohistochemistry for the striatal TH protein expression. Results: As expected, the unilateral 6-OHDA rats presented a tendency to an ipsilateral head turning and a low locomotor velocity. In 6-OHDA rats only, we observed a significant and positive correlation between locomotor velocity and both D1-class dopamine receptor (D1R) (direct pathway) and enkephalin (ENK) (indirect pathway) mRNA in the lesioned striatum, as well as between D1R and ENK mRNA. Conclusions: Our results demonstrate a strong relationship between both direct and indirect pathways and spontaneous locomotor activity in the parkinsonian rat model. We suggest a synergy between both pathways which could play a role in compensatory mechanisms and may contribute to the delayed appearance of bradykinesia in PD.
Walking Economy During Cued versus Non-Cued Treadmill Walking in Persons with Parkinson's Disease
Authors: Gallo Paul M. , McIsaac Tara L. , Garber Carol Ewing
Published: December 2019

Background: Gait impairment is common in Parkinson's disease (PD) and may result in greater energy expenditure, poorer walking economy, and fatigue during activities of daily living. Auditory cueing is an effective technique to improve gait; but the effects on energy expenditure are unknown. Objective: To determine whether energy expenditure differs in individuals with PD compared with healthy controls and if auditory cueing improves walking economy in PD. Methods: Twenty participants (10 PD and 10 controls) came to the laboratory for three sessions. Participants performed two, 6-minute bouts of treadmill walking at two speeds (1.12 m·sec−1 and 0.67 m·sec−1). One session used cueing and the other without cueing. A metabolic cart measured energy expenditure and walking economy was calculated (energy expenditure/power). Results: PD had worse walking economy and higher energy expenditure than control participants during cued and non-cued walking at the 0.67 m·sec−1 speed and during non-cued walking at the 1.12 m·sec−1. With auditory cueing, energy expenditure and walking economy worsened in both participant groups. Conclusions: People with PD use more energy and have worse walking economy than adults without PD. Walking economy declines further with auditory cuing in persons with PD.
The Role of Oxidative Stress in Parkinson's Disease
Authors: Dias Vera , Junn Eunsung , Mouradian M. Maral
Published: December 2019

Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.
Parkinsonian Features in a Case of Pellagra: A Historical Report
Authors: Cavanna Andrea E. , Nani Andrea , Williams Adrian C.
Published: December 2019

Pellagra is a complex systemic disease resulting from inadequate dietary intake of coenzyme precursors nicotinamide and tryptophan. Improved nutritional habits in most developed economies have led to a decrease in clinicians' and researchers' attention to this condition and its pathophysiological bases, although new cases of pellagra have recently been identified in association with alcohol abuse and HIV infection in Western countries. Pellagra is characterized by a complex clinical picture, which can include neuropsychiatric symptoms and Parkinsonian features. Interestingly, pellagra and Parkinson's disease could share some basic pathophysiological mechanisms at the level of nicotinamide metabolism, resulting in mitochondrial dysfunction and alterations in dopaminergic pathways. Both neuropsychiatric and motor symptoms were mentioned in historical reports of pellagra cohorts. Here we present the English translation of the first detailed description of an original case of pellagra with Parkinsonian features, documented in a clinical note by Dr Giuseppe Paravicini one century ago.
Falls in Parkinson Disease: Analysis of a Large Cross-Sectional Cohort
Authors: Parashos Sotirios A. , Wielinski Catherine L. , Giladi Nir , Gurevich Tanya ,   on behalf of The National Parkinson Foundation Quality Improvement Initiative Investigators
Published: December 2019

Background: Falls remain a significant cause of morbidity in PD. Risk factors are not well understood. Objective: In this study we explore risk factors for falls in PD utilizing the cross-sectional, baseline data in the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) database. Subjects are being followed prospectively, and this study will provide the basis for subsequent longitudinal analyses. Methods: A cross-sectional analysis of data from 2,876 ambulatory patients with Parkinson disease enrolled in the NPF-QII at 18 sites. Main outcome measure was falling history in the 3 months preceding assessment. The following were considered as possible predictor variables: age, sex, height, weight, body mass index, disease duration, age at disease onset, investigator's confidence in the diagnosis, Hoehn and Yahr stage, rest tremor, ability to stand unassisted, coexistent pathologies (cardiovascular, respiratory, diabetes, cancer, neurological, osteoarthritis, and “other” comorbidities), anticholinergics, antidepressants, antipsychotics, cognitive enhancers, deep brain stimulation surgery, timed-up-and-go, semantic fluency, and 5 word recall. Variables with associations to the outcome measure in univariate analyses were analyzed in multivariable models using logistic regression. Results: 37.2% of subjects experienced falls. In the multivariable regression model the following variables were found to be independently associated with falls: disease duration; Hoehn and Yahr stage; absence of rest tremor; cardiovascular, arthritis, or “other” comorbidity; antidepressants; deep brain stimulation surgery; timed-up-and-go; and, semantic fluency. Conclusion: Disease duration but not age is independently associated with falls in Parkinson disease. Timed-up-and-go accurately reflects falls risk. Impaired semantic fluency is independently associated with falls, while verbal memory is not. Comorbidities, antidepressants, and deep brain stimulation also contribute to falls risk.
Dopamine Replacement Therapy and Deep Brain Stimulation of the Subthalamic Nuclei Induce Modulation of Emotional Processes at Different Spatial Frequencies in Parkinson's Disease
Authors: Mermillod Martial , Mondillon Laurie , Rieu Isabelle , Devaux Damien , Chambres Patrick , Auxiette Catherine , Dalens Hélène , Coulangeon Louise Marie , Jalenques Isabelle , Durif Franck
Published: December 2019

Background: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is an effective treatment for the most severe forms of Parkinson's disease (PD) and is intended to suppress these patients' motor symptoms. However, be it in association with Dopamine Replacement Therapy (DRT) or not, STN-DBS may in some cases induce addictive or emotional disorders. Objective: In the current study, we suggest that PD patients suffer from emotional deficits that have not been revealed in previous studies because in those experiments the stimuli were displayed for a time long enough to allow patients to have recourse to perceptual strategies in order to recognize the emotional facial expressions (EFE). Methods: The aim of the current article is to demonstrate the existence of emotional disorders in PD by using a rapid presentation of the visual stimuli (200-ms display time) which curtails their perceptual analysis, and to determine whether STN-DBS, either associated or not associated with DRT, has an impact on the recognition of emotions. Results: The results show that EFE recognition performance depends on both STN-DBS (‘on’ vs. ‘off’) and medication (‘on’ vs. ‘off’), but also that these variables have an interactive influence on EFE recognition performance. Moreover, we also reveal how these EFE impairments depend on different spatial frequencies perceptual channels (related to different cortical vs. subcortical neural structures). Conclusions: The effect of PD without therapy seems to be particularly acute for LSF emotional faces, possibly due to a subcortical dysfunction. However, our results indicate that the joint action of STN-DBS and DRT could also disrupt recognition of emotional expressions at the level of occipito-temporal cortical areas (processing HSF visual information) inducing broad global impairment of EFE at the level of HSF visual channels.
Asymmetric Postural Tremor Preceding DOPA-Responsive Parkinsonism – the Transition Disease
Authors: Wolters Alexander , Walter Uwe , Wittstock Matthias , Benecke Reiner
Published: December 2019

Background: Tremulous Parkinson's disease (PD) and essential tremor are well known to be associated, but characteristics of progression of pure tremor state to PD remain unclear. Objective: In this prospective study a cohort of 16 patients suffering from a suggested new disease entity was clinically, pharmacologically, and sonographically analyzed to evaluate whether characteristics giving rise to a new entity in this field can be detected. Methods: All patients had a history of asymmetric postural tremor (aPT) who either already had developed surplus Parkinsonism (PARK group), or were still in the state of a pure asymmetric postural tremor syndrome (APT group). Asymmetry of aPT was assessed by tremor scores including an asymmetry index. DOPA-responsivity was analyzed by tremor scores and the score of the motor part of the Unified Parkinson's disease rating scale. Transcranial brain sonography was performed to evaluate echogenicity of the substantia nigra. Results: Mean age at onset of asymmetric postural tremor was 57 ± 8.5 years without significant differences between both groups. Family history was compatible with an autosomal-dominant inheritance pattern in the majority of patients of both the APT and PARK group. All patients in the PARK group and 3 out of 8 patients in the APT group (38%) with respect to their asymmetric postural tremor were DOPA-responsive. All patients of both groups eligible to transcranial brain sonography showed hyperechogenicity of substantia nigra. In both groups, there was no correlation between tremor severity and duration of asymmetric postural tremor. Conclusions: Our data indicate that patients with an initial asymmetric and sometimes DOPA-responsive postural tremor syndrome and PARK patients are at various stages within the transition from aPT to a later developed DOPA-responsive Parkinsonian syndrome. It is postulated that the described group of patients may represent a separate disease entity with a hereditary background.
Prepulse Inhibition is Associated with Attention, Processing Speed, and 123I-FP-CIT SPECT in Parkinson's Disease
Authors: Zoetmulder Marielle , Biernat Heidi B. , Nikolic Miki , Korbo Lise , Friberg Lars , Jennum Poul J.
Published: December 2019

Background: Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or ‘gate’ irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding cognitive information processing deficits such as slowed processing speed. Parkinson's disease is characterised by the degeneration of the midbrain dopaminergic system and is associated with cognitive dysfunction, including slowed information processing. Although sensorimotor processes in Parkinson's disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. Objective: We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I-FP-CIT-SPECT scanning, in patients with Parkinson's disease. Methods: 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. Results: Patients with a higher level of prepulse inhibition performed better on cognitive measures tapping attention and processing speed than patients with a lower level of prepulse inhibition. Furthermore, there were significant correlations between prepulse inhibition and 123I-FP-CIT uptake in the striatum. Conclusions: Our results suggest that the level of prepulse inhibition is related to the efficiency of information processing in Parkinson's disease, and to the density of dopamine transporters in the striatum.
Can Cognitive Remediation Improve Mobility in Patients with Parkinson's Disease? Findings from a 12 week Pilot Study
Authors: Milman Uzi , Atias Hagit , Weiss Aner , Mirelman Anat , Hausdorff Jeffrey M.
Published: December 2019

Background: Patients with Parkinson's disease (PD) suffer from impaired gait and mobility. These changes in motor function have been associated with cognitive deficits that also commonly co-occur in PD, especially executive function (EF) and attention. Objective: We hypothesized that a cognitive remediation program would enhance gait and mobility. Methods: The 18 PD patients in this study were assessed at baseline and again one and four weeks after completion of a 12 week long, home-based computerized cognitive training program. Subjects were asked to “play” computer games designed to improve EF and attention for 30 minutes a day, three times per week for 12 weeks, while seated. The Timed Up and Go (TUG), gait speed, and stride time variability quantified mobility. A previously validated, computerized neuropsychological battery quantified global cognitive function and its sub-domains. Results: Compared to pre-training values, global cognitive scores and time to complete the TUG significantly improved after the training. TUG components of turning speed and duration also improved. Other TUG components, gait speed, and variability did not change after training. Conclusions: These initial findings suggest that computerized cognitive training can improve cognitive function and has a beneficial carryover effect to certain aspects of mobility in patients with PD. Additional studies are required to replicate these findings and more fully assess the underlying mechanisms. Nonetheless, the present results underscore the motor-cognitive link in PD and suggest that computerized cognitive training may be applied as a therapeutic option to enhance mobility in patients with PD.
Peripheral Autonomic Nervous System Involvement in Gaucher-Related Parkinsonism
Authors: Lebouvier Thibaud , Clairembault Thomas , Devos David , Pallardy Amandine , Coron Emmanuel , Neunlist Michel , Derkinderen Pascal
Published: December 2019

The pathological process affects the peripheral autonomic nervous system in the vast majority of sporadic PD patients. Recent reports have shown that patients with a familial form of the disease caused by mutation of the gene encoding LRRK2 and alpha-synuclein also display autonomic abnormalities, especially cardiac sympathetic denervation. In the present report, we have studied the involvement of the peripheral autonomic system in a patient with Gaucher disease-associated parkinsonism. Using colonic biopsies and quantitative 123I-MIBG scintigraphy respectively, we show that both Lewy pathology and cardiac denervation were present in this case of Gaucher-associated Parkinsonism. We discuss the consequence of these findings on the pathophysiology of the disease.
Linked Clinical Trials – The Development of New Clinical Learning Studies in Parkinson's Disease Using Screening of Multiple Prospective New Treatments
Authors: Brundin Patrik , Barker Roger A. , Conn P. Jeffrey , Dawson Ted M. , Kieburtz Karl , Lees Andrew J. , Schwarzschild Michael A. , Tanner Caroline M. , Isaacs Tom , Duffen Joy , Matthews Helen , Wyse Richard K.H.
Published: December 2019

Finding new therapies for Parkinson's disease (PD) is a slow process. We assembled an international committee of experts to examine drugs potentially suitable for repurposing to modify PD progression. This committee evaluated multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering several natural, non-pharmaceutical compounds. The committee prioritized which of these putative treatments were most suited to move immediately into pilot clinical trials. Aspects considered included known modes of action, safety, blood-brain-barrier penetration, preclinical data in animal models of PD and the possibility to monitor target engagement in the brain. Of the 26 potential interventions, 10 were considered worth moving forward into small, parallel ‘learning’ clinical trials in PD patients. These trials could be funded in a multitude of ways through support from industry, research grants and directed philanthropic donations. The committee-based approach to select the candidate compounds might help rapidly identify new potential PD treatment strategies for use in clinical trials.
Side and Type of Initial Motor Symptom Influences Visuospatial Functioning in Parkinson's Disease
Authors: Seichepine Daniel R. , Neargarder Sandy , Davidsdottir Sigurros , Reynolds Gretchen O. , Cronin-Golomb Alice
Published: December 2019

Background/Objectives: Visuospatial problems are common in Parkinson's disease (PD) and likely stem from dysfunction in dopaminergic pathways and consequent disruption of cortical functioning. Characterizing the motor symptoms at disease onset provides a method of observing how dysfunction in these pathways influences visuospatial cognition. We examined two types of motor characteristics: Body side (left or right) and type of initial symptom (tremor or symptom other than tremor). Methods: 31 non-demented patients with PD, 16 with left-side onset (LPD) and 15 with right-side onset (RPD), as well as 17 healthy control participants (HC). The PD group was also divided by type of initial motor symptom, 15 having tremor as the initial symptom and 16 having an initial symptom other than tremor. Visuospatial function was assessed with the Clock Drawing Test. Results: Of the four Clock Drawing scoring methods used, the Rouleau method showed sensitivity to subgroup differences. As predicted, the LPD and non-tremor subgroups, but not the other subgroups, performed more poorly than the HC group. Conclusion: The findings provide further evidence for differences in cognition between these subtypes of PD and highlight the importance of considering disease subtypes when examining cognition.
Effects of Endurance Exercise Training on The Motor and Non-Motor Features of Parkinson's Disease: A Review
Authors: Lamotte Guillaume , Rafferty Miriam R. , Prodoehl Janey , Kohrt Wendy M. , Comella Cynthia L. , Simuni Tanya , Corcos Daniel M.
Published: December 2019

Background: Despite the benefits of medications and surgical interventions for Parkinson's disease (PD), these treatments are not without complications and neuroprotective strategies are still lacking. Therefore, there is a need for effective alternative approaches to treat motor and non-motor symptoms in PD. During the last decade, several studies have investigated endurance exercise training as a potential treatment for individuals with PD. Objective: This paper reviews the therapeutically beneficial effects of endurance exercise training on motor and non-motor symptoms in PD. Methods: First, we performed a systematic review of the literature on the effects of endurance exercise training on motor and non-motor signs of parkinsonism, functional outcomes including gait, balance and mobility, depression and fatigue, quality of life and perceived patient improvement, cardiorespiratory function, neurophysiological measures, and motor control measures in PD. Second we performed a meta-analysis on the motor section of the UPDRS. Then, we focused on several important factors to consider when prescribing endurance exercise training in PD such as intensity, duration, frequency, specificity and type of exercise. In addition, we identified current knowledge gaps regarding endurance exercise training in PD and made suggestions for future research. Results: A total of eight randomized controlled trials met the inclusion criteria and were reviewed. This systematic review synthesizes evidence that endurance exercise training at a sufficiently high level enhances cardiorespiratory capacity and endurance by improving VO2 max and gait in moderately to mildly affected individuals with PD. However, there is not yet a proven effect of endurance exercise training on specific features of PD such as motor signs of parkinsonism. Conclusion: Endurance exercise training improves physical conditioning in PD patients; however, to date, there is insufficient evidence to include endurance exercise training as a specific treatment for PD. There is a need for well-designed large-scale randomized controlled trials to confirm benefits and safety of endurance exercise training in PD and to explore potential benefits on the motor and non-motor signs of PD.
Long-Term Safety and Maintenance of Efficacy of Levodopa-Carbidopa Intestinal Gel: An Open-Label Extension of the Double-Blind Pivotal Study in Advanced Parkinson's Disease Patients
Authors: Slevin John T. , Fernandez Hubert H. , Zadikoff Cindy , Hall Coleen , Eaton Susan , Dubow Jordan , Chatamra Krai , Benesh Janet
Published: December 2019

Background: Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via intrajejunal percutaneous gastrostomy tube. Objective: To examine long-term safety, efficacy and quality of life of LCIG in an open-label extension study. Methods: Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG vs. LCIG-naïve patients). Results: Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 adverse event (AE); only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naïve patients (N = 29) showed a decrease in “Off” time and an increase in “On” time without troublesome dyskinesia (change from baseline to final visit in mean [SD] hours = −2.34 [2.78] P < 0.001 and 2.19 [3.70] P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained “Off” time duration and further improvement in “On” time without troublesome dyskinesia (−0.42 [2.67] P = 0.377 and 1.00 [2.58] P = 0.036, respectively). The majority of patients in both groups (LCIG-naïve, continuing-LCIG, respectively) were rated ‘Much Improved’ or ‘Very Much Improved’ at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%). Conclusions: Continuing-LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naïve patients was similar to that observed for patients on LCIG in the preceding double-blind study. The overall AE profile was consistent with previous phase 3 clinical trials involving the LCIG system.
Detecting and Predicting Balance Decline in Parkinson Disease: A Prospective Cohort Study
Authors: Duncan Ryan P. , Leddy Abigail L. , Cavanaugh James T. , Dibble Leland E. , Ellis Terry D. , Ford Matthew P. , Foreman K. Bo , Earhart Gammon M.
Published: December 2019

Background: The natural progression of balance decline in individuals with Parkinson disease (PD) is not well understood. Objectives: We aimed to: 1) compare the utility of three standardized clinical measures for detecting balance decline over 1-year, 2) identify components of balance susceptible to decline, and 3) identify factors useful for predicting future balance decline. Methods: Eighty people with PD (59% male; mean age 68.2 ± 9.3; Hoehn & Yahr range I–IV) completed Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Berg Balance Scale (BBS) assessments. Baseline predictor variables included the MDS-UPDRS III sub-score, presence of freezing, 6-month fall history, age, gender, and physical activity. Balance and MDS-UPDRS III assessments were repeated at 6 (n = 51) and 12 months (n = 44). Results: BESTest and Mini-BESTest score declined over 6 and 12 months (P < 0.01). Postural responses, stability limits, and sensory orientation were most susceptible to decline. BBS score did not change (P > 0.01). MDS-UPDRS III score was unchanged over 6 months (P > 0.01), but declined over 12 months (P < 0.01). Change in BESTest score over 6 months was related to baseline MDS-UPDRS III, H&Y, freezing, and fall history (P < 0.05). Change in BESTest score over 12 months was related to baseline MDS-UPDRS III and freezing (P < 0.05). Change in Mini-BESTest over 12 months was related to baseline MDS-UPDRS III and age (P < 0.05). Conclusions: The BESTest and Mini-BESTest were responsive to balance decline in individuals with PD and helped to identify decline in underlying balance components. Disease severity and freezing most consistently predicted balance decline in persons with PD.
Role of α-Synuclein in Inducing Innate and Adaptive Immunity in Parkinson Disease
Authors: Allen Reish Heather E. , Standaert David G.
Published: December 2019

Alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson disease (PD). Gene duplications, triplications and point mutations in SNCA1, the gene encoding α-syn, cause autosomal dominant forms of PD. Aggregated and post-translationally modified forms of α-syn are present in Lewy bodies and Lewy neurites in both sporadic and familial PD, and recent work has emphasized the prion-like ability of aggregated α-syn to produce spreading pathology. Accumulation of abnormal forms of α-syn is a trigger for PD, but recent evidence suggests that much of the downstream neurodegeneration may result from inflammatory responses. Components of both the innate and adaptive immune systems are activated in PD, and influencing interactions between innate and adaptive immune components has been shown to modify the pathological process in animal models of PD. Understanding the relationship between α-syn and subsequent inflammation may reveal novel targets for neuroprotective interventions. In this review, we examine the role of α-syn and modified forms of this protein in the initiation of innate and adaptive immune responses.
Design and Evaluation of Levodopa Methyl Ester Intranasal Delivery Systems
Authors: Chun In Koo , Lee Yeon Hong , Lee Kyung Eun , Gwak Hye Sun
Published: December 2019

Objectives: This study aimed to examine the feasibility of nasal powder formulations for the delivery of levodopa (L-dopa) into the brain using highly water-soluble levodopa methyl ester hydrochloride (LDME). Methods: For designing nasal LDME powders, pH-rate stabilities of LDME in buffer solutions and their enzymatic degradations in rabbit nasal mucosal and serosal extracts were investigated. In vitro permeation studies were carried out with four LDME nasal powders. Results: LDME was degraded fast in weakly acidic and neutral solutions, but relatively stable in acidic solutions. In nasal extracts, LDME (50 and 200 μg/mL) was rapidly hydrolyzed, forming L-dopa, and there were no significant differences in first-order degradation rates between mucosal and serosal extracts. From the in vitro permeation studies, LDME powder formulations resulted in faster appearance rates (1.07 ± 0.39 mg/cm2/hr) of L-dopa than solution formulations (0.35 ± 0.08 mg/cm2/hr). Conclusions: These results suggested that LDME nasal powder formulations could be useful delivery systems of L-dopa.
Striatal Dopamine Depletion Induces Forelimb Motor Impairments and Disrupts Forelimb Movement Representations within the Motor Cortex
Authors: Plowman Emily K. , Thomas Nagheme J. , Kleim Jeffrey A.
Published: December 2019

While limb motor deficits of Parkinson's disease are well characterized, the effects of striatal dopamine depletion on the motor cortex is poorly understood. We therefore aimed to 1) examine the effects of striatal dopamine depletion on forelimb function and cortical motor map topography and 2) explore potential relationships between forelimb function and cortical movement representations in an animal model of PD. Twenty-four male Long Evans rats were randomized to control or 6-hydroxydopamine (6-OHDA) groups. Animals in the 6-OHDA group underwent four unilateral 6-OHDA infusions into the striatum to induce striatal dopamine depletion. Four weeks later, animals were tested on a comprehensive battery of behavioral limb motor tasks followed by intracortical microstimulation to derive high-resolution topographic maps of forelimb movement representations. Standard tyrosine hydroxylase (TH) immunohistochemistry was performed and near infrared densitometry analysis utilized to assess TH depletion. Unilateral striatal dopamine depletion induced significant reductions in limb motor function that were reflected neurophysiologically as a reduction in cortical forelimb movement representations. Voluntary forelimb use, pasta handling, sunflower seed manipulation, and forelimb motor maps were all significantly impaired in 6-OHDA animals. A positive correlation was observed between forelimb function and motor map size, as well as two negative correlations between TH depletion with 1) motor map size and 2) forelimb function. The results clearly show how dysfunction within the basal ganglia thalamocortical loop resulting from nigrostriatal dopamine depletion disrupts corticospinal function.
Measurement Properties of the SF-12 Health Survey in Parkinson's Disease
Authors: Hagell Peter , Westergren Albert
Published: December 2019

The 12-item Short-Form Health Survey (SF-12) is an abbreviated version of the SF-36, one of the most widely used patient-reported health outcome rating scales. Similar to the SF-36, it yields summary scores of physical and mental health (PCS and MCS, respectively). However, SF-36 derived PCS and MCS scores have not been found valid in neurological disorders such as Parkinson's disease (PD). Here we used modern psychometric methodology (Rasch analysis) to test the SF-12 in PD, and explored the appropriateness of a total SF-12 score representing overall health. SF-12 data from 150 non-demented people with PD (56% men; mean age/PD-duration, 70/5 years) were analyzed regarding Rasch model fit for the PCS, MCS, as well as for the full SF-12. Data showed some signs of misfit to the Rasch model for all three scales (overall item-trait interaction, P ≥ 0.003; reliability, ≥ 0.85). For example, all scales exhibited signs of dependency between item responses, and the PCS measured with relatively low precision. Model fit (but not measurement precision) was improved following deletion of one PCS and one MCS item (overall item-trait interaction, P ≥ 0.387; reliability, ≥ 0.82). These observations suggest that the SF-12 can be used as a coarse health survey tool in PD and that a total SF-12 may be useful as a measure of overall health. However, its appropriateness as an outcome measure can be questioned and it is somewhat unclear exactly what the derived scores represent. As such, the SF-12 should probably be considered an assessment tool (or index) rather than a measurement instrument.
Animal Models of Gastrointestinal Problems in Parkinson's Disease
Authors: Greene James G.
Published: December 2019

Gastrointestinal (GI) symptoms are being increasingly recognized as early, common, and severe features of Parkinson's disease (PD), and they are important determinants of quality of life and disability throughout the disease course. In addition, the concept that GI symptoms could represent “pre-motor” PD has been hotly debated and has recently become a driving force for investigations into the pathophysiology and neuropathology of PD. Clinical data has been supported by many pathological studies demonstrating α-synuclein neuritic pathology and neuronal loss in central and peripheral areas relevant to GI function. As understanding has matured concerning the impact of GI dysmotility on patients and its potential relationship to incipient PD, behavioral and neuropathological examination of the GI tract has become a critical aspect of evaluation and validation of PD animal models. This review will briefly summarize GI symptoms and neuropathology in PD important to model in animals, behavioral and neuropathological examination of the GI tract in animals, and the current state of modeling parkinsonian GI dysfunction in animal model systems.
Membrane Interaction of α-Synuclein in Different Aggregation States
Authors: Grey Marie , Linse Sara , Nilsson Hanna , Brundin Patrik , Sparr Emma
Published: December 2019

Aggregated α-synuclein in Lewy bodies is one of the hallmarks of Parkinson's disease (PD). Earlier observations of α-synuclein aggregates in neurons grafted into brains of PD patients suggested cell-to-cell transfer of α-synuclein and a prion-like mechanism. This prompted the current investigation of whether α-synuclein passes over model phospholipid bilayers. We generated giant unilamellar vesicles (GUVs) containing a small amount of a lipid-conjugated red emitting dye (rhodamine B) and varied the membrane charge by using different molar ratios of DOPC and DOPS or cardiolipin. We then used confocal fluorescence microscopy to examine how monomer, fibril as well as on-pathway α-synuclein species labeled with a green emitting fluorophore (Alexa488) interacted with the phospholipid bilayers of the GUV. We defined conditions that yielded reproducible aggregation kinetics under basal conditions and with none or moderate shaking. We found that on-pathway α-synuclein species and equilibrium amyloid aggregates, but not α-synuclein monomers, bound to lipid membranes. α-Synuclein was particularly strongly associated with GUVs containing the anionic lipids cardiolipin or DOPS, whereas it did not associate with GUVs containing only zwitterionic DOPC. We found that α-synuclein progressively aggregated at the surface of the GUVs, typically in distinct domains rather than uniformly covering the membrane, and that both lipid and protein were incorporated in the aggregates. Importantly, we never observed transport of α-synuclein over the GUV bilayer. This suggests that α-synuclein transport over membranes requires additional molecular players and that it might rely on active transport.
Prevalence and Clinical Course of Olfactory Hallucinations in Idiopathic Parkinson's Disease
Authors: McAuley J.H. , Gregory S.
Published: December 2019

Background: Olfactory hallucinations are known to occur in idiopathic Parkinson's disease (IPD) but are much less well-described than visual hallucinations. Objective: To report the prevalence, clinical features, response to treatment and prognosis of olfactory hallucinations in IPD. Methods: 205 consecutively reviewed IPD patients and 205 non-IPD control patients attending the local hospital were surveyed for the presence of olfactory hallucinations by specific questioning; the IPD patients were followed up for at least three years. Results: Of 188 patients who had a clinical course remaining consistent with IPD, four were initially found to have olfactory hallucinations, yielding a prevalence of 2.1% (95% confidence interval 0.4–5.4%). Two further patients developed such hallucinations later during the study. Olfactory hallucinations were not always accompanied by other hallucination modalities. The patients had a long duration of disease treated with dopaminergic medication, loss of sense of smell typical for IPD, no dementia or features suggestive of non-idiopathic PD after three years follow-up, a lack of insight into their hallucinations with consequent failure to report them spontaneously, and a good and lasting response to modest doses of atypical antipsychotics. Conclusions: This study confirms the significant prevalence of olfactory hallucinations, describes their clinical features and indicates that they may occur in isolation and not predict other psychotic or dementing features. The nuisance that such hallucinations cause, their ease of treatment and their failure to be volunteered as a symptom means that specific questioning for their presence should be included in routine assessment of patients with IPD.