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1.  Short and valid assessment of apraxia in Parkinson’s disease 
Parkinsonism & related disorders  2011;18(4):348-350.
Background
Valid assessment of apraxia in usually non-apraxic Parkinson’s disease helps to delineate atypical parkinsonism frequently associated with apraxia. Furthermore, in a subgroup of late Parkinson’s disease apraxia, typically the ideomotor subtype, may gradually superimpose onto parkinsonian motor symptoms contributing to defective manual skill. Here we evaluate the utility of a brief, standardized test, the apraxia screen of TULIA (AST).
Methods
Seventy five Parkinson’s disease patients were tested with the AST. Parkinsonian motor deficits were measured using Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III and difficulties in activities of daily living (ADL) by modified MDS-UPDRS part II (eating, dressing, personal hygiene, and writing).
Results
No association was found between the AST and MDS-UPDRS part III, indicating that AST discriminates well (discriminative validity) between apraxia and parkinsonism. Furthermore, AST was associated with ADL and Hoehn & Yahr stage (convergent validity).
Conclusions
AST is a short and valid test to rule out or detect apraxia in Parkinson’s disease.
doi:10.1016/j.parkreldis.2011.11.023
PMCID: PMC4314207  PMID: 22177625
Apraxia; validity; AST; Parkinson’s disease
2.  [No title available] 
PMCID: PMC3946616  PMID: 24269283
3.  [No title available] 
PMCID: PMC3946668  PMID: 24280022
4.  Aldehyde dehydrogenase inhibition generates a reactive dopamine metabolite autotoxic to dopamine neurons 
Parkinsonism & related disorders  2014;20(0 1):S73-S75.
SUMMARY
The neurotransmitter dopamine (DA) is important for numerous biological functions, including control of movement. Oxidation of DA to highly toxic and reactive species has been hypothesized to contribute to the selective neurodegeneration observed in Parkinson's disease (PD). DA catabolism is initiated by oxidative deamination via monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL). Such metabolism can be problematic as it greatly increases the toxicity of DA by production of DOPAL, known to be a toxic and reactive intermediate. DOPAL undergoes carbonyl metabolism primarily via aldehyde dehydrogenase (ALDH) enzymes to a less toxic acid product. Previous studies from our laboratory have shown that cellular ALDH enzymes are sensitive towards products of oxidative stress and lipid peroxidation, which are thought to be elevated during PD pathogenesis. Inhibition of ALDH and the resulting accumulation of DOPAL are concerning as DOPAL is toxic to dopaminergic cells, readily modifies proteins and causes protein aggregation. In addition, pesticides with association between exposure and PD incidence can interfere with DA metabolism and trafficking and/or ALDH activity, directly or indirectly, yielding elevation of DOPAL. Therefore, impairment of carbonyl metabolism is a potential mechanistic link between cellular insult and generation of a toxic and reactive intermediate endogenous to dopamine neurons.
doi:10.1016/S1353-8020(13)70019-1
PMCID: PMC3932615  PMID: 24262193
Aldehyde dehydrogenase; Dopamine; 3,4-Dihydroxyphenylacetaldehyde; Pesticides
5.  Dietary Fat Intake, Pesticide Use, and Parkinson’s Disease 
Background
Dietary fat intake may modify Parkinson’s disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides.
Methods
We conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses. We evaluated diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls. Associations were evaluated using multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
Results
In the AHS, PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4,95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor α-linolenic acid (0.4, 0.2-0.8). In a meta-analysis of nine studies, including the present one, PD was inversely associated with α-linolenic acid (0.81, 0.68-0.96). In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake p-interaction=0.02).
Conclusions
PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.
doi:10.1016/j.parkreldis.2013.09.023
PMCID: PMC3936597  PMID: 24120951
Parkinson’s disease; dietary fat; polyunsaturated fatty acids; pesticides
6.  Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson Disease 
Background
It is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration.
Objective
To investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving.
Methods
Thirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+)-[11C] dihydrotetrabenazine vesicular monoamine transporter 2 and [11C] methyl-4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity.
Results
Eight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 ± 0.006 vs. 0.0570 ± 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration.
Conclusions
Risky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive.
doi:10.1016/j.parkreldis.2013.08.021
PMCID: PMC3946835  PMID: 24070538
Parkinson disease; PET imaging; Driving
7.  Continuous In-Home Monitoring of Essential Tremor 
Background
Essential tremor (ET) is typically measured in the clinic with subjective tremor rating scales which require the presence of a clinician for scoring and are not appropriate for measuring severity throughout the day. Motion sensors can accurately rate tremor severity during a set of predefined tasks in a laboratory.
Methods
We evaluated the ability of motion sensors to quantify tremor during unconstrained activities at home. 20 ET subjects wore a wireless sensor continuously for up to 10 hours daily on two days and completed hourly standardized tremor assessments involving pre-defined tasks. Mathematical models were used to predict tremor rating scores from the sensor data.
Results
At home tremor scores from hourly standardized assessments correlated with at home tremor scores estimated during unconstrained activities immediately following the standardized assessments. The hourly standardized assessments did not significantly fluctuate throughout the day, while fluctuations in the continuous assessments tended to follow changes in voluntary activity level. Both types of tremor ratings (standardized and continuous) showed high day-to-day test-retest reliability with intraclass correlation coefficients ranging from 0.67 to 0.90 for continuous ratings and 0.77 to 0.95 for standardized ratings.
Conclusions
Results demonstrate the feasibility of continuous monitoring of tremor severity at home, which should provide clinicians with a measure of the temporal pattern of tremor in the context of daily life and serve as a useful tool for the evaluation of novel anti-tremor medications in clinical trials.
doi:10.1016/j.parkreldis.2013.09.009
PMCID: PMC3946846  PMID: 24126021
Essential tremor; ambulatory monitoring; Kinesia; accelerometer; gyroscope
8.  Association mapping of the PARK10 region for Parkinson’s disease susceptibility genes 
Background
Previous studies indicate that as many as six genes within the PARK10 region (RNF11, UQCRH, HIVEP3, EIF2B3, USP24, ELAVL4) might modify susceptibility or age at onset in Parkinson’s disease (PD).
Methods
We sought to identify new PD susceptibility genes and to validate previously nominated candidate genes within the PARK10 region using a two-stage design. We used data from a large, publicly-available genome-wide association study (GWAS) in the discovery stage (n=2000 cases and 1986 controls) and data from three independent studies for the replication stage (total n=2113 cases and 2095 controls). Marker density was increased by imputation using HapMap3 and 1000 Genomes reference panels, and over 40,000 single nucleotide polymorphisms (SNPs) were used in the final analysis. The association between each SNP and PD was modeled using logistic regression with an additive allele dosage effect and adjusted for sex, age, and axes of geographical variation.
Results
Although the discovery stage yielded promising findings for SNPs in several novel genes, including DAB1, none of the results were validated in the replication stage. Furthermore, in meta-analyses across all datasets no genes within PARK10 reached significance after accounting for multiple testing.
Conclusion
Our results suggest that common variation in the PARK10 region is not associated with PD risk. However, additional studies are needed to assess the role of PARK10 in modifying age at onset and to determine whether rare variants in this region might affect PD susceptibility.
doi:10.1016/j.parkreldis.2013.10.001
PMCID: PMC3946853  PMID: 24156912
PARK10; Parkinson’s Disease; Replication; GWAS
9.  Dopaminergic modulation of motor coordinaton in Parkinson’s disease 
Background
We applied the idea of synergies and the framework of the uncontrolled manifold hypothesis to explore the effects of dopamine replacement therapy on finger interaction and coordination in patients with early-stage Parkinson’s disease (PD).
Methods
Eight patients performed single-finger and multi-finger force production tasks with both the dominant and non-dominant hand before (off-drug) and after (on-drug) taking their dopaminergic medications. Synergy indices were defined as co-varied adjustments of commands to fingers that stabilized the total force produced by the hand.
Results
PD patients showed significantly lower maximal finger forces off-drug compared to the on-drug condition, while indices of finger individuation (enslaving) were unchanged. The synergy indices were weaker during steady-state force production off-drug compared to on-drug. Anticipatory adjustments of synergies prior to the quick force pulse initiation were delayed and reduced off-drug as compared to the on-drug condition. These drug effects were observed in both the symptomatic and asymptomatic hands of the patients whose symptoms were limited to one side of the body.
Conclusions
The study demonstrates dopaminergic modulation of motor coordination in PD and supports that the analysis of different components of multi-finger synergies offers a set of indices sensitive to the effects of dopamine replacement therapy in early-stage PD. The results suggest an important role of the basal ganglia in synergy formation and in feed-forward synergy adjustments. Future studies using these methods may yield more objective, quantitative biomarker(s) of motor coordination impairments in PD, and better understanding of subcortical involvement in the neural control of natural actions.
doi:10.1016/j.parkreldis.2013.09.019
PMCID: PMC3946854  PMID: 24090949
Parkinson’s disease; Synergy; Finger; Uncontrolled manifold hypothesis; Feed-forward control
10.  Update on novel familial forms of Parkinson’s disease and multiple system atrophy 
Parkinsonism & related disorders  2014;20(0 1):S29-S34.
Parkinson’s disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.
doi:10.1016/S1353-8020(13)70010-5
PMCID: PMC4215194  PMID: 24262183
SNCA; VPS35; PD; MSA; Genetics; Familial
11.  Update on models of basal ganglia function and dysfunction 
Parkinsonism & related disorders  2009;15(0 3):S237-S240.
Circuit models of basal ganglia function and dysfunction have undergone significant changes over time. The previous view that the basal ganglia are centers in which massive convergence of cortical information occurred has now been replaced by a view in which these structures process information in a highly specific manner, participating in anatomical and functional modules that also involve cortex and thalamus. In addition, much has been learned about the intrinsic connections of the basal ganglia. While the basal ganglia-thalamocortical circuitry was originally seen almost exclusively in its relationship to the control of movement, these structures are now viewed as essential for higher level behavioral control, for instance in the regulation of habit learning or action selection. Probably the greatest benefit of these models has been that they have motivated a wealth of studies of the pathophysiology of movement disorders of basal ganglia origin, such as Parkinson’s disease. Such studies, in turn, have helped to reshape the existing circuit models. In this paper we review these fascinating changes of our appreciation of the basal ganglia circuitry, and comment on the current state of our knowledge in this field.
doi:10.1016/S1353-8020(09)70822-3
PMCID: PMC4275124  PMID: 20082999
Basal ganglia circuits; Striatum; Subthalamic nucleus; Globus pallidus; Parkinson’s disease
12.  Two cases of pregnancy in Parkinson’s disease 
Parkinsonism & related disorders  2013;20(2):239-240.
doi:10.1016/j.parkreldis.2013.10.013
PMCID: PMC4265576  PMID: 24182521
Pregnancy; PD; Parkinson’s disease
13.  EARLY CORTICAL GRAY MATTER LOSS AND COGNITIVE CORRELATES IN NON-DEMENTED PARKINSON’S PATIENTS 
Parkinsonism & related disorders  2013;19(12):10.1016/j.parkreldis.2013.07.018.
Background
Whereas the motor dysfunction in Parkinson’s disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.
Methods
High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.
Results
PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.
Conclusions
Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.
doi:10.1016/j.parkreldis.2013.07.018
PMCID: PMC3858507  PMID: 23932064
Parkinson’s disease; Cognition; MRI; Voxel-based morphometry; Gray Matter Volume
14.  Parkinson's disease and history of outdoor occupation 
Parkinsonism & related disorders  2013;19(12):1164-1166.
Background
Human and animal studies, albeit not fully consistent, suggest that vitamin D may reduce risk of Parkinson's disease (PD). Ultraviolet radiation converts vitamin D precursor to the active form. This study examined the hypothesis that working outdoors is associated with a decreased risk of PD.
Methods
PD cases were enrolled from Group Health Cooperative, a health maintenance organization in the Puget Sound region in western Washington State, and the University of Washington Neurology Clinic in Seattle. Participants included 447 non-Hispanic Caucasian newly diagnosed PD cases diagnosed between 1992 and 2008 and 578 unrelated neurologically normal controls enrolled in Group Health Cooperative, frequency matched by race/ethnicity, age and gender. Subjects' amount of outdoor work was estimated from self-reported occupational histories. Jobs were categorized by degree of time spent working outdoors. A ten-year lag interval was included to account for disease latency. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression, with adjustment for age, gender, and smoking.
Results
Outdoor work was inversely associated with risk of PD (outdoor only compared to indoor only): OR= 0.74, 95% CI 0.44-1.25. However, there was no trend in relation to portion of the workday spent laboring outdoors and PD risk.
Conclusion
Occupational sunlight exposure and other correlates of outdoor work is not likely to have a substantial role in the etiology of PD.
doi:10.1016/j.parkreldis.2013.08.014
PMCID: PMC3927788  PMID: 24044947
Parkinson's disease; occupation; ultraviolet radiation; vitamin D
15.  Sleep and Impulsivity in Parkinson’s Disease 
Parkinsonism & related disorders  2013;19(11):10.1016/j.parkreldis.2013.06.018.
Background
Impulsive behavior and poor sleep are important non-motor features of Parkinson’s disease (PD) that negatively impact the quality of life of patients and their families. Previous research suggests a higher level of sleep complaints in PD patients who demonstrate impulsive behaviors, but the nature of the sleep disturbances has yet to be comprehensively tested.
Methods
Consecutive idiopathic PD patients (N=143) completed the Minnesota Impulse Disorder Interview and a sleep questionnaire that assessed sleep efficiency, excessive daytime sleepiness, restless legs symptoms, snoring, dreams/nightmares, and nocturia. Patients were also given a Unified Parkinson’s Disease Rating Scale motor examination and they completed cognitive testing.
Results
Impulsive PD patients endorsed more sleep complaints than non-impulsive PD patients. The group difference was primarily attributable to poor sleep efficiency (e.g., greater nocturnal awakenings), p < .01, and greater daytime sleepiness, p < .01, in the impulsive PD patients. Interestingly, restless legs symptoms were also greater in the impulsive PD patients, p < .05. The results could not be explained by medications or disease severity.
Conclusions
Poor sleep efficiency, restless legs symptoms, and increased daytime sleepiness are associated with impulsivity in PD. Longitudinal studies are needed to determine whether sleep disturbances precede impulsivity in PD.
doi:10.1016/j.parkreldis.2013.06.018
PMCID: PMC3878049  PMID: 23880026
Parkinson s disease; sleep; impulse control disorder; excessive daytime sleepiness
16.  The MDS–UPDRS tracks motor and non–motor improvement due to subthalamic nucleus deep brain stimulation in Parkinson disease 
Parkinsonism & related disorders  2013;19(11):10.1016/j.parkreldis.2013.06.010.
Background
The Movement Disorders Society revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) improves upon the original UPDRS by adding more non-motor items, making it a more robust tool to evaluate the severity of motor and non-motor symptoms of Parkinson disease. Previous studies on deep brain stimulation have not used the MDS-UPDRS.
Objective
To determine if the MDS-UPDRS could detect improvement in both motor and non-motor symptoms after bilateral subthalamic nucleus deep brain stimulation for Parkinson disease.
Methods
We compared scores on the entire MDS-UPDRS prior to surgery (baseline) and approximately six months following the initial programming visit in twenty subjects (12M/8F) with Parkinson disease undergoing bilateral subthalamic nucleus deep brain stimulation.
Results
STN DBS significantly improved the scores for every section of the MDS-UPDRS at the 6 month follow-up. Part I improved by 3.1 points (22%), Part II by 5.3 points (29%), Part III by 13.1 points (29%) with stimulation alone, and Part IV by 7.1 points (74%). Individual non-motor items in Part I that improved significantly were constipation, light-headedness, and fatigue.
Conclusions
Both motor and non-motor symptoms, as assessed by the MDS-UPDRS, improve with bilateral subthalamic nucleus stimulation six months after the stimulator is turned on. We recommend that the MDS-UPDRS be utilized in future deep brain stimulation studies because of the advantage of detecting change in non-motor symptoms.
doi:10.1016/j.parkreldis.2013.06.010
PMCID: PMC3825788  PMID: 23849499
Parkinson disease; deep brain stimulation; subthalamic nucleus; motor symptoms; non-motor symptoms
17.  The Effect of Tai Chi Exercise on Gait Initiation and Gait Performance in Persons with Parkinson’s Disease 
Parkinsonism & related disorders  2013;19(11):10.1016/j.parkreldis.2013.06.007.
Gait dysfunction and postural instability are two debilitating symptoms in persons with Parkinson’s disease (PD). Tai Chi exercise has recently gained attention as an attractive intervention for persons with PD because of its known potential to reduce falls and improve postural control, walking abilities, and safety at a low cost. The purpose of this report is to investigate the effect of Tai Chi exercise on dynamic postural control during gait initiation and gait performance in persons with idiopathic PD, and to determine whether these benefits could be replicated in two different environments, as complementary projects. In these two separate projects, a total of 45 participants with PD were randomly assigned to either a Tai Chi group or a control group. The Tai Chi groups in both projects completed a 16-week Tai Chi exercise session, while the control groups consisted of either a placebo (i.e., Qi-Gong) or non-exercise group. Tai Chi did not significantly improve Unified Parkinson’s Disease Rating Scale Part III score, selected gait initiation parameters or gait performance in either project. Combined results from both projects suggest that 16 weeks of class-based Tai Chi were ineffective in improving either gait initiation, gait performance, or reducing parkinsonian disability in this subset of persons with PD. Thus the use of short-term Tai Chi exercise should require further study before being considered a valuable therapeutic intervention for these domains in PD.
doi:10.1016/j.parkreldis.2013.06.007
PMCID: PMC3825828  PMID: 23835431
Balance; Gait; Parkinson’s Disease; Tai Chi; Exercise; Rehabilitation
18.  Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease 
Parkinsonism & related disorders  2013;19(11):1057-1060.
Objective
Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin.
Methods
Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function.
Results
We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants.
Conclusions
Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.
doi:10.1016/j.parkreldis.2013.07.011
PMCID: PMC4055791  PMID: 23916651
α-synuclein; SNCA gene; Parkinson's disease; Genetic etiology; Missense mutations
19.  Glucocerebrosidase mutations in primary parkinsonism 
Parkinsonism & Related Disorders  2014;20(11):1215-1220.
Introduction
Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson's Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism.
Methods
We studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P.
Results
Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR = 7.2, CI = 3.3–15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR = 21.9, CI = 6.8–70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52 ± 10 vs. 57 ± 10 years, P < 0.0001) and were more likely to have a positive family history of PD (34% vs. 20%, P < 0.001).
Conclusion
GBA dysfunction is relevant for synucleinopathies, such as PD and DLB, except for MSA, in which pathology involves oligodendrocytes, and the tauopathies PSP and CBD. The risk of developing DLB is three-fold higher than PD, suggesting a more aggressive phenotype.
Highlights
•We screened a large case–control cohort with parkinsonism for common GBA mutations.•GBA mutations in the Italian population are a risk factor for Lewy Bodies Diseases (PD and DLB).•GBA mutations were not increased in the other forms of parkinsonism: PSP, CBD and MSA.•GBA dysfunction does not seem to be involved in MSA and tauopathies.
doi:10.1016/j.parkreldis.2014.09.003
PMCID: PMC4228056  PMID: 25249066
Parkinson's disease; GBA; Parkinsonism; Association analysis; Splicing mutation; Functional characterization
20.  Does a specialist unit improve outcomes for hospitalized patients with Parkinson's disease? 
Parkinsonism & Related Disorders  2014;20(11):1242-1247.
Objective
Suboptimal management of Parkinson's disease (PD) medication in hospital may lead to avoidable complications. We introduced an in-patient PD unit for those admitted urgently with general medical problems. We explored the effect of the unit on medication management, length of stay and patient experience.
Methods
We conducted a single-center prospective feasibility study. The unit's core features were defined following consultation with patients and professionals: specially trained staff, ready availability of PD drugs, guidelines, and care led by a geriatrician with specialty PD training. Mandatory staff training comprised four 1 h sessions: PD symptoms; medications; therapy; communication and swallowing. Most medication was prescribed using an electronic Prescribing and Administration system (iSOFT) which provided accurate data on time of administration. We compared patient outcomes before and after introduction of the unit.
Results
The general ward care (n = 20) and the Specialist Parkinson's Unit care (n = 24) groups had similar baseline characteristics. On the specialist unit: less Parkinson's medication was omitted (13% vs 20%, p < 0.001); of the medication that was given, more was given on time (64% vs 50%, p < 0.001); median length of stay was shorter (9 days vs 13 days, p = 0.043) and patients' experience of care was better (p = 0.01).
Discussion
If replicated and generalizable to other hospitals, reductions in length of stay would lead to significant cost savings. The apparent improved outcomes with Parkinson's unit care merit further investigation. We hope to test the hypothesis that specialized units are cost-effective and improve patient care using a randomized controlled trial design.
Highlights
•We prospectively evaluated a specialist Parkinson's unit for in-patients.•Patients who received Parkinson's unit care had shorter length of stay.•Patients who received Parkinson's unit care had better experience of care.•More Parkinson's medication was given on time.•Less Parkinson's medication was omitted.
doi:10.1016/j.parkreldis.2014.09.015
PMCID: PMC4228081  PMID: 25264022
Parkinson's disease; Hospitalization; Errors; Medication; Length of stay; Specialist unit
21.  Tremulous cervical dystonia is likely to be familial: Clinical characteristics of a large cohort 
Parkinsonism & related disorders  2013;19(6):634-638.
Background
Primary cervical dystonia is the most common form of adult-onset focal dystonia. Although most frequently sporadic, 15–20% of patients report a positive family history, suggesting a possible genetic cause. Head tremor is often present in patients with cervical dystonia and may be a prominent symptom.
Objective
To describe the clinical characteristics of patients with tremulous cervical dystonia.
Methods
Patients with primary cervical dystonia attending our botulinum toxin clinic were assessed with an interview and neurological examination and their notes reviewed. Patients were classified as having either tremulous or non-tremulous cervical dystonia, according to the presence or absence of head tremor on examination. Clinical and demographic data were compared between groups.
Results
From 273 patients included (190 females, 83 males), 125 (46%) were classified as tremulous and 148 (54%) as non-tremulous. Tremulous patients were more likely to have a segmental distribution (61% vs 25%), often involving the arms (48%), and had more frequently associated arm tremor (55% vs 10%). A positive family history of dystonia and/or tremor was more frequent in tremulous patients (50% vs 18%).
Conclusions
Patients with cervical dystonia with associated head tremor are more likely to have a segmental distribution (with frequent arm involvement), associated arm tremor and a positive family history, suggesting a genetic etiology in this subgroup of patients.
doi:10.1016/j.parkreldis.2013.02.017
PMCID: PMC4199095  PMID: 23523105
Tremor; Dystonia; Familial tremor; Familial dystonia
22.  Preclinical and Clinical Neural Network Changes in SCA2 Parkinsonism 
Parkinsonism & related disorders  2012;19(2):158-164.
Background
The pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage.
Methods
We performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects.
Results
Both the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalised after levodopa administration.
Conclusions
In the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms.
doi:10.1016/j.parkreldis.2012.08.011
PMCID: PMC4182914  PMID: 23000299
parkinsonism; SCA2 mutation; Functional connectivity; Basal ganglia motor circuits; Compensation
23.  Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations 
Parkinsonism & related disorders  2013;19(10):869-877.
Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11).
We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
doi:10.1016/j.parkreldis.2013.05.013
PMCID: PMC3977389  PMID: 23787135
HDLS; CSF1R mutation; Parkinsonism; Autosomal dominant; White matter disorders
24.  Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life 
Parkinsonism & Related Disorders  2014;20(10):1071-1075.
Background
Poor quality of life (QoL) is a feature of people with Parkinson's disease (PD) who develop dementia. The relationship between mild cognitive impairment in PD (PD-MCI) and QoL is less clear. To address this, we studied the impact of varying severities of cognitive impairment on QoL in a cohort of non-demented patients with early PD.
Method
Patients with newly diagnosed PD (n = 219) and age and sex matched healthy controls (n = 99) completed a schedule of neuropsychological tests, in addition to scales assessing QoL (PDQ-39), depression, sleep, neuropsychiatric symptoms and a clinical examination. The Movement Disorder Society criteria were used to define and classify PD-MCI.
Results
Participants with PD-MCI were significantly older than those with normal cognition, had more severe motor symptoms, scored higher for depression and had poorer quality of life. Logistic regression showed that mild cognitive impairment, independent of other factors, was an indicator of poorer QoL. Using cognitive performance 2.0 standard deviations (SD) below normative data as a cut-off to define PD-MCI, there was a significant difference in QoL scores between patients with PD-MCI and those classified as having normal cognition. Subjects with less severe mild cognitive impairment did not exhibit significant differences in QoL.
Conclusions
PD-MCI is a significant, independent factor contributing to poorer QoL in patients with newly diagnosed PD. Those classified with greatest impairment (2.0 SD below normal values) have lower QoL. This has implications for clinical practice and future interventions targeting cognitive impairments.
Highlights
•Quality of life declines with increased severity of cognitive impairment in PD.•Mild cognitive impairment in PD (PD-MCI) independently contributes to poorer QoL.•PD-MCI at 2 standard deviations below controls had the greatest impact on QoL.•The optimal operational cut-off for PD-MCI may be 2 standard deviations.
doi:10.1016/j.parkreldis.2014.07.004
PMCID: PMC4194347  PMID: 25074728
Parkinson's disease; Mild cognitive impairment; Quality of life
25.  Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases☆ 
Parkinsonism & related disorders  2009;15(7):516-520.
Background
Pure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.
Method
The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[18F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[18F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.
Results
The PAF group had a low mean UPSIT score (22 ± 3), similar to that in PD (20 ± 2) and lower than in MSA (31 ± 2, p = 0.004). Individual UPSIT scores correlated positively with cardiac 6-[18F]fluorodopamine-derived radioactivity (r = 0.63 in the septum, p < 0.0001; r = 0.64 in the free wall, p < 0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[18F]fluorodopa-derived radioactivity.
Discussion
In synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.
doi:10.1016/j.parkreldis.2008.12.009
PMCID: PMC4164391  PMID: 19201246
Olfaction; Parkinson; Multiple system atrophy; Fluorodopa; Fluorodopamine; PET; Biomarker

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