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1.  Autonomic complaints in patients with Restless Leg Syndrome 
Sleep medicine  2013;14(12):1413-1416.
Background
Data regarding autonomic function in restless legs syndrome (RLS) is limited to heart rate and blood pressure changes in cases having periodic limb movements (PLMS).
Methods
We compared autonomic symptoms of 49 subjects with RLS vs. 291 Controls using the SCOPA-Autonomic questionnaire (23 items in six domains scored 0–3). The total score and domain scores were transformed to 0 to 100 points. Subjects with neurodegenerative disorders (i.e. dementia, parkinsonism) were excluded.
Results
The RLS group was younger (mean±SD 77.9 ± 8.0 vs. 80.5 ± 7.9 yrs, p=.03) and had more women (84% vs. 69%, p=.04). The mean SCOPA-Aut Total score was higher in the RLS group compared with Controls (20 ± 11 vs. 16 ± 9, p= .005). Additionally the RLS group had abnormalities in GI, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ≥ 1) the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance.
Conclusions
Autonomic complaints, especially GI, cardiovascular, and oversensitivity to light, are significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation.
doi:10.1016/j.sleep.2013.08.781
PMCID: PMC4105217  PMID: 24152795
Restless Leg Syndrome; Autonomic symptoms
2.  SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA Screening 
PLoS ONE  2013;8(10):e77711.
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
doi:10.1371/journal.pone.0077711
PMCID: PMC3813773  PMID: 24204929
3.  Autonomic function, as self-reported on the SCOPA-autonomic questionnaire, is normal in essential tremor but not in Parkinson’s disease 
Parkinsonism & related disorders  2012;18(10):1089-1093.
Objective
To compare autonomic function of subjects with Parkinson’s disease (PD) and essential tremor (ET) relative to controls.
Background
It has been reported that patients with PD have autonomic dysfunction while no literature exists regarding autonomic function in ET.
Methods
Subjects with PD, ET, and controls had autonomic function measured using the SCOPA-Autonomic questionnaire, with the total and domain scores transformed to a scale of 0–100 points.
Results
62 subjects with PD, 84 with ET, and 291 controls were included. Women were more prevalent in control (69%) compared to PD (44%) and ET (44%) groups, and mean age was significantly younger in PD (73 yrs) and older in ET (83) compared to controls (81). The mean SCOPA-Aut Total score in PD was significantly higher than controls, with no difference in ET. No autonomic dysfunction was found in any domain in ET but in PD there were significant abnormalities in gastrointestinal, cardiovascular, urinary, and thermoregulatory domains. Individual question data revealed a significantly higher percentage of subjects with dysfunction on 11/23 questions in the PD group but only 1 question (sialorrhea) in the ET group compared with controls.
Conclusion
Autonomic scores, particularly gastrointestinal, cardiovascular, urinary, and thermoregulatory were increased in patients with PD, as assessed by SCOPA-Aut. Patients with ET did not exhibit autonomic dysfunction, with the exception of sialorrhea.
doi:10.1016/j.parkreldis.2012.06.008
PMCID: PMC3665503  PMID: 22771283
Autonomic dysfunction; Parkinson’s disease; Essential tremor
4.  Incidental Lewy Body Disease: Electrophysiological Findings Suggesting Pre-clinical Lewy Body Disorders 
Objective
Evaluate electrophysiologic findings in incidental Lewy Body disease (ILBD).
Methods
ILBD, Control, and Parkinson's disease (PD) subjects had electrophysiological evaluation within two years prior to autopsy. Data analyzed included surface electromyography (EMG) of upper extremity muscles during rest and muscle activation, and electroencephalography (EEG) recording at rest. For EMG, gross tracings and spectral peaks were analyzed. EEG measures analyzed were background frequency and power in delta, theta, alpha, and beta bands.
Results
Three of ten ILBD subjects (30%) showed unilateral rhythmic EMG discharges at rest without a visually apparent rest tremor. The ILBD resting EMG frequency was lower than in the Control group with no overlap (P=0.03) and close to that of the PD group. The ILBD group had significantly lower background rhythm frequency than the Control group (P=0.001) but was greater than the PD group (P=0.01).
Conclusions
The electrophysiologic changes in ILBD cases are between those of Control and PD, suggesting that these findings may reflect changes correlating with ILBD as a possible precursor to PD.
Significance
Electrophysiologic changes in ILBD may assist with the identification of a preclinical stage for Lewy body disorders and help the development of a therapeutic agent for modifying Lewy body disease progression.
doi:10.1016/j.clinph.2011.03.033
PMCID: PMC3164932  PMID: 21616709
Lewy body; Electromyography; Electroencephalography; Pathology; Parkinson's disease; Tremor
5.  Probable RBD is Increased in Parkinson’s Disease But Not in Essential Tremor or Restless Legs Syndrome 
Parkinsonism & related disorders  2011;17(6):456-458.
Objective
Compare the frequency of REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD), restless legs syndrome (RLS), essential tremor (ET), and control subjects.
Methods
Subjects enrolled in a longitudinal clinicopathologic study, and when available an informant, completed the Mayo Sleep Questionnaire, which asks “Have you ever been told that you act out your dreams?”, and the Epworth Sleepiness Scale (ESS).
Results
Probable RBD (based on informant response to the questionnaire) was much more frequent in PD (34/49, 69%, p<0.001) than in RLS (6/30, 20%), ET (7/53, 13%), or control subjects (23/175, 13%), with an odds ratio of 11 for PD compared to controls. The mean ESS and the number of subjects with an ESS ≥ 10 was higher in PD (29/60, 48%, p<0.001) and RLS (12/39, 31%, p<0.001) compared with ET (12/93, 13%) and Controls (34/296, 11%).
Conclusions
Probable RBD is much more frequent in PD with no evidence to suggest an increase in either RLS or ET. Given the evidence that RBD is a synucleinopathy, the lack of an increased frequency of RBD in subjects with ET or RLS suggests the majority of ET and RLS subjects are unlikely to be at increased risk for developing PD.
doi:10.1016/j.parkreldis.2011.03.007
PMCID: PMC3119772  PMID: 21482171
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
6.  Parkinson’s Disease, Cortical Dysfunction, and Alpha-Synuclein 
Background
The ability to understand how Parkinson’s disease (PD) neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in PD dementia (PD-D). The overall purpose of this project was to study the small amplitude cortical myoclonus in PD as an in vivo model of focal cortical dysfunction secondary to PD neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in PD is linked to abnormal levels of α-synuclein in primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures.
Methods
Primary motor cortex was evaluated for 11 PD subjects with (PD+Myoclonus group) and 8 without (PD group) electrophysiologically confirmed cortical myoclonus who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α-synuclein, Aβ-42 peptide, and other biochemical measures were made in primary motor cortex.
Results
A 36% increase in α-synuclein was found in the motor cortex of PD+Myoclonus cases when compared to PD without myoclonus. This occurred without significant differences in insoluble α-synuclein, phosphorylated to total α-synuclein ratio, or Aβ-42 peptide levels. Higher total motor cortex α-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings.
Conclusions
These results suggest an association between elevated α-synuclein and the dysfunctional physiology arising from the motor cortex in PD+Myoclonus cases. Alzheimer’s disease pathology was not associated with cortical myoclonus in PD. Cortical myoclonus arising from motor cortex is a model to study cortical dysfunction in PD.
doi:10.1002/mds.23697
PMCID: PMC3154995  PMID: 21542019
7.  Patient versus informant reporting of ICD symptoms in Parkinson’s disease using the QUIP: Validity and variability☆ 
Parkinsonism & related disorders  2010;17(3):153-155.
Questions exist regarding the validity of patient-reporting of psychiatric symptoms in Parkinson’s disease (PD). We assessed observer variability and validity in reporting of impulse control disorder (ICD) symptoms in PD by using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP). PD patients and their informants (71 pairs) completed the QUIP to assess four ICDs (compulsive gambling, buying, sexual behavior, and eating) in patients. Trained raters then administered a diagnostic interview. Sensitivity of the QUIP for a diagnosed ICD was 100% for both patient- and informant-completed instruments, and specificity was 75% for both raters. Approximately 40% of patients without an ICD diagnosis had a positive QUIP, suggesting that many PD patients experience subsyndromal ICD symptoms that require ongoing monitoring. Agreement between patient- and informant-reporting of any ICD behaviors on the QUIP was moderate (kappa = 0.408), and for individual ICDs was highest for gambling (kappa = 0.550). Overall, a negative QUIP from either the patient or informant rules out the possibility of an ICD, while a positive QUIP requires a follow-up diagnostic interview and ongoing monitoring to determine if symptoms currently are, or in the future become, clinically significant.
doi:10.1016/j.parkreldis.2010.11.015
PMCID: PMC3073062  PMID: 21186135
Impulse control disorders; Parkinson’s disease; QUIP
9.  No Evidence for Cognitive Dysfunction or Depression in Patients with Mild Restless Legs Syndrome 
Restless legs syndrome is a common disoder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.
doi:10.1002/mds.22701
PMCID: PMC2935658  PMID: 19609905
restless legs syndrome; cognitive dysfunction
10.  Validation of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) 
Objective
As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson’s disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD.
Methods
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored.
Results
The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling=0.95, sexual behavior=0.97, buying=0.87, eating=0.88, punding=0.78, hobbyism=0.93, walkabout=0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling=0.95, sexual behavior=0.96, buying=0.87, eating=0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96% and 94%, respectively.
Conclusions
Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.
doi:10.1002/mds.22571
PMCID: PMC2848971  PMID: 19452562
Parkinson’s disease; impulse control disorders; dopamine dysregulation syndrome; punding; pathological gambling
11.  Cerebellar Ataxia from Multiple Potential Causes: Hypothyroidism, Hashimoto's Thyroiditis, Thalamic Stimulation, and Essential Tremor 
Tremor and Other Hyperkinetic Movements  2012;2:tre-02-44-309-2.
Background
Both hypothyroidism and Hashimoto's thyroiditis (HT) can rarely be associated with cerebellar ataxia. Severe essential tremor (ET) as well as bilateral thalamic deep brain stimulation (DBS) may lead to subtle cerebellar signs.
Case Report
We report a 74-year-old male with hypothyroidism and a 20-year history of ET who developed cerebellar ataxia after bilateral thalamic DBS. Extensive workup revealed elevated thyroid stimulating hormone and thyroperoxidase antibody titers confirming the diagnosis of HT.
Discussion
Our case demonstrates multiple possible causes of cerebellar ataxia in a patient, including hypothyroidism, HT, chronic ET, and bilateral thalamic DBS. Counseling of patients may be appropriate when multiple risk factors for cerebellar ataxia coexist in one individual.
PMCID: PMC3569994  PMID: 23439792
Ataxia; tremor; Hashimoto's thyroiditis; thalamic stimulation; deep brain stimulation; hypothyroidism

Results 1-11 (11)