Publications by authors named "Eric Molho"

54 Publications

Narcolepsy genetic marker HLA DQB1*06:02 and excessive daytime sleepiness in Parkinson disease patients treated with dopaminergic agents.

J Neurol 2021 Sep 24. Epub 2021 Sep 24.

Parkinson Disease and Movement Disorders Center, Albany Medical College, 47 New Scotland Ave, Albany, NY, 12208, USA.

Objective: To determine whether narcolepsy Human Leukocyte Antigen (HLA) risk allele DQB1*0602 is associated with excessive daytime sleepiness (EDS) and inappropriate sleep in patients with Parkinson disease (PD).

Background: EDS is a common and disabling non-motor manifestation of PD, affecting quality of life and driving performance. DQB1*0602 is an HLA risk allele for narcolepsy. It is present in 12-30% of the general population. We hypothesize that DQB1*0602 is associated with an increased risk of EDS and inappropriate sleep in PD patients.

Methods: This was a cross-sectional observational study of 150 PD individuals on dopaminergic agents. Main outcome measures were DQB1*0602 status and the modified Epworth Sleepiness Scale. Individuals with dementia, loss of independence, narcolepsy and untreated sleep apnea were excluded. Confounding variables for EDS were assessed using Parkinson Disease Sleep Scale, Mayo Sleep Questionnaire, Unified PD Rating Scale, Hoehn and Yahr scale.

Results: DQB1*06:02 positive PD patients were approximately three times more likely to experience EDS and fall asleep inappropriately during activities that required sustained alertness (e.g. driving, eating, attending work etc.). Exploratory post hoc analysis showed a dopaminergic drug dose- and type- dependent effect on daytime sleepiness in DQB1*06:02 positive individuals. No significant differences were found in confounding variables.

Conclusion: PD individuals are more likely to experience EDS and fall asleep inappropriately during activities if DQB1*0602 positive. Genetic vulnerability may explain EDS risk in PD.
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http://dx.doi.org/10.1007/s00415-021-10813-1DOI Listing
September 2021

Exploring human-genome gut-microbiome interaction in Parkinson's disease.

NPJ Parkinsons Dis 2021 Aug 18;7(1):74. Epub 2021 Aug 18.

Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson's disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we found evidence that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. Results put forth testable hypotheses on the role of gut microbiome in the pathogenesis of PD, the incomplete penetrance of PD susceptibility genes, and potential triggers of pathology in the gut.
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http://dx.doi.org/10.1038/s41531-021-00218-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373869PMC
August 2021

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Ann Neurol 2021 07 17;90(1):76-88. Epub 2021 May 17.

23andMe, Inc., Sunnyvale, CA.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252519PMC
July 2021

Motor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson's Disease Symptoms in a Rat Model.

Neuroscience 2021 04 23;460:88-106. Epub 2021 Feb 23.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA; Department of Neurology, Albany Medical Center, Albany, NY, USA. Electronic address:

Deep brain stimulation (DBS) in Parkinson's disease (PD) alters neuronal function and network communication to improve motor symptoms. The subthalamic nucleus (STN) is the most common DBS target for PD, but some patients experience adverse effects on memory and cognition. Previously, we reported that DBS of the ventral anterior (VA) and ventrolateral (VL) nuclei of the thalamus and at the interface between the two (VA|VL), collectively VA-VL, relieved forelimb akinesia in the hemiparkinsonian 6-hydroxydopamine (6-OHDA) rat model. To determine the mechanism(s) underlying VA-VL DBS efficacy, we examined how motor cortical neurons respond to VA-VL DBS using single-unit recording electrodes in anesthetized 6-OHDA lesioned rats. VA-VL DBS increased spike frequencies of primary (M1) and secondary (M2) motor cortical pyramidal cells and M2, but not M1, interneurons. To explore the translational merits of VA-VL DBS, we compared the therapeutic window, rate of stimulation-induced dyskinesia onset, and effects on memory between VA-VL and STN DBS. VA-VL and STN DBS had comparable therapeutic windows, induced dyskinesia at similar rates in hemiparkinsonian rats, and adversely affected performance in the novel object recognition (NOR) test in cognitively normal and mildly impaired sham animals. Interestingly, a subset of sham rats with VA-VL implants showed severe cognitive deficits with DBS off. VA-VL DBS improved NOR test performance in these animals. We conclude that VA-VL DBS may exert its therapeutic effects by increasing pyramidal cell activity in the motor cortex and interneuron activity in the M2, with plausible potential to improve memory in PD.
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http://dx.doi.org/10.1016/j.neuroscience.2021.02.019DOI Listing
April 2021

Dissociative Tremor Response with Pallidal Deep Brain Stimulation in Parkinson's Disease.

Tremor Other Hyperkinet Mov (N Y) 2020 12 16;10:53. Epub 2020 Dec 16.

Department of Neurology, University of Florida, Gainesville, FL, US.

Background: Pallidal and subthalamic targets are commonly used for deep brain stimulation in Parkinson's disease (PD), with similar efficacy for resting tremor control. However, neuromodulatory effects on kinetic and postural tremor in PD is less clear.

Case Report: We present a 67-year-old PD patient with marked dissociative tremor response following pallidal neuromodulation. We observed excellent resting tremor suppression, but postural and kinetic tremors remained severe, requiring additional thalamic VIM stimulation for management.

Discussion: Our findings illustrate the phenotypical differences in PD and differential response to diverse tremor characteristics with distinctive stimulation targets. Additional studies are necessary to understand these differences.
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http://dx.doi.org/10.5334/tohm.568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747761PMC
December 2020

Effects of subthalamic nucleus deep brain stimulation on neuronal spiking activity in the substantia nigra pars compacta in a rat model of Parkinson's disease.

Neurosci Lett 2020 11 24;739:135443. Epub 2020 Oct 24.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, United States; Department of Neurology, Albany Medical Center, Albany, NY, United States. Electronic address:

Parkinson's Disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) therapy can reduce levodopa equivalent daily dose (LEDD) by approximately 50 %, leading to less symptoms of dyskinesia. The underlying mechanisms contributing to this reduction remain unclear, but studies posit that STN-DBS may increase striatal dopamine levels by exciting remaining dopaminergic cells in the substantia nigra pars compacta (SNc). Yet, no direct evidence has shown how SNc neuronal activity responds during STN-DBS in PD. Here, we use a hemiparkinsonian rat model of PD and employ in vivo electrophysiology to examine the effects of STN-DBS on SNc neuronal spiking activity. We found that 43 % of SNc neurons in naïve rats reduced their spiking frequency to 29.8 ± 18.5 % of baseline (p = 0.010). In hemiparkinsonian rats, a higher number of SNc neurons (88 % of recorded cells) decreased spiking frequency to 61.6 ± 4.4 % of baseline (p = 0.030). We also noted that 43 % of SNc neurons in naïve rats increased spiking frequency from 0.2 ± 0.0 Hz at baseline to 1.8 ± 0.3 Hz during stimulation, but only 1 SNc neuron from 1 hemiparkinsonian rat increased its spiking frequency by 12 % during STN-DBS. Overall, STN-DBS decreased spike frequency in the majority of recorded SNc neurons in a rat model of PD. Less homogenous responsiveness in directionality in SNc neurons during STN-DBS was seen in naive rats. Plausibly, poly-synaptic network signaling from STN-DBS may underlie these changes in SNc spike frequencies.
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http://dx.doi.org/10.1016/j.neulet.2020.135443DOI Listing
November 2020

Ziconotide-Induced Oro-lingual Dyskinesia: 3 Cases.

Tremor Other Hyperkinet Mov (N Y) 2020 10 6;10:37. Epub 2020 Oct 6.

Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.

Background: Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.

Cases: Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.

Conclusions: Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.
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http://dx.doi.org/10.5334/tohm.431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546104PMC
October 2020

Sex-specific effects of subthalamic nucleus stimulation on pain in Parkinson's disease.

J Neurosurg 2020 Oct 9:1-8. Epub 2020 Oct 9.

Departments of1Neuroscience and Experimental Therapeutics.

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD.

Methods: The authors prospectively evaluated 20 patients preoperatively and postoperatively after bilateral STN DBS with the validated numeric rating scale (NRS), Revised Oswestry Disability Index for low-back pain (RODI), and King's Parkinson's Disease Pain Scale (KPDPS) and assessed the impact of sex as a biological variable.

Results: The cohort consisted of 6 female and 14 male patients with a mean duration of 11.8 ± 2.0 months since DBS surgery. Females were significantly older (p = 0.02). Covariate analysis, however, showed no effect of age, stimulation settings, or other confounding variables. KPDPS total scores statistically significantly improved only among males (p < 0.001). Males improved more than females in musculoskeletal and chronic subsets of the KPDPS (p = 0.03 and p = 0.01, respectively). RODI scores significantly improved in males but not in females (p = 0.03 and p = 0.30, respectively). Regarding the NRS score, the improvements seen in both sexes in NRS were not significant.

Conclusions: Although it is well recognized that pain complaints in PD are different between men and women, this study is unique in that it examines the sex-specific DBS effects on this symptom. Considering sex as a biological variable may have important implications for DBS pain outcome studies moving forward.
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http://dx.doi.org/10.3171/2020.6.JNS201126DOI Listing
October 2020

Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens.

NPJ Parkinsons Dis 2020 12;6:11. Epub 2020 Jun 12.

Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294 USA.

In Parkinson's disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD; all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small ( = 20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication ( = 333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather they represented three clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens and all were elevated in PD. Cluster 2 was short-chain fatty acid (SCFA)-producing bacteria and all were reduced in PD. Cluster 3 was carbohydrate-metabolizing probiotics and were elevated in PD. Depletion of anti-inflammatory SCFA-producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is an original finding and their identity provides a lead to experimentally test their role in PD.
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http://dx.doi.org/10.1038/s41531-020-0112-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293233PMC
June 2020

Safety and Efficacy of RimabotulinumtoxinB for Treatment of Sialorrhea in Adults: A Randomized Clinical Trial.

JAMA Neurol 2020 04;77(4):461-469

James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio.

Importance: RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders.

Objective: To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults.

Design, Setting, And Participants: This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4.

Exposures: Patients were randomized 1:1:1 to RIMA, 2500 U (n = 63); RIMA, 3500 U (n = 64); or placebo (n = 60).

Main Outcomes And Measures: Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period.

Results: Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, -0.30 g/min [95% CI, -0.39 to -0.21] for both doses vs placebo, P < .001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (-1.21 [95% CI, -1.56 to -0.87] for 2500 U, -1.14 [95% CI, -1.49 to -0.80] for 3500 U, both P < .001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries.

Conclusions And Relevance: Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults.

Trial Registration: ClinicalTrials.gov Identifier: NCT01994109.
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http://dx.doi.org/10.1001/jamaneurol.2019.4565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990829PMC
April 2020

Functional MRI Signature of Chronic Pain Relief From Deep Brain Stimulation in Parkinson Disease Patients.

Neurosurgery 2019 12;85(6):E1043-E1049

Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York.

Background: Chronic pain occurs in 83% of Parkinson disease (PD) patients and deep brain stimulation (DBS) has shown to result in pain relief in a subset of patients, though the mechanism is unclear.

Objective: To compare functional magnetic resonance imaging (MRI) data in PD patients with chronic pain without DBS, those whose pain was relieved (PR) with DBS and those whose pain was not relieved (PNR) with DBS.

Methods: Functional MRI (fMRI) with blood oxygen level-dependent activation data was obtained in 15 patients in control, PR, and PNR patients. fMRI was obtained in the presence and absence of a mechanical stimuli with DBS ON and DBS OFF. Voxel-wise analysis using pain OFF data was used to determine which regions were altered during pain ON periods.

Results: At the time of MRI, pain was scored a 5.4 ± 1.2 out of 10 in the control, 4.25 ± 1.18 in PNR, and 0.8 ± 0.67 in PR cohorts. Group analysis of control and PNR groups showed primary somatosensory (SI) deactivation, whereas PR patients showed thalamic deactivation and SI activation. DBS resulted in more decreased activity in PR than PNR (P < .05) and more activity in anterior cingulate cortex (ACC) in PNR patients (P < .05).

Conclusion: Patients in the control and PNR groups showed SI deactivation at baseline in contrast to the PR patients who showed SI activation. With DBS ON, the PR cohort had less activity in SI, whereas the PNR had more anterior cingulate cortex activity. We provide pilot data that patients whose pain responds to DBS may have a different fMRI signature than those who do not, and PR and PNR cohorts produced different brain responses when DBS is employed.
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http://dx.doi.org/10.1093/neuros/nyz269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855980PMC
December 2019

Deep brain stimulation of the ventroanterior and ventrolateral thalamus improves motor function in a rat model of Parkinson's disease.

Exp Neurol 2019 07 16;317:155-167. Epub 2019 Mar 16.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, United States of America; Department of Neurology, Albany Medical Center, Albany, NY, United States of America. Electronic address:

Parkinson's disease (PD) is a neurodegenerative disease with affected individuals exhibiting motor symptoms of bradykinesia, muscle rigidity, tremor, postural instability and gait dysfunction. The current gold standard treatment is pharmacotherapy with levodopa, but long-term use is associated with motor response fluctuations and can cause abnormal movements called dyskinesias. An alternative treatment option is deep brain stimulation (DBS) with the two FDA-approved brain targets for PD situated in the basal ganglia; specifically, in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi). Both improve quality of life and motor scores by ~50-70% in well-selected patients but can also elicit adverse effects on cognition and other non-motor symptoms. Therefore, identifying a novel DBS target that is efficacious for patients not optimally responsive to current DBS targets with fewer side-effects has clear clinical merit. Here, we investigate whether the ventroanterior (VA) and ventrolateral (VL) motor nuclei of the thalamus can serve as novel and effective DBS targets for PD. In the limb-use asymmetry test (LAT), hemiparkinsonian rats showcased left forelimb akinesia and touched only 6.5 ± 1.3% with that paw. However, these animals touched equally with both forepaws with DBS at 10 Hz, 100 μsec pulse width and 100 uA cathodic stimulation in the VA (n = 7), VL (n = 8) or at the interface between the two thalamic nuclei which we refer to as the VA|VL (n = 12). With whole-cell patch-clamp recordings, we noted that VA|VL stimulation in vitro increased the number of induced action potentials in proximal neurons in both areas albeit VL neurons transitioned from bursting to non-bursting action potentials (APs) with large excitatory postsynaptic potentials time-locked to stimulation. In contrast, VA neurons were excited with VA|VL electrical stimulation but with little change in spiking phenotype. Overall, our findings show that DBS in the VA, VL or VA|VL improved motor function in a rat model of PD; plausibly via increased excitation of residing neurons.
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http://dx.doi.org/10.1016/j.expneurol.2019.03.008DOI Listing
July 2019

Pallidal deep brain stimulation and intraoperative neurophysiology for treatment of poststroke hemiballism.

Ann Clin Transl Neurol 2018 Jul 21;5(7):865-869. Epub 2018 May 21.

Department of Neurosurgery Albany Medical Center Albany New York.

Deep brain stimulation is a recognized and effective treatment for several movement disorders. Nevertheless, the efficacy of this intervention on abnormal movements secondary to structural brain pathologies is less consistent. In this report, we describe a case of hemiballism-hemichorea due to a peripartum ischemic stroke-treated with deep brain stimulation of the globus pallidus internus. Patient observed marked improvement in her symptoms at long-term follow-up. Neurophysiologic data revealed lower globus pallidus internus firing rates compared to other hyperkinetic disorders. Pallidal deep brain stimulation is a plausible option for medically refractory hemiballism-hemichorea and cumulative data from multiple centers may be used to fully evaluate its efficacy.
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http://dx.doi.org/10.1002/acn3.573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043765PMC
July 2018

Anatomical Correlates of Uncontrollable Laughter With Unilateral Subthalamic Deep Brain Stimulation in Parkinson's Disease.

Front Neurol 2018 25;9:341. Epub 2018 May 25.

Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, United States.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for the management of motor complications in Parkinson's disease. Uncontrollable laughter has been reported as a rare side effect of STN stimulation. The precise mechanism responsible for this unique phenomenon remains unclear. We examined in detail the DBS electrode position and stimulation parameters in two patients with uncontrollable laughter during programming after STN-DBS surgery and illustrated the anatomical correlates of the acute mood changes with STN stimulation.

Case Report: Unilateral STN-DBS induced uncontrollable laughter with activation of the most ventral contacts in both patients. However, the location of the electrodes responsible for this adverse effect differed between the patients. In the first patient, the DBS lead was placed more inferiorly and medially within the STN. In the second patient, the DBS lead was implanted more anteriorly and inferiorly than initially planned at the level of the substantia nigra reticulata (SNr).

Conclusion: Unilateral STN-DBS can induce acute uncontrollable laughter with activation of electrodes located more anterior, medial, and inferior in relationship with the standard stereotactic STN target. We suggest that simulation of ventral and medial STN, surrounding limbic structures or the SNr, is the most plausible anatomical substrate responsible for this acute mood and behavioral change. Our findings provide insight into the complex functional neuroanatomical relationship of the STN and adjacent structures important for mood and behavior. DBS programming with more dorsal and lateral contacts within the STN should be entertained to minimize the emotional side effects.
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http://dx.doi.org/10.3389/fneur.2018.00341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980955PMC
May 2018

King's Parkinson's Disease Pain Scale for Assessment of Pain Relief Following Deep Brain Stimulation for Parkinson's Disease.

Neuromodulation 2018 Aug 2;21(6):617-622. Epub 2018 Apr 2.

Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA.

Objective: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain.

Methods: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale-III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation.

Results: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS.

Conclusions: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.
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http://dx.doi.org/10.1111/ner.12778DOI Listing
August 2018

Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease.

Mov Disord 2018 05 23;33(5):793-804. Epub 2018 Mar 23.

Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: Gastrointestinal symptoms are common in Parkinson's disease and frequently precede the development of motor impairments. Intestinal inflammation has been proposed as a driver of disease pathology, and evaluation of inflammatory mediators in stool could possibly identify valuable early-stage biomarkers. We measured immune- and angiogenesis-related proteins in human stool to examine inflammatory profiles associated with Parkinson's disease.

Methods: Stool samples and subjects' self-reported metadata were obtained from 156 individuals with Parkinson's disease and 110 without, including spouse and nonhousehold controls. Metadata were probed for disease-associated differences, and levels of 37 immune and angiogenesis factors in stool homogenates were measured by multiplexed immunoassay and compared across experimental groups.

Results: Parkinson's disease patients reported greater incidence of intestinal disease and digestive problems than controls. Direct comparison of levels of stool analytes in patients and controls revealed elevated vascular endothelial growth factor receptor 1, interleukin-1α, and CXCL8 in patients' stool. Paired comparison of patients and spouses suggested higher levels of multiple factors in patients, but this was complicated by sex differences. Sex, body mass index, a history of smoking, and use of probiotics were found to strongly influence levels of stool analytes. Multivariate analysis accounting for these and other potential confounders confirmed elevated levels of interleukin-1α and CXCL8 and also revealed increased interleukin-1β and C-reactive protein in stool in Parkinson's disease. These differences were not dependent on subject age or disease duration.

Conclusions: Levels of stool immune factors indicate that intestinal inflammation is present in patients with Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992021PMC
May 2018

Effect of diazepam and yohimbine on neuronal activity in sham and hemiparkinsonian rats.

Neuroscience 2017 05 4;351:71-83. Epub 2017 Apr 4.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA; Department of Neurology, Movement Disorders Center, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA. Electronic address:

The prefrontal cortex and the amygdala are critical for the emotional guidance of behavior and are believed to be a site of action for many anxiolytics and anxiogenics. Despite extensive studies examining how these drugs affect behavior, there is little information regarding their effects on neuronal activity. Additionally, with recent recognition of anxiety as a non-motor symptom of Parkinson's disease, it is unknown if activity in the cortex and the amygdala is altered. Previously, we reported that hemiparkinsonian rats had higher baseline anxiety-like behavior and diminished responsiveness to the acute anxiolytic, diazepam. In contrast, sham-lesioned rats exhibited anxiolytic behavior to diazepam. In this study, we monitored in vivo single-unit spiking activity simultaneously from the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA) in anesthetized sham-lesioned and hemiparkinsonian rats to unmask neuro-circuits underpinning the difference in diazepam responsiveness. We found that baseline spiking activity in the ACC was the same in both sham and hemiparkinsonian rats. We also noted a similar phenomenon for baseline activity in the BLA between sham and hemiparkinsonian rats. However, neuronal spiking activity after diazepam administration (1.5mg/kg, SubQ) was lower than in controls in the ACC of sham-lesioned rats whereas no difference was noted after diazepam treatment in hemiparkinsonian rats. BLA neuronal spiking activity was unaffected by diazepam administration in either animal group. On the other hand, yohimbine treatment (5mg/kg, SubQ) coincided with lower neuronal spiking activity compared to controls in the BLA of sham-lesioned rats, but was unchanged from controls in hemiparkinsonian rats. Yohimbine did not affect ACC neuronal spiking activity in either group. Overall, the lack of ACC responsiveness to diazepam in hemiparkinsonian, but not sham-lesioned rats underscores a plausible fundamental difference in anxiety-related neural signaling between animal groups.
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http://dx.doi.org/10.1016/j.neuroscience.2017.03.039DOI Listing
May 2017

Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome.

Mov Disord 2017 05 14;32(5):739-749. Epub 2017 Feb 14.

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD.

Objective: The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research.

Methods: A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways.

Results: Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation.

Conclusion: PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469442PMC
May 2017

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

Neurology 2017 Jan 2;88(2):152-159. Epub 2016 Dec 2.

From Cooper University Healthcare at Rowan University (A.M.), Camden, NJ; University of Rochester (M.M., K.K., E.A.d.B., K.B., P.C.); Weill Cornell Medical Center (F.B.); Columbia Presbyterian Medical Center (K.M.), New York, NY; Johns Hopkins Medical Center (C.R.), Baltimore, MD; Georgetown University (I.S.), Washington, DC; NINDS (P.G.), Bethesda, MD; Hereditary Neurological Disease Center (W.M.M.), Wichita, KS; The Centre for Movement Disorders (M.G.), Toronto, Canada; Indiana University School of Medicine (J.W.), Indianapolis; Colorado Neurological Institute (R.K.), Englewood; University of Tennessee Health Science Center (M.S.L.), Memphis; London Health Sciences Centre (M.J.), Canada; Massachusetts General Hospital (H.D.R.), Boston; Struthers Parkinson's Center (M.N.), Minneapolis, MN; University of Kansas Medical Center (R.M.D.), Kansas City; Rush University Medical Center (K.M.S.), Chicago, IL; University of Texas Southwestern Medical Center (P.O.), Dallas; University of Michigan (K.C.), Ann Arbor; Wake Forest University (F.W.), Winston-Salem, NC; University of Alberta (W.M.), Edmonton, Canada; University of California Davis (V.L.W.), Sacramento; Westmead Hospital (E. McCusker), Westmead, Australia; Baylor College of Medicine (J.J.), Houston, TX; University of Miami Miller School of Medicine (C.S.), FL; University of South Florida (J.S.-R.), Tampa; Duke University (B.S.), Durham, NC; University of Calgary (O.S.), Canada; Emory University School of Medicine (S.A.F.), Atlanta, GA; Albany Medical College (D.S.H., Eric Molho), NY; University of Cincinnati (F.R.), OH; Mayo Clinic Arizona (J.N.C.), Scottsdale; Butler Hospital (J.H.F.), Providence, RI; Washington University (J.S.P.), St. Louis, MO; Feinstein Institute for Medical Research (A.F.), Manhasset, NY; Georgetown University (K.A.), Washington, DC; University of Florida (R.R., N.R.M.), Gainesville; Johns Hopkins University (R.L.M.), Baltimore, MD; University of Nevada School of Medicine (E.S.F.), Reno; University of British Columbia (L.A.R.), Vancouver, Canada; University of Pittsburgh (V.S.), PA; Ohio State University (S.K.), Columbus; The Cooper University Health System (A.C.), Camden, NJ; Idaho Elks Rehabilitation Hospital (L.S.), Boise, ID; University of Iowa (E.E.), Iowa City; North York General Hospital 1 (S.E.), Toronto, Canada; St. Luke's Hospital (N.D.), Allentown, PA; North York General Hospital 2 (W.L.A.F.), University of Toronto, Canada; Washington Regional Medical Center (A.D.), Fayetteville, AR; Beth-Israel Deaconess Medical Center (S.F.), Boston, MA; NJ Neuroscience Institute (P.H.), Edison; University of California Irvine (N.H.); The University of Alabama at Birmingham (L.S.D.); and Massachusetts General Hospital (M.C.), Harvard Medical School, Boston.

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.

Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.

Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.

Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD.

Clinicaltrialsgov Identifier: NCT00608881.

Classification Of Evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.
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http://dx.doi.org/10.1212/WNL.0000000000003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224719PMC
January 2017

Impact of Cervical Dystonia on Work Productivity: An Analysis From a Patient Registry.

Mov Disord Clin Pract 2016 Mar-Apr;3(2):130-138. Epub 2015 Dec 16.

Allergan, Inc.Irvine California USA; University of California Irvine California USA.

Background: Cervical dystonia is thought to result in high disease burden, but limited information exists on its impact on employment and work productivity. We utilized data from the Cervical Dystonia Patient Registry for the Observation of OnabotulinumtoxinA Efficacy (ClinicalTrials.gov identifier: NCT00836017) to assess the impact of cervical dystonia on employment and work productivity and examine the effect of onabotulinumtoxinA treatments on work productivity.

Methods: Subjects completed a questionnaire on employment status and work productivity at baseline and final visit. Baseline data were examined by severity of cervical dystonia, predominant subtype, presence of pain, prior exposure to botulinum toxin, and/or utility of a sensory trick. Work productivity results at baseline and final visit were compared in subjects who were toxin-naïve at baseline and received three onabotulinumtoxinA treatments.

Results: Of 1,038 subjects, 42.8% were employed full- or part-time, 6.1% unemployed, 32.7% retired, and 11.8% disabled. Of those currently employed, cervical dystonia affected work status of 26.0%, caused 29.8% to miss work in the past month (mean, 5.1 ± 6.4 days), and 57.8% reported decreased productivity. Half of those unemployed were employed when symptoms began, and 38.5% attributed lost employment to cervical dystonia. Pain, increasing severity, and anterocollis/retrocollis had the largest effects on work status/productivity. Preliminary analyses showed that absenteeism and presenteeism were significantly decreased following onabotulinumtoxinA treatments in the subpopulation that was toxin-naïve at baseline.

Conclusions: This analysis confirms the substantial negative impact of cervical dystonia on employment, with cervical dystonia-associated pain being a particularly important driver. OnabotulinumtoxinA treatment appears to improve work productivity.
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http://dx.doi.org/10.1002/mdc3.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064605PMC
December 2015

Clinical outcome and intraoperative neurophysiology for focal limb dystonic tremor without generalized dystonia treated with deep brain stimulation.

Clin Neurol Neurosurg 2016 Nov 17;150:169-176. Epub 2016 Sep 17.

Center for Neuroscience and Neuropharmacology, Albany, NY, United States; Department of Neurosurgery, Albany Medical Center, Albany, NY, United States. Electronic address:

Objectives: Dystonic tremor (DT) is defined as a postural/kinetic tremor occurring in the body region affected by dystonia. DT is typically characterized by focal tremors with irregular amplitudes and variable frequencies typically below 7Hz. Pharmacological treatment is generally unsuccessful and guidelines for deep brain stimulation (DBS) targeting and indications are scarce. In this article, we present the outcome and neurophysiologic data of two patients with refractory, focal limb DT treated with Globus Pallidus interna (Gpi) DBS and critically review the current literature regarding surgical treatment of DT discussing stereotactic targets and treatment considerations.

Patients And Methods: A search of literature concerning treatment of DT was conducted. Additionally, Gpi DBS was performed in two patients with DT and microelectrode recordings for multi unit analysis (MUAs) and local field potentials (LFPs) were obtained.

Results: The mean percentage improvement in tremor severity was 80.5% at 3 years follow up. MUAs and LFPs did not show significant differences in DT patients compared with other forms of dystonia or PD except for higher interspikes bursting indices. LFP recordings in DT demonstrated high power at low frequencies with action (<3.5Hz).

Conclusions: Gpi DBS is an effective treatment in patients with focal limb DT without associated generalized dystonia. Intraoperative neurophysiologic findings suggest that DT is part of phenotypic motor manifestations in dystonia.
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http://dx.doi.org/10.1016/j.clineuro.2016.06.006DOI Listing
November 2016

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

JAMA 2016 Jul;316(1):40-50

Boston University Medical Campus, Boston, Massachusetts.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.

Main Outcomes And Measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.

Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.

Conclusions And Relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT01795859.
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http://dx.doi.org/10.1001/jama.2016.8655DOI Listing
July 2016

Investigation of diazepam efficacy on anxiety-like behavior in hemiparkinsonian rats.

Behav Brain Res 2016 Mar 31;301:226-37. Epub 2015 Dec 31.

Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA. Electronic address:

There is growing recognition that anxiety disorders have a greater impact on quality of life in Parkinson's disease than motor symptoms. Yet, little is known about the pathophysiology underlying this non-motor symptom in Parkinson's disease which poses a considerable barrier in developing effective treatment strategies. Here, we administered diazepam to hemiparkinsonian and non-parkinsonian rats and assessed its efficacy in three anxiety behavioral tests. At present, no information about this exists in preclinical research with sparse data in the clinical literature. Moreover, diazepam is an acute anxiolytic which makes this drug a suitable research tool to unmask differences in anxiety-like behavior. Using the unilateral, medial forebrain bundle 6-hydroxydopamine rat model of Parkinson's disease, we noted that hemiparkinsonian rats had more baseline anxiety-like behavior with 60% of them exhibiting high anxiety (HA) behavior in the elevated plus maze. In contrast, 41% of sham-lesioned rats and 8% of naïve rats exhibited HA behavior. Next, we employed the elevated plus maze and noted that diazepam (1.5mg/kg) was anxiolytic in low anxiety (LA) sham-lesioned (p=0.006) and HA sham-lesioned rats (p=0.016). Interestingly, diazepam was anxiolytic for LA hemiparkinsonian rats (p=0.017), but not for HA hemiparkinsonian rats (p=0.174) despite both groups having similar motor impairment and parkinsonian phenotype. Overall, diazepam administration unmasked differences in anxiolytic efficacy between HA hemiparkinsonian rats, LA hemiparkinsonian rats and non-parkinsonian rats. Our data suggests that neuro-circuits involved in anxiety-like behavior may differ within these groups and posits that diazepam may have reduced efficacy in certain individuals with PD anxiety disorders.
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http://dx.doi.org/10.1016/j.bbr.2015.12.045DOI Listing
March 2016

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

JAMA Neurol 2016 Jan;73(1):102-10

Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Importance: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.

Objective: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

Design, Setting, And Participants: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.

Exposure: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.

Main Outcomes And Measures: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.

Results: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups.

Conclusions And Relevance: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.
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http://dx.doi.org/10.1001/jamaneurol.2015.2736DOI Listing
January 2016

The Influence of Bilateral Subthalamic Nucleus Deep Brain Stimulation on Impulsivity and Prepulse Inhibition in Parkinson's Disease Patients.

Stereotact Funct Neurosurg 2015 10;93(4):265-70. Epub 2015 Jun 10.

Department of Neurosurgery, Albany Medical College, Albany, N.Y., USA.

Background: At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remain unclear.

Objectives: We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity.

Methods: Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analogue Risk Task (BART) and auditory prepulse inhibition (PPI) testing.

Results: Analysis revealed 12 patients had an improvement in score assessing ICDs ('good responders'; p = 0.006) while 4 had a worse or stable score ('poor responders'; p > 0.05). Good responders further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = -0.72, p = 0.044).

Discussion: Following bilateral STN-DBS, 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.
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http://dx.doi.org/10.1159/000381558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540608PMC
July 2016

Deep brain stimulation significantly decreases disability from low back pain in patients with advanced Parkinson's disease.

Stereotact Funct Neurosurg 2015 21;93(3):206-11. Epub 2015 Apr 21.

Department of Neurosurgery, Albany Medical College, Albany, N.Y., USA.

Background: Up to 60% of Parkinson's disease (PD) patients suffer from low back pain (LBP) during the course of their disease. How LBP affects daily functional status and how to manage this aspect of PD has not been adequately explored.

Methods: We examined 16 patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN DBS) who met the inclusion criteria for moderate disability from LBP, as classified by the Oswestry Low Back Pain Disability Index (OLBPD).

Results: Thirteen of 16 patients had attempted additional treatments for LBP, including medical management, massage, chiropractic, epidural steroid injections and/or surgery, with minimal relief. Following DBS, there was a significant improvement in the OLBPD at both the 6-month and 1-year time points (p < 0.02, p < 0.005, respectively). A mean improvement of 31.7% on the OLBPD score was noted. The Visual Analogue Scale (VAS) similarly decreased significantly at 1 year (p = 0.015). There was no correlation between the OLBPD score and other measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), age and other nonmotor symptoms.

Conclusion: Given the prevalent yet undertreated disability associated with LBP in PD, these results are novel in that they show that STN DBS has a significant positive effect on disability associated with LBP.
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http://dx.doi.org/10.1159/000380827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441839PMC
April 2016

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

Mov Disord 2015 Feb 12;30(2):278-83. Epub 2014 Nov 12.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).

Methods: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.

Results: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).

Conclusions: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318772PMC
February 2015

Raman spectroscopy of blood serum for Alzheimer's disease diagnostics: specificity relative to other types of dementia.

J Biophotonics 2015 Jul 25;8(7):584-96. Epub 2014 Sep 25.

Department of Chemistry, University at Albany, SUNY, 1400 Washington Avenue, Albany, NY 12222, USA.

The key moment for efficiently and accurately diagnosing dementia occurs during the early stages. This is particularly true for Alzheimer's disease (AD). In this proof-of-concept study, we applied near infrared (NIR) Raman microspectroscopy of blood serum together with advanced multivariate statistics for the selective identification of AD. We analyzed data from 20 AD patients, 18 patients with other neurodegenerative dementias (OD) and 10 healthy control (HC) subjects. NIR Raman microspectroscopy differentiated patients with more than 95% sensitivity and specificity. We demonstrated the high discriminative power of artificial neural network (ANN) classification models, thus revealing the high potential of this developed methodology for the differential diagnosis of AD. Raman spectroscopic, blood-based tests may aid clinical assessments for the effective and accurate differential diagnosis of AD, decrease the labor, time and cost of diagnosis, and be useful for screening patient populations for AD development and progression. Multivariate data analysis of blood serum Raman spectra allows for the differentiation between patients with Alzheimer's disease, other types of dementia and healthy individuals.
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http://dx.doi.org/10.1002/jbio.201400060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575592PMC
July 2015

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

JAMA Neurol 2014 May;71(5):543-52

Columbia University Medical Center, Neurological Institute, New York, New York.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, And Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes And Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions And Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT00740714.
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http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

Treatment of motor fluctuations in Parkinson's disease: recent developments and future directions.

Expert Rev Neurother 2014 Jan 13;14(1):93-103. Epub 2013 Dec 13.

Department of Neurology, Parkinson's Disease and Movement Disorders Center of Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA.

Parkinson's disease (PD) is characterized clinically by rest tremor, rigidity, bradykinesia and pathologically by degeneration of nigrostriatal dopamine neurons. Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of PD. Ongoing clinical and preclinical research has led to the discovery of promising new therapeutic targets that might prevent or reduce motor complications. Newer approaches modulating non-dopaminergic systems including adenosine A2A antagonists, monoamine oxidase-B inhibitors, glutamatergic antagonists, adrenergic receptor antagonists and serotonergic agents are encouraging strategies for management of advanced PD. Recent developments in levodopa delivery formulations include duodenal infusion of a levodopa/carbidopa, new extended-release levodopa and oral pro-levodopa forms. Recent clinical trials revealed diverse but promising results raising the possibility of new therapeutic modalities for PD in the near future.
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http://dx.doi.org/10.1586/14737175.2014.868306DOI Listing
January 2014
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