The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydro... more The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydrofolic acid (THF) and dihydrofolic acid (DHF) to mimic the actions of kainic acid (KA) in a number of in vitro and in vivo systems known to be sensitive to KA was examined. None of the three folate derivatives at 100 microM concentration significantly inhibited the specific binding of [3H]-KA to striatal membranes although 2 microM L-glutamate produced a 40% inhibition. None of the three folate derivatives stimulated the formation of cyclic GMP in cerebellar slices incubated in vitro although KA (0.5 mM) increased cyclic GMP levels by 2.5-fold. Whereas intrahippocampal injection of 2.3 nmoles of KA produces prolonged abnormalities of the EEG, limbic-type seizures and a characteristic pattern of neuronal degeneration in the hippocampal formation and related structures, intrahippocampal injection of a 100-fold greater dose of THF caused only minor and transient EEG abnormalities, no overt s...
Levels of monoamines and metabolites in rostral and caudal hypothalamic fragments of young (3-4 m... more Levels of monoamines and metabolites in rostral and caudal hypothalamic fragments of young (3-4 months) and old (25-26 months) Fischer 344-rats were compared. There were no differences between fragments of young animals. In senescent rats, 5-hydroxyindoleacetic acid (5HIAA) increased in both rostral and caudal hypothalamus. The ratio 5HIAA/5HT (serotonin), an index of serotonin turnover, increased only rostrally. This age-related increase of 5HIAA/5HT in rostral hypothalamus was associated with a decrease in [3H]-spiperone binding. There were no age-related changes of MAO-A activity in the hypothalamus or of serum tyrosine or tryptophan levels.
Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in ap... more Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it predates PD diagnosis in about 30% of patients. Between 20% and 60% of depressed patients with PD are either without recognition or treatment of their depression. Areas covered: The pathophysiology of depression in PD is unclear. There are several structural changes seen in depressed patients with PD that are also seen in patients with depression. In addition, the neurotransmitters dopamine, serotonin, and norepinephrine are all depleted in PD. This article covers the pharmacological treatment of depression in PD; this involves standard antidepressant treatment such as selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. As with depression not associated with PD, most treatment is partially successful. Non-pharmacological approaches are also touched upon. Expert opinion: Most antidepressant therapy shows partial efficacy in patients with PD. However, there is a need for better study design as well as more comparative studies for the treatment of depression in PD. Biomarkers will help identify patients with PD and depression earlier in the future.
Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Openla... more Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Openlabel studies have suggested improved gait after treatment with methylphenidate (MPD). Objective: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. Methods: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length ϩ velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. Results: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. Conclusions: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. Classification of evidence: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630. Neurology ® 2011;76: 1256-1262 GLOSSARY ESS ϭ Epworth Sleepiness Scale; FOGQ ϭ Freezing of Gait Questionnaire; GDS ϭ Geriatric Depression Scale; MADRS ϭ Montgomery-Åsberg Depression Rating Scale; MPD ϭ methylphenidate; PD ϭ Parkinson disease; STN DBS ϭ subthalamic deep brain stimulation; UPDRS ϭ Unified Parkinson's Disease Rating Scale. Gait impairment in the form of shuffling and freezing of gait often occurs during the course of Parkinson disease (PD), generating substantial disability. 1 Dopaminergic treatments and currently available surgical therapies are often insufficiently effective for gait disorders in PD. 2,3 Freezing of gait has been proposed to result in part from the noradrenaline reduction due to locus ceruleus degeneration and the subsequent dopamine-noradrenergic imbalance. 4 Methylphenidate (MPD, Ritalin ®), an amphetamine-like psychomotor stimulant, is a candidate to support this hypothesis given its inhibitory action on the striatal and cortical presynaptic transporter for dopamine 5 and norepinephrine, 6 thus enhancing synaptic levels of both neurotransmitters. Three open-label studies have reported efficacy of MPD in PD-associated gait impairment. In the first, gait speed, stride time variability, and a timed gait test improved following a single 20-mg dose of MPD given to 21 patients with PD. 7 In the second, total walking time, total freezing time,
We sought to design a data visualization platform to represent the Movement Disorder Society- Uni... more We sought to design a data visualization platform to represent the Movement Disorder Society- Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) item scores in an easy-to-use display without modification of the raw data or summary scores. Score items for Parts I, II, and IV were arranged as separate inline blocks, while Part III item blocks were arranged in an anatomical fashion. A color scale was created to represent symptom severity and changes observed from one exam to another. We have found the visualization helpful for quickly defining the most troublesome symptoms and their anatomical location enabling communication of the results and interpretations.
Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in th... more Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in the putamen and caudate nucleus of a patient who lived 36 hours after a unilateral mechanical lesion of the mesencephalon. After cessation of impulse flow along the nigrostriatal tract, dopamine was elevated, dihydroxyphenylacetic acid was diminished, and CAT and tyrosine hydroxylase activity were enhanced in the putamen ipsilateral to the lesion. [3H]-spiperone binding indicated an increase in D2-dopamine receptor density in the caudate nucleus. These findings indicate that the changes predicted from experimental neurochemical models occur in human nigrostriatal systems.
EEGs of 55 subjects with classic or common migraine were correlated with headache subtype, age of... more EEGs of 55 subjects with classic or common migraine were correlated with headache subtype, age of onset, duration of illness, family history, and time span either from last headache or medication. Eleven patients (20%) had abnormal EEGs: five were diffusely slow, one demonstrated bitemporal slowing, one generalized spikes, and two each showed either a photoconvulsive response or excessive buildup to hyperventilation. EEG abnormalities did not correlate chronologically with medication or headache. Six of 30 patients with headache and/or medication within 48 hours of the EEG had abnormal records, a number not statistically different from the five of 25 who had abnormal EEGs in the absence of headache or medication in the previous 48 hours. EEG abnormalities in migraine, while varied and nonspecific, do persist during asymptomatic intervals. This suggests more permanent alterations of cerebral physiology than can be accounted for by transient vascular changes during migraine attacks themselves.
OBJECTIVE: To describe a unique support network provided by clinical nurse educators (CNEs) to st... more OBJECTIVE: To describe a unique support network provided by clinical nurse educators (CNEs) to study sites in the levodopa-carbidopa intestinal gel (LCIG/carbidopa-levodopa enteral suspension [CLES]) development program for patients with advanced Parkinson’s disease (PD). BACKGROUND: LCIG is delivered via a percutaneous gastrojejunostomy tube (PEG-J) to provide PD patients with more stable levodopa levels. Execution of clinical trials requiring PEG-J placement for this novel drug delivery system necessitated a unique multidisciplinary model. METHODS: CNEs with intensive LCIG system training were assigned to study sites to provide technical support for healthcare professionals (HCPs). RESULTS: CNEs were present for 391/425 (92[percnt]) of the PEG-J placements and LCIG dose titrations, but not directly involved in patient care. CNEs developed training materials, provided hands-on device training, supported gastroenterologists in real-time during PEG-J placement, and provided broad knowledge of titration options to HCPs performing LCIG titrations. CNEs were the first point of contact for new sites with regard to PEG-J procedures and LCIG titration. They collaborated with the sponsor to develop a “dry-run” model for site initiation, and liaised critically between members of the multidisciplinary team. CONCLUSIONS: Implementation of the CNE model provided benefits to clinicians and clinical research sites, ultimately improving the patient experience. Involvement of CNEs optimized and streamlined site initiation, study/product monitoring, issue resolution, and communication within a multidisciplinary care model. This approach could be considered for future studies of complex drug delivery systems that require a multidisciplinary team to optimize patient care. Study Supported by: AbbVie Inc. Disclosure: Dr. Olson holds stock and/or stock options in AbbVie. Dr. Greene has received personal compensation for activities with Quintiles. Dr. Espay has received personal compensation for activities with AbbVie as a study coordinator and advisory board member. Dr. Wagner has received personal compensation for activities with AbbVie. Dr. Krai Chatamra holds stock and/or stock options in AbbVie, which sponsored research in which Dr. Catamra was involved as an investigator. Dr. Benesh holds stock and/or stock options in AbbVie, which sponsored research in which Dr. Benesh was involved as an investigator. Dr. Slevin has received research support from Abbott Laboratories, BioTie, and Teva. Dr. Espay has received personal compensation as a consultant/scientific advisory board member for Abbvie, Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Acadia, Cynapsus, Solstice Neurosciences, Lundbeck, and USWorldMeds; and honoraria from Abbvie, UCB,
The epilepsies are chronic disorders of the central nervous system characterized by recurrent con... more The epilepsies are chronic disorders of the central nervous system characterized by recurrent convulsive or non-convulsive seizures. Recent estimates suggest between 20 and 40 million people may be affected worldwide. One research strategy for investigating the neurobiological mechanisms underlying the induction and maintenance of the epileptic state has been the development of experimental animal models. Recently, one major model in particular has emerged as a focus of intense research effort: the kindling phenomenon first described by Goddard et al. (1969). The partial seizures, which constitute the behavioral manifestations of the amygdala-kindled model, are considered to represent the best available analogy to human complex partial (temporal lobe, ‘psychomotor’, limbic) epilepsy (McNamara, 1984a).
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydro... more The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydrofolic acid (THF) and dihydrofolic acid (DHF) to mimic the actions of kainic acid (KA) in a number of in vitro and in vivo systems known to be sensitive to KA was examined. None of the three folate derivatives at 100 microM concentration significantly inhibited the specific binding of [3H]-KA to striatal membranes although 2 microM L-glutamate produced a 40% inhibition. None of the three folate derivatives stimulated the formation of cyclic GMP in cerebellar slices incubated in vitro although KA (0.5 mM) increased cyclic GMP levels by 2.5-fold. Whereas intrahippocampal injection of 2.3 nmoles of KA produces prolonged abnormalities of the EEG, limbic-type seizures and a characteristic pattern of neuronal degeneration in the hippocampal formation and related structures, intrahippocampal injection of a 100-fold greater dose of THF caused only minor and transient EEG abnormalities, no overt s...
Levels of monoamines and metabolites in rostral and caudal hypothalamic fragments of young (3-4 m... more Levels of monoamines and metabolites in rostral and caudal hypothalamic fragments of young (3-4 months) and old (25-26 months) Fischer 344-rats were compared. There were no differences between fragments of young animals. In senescent rats, 5-hydroxyindoleacetic acid (5HIAA) increased in both rostral and caudal hypothalamus. The ratio 5HIAA/5HT (serotonin), an index of serotonin turnover, increased only rostrally. This age-related increase of 5HIAA/5HT in rostral hypothalamus was associated with a decrease in [3H]-spiperone binding. There were no age-related changes of MAO-A activity in the hypothalamus or of serum tyrosine or tryptophan levels.
Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in ap... more Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it predates PD diagnosis in about 30% of patients. Between 20% and 60% of depressed patients with PD are either without recognition or treatment of their depression. Areas covered: The pathophysiology of depression in PD is unclear. There are several structural changes seen in depressed patients with PD that are also seen in patients with depression. In addition, the neurotransmitters dopamine, serotonin, and norepinephrine are all depleted in PD. This article covers the pharmacological treatment of depression in PD; this involves standard antidepressant treatment such as selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. As with depression not associated with PD, most treatment is partially successful. Non-pharmacological approaches are also touched upon. Expert opinion: Most antidepressant therapy shows partial efficacy in patients with PD. However, there is a need for better study design as well as more comparative studies for the treatment of depression in PD. Biomarkers will help identify patients with PD and depression earlier in the future.
Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Openla... more Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Openlabel studies have suggested improved gait after treatment with methylphenidate (MPD). Objective: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. Methods: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length ϩ velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. Results: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. Conclusions: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. Classification of evidence: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630. Neurology ® 2011;76: 1256-1262 GLOSSARY ESS ϭ Epworth Sleepiness Scale; FOGQ ϭ Freezing of Gait Questionnaire; GDS ϭ Geriatric Depression Scale; MADRS ϭ Montgomery-Åsberg Depression Rating Scale; MPD ϭ methylphenidate; PD ϭ Parkinson disease; STN DBS ϭ subthalamic deep brain stimulation; UPDRS ϭ Unified Parkinson's Disease Rating Scale. Gait impairment in the form of shuffling and freezing of gait often occurs during the course of Parkinson disease (PD), generating substantial disability. 1 Dopaminergic treatments and currently available surgical therapies are often insufficiently effective for gait disorders in PD. 2,3 Freezing of gait has been proposed to result in part from the noradrenaline reduction due to locus ceruleus degeneration and the subsequent dopamine-noradrenergic imbalance. 4 Methylphenidate (MPD, Ritalin ®), an amphetamine-like psychomotor stimulant, is a candidate to support this hypothesis given its inhibitory action on the striatal and cortical presynaptic transporter for dopamine 5 and norepinephrine, 6 thus enhancing synaptic levels of both neurotransmitters. Three open-label studies have reported efficacy of MPD in PD-associated gait impairment. In the first, gait speed, stride time variability, and a timed gait test improved following a single 20-mg dose of MPD given to 21 patients with PD. 7 In the second, total walking time, total freezing time,
We sought to design a data visualization platform to represent the Movement Disorder Society- Uni... more We sought to design a data visualization platform to represent the Movement Disorder Society- Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) item scores in an easy-to-use display without modification of the raw data or summary scores. Score items for Parts I, II, and IV were arranged as separate inline blocks, while Part III item blocks were arranged in an anatomical fashion. A color scale was created to represent symptom severity and changes observed from one exam to another. We have found the visualization helpful for quickly defining the most troublesome symptoms and their anatomical location enabling communication of the results and interpretations.
Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in th... more Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in the putamen and caudate nucleus of a patient who lived 36 hours after a unilateral mechanical lesion of the mesencephalon. After cessation of impulse flow along the nigrostriatal tract, dopamine was elevated, dihydroxyphenylacetic acid was diminished, and CAT and tyrosine hydroxylase activity were enhanced in the putamen ipsilateral to the lesion. [3H]-spiperone binding indicated an increase in D2-dopamine receptor density in the caudate nucleus. These findings indicate that the changes predicted from experimental neurochemical models occur in human nigrostriatal systems.
EEGs of 55 subjects with classic or common migraine were correlated with headache subtype, age of... more EEGs of 55 subjects with classic or common migraine were correlated with headache subtype, age of onset, duration of illness, family history, and time span either from last headache or medication. Eleven patients (20%) had abnormal EEGs: five were diffusely slow, one demonstrated bitemporal slowing, one generalized spikes, and two each showed either a photoconvulsive response or excessive buildup to hyperventilation. EEG abnormalities did not correlate chronologically with medication or headache. Six of 30 patients with headache and/or medication within 48 hours of the EEG had abnormal records, a number not statistically different from the five of 25 who had abnormal EEGs in the absence of headache or medication in the previous 48 hours. EEG abnormalities in migraine, while varied and nonspecific, do persist during asymptomatic intervals. This suggests more permanent alterations of cerebral physiology than can be accounted for by transient vascular changes during migraine attacks themselves.
OBJECTIVE: To describe a unique support network provided by clinical nurse educators (CNEs) to st... more OBJECTIVE: To describe a unique support network provided by clinical nurse educators (CNEs) to study sites in the levodopa-carbidopa intestinal gel (LCIG/carbidopa-levodopa enteral suspension [CLES]) development program for patients with advanced Parkinson’s disease (PD). BACKGROUND: LCIG is delivered via a percutaneous gastrojejunostomy tube (PEG-J) to provide PD patients with more stable levodopa levels. Execution of clinical trials requiring PEG-J placement for this novel drug delivery system necessitated a unique multidisciplinary model. METHODS: CNEs with intensive LCIG system training were assigned to study sites to provide technical support for healthcare professionals (HCPs). RESULTS: CNEs were present for 391/425 (92[percnt]) of the PEG-J placements and LCIG dose titrations, but not directly involved in patient care. CNEs developed training materials, provided hands-on device training, supported gastroenterologists in real-time during PEG-J placement, and provided broad knowledge of titration options to HCPs performing LCIG titrations. CNEs were the first point of contact for new sites with regard to PEG-J procedures and LCIG titration. They collaborated with the sponsor to develop a “dry-run” model for site initiation, and liaised critically between members of the multidisciplinary team. CONCLUSIONS: Implementation of the CNE model provided benefits to clinicians and clinical research sites, ultimately improving the patient experience. Involvement of CNEs optimized and streamlined site initiation, study/product monitoring, issue resolution, and communication within a multidisciplinary care model. This approach could be considered for future studies of complex drug delivery systems that require a multidisciplinary team to optimize patient care. Study Supported by: AbbVie Inc. Disclosure: Dr. Olson holds stock and/or stock options in AbbVie. Dr. Greene has received personal compensation for activities with Quintiles. Dr. Espay has received personal compensation for activities with AbbVie as a study coordinator and advisory board member. Dr. Wagner has received personal compensation for activities with AbbVie. Dr. Krai Chatamra holds stock and/or stock options in AbbVie, which sponsored research in which Dr. Catamra was involved as an investigator. Dr. Benesh holds stock and/or stock options in AbbVie, which sponsored research in which Dr. Benesh was involved as an investigator. Dr. Slevin has received research support from Abbott Laboratories, BioTie, and Teva. Dr. Espay has received personal compensation as a consultant/scientific advisory board member for Abbvie, Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Acadia, Cynapsus, Solstice Neurosciences, Lundbeck, and USWorldMeds; and honoraria from Abbvie, UCB,
The epilepsies are chronic disorders of the central nervous system characterized by recurrent con... more The epilepsies are chronic disorders of the central nervous system characterized by recurrent convulsive or non-convulsive seizures. Recent estimates suggest between 20 and 40 million people may be affected worldwide. One research strategy for investigating the neurobiological mechanisms underlying the induction and maintenance of the epileptic state has been the development of experimental animal models. Recently, one major model in particular has emerged as a focus of intense research effort: the kindling phenomenon first described by Goddard et al. (1969). The partial seizures, which constitute the behavioral manifestations of the amygdala-kindled model, are considered to represent the best available analogy to human complex partial (temporal lobe, ‘psychomotor’, limbic) epilepsy (McNamara, 1984a).
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Uploads
Papers by John Slevin