Christopher Kobylecki

Calcium-permeable AMPA receptors are involved in the induction and expression of L-DOPA-induced dyskinesia in Parkinson's disease

J. Neurochem. (2010) 114, 409–511.

Synaptic recruitment of AMPA glutamate receptor subunits in levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate

MONTY A. SILVERDALE,* CHRISTOPHER KOBYLECKI, PENELOPE J. HALLETT, QIN LI, ANTHONE W. DUNAH, PAULA RAVENSCROFT, ERWAN BEZARD, AND JONATHAN M. BROTCHIE Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, United Kingdom MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China Université Victor Segalen-Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France Toronto Western Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada

Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study

Autonomic and somatic denervation is well established in Parkinsons disease (PD). Objectives (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. Methods Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinsons disease – autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III “ON”] and cumulative Levodopa dose. Results PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. Conclusion CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD.

Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease

L‐Dopa‐induced dyskinesia in patients with Parkinsons disease can be alleviated by amantadine, an antagonist at N‐methyl‐D‐aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L‐dopa‐induced dyskinesia. The effects of topiramate (5–20 mg/kg) and amantadine (5–20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6‐hydroxydopamine‐lesioned rat following chronic L‐dopa treatment. Dyskinesia, parkinsonian disability, and “on‐time” were assessed in the MPTP‐lesioned nonhuman primate following administration of topiramate (5–20 mg/kg) and amantadine (0.1–1.0 mg/kg) alone and in combination. Topiramate and amantadine dose‐dependently reduced dyskinesia in the 6‐hydroxydopamine‐lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP‐lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6‐hydroxydopamine‐lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP‐lesioned nonhuman primate, with a selective reduction in “bad on‐time.” These data confirm the antidyskinetic potential of topiramate and suggest that combination with low‐dose amantadine may allow better reduction of dyskinesia with no adverse motor effects.

18F-Florbetapir PET in Patients with Frontotemporal Dementia and Alzheimer Disease

Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using 18F-florbetapir in healthy controls and patients with AD and FTD. Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic 18F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent 18F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis. Results: Total cortical gray matter 18F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). 18F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical 18F-florbetapir retention, whereas 18F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control. Conclusion: Cortical 18F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.

Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson's disease.

Pain is a common nonmotor symptom in Parkinsons disease (PD). The pathophysiology of pain in PD is not well understood. Pain characteristics have rarely been studied in atypical parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP).

Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.

Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinsons disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5 μg 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L-DOPA/benserazide (6/15 mg/kg, i.p.) or vehicle for 21 days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3 mg/kg, i.p.) for 21 days. Animals were humanely killed 1h following final treatment in experiment 1, and 48 h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48 h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies.

Sporadic creutzfeldt-jakob disease presenting as progressive nonfluent aphasia with speech apraxia

Progressive non-fluent aphasia (PNFA) is typically associated with pathological changes consistent with frontotemporal lobar degeneration. A 65-year-old male presented with effortful speech, markedly impaired naming and features of speech apraxia, consistent with PNFA. Perceptuospatial function, calculation and executive function were intact. Brain SPECT showed left perisylvian hypoperfusion. He deteriorated profoundly over the subsequent eight months, with appearances on diffusion-weighted magnetic resonance imaging typical of sporadic Creutzfeldt-Jakob disease, which was confirmed pathologically at postmortem examination. While the presence of PNFA with speech apraxia is thought to predict underlying tauopathy, sporadic Creutzfeldt-Jakob disease may mimic this presentation and present in a highly circumscribed form not previously described.

No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix

The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO2 (r=−0.091, P=0.59, n=87) or pimonidazole binding (r=0.13, P=0.45, n=38). There was no relationship between TP and HIF-1α, but there was a weak borderline significant relationship with HIF-2α expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P=0.032) and metastasis-free (P=0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.

Lung Function Testing On and Off Dopaminergic Medication in Parkinson's Disease Patients With and Without Dysphagia

Swallowing function in individuals with Parkinsons disease (PD) can be negatively affected by dopaminergic medication with associated inhibition of brainstem reflexes. Three different “swallowing‐safety” profiles of PD patients were previously observed, classified according to swallowing safety on and off levodopa.