Spyridon Konitsiotis

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys

Objective: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. Background: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. Methods: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. Results: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). Conclusions: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms

Abstract Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson’s disease, and their prevention or reversal could prove useful in the treatment of this disorder.

MRI evaluation of the basal ganglia size and iron content in patients with Parkinson's disease

AbstractObjectiveTo evaluate by MRI the area size and the degree of iron accumulation in basal ganglia nuclei that are implicated in the pathogenesis of Parkinsons disease (PD).Methods40 patients with idiopathic PD and 40 controls were examined on a 1. 5 Tesla MR imager, using a multiecho SE sequence 2000/20, 40, 60, 80, 100, 120, 140, 160 (TR/TE). The T2 relaxation time (T2) and the area of substantia nigra zona compacta (SNc), substantia nigra zona reticulata (SNr), putamen (Pu), globus pallidus external (GPe), globus pallidus internal (GPi), caudate nucleus (CN), locus coeruleus (LC) and subthalamic nucleus (STN) were assessed.ResultsThe T2 of SNc (76. 8 ± 6. 0) was lower and of Pu (79.5 ± 6.0) and GPe (69.5 ± 7.0) was higher in patients than in controls (78.6 ± 3.8, 77.4 ± 3.9 and 67.3 ± 5.7, respectively), p < 0.05. The area of CN (125.9 ± 20.2) and Pu (201.5 ± 48.7) was higher in patients than in controls (110.7 ± 21.5 and 180.1 ± 41.1, respectively), p < 0.05. A more pronounced decrease in the T2 of SNc (73.6 ± 8.9) was observed when the more affected side of patients was evaluated separately. In patients with disease duration > 5 years the T2 of STN (71.5 ± 6.3) was lower and the area of Pu was higher (215.3 ± 54.9) compared with those with disease duration ≤ 5 years (75.8 ± 10.9 and 190.9 ± 41.0 respectively), p < 0.05.ConclusionsThese findings suggest that dysfunction of the basal ganglia circuitry in PD may affect iron content not only in SNc but in STN, Pu and GPe as well. Compensatory sprouting of the remaining dopaminergic fibers could account for the increased area of the CN and Pu.

Demyelination and other neurological adverse events after anti-TNF therapy

Tumor necrosis factor (TNF) α inhibitors are an essential therapeutic option for several inflammatory diseases, like rheumatoid arthritis, spondyloarthropathies and inflammatory bowel diseases. As TNFα antagonists have become increasingly utilized, there have been a number of reports of neurological adverse events in patients receiving anti-TNFα therapy. The frequency of central nervous system adverse events after initiation of anti-TNFα therapy is unknown. However, questions have been raised about a possible causal association. Although several hypotheses have been proposed in an attempt to explain the possible relationship between TNFα antagonist and demyelination, none is considered to be adequate. Thus, in this report we deal with the implication of TNFα in multiple sclerosis and we discuss the possible relationship of TNFα antagonist and demyelinating diseases.

Assessment of Tremor Activity in the Parkinson’s Disease Using a Set of Wearable Sensors

Tremor is the most common motor disorder of Parkinsons disease (PD) and consequently its detection plays a crucial role in the management and treatment of PD patients. The current diagnosis procedure is based on subject-dependent clinical assessment, which has a difficulty in capturing subtle tremor features. In this paper, an automated method for both resting and action/postural tremor assessment is proposed using a set of accelerometers mounted on different patients body segments. The estimation of tremor type (resting/action postural) and severity is based on features extracted from the acquired signals and hidden Markov models. The method is evaluated using data collected from 23 subjects (18 PD patients and 5 control subjects). The obtained results verified that the proposed method successfully: 1) quantifies tremor severity with 87 % accuracy, 2) discriminates resting from postural tremor, and 3) discriminates tremor from other Parkinsonian motor symptoms during daily activities.

T2 relaxometry and fMRI of the brain in late-onset restless legs syndrome

Objective: To assess in patients with late-onset idiopathic restless legs syndrome (RLS) the brain iron content with magnetic resonance relaxometry, and brain activation during dorsiflexion and plantar flexion of both feet, using fMRI. Methods: The study was approved by the institutional review board, and informed consent was obtained. Twenty-five RLS patients (14 women, 11 men; age range 55–82 years; mean 66.5 ± 8.9 years; disease duration 6.5 ± 4.5 years) and 12 sex- and age-matched controls were studied. A T1-weighted high-resolution three-dimensional spoiled gradient echo sequence was used for structural imaging, a multislice spin echo Τ2-weighted sequence was used for T2 relaxometry, and a single-shot multislice gradient echo planar sequence was used for fMRI. The motor paradigm consisted of alternating periods of rest and movement, each 40 seconds in duration. Region of interest analysis was used on the T2 relaxometry maps. Statistical parametric mapping software was used for analysis of the functional data. Results: T2 relaxation time was significantly higher in patients than in controls in the substantia nigra pars compacta. Within-group analysis showed that both patients and controls activated the primary motor cortex, the primary somatosensory cortex, the somatosensory association cortex, and the middle cerebellar peduncles. Patients also activated the thalamus, putamen, middle frontal gyrus, and cingulate gyrus. Between-group analysis showed that patients had higher activation of the dorsolateral prefrontal cortex. Conclusion: Late-onset restless legs syndrome is associated with low iron content of the basal ganglia and increased activity of the dorsolateral prefrontal cortex. GLOSSARY: C = constant offset parameter added to compensate for background noise bias; CN = caudate nucleus; DMT1 = divalent metal transporter 1; DN = dentate nucleus; EPI = echo planar imaging; GP = globus pallidus; IRLS = International RLS Study Group Rating Scale; JHRLSS = Johns Hopkins RLS Severity Scale; MIP = maximum intensity projection; MR = magnetic resonance; PLMS = periodic limb movements in sleep; Pu = putamen; RLS = restless leg syndrome; RN = red nucleus; ROI = region of interest; SN = substantia nigra; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; So = signal amplitude at echo time = 0; SPM = statistical parametric mapping; S(TE) = signal intensity at echo time; TE = echo time; Th = thalamus; TR = repetition time.

Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease†

The efficacy and safety of levetiracetam (LEV), administered for management of levodopa‐induced dyskinesias (LID) in Parkinsons disease (PD), was examined using a multicenter, double‐blind, placebo‐controlled, parallel groups, crossover trial. Because of having a period effect, data after crossover point was excluded from analysis. Levodopa‐treated PD participants with LID (n = 38) received LEV 500 mg/day, were assessed, titrated to 1,000 mg/day and reassessed, before and after crossover. The placebo group followed the same routine. Primary efficacy was defined from percent change in “On with LID” time from patient diaries. Secondary efficacy assessment used “On without LID,” “Off” time, unified PD rating scale (UPDRS), clinical global impression (CGI), and Goetz dyskinesia scale after levodopa challenge. Safety measures were also performed. On with LID time decreased 37 minutes (95% confidence interval [CI] 0.59, 7.15; P = 0.02) at 500 mg/day, 7.85% 75 minutes (95% CI 3.3, 12.4; P = 0.002) at 1,000 mg/day. On without LID time increased by 46 minutes (95% CI −1.55, −0.03; P = 0.04) at 500 mg/day and 55 minutes (95% CI −10.39, −1.14; P = 0.018) at 1,000 mg/day. UPDRS 32 showed decreased dyskinesia duration mean change 0.35 (95% CI 0.09, 0.5; P = 0.009) at 1,000 mg/day. CGI showed LID decreased by 0.7 (95% CI 0.21, 1.18; P = 0.006) at 1,000 mg/day. Patient diaries and UPDRS show no increase in Off time. This exploratory trial provides evidence that LEV in 1,000 mg/day, slowly titrated, could be useful in improving LID as was assessed with patient diaries, UPDRS, and CGI scales, safely, with minimal side effects.

Investigation of Unmedicated Early Onset Restless Legs Syndrome by Voxel-Based Morphometry, T2 Relaxometry, and Functional MR Imaging during the Night-Time Hours

BACKGROUND AND PURPOSE: The pathophysiology of eRLS has not yet been elucidated. The purpose of the study was to assess, in patients with eRLS, the volume, iron content, and activation of the brain during night-time episodes of SLD and PLMs. MATERIALS AND METHODS: Eleven right-handed unmedicated patients with eRLS (mean age, 55.3 ± 8.4 years; disease duration, 17.5 ± 14.05 years) and 11 matched control subjects were studied with a T1-weighted high-resolution 3D spoiled gradient-echo sequence used for VBM and a multisection spin-echo T2-weighted sequence used for T2 relaxometry. Additionally, a single-shot multisection gradient echo-planar sequence was used for fMRI. Brain activation was recorded during spontaneous SLD and PLMs. SPM software was used for analysis of the functional data. RESULTS: The patients showed no regional brain volume change, but T2 relaxometry revealed decreased T2 relaxation time in the right globus pallidus internal and the STN, indicating increased iron content. The patients were observed to activate the following areas: in the left hemisphere, the primary motor and somatosensory cortex, the thalamus, the pars opercularis, and the ventral anterior cingulum; and in the right hemisphere, the striatum, the inferior and superior parietal lobules, and the dorsolateral prefrontal cortex. Bilateral activation was observed in the cerebellum, the midbrain, and the pons. CONCLUSIONS: eRLS is associated with increased iron content of the globus pallidus internal and STN, suggesting dysfunction of the basal ganglia. Activation of the striatofrontolimbic area may represent the neurofunctional substrate mediating the repetitive compulsive movements seen in RLS.

Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: a meta‐analysis

Nocebo refers to adverse events (AEs) generated by patients negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo‐controlled randomized controlled trials (RCTs). We examined AEs following placebo administration in RCTs for Parkinsons disease (PD).

Automated Levodopa-induced dyskinesia assessment

An automated methodology for Levodopa-induced dyskinesia (LID) assessment is presented in this paper. The methodology is based on the analysis of the signals recorded from accelerometers and gyroscopes, which are placed on certain positions on the subjects body. The obtained signals are analyzed and several features are extracted. Based on these features a classification technique is used for LID detection and classification of its severity. The method has been evaluated using a group of 10 subjects. Results are presented related to each individual sensor as well as for various sensor combinations. The obtained results indicate high classification ability (93.73% classification accuracy).