PubMed | Tohoku University, National Center Hospital of Neurology and Psychiatry Tokyo, University of California at San Diego, University of Pennsylvania and 32 more.
Type: Journal Article | Journal: Annals of clinical and translational neurology | Year: 2015
Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P=7.310(-3)).The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
Ostrem J.L.,University of California at San Francisco |
Ostrem J.L.,Parkinsons Disease Research Education and Clinical Center |
Markun L.C.,University of California at San Francisco |
Markun L.C.,Parkinsons Disease Research Education and Clinical Center |
And 8 more authors.
Parkinsonism and Related Disorders | Year: 2014
Background: Subthalamic nucleus deep brain stimulation (DBS) is an alternative target choice for treating primary dystonia, but little is known about the most effective programming parameters. Objective: Here we prospectively evaluate the effect of low versus high frequency subthalamic nucleus DBS in patients with predominantly cervical or upper extremity primary dystonia. Methods: Seven patients were stimulated at low frequency stimulation (60Hz) for the first three months and then switched to high frequency stimulation (130Hz) until month six. Severity of dystonia was determined by a blinded rater (unaware of the patient's pre or post-operative status) who scored the Burke Fahn Marsden dystonia rating scale movement score (BFMDRS-M) and the Toronto Western Spasmodic Torticollis Rating Scale severity score (TWSTRS-S) preoperatively, three, six, and twelve months post-surgery. Results: Patients had a lower mean improvement of 16.6% in BFMDRS-M and 9.5% in TWSTRS-S at three months using low frequency stimulation compared to a 52.3% (p=0.018) and 45.2% (p=0.028), respectively, noted at six months using high frequency stimulation. At 12 months (using 130Hz), the BFMDRS-M and TWSTRS-S improved by 51.8% (p=0.022) and 56% (p=0.034). Patients developed transient dyskinesia (during low and high frequency stimulation) which improved with programming adjustments. Conclusion: This study offers further support of the effectiveness of subthalamic nucleus DBS in the treatment of primary dystonia and finds that high frequency stimulation was more effective than low frequency stimulation. © 2014.
Liachko N.F.,Geriatric Research Education and Clinical Center |
Liachko N.F.,University of Washington |
McMillan P.J.,Mental Illness Research Education and Clinical Center |
Guthrie C.R.,Geriatric Research Education and Clinical Center |
And 7 more authors.
Annals of Neurology | Year: 2013
Objective Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP-43-specific kinases are candidate targets for intervention. Methods To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic Caenorhabditis elegans. Results We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathology found in frontal cortex. Furthermore, PHA767491, a small molecule inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43-transgenic animals. Interpretation Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis. Copyright © 2013 American Neurological Association.
McMillan P.J.,Mental Illness Research Education and Clinical Center |
Kraemer B.C.,Geriatric Research Education and Clinical Center |
Kraemer B.C.,University of Washington |
Robinson L.,Geriatric Research Education and Clinical Center |
And 5 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2011
Proteolytic cleavage of tau at glutamic acid 391 (E391) is linked to the pathogenesis of Alzheimer disease (AD). This C-terminal-truncated tau species exists in neurofibrillary tangles and abnormal neurites in the brains of AD patients and may potentiate tau polymerization. We generated a mouse model that expresses human tau truncated at E391 to begin to elucidate the role of this C-terminal-truncated tau species in the development of tau pathology. Our results show that truncated but otherwise wild-type human tau is sufficient to drive pretangle pathologic changes in tau, including accumulation of insoluble tau, somatodendritic redistribution, formation of pathologic conformations, and dual phosphorylation of tau at sites associated with AD pathology. In addition, these mice exhibit atypical neuritic tau immunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes in tau proteolysis can initiate tauopathy. © 2011 by the American Association of Neuropathologists, Inc.
Weintraub D.,University of Pennsylvania |
Weintraub D.,Parkinsons Disease Research Education and Clinical Center |
Weintraub D.,Mental Illness Research Education and Clinical Center |
Mamikonyan E.,University of Pennsylvania |
And 5 more authors.
Movement Disorders | Year: 2012
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson's disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time. © 2011 Movement Disorder Society.
Kleiner-Fisman G.,University of Toronto |
Martine R.,Parkinsons Disease Research Education and Clinical Center |
Lang A.E.,University of Toronto |
Stern M.B.,Parkinsons Disease Research Education and Clinical Center |
Stern M.B.,University of Pennsylvania
Parkinson's Disease | Year: 2011
Patients with Parkinson disease are increasingly recognized to suffer from non-motor symptoms in addition to motor symptoms. Many non-motor symptoms fluctuate in parallel with motor symptoms and in relationship to plasma levodopa levels. Though these symptoms are troublesome and result in reduced quality of life to patients and their caregivers, there has not been an objective method of recognizing and quantifying non-motor fluctuations (NMFs). This study sought to develop a patient-based instrument that would accurately capture the experience of patients with NMFs. Patient-based nominal group technique sessions, focus groups, and expert opinion were utilized in developing this questionnaire. © 2011 Galit Kleiner-Fisman et al.
Jacobs J.V.,University of Vermont |
Nutt J.G.,Oregon Health And Science University |
Nutt J.G.,Parkinsons Disease Research Education and Clinical Center |
Carlson-Kuhta P.,Oregon Health And Science University |
And 3 more authors.
Parkinsonism and Related Disorders | Year: 2014
Purpose: Although falls in people with Parkinson's disease (PD) associate with dual tasking and freezing of gait (FoG), it is not known whether falls during dual tasking are due to FoG. This study investigated the effects of a cognitive task on the occurrence of falls and FoG when subjects with PD step in response to a postural perturbation. Methods: Ten subjects with PD and a history of FoG as well as 10 age-matched subjects without PD stepped in response to large, backward displacements of the support surface, with and without performing a fluency task of listing items in a category. Subjects with PD performed the task in the "off" and "on" dopaminergic medication states. We recorded the percentage of trials with FoG (a lack of step in response to the perturbation), foot-lift latencies, and trials with falls into a safety harness. Results: Dual tasking significantly increased the incidence of falls in people with PD, but subjects without PD did not fall in any condition. Dual tasking did not significantly increase trials without steps or foot-lift latencies. Falls were often coincident with a lack of step (FoG) in the single-task condition, but the increased falls with dual tasking occurred on trials with steps. Levodopa tended to decrease FoG and falls with or without dual tasking. However, medication did not significantly alter the effects of dual tasking on FoG or falls. Conclusions: For people with PD and FoG, forward falls may not always be caused by FoG, particularly under attention-distracting conditions. © 2014 Elsevier Ltd.
Roy B.,University of Texas Medical Branch |
Jackson G.R.,University of Texas Medical Branch |
Jackson G.R.,Baylor College of Medicine |
Jackson G.R.,Parkinsons Disease Research Education and Clinical Center
Human Molecular Genetics | Year: 2014
Clinical and pathological studies have suggested considerable overlap between tauopathies and synucleinopathies. Several genome-wide association studies have identified alpha-Synuclein (SNCA) and Tau (MAPT) polymorphisms as common risk factors for sporadic Parkinson's disease (PD). However, the mechanisms bywhich subtle variations in the expression of wild-type SNCAandMAPT influence risk forPDand the underlying cellular events that effect neurotoxicity remain unclear. To examine causes of neurotoxicity associated with the α-Syn/ Tauinteraction,weusedthe fruit flyasamodel.Weutilized misexpressionparadigmsinthree different tissues to probe the α-Syn/Tau interaction: the retina, dopaminergic neurons and the larval neuromuscular junction. Misexpression of Tau and α-Syn enhanced a rough eye phenotype and loss of dopaminergic neurons in fly tauopathy and synucleinopathy models, respectively. Our findings suggest that interactions between α-Syn and Tau at the cellular level cause disruption of cytoskeletal organization, axonal transport defects and aberrant synaptic organization that contribute to neuronal dysfunction and death associated with sporadic PD.α-Syn did not alter levels of Tau phosphorylated at the AT8 epitope. However, α-Syn and Tau colocalized in ubiquitinpositive aggregates in eye imaginal discs. The presence of Tau also led to an increase in urea soluble α-Syn. Our findings have important implications in understanding the cellular and molecular mechanisms underlying α-Syn/Tau-mediated synaptic dysfunction, which likely arise in the early asymptomatic phase of sporadic PD. © The Author 2014. Published by Oxford University Press. All rights reserved. Published by Oxford University Press. All rights reserved.
Bryant M.S.,Baylor College of Medicine |
Bryant M.S.,University of Houston |
Workman C.D.,Baylor College of Medicine |
Workman C.D.,University of Houston |
And 2 more authors.
International Journal of Rehabilitation Research | Year: 2015
Gait parameters of forward, backward, and sideways walk were studied when the participants walked overground in four directions at their self-selected speed and were compared with walking in the four directions on an instrumented GAITRite walkway. Intraclass correlation coefficients between the overground walk test measures and the instrumented walkway measures of gait speed, cadence, and stride length for the forward walk were 0.85, 0.88, and 0.87, respectively. For the backward walk, the coefficients were 0.91 for gait speed, 0.75 for cadence, and 0.93 for stride length. For the sideways walk, the coefficients were 0.92 for gait speed, 0.93 for cadence, and 0.94 for stride length. Gait parameters of forward, backward, and sideways walk obtained by the overground walk test had excellent agreement with those obtained by the instrumented walkway. The quick timed test provided quantitative data for gait evaluation and was valid for clinical use. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
PubMed | Parkinsons Disease Research Education and Clinical Center
Type: Journal Article | Journal: The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses | Year: 2016
Deep brain stimulation (DBS) has developed into an important therapy for Parkinson disease, essential tremor, and dystonia with more nurses in varied settings often preparing patients and families for this type of surgery. This exploratory study sought to obtain patient and caregiver perspectives of the current DBS teaching for Parkinson disease, essential tremor, and dystonia; to improve the teaching; and to standardize the education. Using survey methodology, 41 patients with movement disorder and 32 caregivers completed surveys about the preoperative instructions they received. Data analysis calculated frequencies for response rate, demographic information, multiple-choice questions, and Likert scale responses. Fill-in questions were summarized. Results overall showed that, because of the teaching, two thirds of patients and nearly two thirds of caregivers felt fully prepared for the DBS surgery. Patients and caregivers suggested recommendations for nurses and surgeons included requests for specific information such as attention to delivery of the education, more individualized care during the education, attention to pain during and after procedure, and postdischarge follow-up. The study identified unmet patient and caregiver needs, resulted in changes in practice, and serves as a guide toward standardization of educational approach and/or content.