Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a polyglutamine tract in the huntingtin protein. We have developed PC12 cell lines in which the expression of an N-terminal truncation of huntingtin (N63) with either wild type (23Q) or expanded polyglutamine (148Q) can be induced by the removal of doxycycline. Differentiated PC12 cells induced to express N63-148Q showed cellular toxicity reaching up to 50% at 6 days post-induction. Histone acetyltransferase (HAT) activity and global histone acetylation was significantly decreased in cells expressing truncated huntingtin with mutant but not normal huntingtin. These data suggest that altered chromatin modification via reduction in coactivator activity may cause neuronal transcriptional dysregulation and contribute to cellular toxicity.
The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and mutations in alpha-synuclein cause autosomal-dominant hereditary PD. Here, we generated A53T mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular ROS level and caused up to ∼40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities. Cell death was partially blocked by cyclosporine A [an inhibitor of the mitochondrial permeability transition (MPT) process], z-VAD (a pan-caspase inhibitor) and inhibitors of caspase-9 and -3 but not by a caspase-8 inhibitor. Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 activity. RNA interference to knock down caspase-12 levels or salubrinal (an ER stress inhibitor) partially protected against cell death and further reduced A53T toxicity after treatment with z-VAD. Our results indicate that both ER stress and mitochondrial dysfunction contribute to A53T alpha-synuclein-induced cell death. This study sheds light into the pathogenesis of alpha-synuclein cellular toxicity in PD and provides a cell model for screening PD therapeutic agents.
OBJECTIVE: To implement a standardized documentation template for physician use during transfer from the neurosciences intensive care unit (ICU) to non-ICU neurology hospital services. BACKGROUND: Transfer of neurologic patients from an ICU to hospital services is a complex process leading to discontinuity in care with potential for errors. DESIGN/METHODS: A survey methodology was used to identify problem areas in the Neurosciences ICU to non-ICU transfer process. A standardized documentation template was developed with sections addressing medication reconciliation, urinary catheter use, vital sign parameters, rehabilitation consultation and outstanding test results. Physicians during the three-month intervention period were trained to incorporate elements of the template into the transfer note. Physician satisfaction regarding the transfer process was assessed before and after intervention. RESULTS: The survey response rate was 37.5% pre-intervention and 19% post-intervention. The compliance rate of the standardized transfer template was 93%. Overall, satisfaction with the transfer process by accepting physicians was unchanged in the post-intervention period (p=0.34). There was a significant decline in the average number of patient transfers with urinary catheter (1.74 to 0.79; p=0.04), but not in the number of times that medications had not been reconciled (1.84 to 1.26; p=0.20). The majority of accepting physicians felt that the transfer template made documentation easier to complete (74%) and saved time for the physician in the transfer process (95%). Of accepting physicians, 84% felt that the template should continue, with the most useful aspects being medication reconciliation and reducing urinary catheter use. Of transferring physicians, 88% felt that the template reminded them to address an issue prior to patient transfer. CONCLUSIONS: The implementation of standardized documentation for the transfer of neurologic patients from the ICU to the non-ICU hospital services was beneficial to both transferring and accepting physicians, and decreased the number of patients transferred with urinary catheters, potentially preventing infections. Disclosure: Dr. Morparia has nothing to disclose. Dr. Coon has nothing to disclose. Dr. Fabris has nothing to disclose. Dr. Klaas has nothing to disclose. Dr. Burkholder has nothing to disclose. Dr. Broomall has nothing to disclose. Dr. Graff-Radford has nothing to disclose. Dr. Moore has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Rubin has nothing to disclose. Dr. Britton has nothing to disclose.
Objective: Quantify the utility of pre-operative deep brain stimulation (DBS) interdisciplinary assessments on preventing unintended hospitalizations and improving quality of life (QOL).
Background:
Most DBS expert centers utilize interdisciplinary screening to determine DBS candidates, however no data exists quantifying the utility of this practice. We review the outcomes of the UF interdisciplinary model that utilizes evaluations from seven specialties to pre-operatively assess DBS candidates.
Design/Methods:
The UF INFORM database was queried for PD patients who had DBS implantations performed between January 2011 and February 2013. Records were reviewed to uncover unintended hospitalizations. As part of the interdisciplinary pre-operative screening, seven specialties independently evaluated DBS candidates and minor and major concerns were quantified. Clinical outcomes were assessed through the use of validated questionnaires.
Results:
164 cases were evaluated for possible DBS candidacy and 133 subjects were approved following interdisciplinary screening for DBS surgery (81.1 [percnt]). There were 28 cases (21.1[percnt]) experiencing unintended hospitalizations within the first 12 months following DBS. Patients identified as having major or minor concerns from any specialty service had more unintended hospitalizations (92.9[percnt]) when compared to those without concerns (7.1 [percnt]). The majority of unintended hospitalizations (82.1[percnt]) were not directly related to the DBS itself. When the preoperative concern shifted from “major” to “minor” to “no concerns,” the rate of hospitalization decreased from 88.9[percnt] to 33.3[percnt] to 2.9[percnt], respectively. There was a strong association between subjects with the smallest PDQ-39 improvements at 12 months and increased hospitalizations. Falls and infections were not related to unintended hospitalizations or to interdisciplinary screening.
Conclusions: There was correlation between the number of minor and major concerns raised by a seven specialty interdisciplinary pre-operative DBS screening and unintended hospitalizations and QOL scores. Our data supports the importance of interdisciplinary teams in the care of the DBS patient. Disclosure: Dr. Morita has nothing to disclose. Dr. Higuchi has nothing to disclose. Dr. Topiol has nothing to disclose. Dr. Bowers has nothing to disclose. Dr. Ward has nothing to disclose. Dr. Warren has nothing to disclose. Dr. DeFranco has nothing to disclose. Dr. Troche has nothing to disclose. Dr. Kulkarni has nothing to disclose. Dr. Foote has received personal compensation for activities with Medtronic as an advisory board member. Dr. Okun has received royalty payments from Demos, Humana, Amazon, Smashwords, Books4Patients, and Cambridge. Dr. Okun has received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the Parkinson Alliance, the Smallwo
Objective:
To investigate the efficacy of caring for patient’s with Parkinson’s disease (PD) in a rural home-based setting and to have movement disorders fellows coordinate and manage all health care delivery.
Background:
The University of Florida Center for Movement Disorders and Neurorestoration established operation “housecall” to serve patients with PD who could not otherwise afford to travel to an expert center or to pay for medical care. PD is known to lead to significant disability, frequent hospitalizations, early nursing home placement and morbidity.
Methods:
Movement disorders fellows travelled to the home(s) of underserved PD patients and coordinated the care of eight patients. The diagnosis of Parkinson’s disease was confirmed using standardized criteria, and a Unified Parkinson’s Disease Rating Scale was performed and best treatment practices delivered.
Results:
All eight patients have been followed longitudinally every 3 to 6 months in the home setting, and they remain functional and independent. None have been hospitalized for PD related complications. Each patient has a new updatable electronic medical record. All operation housecall cases are presented during video rounds, for the interdisciplinary PD team can make recommendations for care (neurology, neurosurgery, neuropsychology, psychiatry, physical therapy, occupational therapy, speech therapy, and social work). Two operation housecall patients have successfully received deep brain stimulation (DBS). Financial support for medical supplies and transportation remains privately funded.
Conclusion:
This program provides a proof of concept for PD housecalls. Operation housecall provides underserved PD patients’ with quality medical care, allows them to remain in their home setting, and may prevent hospitalizations. Advanced medical care such as evaluation for DBS is possible. This program could provide a proof of concept for the construction of a larger visiting physician or nurse program.
Acknowledgements:
This program is supported by the Smallwood Foundation and the National Parkinson Foundation Center of Excellence located at the University of Florida. Disclosure: Dr. Hack has nothing to disclose. Dr. Akbar has nothing to disclose. Dr. Eilers has nothing to disclose. Dr. Rundle-Gonzalez has nothing to disclose. Dr. Martinez-Ramirez has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Malaty has received personal compensation for activities with Prime-CME as a speaker. Dr. Malaty has received research support from the National Parkinson Foundation, Michael J. Fox Foundation, Tourette Syndrome Association for Parkinson, National Institutes of Health, and Abbott. Dr. Okun has received royalty payments from Demos, Humana, Amazon and Cambridge. Dr. Okun has received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the Parkinson Alliance, the Smallwood Foundation, the Tourette Syndrome Association, the Bachmann-Strauss Foundation, and the National Institutes of Health.
OBJECTIVE: Assess the test-retest reproducibility of gait parameters using quantitative gait analysis for potential use as an outcome measure in the hereditary ataxias.
BACKGROUND: Previous studies have estimated that sample sizes using current subjective clinical scales needed to detect a 50% reduction in disease over 1 year will require 250 patients for hereditary ataxias clinical trials. There is a need for objective, reproducible outcome measures that will allow for smaller sample sizes. SCA specific pathology in the cerebellum and its connections often manifest as gait abnormalities suggesting a role for gait analysis in tracking clinical outcomes.
DESIGN/METHODS: 20 patients with autosomal dominant cerebellar ataxias (SCA1=3, SCA2=3, SCA3=5, SCA6=9) underwent Biomechanical Assessment of Gait (BAG) and Balance Test (BT) using GaitRITE at baseline and at 2 weeks. Gait parameters at baseline and 2 weeks were analyzed with reliability analysis to examine reproducibility. Correlations between gait parameters and currently used clinical scales for ataxia (SARA) were performed.
RESULTS: Objective gait parameters at baseline and 2 weeks showed high internal consistency, high intraclass correlation coefficients including gait velocity (ICC=.976), cadence (ICC=.972), timed 25 foot walk (ICC=.962), single support time left and right (ICC=.981 and .988), double support time (ICC=.98), percentage of gait cycle in double support left and right (ICC=.988 and .987), percentage of gait cycle in single support left and right (ICC=.986 and .971). Measured gait parameters showing highest correlation with SARA scores were double support time (r=.638 p=.002), timed 25 foot walk (r=.672 p=.002), and gait velocity (r=-.673 p=.001).
CONCLUSIONS: Quantitative gait analysis shows high test-retest reliability suggesting potential utility as an outcome measure for clinical trials in the spinocerebellar ataxias. Disclosure: Dr. Morita has nothing to disclose. Dr. Vincent has nothing to disclose. Dr. Hack has nothing to disclose. Dr. Conrad has nothing to disclose. Dr. Ashizawa has received royalty payments from Baylor College of Medicine. Dr. Subramony has received personal compensation for activities with Athena Diagnostics as a speaker. Dr. Xia has nothing to disclose.
