Effects of transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson's disease.

BACKGROUND AND PURPOSE: Pulsed electromagnetic fields induce a protective and anti-inflammatory effect in the nervous system primarily due to growth factor upregulation that possibly abates neurodegeneration in Parkinson's disease (PD). This study investigated treatment effects of transcranial pulsed electromagnetic fields (T-PEMFs) on quality of life in PD and the feasibility and safety of this treatment. METHODS: In this double-blinded clinical study, 97 participants with idiopathic PD (Hoehn & Yahr stage I-IV), on optimal medical anti-parkinsonian treatment, were block randomized (3:3) to either active (n = 49) or placebo treatment (n = 48). Treatment with T-PEMFs entailed one daily 30-min home treatment for eight consecutive weeks. The 39-item Parkinson's Disease Questionnaire (PDQ-39) was assessed at baseline and endpoint. A special questionnaire was used to profile adverse events by interviewing the participants over the full treatment period. Treatment compliance was accounted for by daily treatment registration. RESULTS: The active group improved with respect to clinical effect size for the two dimensions, i.e. mobility and activities of daily living, compared with the placebo group. No between-group differences were found for the remaining PDQ-39 dimensions. There were no between-group difference in adverse events. Treatment compliance was 97.9%. CONCLUSION: Treatment with T-PEMFs improved mobility and activities of daily living scores for clinical effect size only in the active group, indicating a positive treatment response for motor symptoms. No difference was found between the two groups for the remaining PDQ-39 dimensions. The treatment had no or only mild adverse events and was performed with high compliance.

Sympathetic dysfunction of central origin in patients with ALS.

Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease affecting both the central and peripheral parts of the motor nervous system. Some studies have shown unequivocal indications of a more disseminated disease also affecting the autonomic nervous system. We therefore evaluated the centrally and peripherally mediated autonomic vascular reflexes by (i) the local 133-Xenon washout technique, and (ii) the head-up tilt table test. The results correlated to clinical scores. We examined nine ALS patients and 15 age-matched controls. The 133-Xenon washout test showed a significant reduction in the centrally mediated sympathetic vasoconstrictor response, but a preserved locally mediated response in the patients. In the head-up tilt table test, the patients had a significantly higher mean arterial blood pressure (MAP) compared with controls, probably due to a general increase in vascular resistance. There were no correlations between the ALS Severity Scores and blood flow changes, diastolic blood pressure or MAP. Our study supports previous results, but indicates abnormalities consistent with a solely centrally located sympathetic dysfunction in ALS, independent of the stage of the disease.

Unchanged total number of neurons in motor cortex and neocortex in amyotrophic lateral sclerosis: a stereological study.

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.

Four-hundred and fifty-one blood samples from Scandinavian patients with motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Forty-one (9.6%) of the 427 patients with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-associated mutation, and 14 of these patients were apparently sporadic cases. A mutation was found in 12 of the 51 families with recognized familial ALS. The five different mutations found (Ala4Val, Val14Gly, Asp76Tyr, Asp90Ala, Gly127insTGGG) have different genetic characteristics and are associated with very variable phenotypes spanning from rapidly progressing disease with only lower motor neuron signs to very slowly progressing disease with both the upper and lower motor neuron systems affected. The patients showed different sites of onset, though the progressive bulbar palsy form of the disease appears to be rare among patients with a CuZn-superoxide dismutase mutation. The progression of motor signs and symptoms followed the same basic pattern in patients with different mutations. Extra-motor system symptoms were frequent among patients with a CuZn-superoxide dismutase mutation. The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity. The Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the CuZn-superoxide dismutase gene.

A clinical trial of dextromethorphan in amyotrophic lateral sclerosis.

INTRODUCTION: Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, excitotoxicity mediated by glutamate has been implicated. Dextromethorphan is a NMDA-glutamate receptor antagonist with neuroprotective properties. MATERIAL AND METHODS: The effect of treatment with dextromethorphan (150 mg daily) in ALS patients was evaluated in a randomized, double-blind, placebo-controlled study. Forty-five patients were included in the analysis. RESULTS: At the end of the treatment period, 12 months after randomization, 15 patients (65%) in the placebo group and 12 patients (55 %) in the dextromethorphan group were still alive (log rank test, P=0.49). Rates of disease progression, as expressed by rates of decline in pulmonary function and in functional disability, were similar in both groups except for a significantly less pronounced rate of decline in the ability scores for the lower extremities in the dextromethorphan group. CONCLUSION: Treatment with a relatively low dose of dextromethorphan did not result in an improvement in 12-month survival in ALS.

Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy.

We performed proton magnetic resonance spectroscopy (1H-MRS) in patients with motor neuron disease (MND) to determine the absolute in vivo concentrations in the brain of the metabolites N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr/PCr). We examined the spectra acquired from a 20 x 20 x 20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients with both upper and lower motor neuron signs had a significantly decreased concentration of NAA (9.13 +/- 0.28 mM, mean +/- SEM) in the primary motor cortex when compared with healthy controls (10.03 +/- 0.22 mM). In conclusion, the slightly decreased concentration of NAA in the primary motor cortex from ALS patients may represent a loss of neurons in this region.

[Amyotrophic lateral sclerosis and superoxide dismutase--a review]. / Amyotrofisk lateralsklerose og superoxiddismutase--en oversigt.

The recent observation that mutations in cytosolic CuZn-superoxide dismutase (CuZn-SOD) are associated with amyotrophic lateral sclerosis (ALS) suggests that the disease arises from a perturbation of the homeostasis of free radicals resulting in neuronal degeneration by reactive oxygen species. The stability is altered in these mutant molecules, but without necessarily reducing the specific activity of the CuZn-SOD molecule. Substantial evidence argues that the disease arises not from the loss of CuZn-SOD function, but rather from an adverse or novel property of the mutant enzyme molecule. The mechanism for this acquired adverse function is, as yet, completely unknown. SOD research is an important step for a better understanding of the pathogenesis of ALS.

Muscarinic, N-methyl-D-aspartate (NMDA) and benzodiazepine receptor binding sites in cortical membranes from amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing marked pathology in the motoneuron system. The pathophysiology of the selective degeneration of motor neurons in the disease is as yet unknown, but evidence suggests that excitotoxic mechanisms might be involved. The present study was undertaken to determine whether defects in neurotransmitter receptors are involved in the disease, analyzing uniformly sampled specimens from neocortex and motorcortex. The binding to benzodiazepine, muscarinic cholinergic, and NMDA receptors in ALS brains was compared to that in control brains, using a single radioligand concentration of [3H]Ro 15-1788, [3H]QNB and [3H]MK-801. The benzodiazepine and the muscarinic cholinergic receptor binding was unaffected in any cortical region from the ALS subjects compared to controls. NMDA receptor binding labeled by [3H]MK-801 was significantly increased in several neocortical regions in the ALS group compared to the control group. Scatchard analysis of [3H]MK-801 binding in frontal cortex revealed a single binding site with an unaltered maximal binding capacity but an increased binding affinity of the site in the ALS group compared to the controls. The generalized alteration in the affinity of the binding site for [3H]MK-801 in the ALS cortex may indicate a modification of the NMDA receptor due to different sensitivity for endogenous modulators or to a different subunit composition of the NMDA receptor in ALS with altered functional properties. These findings may reflect a pathophysiological phenomenon in ALS.

Cerebrospinal fluid from amyotrophic lateral sclerosis has no effect on intracellular free calcium in cultured cortical neurons.

The data from the literature regarding the presence of a neurotoxic factor in amyotrophic lateral sclerosis (ALS) plasma or cerebrospinal fluid (CSF) remain controversial. As a new approach to this question, we have studied the effect of CSF from ALS patients on the temporal dynamics of the intracellular free calcium concentration ([Ca2+]i) of murine cortical neurons in cultures using Fura-2 fluorescence videomicroscopy and single-cell imaging. CSF from seven ALS patients and controls was added at dilutions up to 20% to cortical neuronal cultures. The in vitro inhibition of CSF on [3H]kainic acid binding showed that the CSF did not contain any substances other than glutamate itself in larger amounts. At the concentrations used, the CSF did not have any effect on [Ca2+]i or on the neuronal responsiveness as defined by the ability of the cells to respond with a transient increase in [Ca2+]i to depolarization induced by KCl. The disturbance of the intracellular calcium homeostasis is one of the key mechanisms of action of excitotoxic compounds mediating delayed neuronal cell death by stimulation of glutamate receptor subtypes. In this study, CSF from ALS patients did not induce immediate rises in [Ca2+]i or disturbances of the intracellular calcium homeostasis when measured over a period of 2 h.

Effects of branched-chain amino acids on plasma amino acids in amyotrophic lateral sclerosis.

Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, biological findings suggest that the excitatory amino acid glutamate contributes to the pathogenesis of ALS. In previous studies of ALS, the therapeutic effect of the branched-chain amino acids (BCAAs) leucine, valine and isoleucine has been evaluated. The present study aimed at investigating the acute effect of BCAAs on plasma glutamate levels in ALS patients. Following two oral doses of BCAAs, significantly increased plasma levels were seen for valine (500%), isoleucine (1,377%) and leucine (927%), however the plasma level of glutamate was not affected. The plasma level of several other amino acids (tryptophan, tyrosine, phenylalanine and methionine) were found decreased after oral BCAAs, which may indicate a diminution in the rate of degradation of muscle protein and/or an increase in tissue disposal of amino acids.

Effect of branched-chain amino acids on glutamate metabolism in amyotrophic lateral sclerosis.

Data from the literature about glutamate metabolism remain controversial. To refine such analysis we have studied plasma glutamate and aspartate levels after glutamate loading (60 mg/kg) in 6 fasting controls and ALS patients, before and after at least 2 weeks treatment with branched-chain amino acids. ALS patients showed no difference from age-matched controls in basal plasma glutamate or aspartate levels, but significantly elevated levels of glutamate and aspartate at 30 and 45 min after loading, and an increased area under the curve in plasma for glutamate following oral glutamate loading. Two weeks BCAAs treatment did not affect plasma glutamate metabolism in ALS patients.

Calcium homeostasis in fibroblasts from patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder of the motor system in the CNS characterized by motor neuron death in the spinal cord, brain stem and cortex. Readily available tissues such as fibroblasts from ALS patients can serve as simple model systems to study the molecular mechanisms leading to degenerative disorders. We have used Fura-2 fluorescence microscopy and single-cell imaging to study the spatiotemporal dynamics of intracellular free calcium ([Ca2+]i) in primary cultures of fibroblasts from skin biopsies from ALS and normal subjects. Increases in [Ca2+]i were induced by stimulation with bradykinin (100 nM); neurotensin (50 nM); N-formyl-Met-Leu-Phe (chemotactic peptide) (1 microM); [Arg8]-vasopressin (1 microM) and histamine (10 microM). The levels of [Ca2+]i in 80-120 individual cells per agonist were monitored for 15 min. No significant differences were found in the resting levels of [Ca2+]i in control (102 +/- 4 nM) and ALS (98 +/- 6 nM) fibroblasts and in the maximal [Ca2+]i levels after stimulation with N-formyl-Met-Leu-Phe, [Arg8]-vasopressin, and histamine. Significantly lower [Ca2+]i transients were found in fibroblasts from ALS donors compared to controls when stimulated with neurotensin (p < 0.002) and bradykinin (p < 0.005). The percentage of individual cells reacting to a given agonist (40-100%) was similar in both groups. The molecular basis of the impaired calcium homeostasis in fibroblasts from ALS patients is not known, but a generalized membrane defect can be excluded since the [Ca2+]i responses are defective only when bradykinin or neurotensin are used as agonists.

Binding of [3H]SCH 23390 to dopamine D-1 receptors in rat retina in vitro.

[3H]SCH 23390 binding was examined in membranes of rat retina. The binding was saturable with a dissociation constant of 0.2 nM and the maximum number of binding sites was 236 +/- 74 fmol/mg protein. The pharmacology of [3H]SCH 23390 binding indicated that the binding was specific for a dopamine D-1 receptor because the binding was preferentially inhibited by D-1-selective agonists and antagonists but not by dopamine D-2-selective agonists and antagonists. The same membrane preparations were used to characterize the dopamine D-2 receptor binding as measured with [3H]spiperone and the amount of binding sites was found to be similar to the amount of D-1 sites. It is concluded that [3H]SCH 23390 is a useful tool to examine dopamine D-1 receptors in the retina.

Target size of dopamine D-1 receptors in rat corpus striatum estimated by binding of the benzazepine 3H-SCH 23390.

The binding characteristics of 3H-SCH 23390 in rat striatum prepared in potassium phosphate buffer are described. The amount of binding sites labeled by 3H-SCH 23390 decreased monoexponentially when exposed to increasing radiation dose. The molecular weight was determined to 78,000 daltons similar to the molecular mass of 3H-piflutixol binding to D-1 receptor previously reported, however lower than the molecular mass of dopamine D-1 agonist binding sites (Gredal & Nielsen 1987).

Different target sizes of the voltage-dependent Ca2+ channel and the [3H]nitrendipine binding site in rat brain.

High energy irradiation of frozen rat frontal cortex was used to determine the molecular target sizes of the [3H]nitrendipine binding site (93,500 +/- 9,700 daltons and of the voltage-dependent Ca2+ channel (340,500 +/- 34,000 daltons) determined as the K+-induced 45Ca2+ uptake into synaptosomes. The conclusion that could be drawn from the target size analysis was that 45Ca2+ flux occurs via a structure of molecular weight very different from that of the dihydropyridine binding site. Furthermore, it was found that [3H]nitrendipine binding to synaptosomes was not influenced by depolarization with K+.

In situ molecular size of agonist dopamine D-2 binding sites in rat striatum.

Specific binding of [3H]N-propylnorapomorphine [( 3H]NPA) to 3,4-dihydroxyphenylethylamine (dopamine) D-2 receptors was investigated in rat striatum in vitro. For various dopamine receptor substances, the rank order of potency to inhibit [3H]NPA binding was spiroperidol greater than or equal to NPA greater than LY 171555 greater than SCH 23390 greater than SKF 38393. A single high-affinity binding site was found in membranes prepared in either Tris-citrate buffer or imidazole buffer; the affinity constants were 0.11 and 0.76 nM, respectively. The number of receptors (33 pmol/g wet weight) was independent of whether the membranes were prepared in Tris-citrate buffer or imidazole buffer and was similar to the number of receptors estimated by [3H]spiroperidol binding to dopamine receptors. Irradiation inactivation of frozen whole rat striata showed a monoexponential loss of [3H]NPA binding sites without a change in the binding affinity. The target size of the [3H]NPA binding site was 81,000 daltons, which shows that the functional molecular entity to bind the dopamine D-2 agonist was smaller than the molecular entity to bind the dopamine D-2 antagonist [3H]spiroperidol (target size, 137,000 daltons).

Binding of [3H]SKF 38393 to dopamine D-1 receptors in rat striatum in vitro; estimation of receptor molecular size by radiation inactivation.

[3H]SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) binds with high affinity to 3,4-dihydroxyphenylethylamine (dopamine) D-1 receptors in rat striatum in vitro (KD = 7 and 14 nM in nonfrozen and frozen striatum, respectively). The number of binding sites (Bmax) was approximately 80.0 pmol/g of original tissue, a value similar to the Bmax for the dopamine D-1 antagonist SCH 23390. Nondisplaceable [3H]SKF 38393 binding was approximately 45% of total binding. Irradiation (0-4 Mrad) of frozen whole striata decreased the number of [3H]SKF 38393 binding sites monoexponentially without changing the binding affinity. The functional molecular mass for the agonist dopamine D-1 binding site was 132,800 daltons, which is higher than the functional molecular mass of the antagonist dopamine D-1 binding site (approximately 80,000 daltons).