Objectives: To explore functional connectivity at a network level with MEG, pre-and post-administ... more Objectives: To explore functional connectivity at a network level with MEG, pre-and post-administration of medications, in cervical dystonia and Meige syndrome. Background: Mechanisms thought to play a critical role in dystonia include reduced intracortical inhibition and distorted somatotopic cortical representation. Prior studies showed altered functional connectivity within the sensorimotor, the executive control and the primary visual network. Methods: MEG Data on 5 patients, 4 with cervical dystonia and 1 with Meige syndrome (age: 16-70 years) were matched to 5 (age and sex matched) healthy controls. All patients (4 on Botulinum toxin, 1 on Diazepam) showed clinical benefit with medications. Two 15-minute MEG scans pre and post intervention were obtained. Synchronization of neuronal activity was quantified by calculating coherence source imaging (CSI) between cortical sites from MEG imaged brain activations. A region-of-interest (ROI) tool was used to identify 54 regions in the brain (27 in each hemisphere). Within the frequency band 3-50Hz, a t-test was conducted to assess group difference in average CSI values for each pair of brain regions (N51,431). A P value was produced for each region pair. Only statistically significant coherence values (p\\u3c0.05) with a large effect size were considered. Results: Using group based analysis, in both pre-treatment and posttreatment groups, the biggest difference in coherence between patients and controls was seen in the fronto-striatal and occipito-striatal regions, with some differences in the parieto-striatal and striato-parietal regions. On comparing pre-and post-treatment dystonia patients, an increase in coherence was observed in these regions post treatment. Conclusion: Our exploratory study using MEG showed increased neuronal connectivity in regions associated with visuospatial and executive function, with an increase post medication in patients with cervical dystonia and Meige syndrome. The latter may be a biomarker for normalization of aberrant connectivity and merits further exploration
The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses ... more The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.
Parkinson’s Disease (PD), characterized by a marked loss of nigrostriatal neurons [1], is general... more Parkinson’s Disease (PD), characterized by a marked loss of nigrostriatal neurons [1], is generally a disorder of progressive disability. While additional neuronal systems of the PD brain are altered [2], the change most closely linked to the clinical symptomatology of Parkinsonism is the impaired generation of striatal dopamine. Dopamine production may also figure in the special vulnerability of substantia nigra pars compacta neurons in PD. Several hypotheses for the decline in dopaminergic neurons have been advanced. One speculation has been that one or more exogenous toxins might produce a metabolic effect damaging these neurons. Several neurotoxins with highly specific actions against nigrostriatal dopaminergic neurons are known. These produce parkinsonian symptomatology both in animal models and, in the case of manganese and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in man. MPTP has been the most intriguing of these because of its need for conversion in the brain prior to exerting toxicity to nigrostriatal dopamine neurons via their mitochondrial metabolism. The unique properties of MPTP have provided grist for speculation that PD could conceivably be the outcome of intermittent or continuous neurotoxicity from exposure to similar types of compounds [3–5].
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer... more Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and
Objective: To evaluate the feasibility and efficacy of a caloric vestibular stimulation (CVS)-med... more Objective: To evaluate the feasibility and efficacy of a caloric vestibular stimulation (CVS)-mediated brainstem modulation device for the treatment of non-motor and motor symptoms in Parkinson\u27s disease (PD). Background: A recent case study showed that repeated sessions of CVS using a solid-state ThermoNeuroModulation (TNM™) device, developed by Scion NeuroStim, LLC, relieved motor and non-motor symptoms associated with PD. Here, we sought to confirm these results in a prospective, double-blind, randomized, placebo treatment-controlled study. The TNM device delivers CVS via continually-varying thermal waveforms through aluminum ear-probes mounted on a wearable headset. Unlike conventional air and water irrigators, treatments can easily be self-administered at home with few side effects and with a high degree of dose control. Methods: 33 PD subjects receiving stable anti-Parkinsonian therapy completed an active (n=16) or placebo (n=17) treatment period. Subjects self-administered TNM treatments at home twice-daily. Subjects were followed over a 4-week baseline period, 8 weeks of treatment and then at 5-and 24-weeks post-treatment. At each study visit, standardized clinical assessments were conducted during ON-medication states to evaluate changes in motor and non-motor symptoms, activities of daily living, and quality of life ratings. Results: Change scores between baseline and the end of treatment showed that active-arm subjects demonstrated clinically-relevant reductions in motor and non-motor symptoms that were significantly greater than placebo-arm subjects. Active treatment was also associated with improved scores on activities of daily living assessments. Therapeutic gains were still evident 5 weeks after the end of active treatment but had started to recede at 24 weeks follow-up. No serious adverse events were associated with device use, and there was high participant satisfaction and tolerability of treatment Conclusions: The results provide evidence that repeated CVS can provide safe and enduring adjuvant relief for motor and non-motor symptoms associated with PD
Dopaminergic agonists are drugs that directly stimulate dopamine receptors (particularly the D-2 ... more Dopaminergic agonists are drugs that directly stimulate dopamine receptors (particularly the D-2 subtype). Like the natural neurotransmitter dopamine, these drugs exert potent effects against signs and symptoms of Parkinson's disease (PD) and restless leg syndrome. Since 1974, more than two dozen dopaminergic agonists have been developed; currently, several are in use worldwide. Dopaminergic agonists can be almost as effective as levodopa in relieving the motor features of PD. These drugs also can serve to augment the control of Parkinsonism beyond the best that monotherapy with levodopa can accomplish. The chronic use of dopaminergic agonists appears to lessen the risk for developing dyskinesias or motor fluctuations in patients treated with levodopa. Pramipexole, ropinirole, and rotigotine are the most widely used dopaminergic agonists.
... Address correspondence and reprint requests to Dr. Jong S. Kim, Department of Neurology, Asan... more ... Address correspondence and reprint requests to Dr. Jong S. Kim, Department of Neurology, Asan Medical ... Brain MRI and 99m Tc ethyl cysteinate dimer (ECD) perfusion SPECT revealed ischemic lesions in the left midbrain and the anterior thalamus, but not in the ...
On analysis of cerebrospinal fluid (CSF) samples from normal volunteer donors by high-resolution ... more On analysis of cerebrospinal fluid (CSF) samples from normal volunteer donors by high-resolution zone electrophoresis on agarose gel, an electrophoretically homogeneous protein band consistently appeared in the gamma-globulin region. Application of immunofixation electrophoresis in attempts to identify the band with use of monospecific antibodies against individual human serum proteins and against heavy- and light-chain immunoglobulins as well as polyvalent antisera did not produce a positive immunoprecipitation reaction with the protein band. The serum samples from these subjects did not show similar bands. Therefore, we conclude that this protein band is a normally occurring protein that is unique to CSF.
ImportanceLevodopa has a short half-life and a limited window of opportunity for absorption in th... more ImportanceLevodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations.ObjectiveTo assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations.Design, Setting, and ParticipantsRISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose,...
Objectives: To explore functional connectivity at a network level with MEG, pre-and post-administ... more Objectives: To explore functional connectivity at a network level with MEG, pre-and post-administration of medications, in cervical dystonia and Meige syndrome. Background: Mechanisms thought to play a critical role in dystonia include reduced intracortical inhibition and distorted somatotopic cortical representation. Prior studies showed altered functional connectivity within the sensorimotor, the executive control and the primary visual network. Methods: MEG Data on 5 patients, 4 with cervical dystonia and 1 with Meige syndrome (age: 16-70 years) were matched to 5 (age and sex matched) healthy controls. All patients (4 on Botulinum toxin, 1 on Diazepam) showed clinical benefit with medications. Two 15-minute MEG scans pre and post intervention were obtained. Synchronization of neuronal activity was quantified by calculating coherence source imaging (CSI) between cortical sites from MEG imaged brain activations. A region-of-interest (ROI) tool was used to identify 54 regions in the brain (27 in each hemisphere). Within the frequency band 3-50Hz, a t-test was conducted to assess group difference in average CSI values for each pair of brain regions (N51,431). A P value was produced for each region pair. Only statistically significant coherence values (p\\u3c0.05) with a large effect size were considered. Results: Using group based analysis, in both pre-treatment and posttreatment groups, the biggest difference in coherence between patients and controls was seen in the fronto-striatal and occipito-striatal regions, with some differences in the parieto-striatal and striato-parietal regions. On comparing pre-and post-treatment dystonia patients, an increase in coherence was observed in these regions post treatment. Conclusion: Our exploratory study using MEG showed increased neuronal connectivity in regions associated with visuospatial and executive function, with an increase post medication in patients with cervical dystonia and Meige syndrome. The latter may be a biomarker for normalization of aberrant connectivity and merits further exploration
The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses ... more The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.
Parkinson’s Disease (PD), characterized by a marked loss of nigrostriatal neurons [1], is general... more Parkinson’s Disease (PD), characterized by a marked loss of nigrostriatal neurons [1], is generally a disorder of progressive disability. While additional neuronal systems of the PD brain are altered [2], the change most closely linked to the clinical symptomatology of Parkinsonism is the impaired generation of striatal dopamine. Dopamine production may also figure in the special vulnerability of substantia nigra pars compacta neurons in PD. Several hypotheses for the decline in dopaminergic neurons have been advanced. One speculation has been that one or more exogenous toxins might produce a metabolic effect damaging these neurons. Several neurotoxins with highly specific actions against nigrostriatal dopaminergic neurons are known. These produce parkinsonian symptomatology both in animal models and, in the case of manganese and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in man. MPTP has been the most intriguing of these because of its need for conversion in the brain prior to exerting toxicity to nigrostriatal dopamine neurons via their mitochondrial metabolism. The unique properties of MPTP have provided grist for speculation that PD could conceivably be the outcome of intermittent or continuous neurotoxicity from exposure to similar types of compounds [3–5].
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer... more Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and
Objective: To evaluate the feasibility and efficacy of a caloric vestibular stimulation (CVS)-med... more Objective: To evaluate the feasibility and efficacy of a caloric vestibular stimulation (CVS)-mediated brainstem modulation device for the treatment of non-motor and motor symptoms in Parkinson\u27s disease (PD). Background: A recent case study showed that repeated sessions of CVS using a solid-state ThermoNeuroModulation (TNM™) device, developed by Scion NeuroStim, LLC, relieved motor and non-motor symptoms associated with PD. Here, we sought to confirm these results in a prospective, double-blind, randomized, placebo treatment-controlled study. The TNM device delivers CVS via continually-varying thermal waveforms through aluminum ear-probes mounted on a wearable headset. Unlike conventional air and water irrigators, treatments can easily be self-administered at home with few side effects and with a high degree of dose control. Methods: 33 PD subjects receiving stable anti-Parkinsonian therapy completed an active (n=16) or placebo (n=17) treatment period. Subjects self-administered TNM treatments at home twice-daily. Subjects were followed over a 4-week baseline period, 8 weeks of treatment and then at 5-and 24-weeks post-treatment. At each study visit, standardized clinical assessments were conducted during ON-medication states to evaluate changes in motor and non-motor symptoms, activities of daily living, and quality of life ratings. Results: Change scores between baseline and the end of treatment showed that active-arm subjects demonstrated clinically-relevant reductions in motor and non-motor symptoms that were significantly greater than placebo-arm subjects. Active treatment was also associated with improved scores on activities of daily living assessments. Therapeutic gains were still evident 5 weeks after the end of active treatment but had started to recede at 24 weeks follow-up. No serious adverse events were associated with device use, and there was high participant satisfaction and tolerability of treatment Conclusions: The results provide evidence that repeated CVS can provide safe and enduring adjuvant relief for motor and non-motor symptoms associated with PD
Dopaminergic agonists are drugs that directly stimulate dopamine receptors (particularly the D-2 ... more Dopaminergic agonists are drugs that directly stimulate dopamine receptors (particularly the D-2 subtype). Like the natural neurotransmitter dopamine, these drugs exert potent effects against signs and symptoms of Parkinson's disease (PD) and restless leg syndrome. Since 1974, more than two dozen dopaminergic agonists have been developed; currently, several are in use worldwide. Dopaminergic agonists can be almost as effective as levodopa in relieving the motor features of PD. These drugs also can serve to augment the control of Parkinsonism beyond the best that monotherapy with levodopa can accomplish. The chronic use of dopaminergic agonists appears to lessen the risk for developing dyskinesias or motor fluctuations in patients treated with levodopa. Pramipexole, ropinirole, and rotigotine are the most widely used dopaminergic agonists.
... Address correspondence and reprint requests to Dr. Jong S. Kim, Department of Neurology, Asan... more ... Address correspondence and reprint requests to Dr. Jong S. Kim, Department of Neurology, Asan Medical ... Brain MRI and 99m Tc ethyl cysteinate dimer (ECD) perfusion SPECT revealed ischemic lesions in the left midbrain and the anterior thalamus, but not in the ...
On analysis of cerebrospinal fluid (CSF) samples from normal volunteer donors by high-resolution ... more On analysis of cerebrospinal fluid (CSF) samples from normal volunteer donors by high-resolution zone electrophoresis on agarose gel, an electrophoretically homogeneous protein band consistently appeared in the gamma-globulin region. Application of immunofixation electrophoresis in attempts to identify the band with use of monospecific antibodies against individual human serum proteins and against heavy- and light-chain immunoglobulins as well as polyvalent antisera did not produce a positive immunoprecipitation reaction with the protein band. The serum samples from these subjects did not show similar bands. Therefore, we conclude that this protein band is a normally occurring protein that is unique to CSF.
ImportanceLevodopa has a short half-life and a limited window of opportunity for absorption in th... more ImportanceLevodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations.ObjectiveTo assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations.Design, Setting, and ParticipantsRISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose,...
Uploads
Papers by Peter Lewitt