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We investigated the environmental and genetic factors for Alzheimer's disease (AD) in Spain and performed a door to door study of a cohort of more than 500 subjects, over 70 years old, from Leganés, a suburban area near Madrid. The cohort was followed for 6 years by neurologists and other health workers and was divided in three groups: normal controls, subjects with aging-associated cognitive decline (AACD) and probable AD or dementia of Alzheimer's type (DAT). Biological variables and polymorphisms of different genes, important in neurodegeneration or reported to be associated with AD, were investigated as putative risk modifiers. These polymorphisms have also been analyzed in 94 brains, 39 from patients with pathologically confirmed AD and 55 controls. The statistical investigation included the evaluation of different individual risks and a multinomial logistic regression analysis to detect predictive factors. The risk of AACD and AD increased with age, feminine gender and history of stroke and decreased with education. The allele ApoE4 increased the risk of AD but not of AACD. When the impact of ApoE4 was added to the model, the effect of education and stroke disappeared as risk modifiers. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD)., Methods: This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA., Results: All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = -0.36) and L-DOPA (r = -0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43)., Conclusions: Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.

Background: There is great interest in developing simple, user-friendly, and inexpensive tools for the quantification and elucidation of motor deficits in patients with Parkinson's disease (PD). These systems could help to monitor the clinical status of patients with PD, to develop better treatments, and to identify individuals who have subtle motor signs that might pass unnoticed in the conventional neurological examination., Methods: Mememtum, a smartphone application that allows for the quantification of several parameters of movement, such as regularity, rhythm, and changes in the number of taps while taping with a single finger and with alternating fingers, was developed and then tested in a pilot study in Madrid and in an extensive study in Quito, Ecuador., Results: Almost all patients could successfully perform single-finger tapping, but approximately 10% of patients with severe parkinsonism had problems taping with alternating fingers. The results revealed changes in the regularity of the pressure applied while tapping and a reduction in the number of taps on the device screen when alternating tapping among patients who had idiopathic PD and vascular parkinsonism compared with controls and individuals who had prediagnostic motor abnormalities of PD., Conclusion: Applications available in smartphones could be used for investigation and treatment of patients with PD, but much research is needed to optimize the ideal parameters to be investigated and the potential usefulness of this technique for patients with PD in different stages of the disease.

In this work we investigate the role of CHIP in a new CHIP-mutation related ataxia and the therapeutic potential of trehalose. The patient's fibroblasts with a new form of hereditary ataxia, related to STUB1 gene (CHIP) mutations, and three age and sex-matched controls were treated with epoxomicin and trehalose. The effects on cell death, protein misfolding and proteostasis were evaluated. Recent studies have revealed that mutations in STUB-1 gene lead to a growing list of molecular defects as deregulation of protein quality, inhibition of proteasome, cell death, decreased autophagy and alteration in CHIP and HSP70 levels. In this CHIP-mutant patient fibroblasts the inhibition of proteasome with epoxomicin induced severe pathophysiological age-associated changes, cell death and protein ubiquitination. Additionally, treatment with epoxomicin produced a dose-dependent increase in the number of cleaved caspase-3 positive cells. However, co-treatment with trehalose, a disaccharide of glucose present in a wide variety of organisms and known as a autophagy enhancer, reduced these pathological events. Trehalose application also increased CHIP and HSP70 expression and GSH free radical levels. Furthermore, trehalose augmented macro and chaperone mediated autophagy (CMA), rising the levels of LC3, LAMP2, CD63 and increasing the expression of Beclin-1 and Atg5-Atg12. Trehalose treatment in addition increased the percentage of immunoreactive cells to HSC70 and LAMP2 and reduced the autophagic substrate, p62. Although this is an individual case based on only one patient and the statistical comparisons are not valid between controls and patient, the low variability among controls and the obvious differences with this patient allow us to conclude that trehalose, through its autophagy activation capacity, anti-aggregation properties, anti-oxidative effects and lack of toxicity, could be very promising for the treatment of CHIP-mutation related ataxia, and possibly a wide spectrum of neurodegenerative disorders related to protein disconformation.

Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK(-/-)/Tau(VLW)). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine beta-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK(-/-)/Tau(VLW) phenotype. The treatment with trehalose of 3-month-old PK(-/-)/Tau(VLW) mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK(-/-)/Tau(VLW) and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK(-/-)/Tau(VLW) mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK(-/-)/Tau(VLW) mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine beta-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.

Parkin suppression induces accumulation of beta-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP(swe) mutant mice. We produced double mutant mice with human mutated APP(swe)+partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP(swe) overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK(+/-) and PK(-/-), respectively), and double mutants (APP/PK(+/-) and APP/PK(-/-)). APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK(+/-) and APP/PK(-/-) mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK(+/-) and APP/PK(-/-) mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK(+/-) and APP/PK(-/-) mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK(+/-) heterozygotic and homozygotic APP/PK(-/-) mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK(+/-) and APP/PK(-/-). Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK(-/-) mice. We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP(swe) mice.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals and abnormal neurotransmitter release. In this study, we have investigated whether partial proteasomal inhibition by epoxomicin, an ubiquitin proteasomal system (UPS) irreversible inhibitor, further aggravates the cellular effects of parkin suppression in midbrain neurons and glia. We observed that parkin null (PK-KO) midbrain neuronal cultures are resistant to epoxomicin-induced cell death. This resistance is due to increased GSH and DJ-1 protein levels in PK-KO mice. The treatment with epoxomicin increases, in wild type (WT) cultures, the pro-apoptotic Bax/Bcl-2 ratio, the phosphorylation of tau, and the levels of chaperones heat-shock protein 70 and C-terminal Hsc-interacting protein, but none of these effects took place in epoxomicin-treated PK-KO cultures. Poly-ubiquitinated proteins increased more in WT than in PK-KO-treated neuronal cultures. Parkin accumulated in WT neuronal cultures treated with epoxomicin. Markers of autophagy, such as LC3II/I, were increased in naïve PK-KO cultures, and further increased after treatment with epoxomicin, implying that the blockade of the proteasome in PK-KO neurons triggers the enhancement of autophagy. The treatment with l-buthionine-S,R-sulfoximine and the inhibition of autophagy, however, reverted the increase resistance to epoxomicin of the PK-KO cultures. We also found that PK-KO glial cells, stressed by growth in defined medium and depleted of GSH, were more susceptible to epoxomicin induced cell death than WT glia treated similarly. This susceptibility was linked to reduced GSH levels and less heat-shock protein 70 response, and to activation of p-serine/threonine kinase protein signaling pathway as well as to increased poly-ubiquitinated proteins. These data suggest that mild UPS inhibition is compensated by other mechanisms in PK-KO midbrain neurons. However the depletion of GSH, as happens in stressed glia, suppresses the protection against UPS inhibition-induced cell death. Furthermore, GSH inhibition regulated differentially UPS activity and in old PK-KO mice, which have depletion of GSH, UPS activity is decreased in comparison with that of old-WT.

The role of glia in Parkinson's disease (PD) is very interesting because it may open new therapeutic strategies in this disease. Traditionally it has been considered that astrocytes and microglia play different roles in PD: Astroglia are considered the "good" glia and have traditionally been supposed to be neuroprotective due to their capacity to quench free radicals and secrete neurotrophic factors, whereas microglia, considered the "bad" glia, are thought to play a critical role in neuroinflammation. The proportion of astrocytes surrounding dopamine (DA) neurons in the substantia nigra, the target nucleus for neurodegeneration in PD, is the lowest for any brain area, suggesting that DA neurons are more vulnerable in terms of glial support than any neuron in other brain areas. Astrocytes are critical in the modulation of the neurotoxic effects of many toxins that induce experimental parkinsonism and they produce substances in vitro that could modify the effects of L-DOPA from neurotoxic to neurotrophic. There is a great interest in the role of inflammation in PD, and in the brains of these patients there is evidence for microglial production of cytokines and other substances that could be harmful to neurons, suggesting that microglia of the substantia nigra could be actively involved, primarily or secondarily, in the neurodegeneration process. There is, however, evidence in favor of the role of neurotoxic diffusible signals from microglia to DA neurons. More recently a third glial player, oligodendroglia, has been implicated in the pathogenesis of PD. Oligodendroglia play a key role in myelination of the nervous system. Recent neuropathological studies suggested that the nigrostriatal dopamine neurons, which were considered classically as the primary target for neurodegeneration in PD, degenerate at later stages than other neurons with poor myelination. Therefore, the role of oligodendroglia, which also secrete neurotrophic factors, has entered the center of interest of neuroscientists.

Progressive supranuclear palsy (PSP) is a mostly sporadic disorder of unknown pathogenesis. Familial PSP have been reported related to mutations of microtubule-associated protein tau (MAPT). Mutations of the Park2 gene cause autosomal recessive parkinsonism with neuropathological findings consistent with neurofibrillary tangles and tau immunoreactive lesions. We analysed the presence of MAPT and Park2 mutations and polymorphisms in sporadic and familial PSP. No patients had mutations of Park2 or MAPT but there was genetic association for the polymorphism Val380Leu in sporadic and familial PSP. Leu380 is associated with less risk of familial or sporadic PSP.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18-20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression. PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme gamma-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe2+ plus H2O2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

Amyloid deposit in the brain causes neurologicaldiseases characterized by dementia. These depositsare constituted by fibrilar proteins with beta-planarshape whose origin is due to mutations, infectionsor exogenous alterations. Treatment of cerebralamyloid angiopathy depends on the cause and atpresent, the manipulation of the synthesis of theresponsible peptides, their chemical solubilizationor extraction outside of the nervous system, arebeing investigated.

Introduction: Factor V Leiden and prothrombin 20210A polymorphisms are the most common mutations related to deep vein thrombosis, however their relationship with stroke is debated. This paper studies the possible relationship between both entities., Material and Methods: A case-control study was conducted during 27 months to study their association. A total of 312 stroke cases were included, 73 were under 60 years. Control group was obtained from blood donors. Factor V Leiden and prothrombin 20210A polymorphism prevalence was studied. Results were analyzed according to the age and the type of stroke (TOAST classification, 1993)., Results: Factor V Leiden was not related to stroke in the general population (OR: 0.65; 95 % CI: 0.18-2.27). The study according to age did not show any association (younger than 60 years: OR: 1.12; 95 % CI: 0.21-5.90; older than 60 years: OR: 0.50; 95 % CI: 0.11-2.14). However, prothrombin 20210A polymorphism OR in cases under 60 was OR: 2.92; 95 % CI: 0.71-11.92 suggesting a possible association between this mutation and stroke. There was no association in the general population (OR: 2.0; 95 % CI: 0.63-6.29) or in people over 60 (OR: 1.73; 95 % CI: 0.51- 5.83). The analysis according to stroke subtype did not show any association in the distribution of any of the polymorphisms studied., Conclusion: This study suggests that prothrombin 20210A polymorphism may play a role in stroke under 60 years of age. Factor V Leiden does not seem to be related to stroke.

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed., (Copyright 2002 Movement Disorder Society)

We present a 45-year-old female with severe parkinsonism induced by kava-kava. The patient, who had a family history of essential tremor, developed severe and persistent parkinsonism after days of treatment with kava extract for anxiety. The symptoms improved with anticholinergics. Kava derivatives could produce severe parkinsonism in individuals with genetic susceptibility., (Copyright 2002 Movement Disorder Society.)

Background: Oculomotor abnormalities, especially slow saccades, have long been recognized in Huntington's disease (HD)., Objectives and Methods: To study prospectively horizontal saccade velocity by videonystagmography in 21 patients with genetically confirmed HD. The study included a baseline analysis and a second evaluation after 18.8 +/- 7.1 months. We included a control group of 15 subjects., Results: HD group exhibited decreased saccade velocity when compared with that from a control group (for predictive and unpredictive target). HD patients showed decreased saccade velocity with the passage of time (for predictive target, p < 0.01). Finally we found statistical significant correlation between saccade velocity and triplet length., Conclusions: The measurement of saccade velocity might be an objective method to study the natural evolution of HD, and thus evaluate the effectiveness of future therapies.

Objectives: To describe specific aspects of the diagnostic process of transmissible spongiform encephalopathies in Spain and to evaluate the 14-3-3 protein test in cerebrospinal fluid., Methods: The annual pattern of diagnostic certainty as well as those of demand and results of biochemical and genetic studies were studied using two sets of patients, those diagnosed for the 1993-1998 period, notified to a National Creutzfeldt-Jakob Disease Register (NCDJR), and those referred to the Tissue Bank for Neurological Research Laboratory (TBNRL). The 14-3-3 protein test was validated taking as a reference two clinical populations., Results: Two-hundred and four Creutzfeldt-Jakob disease cases were registered at the NCDJR: 39 out of them and 28 other patients had been studied at the TBNRL. The proportion of definite Creutzfeldt-Jakob Disease cases decreased since 1996. Among those registered in 1997-1998, 35.5%, 36% and 20% had undergone 14-3-3 protein in LCR, histopathologic and genetic studies. The 14-3-3 test grave, for definite, sporadic Creutzfeldt-Jakob disease as compared for patients with other dementing disorders, the following data: 12/13 sensitivity; 33/35 specificity; and 12/14 and 33/34 predictive values of positive and negative test. Two familial cases were diagnosed by identification of mutations in the TBNRL., Conclusions: The results suggest that: a) the diagnostic certainty of Creutzfeldt-Jakob disease in Spain decreased due to a drop in autopsy rates; b) the 14-3-3 cerebrospinal fluid test has a high diagnostic value, and its use diffused rapid but incompletely; c) genetic studies are useful in some cases, and d) Creutzfeldt-Jakob disease undereporting may be considerable. Creutzfeldt-Jakob disease diagnosis and surveillance, are closely related and being consolidated in Spain.

Parkinsonism is a frequent side effect of some calcium channel blockers (CCB). CCB-induced parkinsonism (CCBIP) usually improves spontaneously after discontinuation of the offending drug, but many patients exhibit persistent symptoms. It is not known whether CCBIP represents subclinical idiopathic Parkinson's disease (IPD) unmasked by drugs. We prospectively studied (mean follow-up 18.9+/-13months) the spontaneous evolution of 36 patients with CCBIP, and compared the clinical and epidemiological characteristics with those of 38 patients with IPD. Most patients with CCBIP improved spontaneously. Twenty-four months after CCB withdrawal, only 14% exhibited akinetic rigid syndrome, but 92% of patients still had tremor. The CCBIP group differed from the IPD group in: age at onset (70.8+/-8.2 versus 59.1+/-10years, p<0.001), gender (30/36 female versus 20/38 male, p<0.01), presenting symptom (tremor at first evaluation: 34/36 in CCBIP versus 28/38 in IPD, p<0.03) and history of arterial hypertension (21/36 versus 7/38, p<0.001). Asymmetrical onset of symptoms was frequent in IPD, but not in the CCBIP group (24/38 versus 13/36, p<0.05).

Spasmodic dysphonia (SD) is at present defined as focal dystonia. Botulinum toxin (BT) injection is the treatment of choice for SD. BT is usually injected by a percutaneous route, but a direct, visually guided transoral approach has also been successful. It is not known whether percutaneous injection is as effective as the transoral approach. This article reviews our experience with both techniques of injection on 29 patients with adductor type SD. Since 1992, we have carried out 48 treatment sessions with the transoral technique and 76 treatment sessions with the percutaneous technique. Two patients did not respond to the percutaneous technique despite several attempts, but they did respond to the transoral approach. Globally, transoral technique was superior to percutaneous technique in terms of effectiveness (48 of 48 responses with transoral technique versus 61 of 76 responses with percutaneous approach, p < 0.01). Dosage of BT, duration, and side effects were similar with both techniques. This article also describes a simple, inexpensive device, composed of materials on hand at every hospital, that facilitates the transoral approach.

Adduction spastic dystonia (SD) is currently considered a focal dystonia involving laryngeal muscles. SD is one of the most poorly known focal dystonias. We reviewed our experience with twentynine patients with adduction SD and compared the clinical and epidemiologic variables with the other focal dystonias studied at our institution in the last five years (132 patients). Mean age of patients (47.2 +/- 13 years), sex, clinical course in years (5.7 +/- 5) and presence of circadian fluctuations did not differ significantly from those observed in patients with other focal dystonias. Likewise, there were no significant differences regarding the presence of a family history of dystonia, essential tremor, or stuttering. Our results confirm the similarity of the clinical and epidemiologic data of SD with the other focal dystonias. All patients with SD were treated with a local injection of botulinum toxin. A total of 108 treatments were performed, 41 with a visually guided transoral technique and 67 with a percutaneous technique. The transoral technique was effective in all cases (41/41) but not all treatments with the percutaneous technique were effective (53/67). Three patients required the shift to the transoral procedure to achieve enough symptomatic alleviation.

This is a multicentric double blind comparison of the effects of standard and slow release levodopa + carbidopa formulations in patients with Parkinson's disease. Sixty four patients with simple fluctuations were included and 43 finished the study. The study had three phases: a) optimal dose findings phase with standard levodopa + carbidopa; b) open label, cross over study with the two formulations, and c) double blind, parallel investigation. The following results were obtained. There was not a difference in the severity of disability according to UPDRS, part 3, scores though the subjective impressions of patients were in favor of standard formulations. The Sustained release levodopa + carbidopa produced significant improvement of dystonia in off period, pain due to akinesia in off and the number of hours in off and the quality and latency of sleep. In addition there was a tendency in favor of slow release compounds for early morning akinesia, global effect and impression of the examining physician. Low protein diet improved the kinetics of levodopa and the clinical response with both formulations. The clinical usefulness of standard and slow release levodopa + carbidopa formulation should be weighted according to individual problems of patients with Parkinson's disease.

Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.

L-DOPA kills dopamine neurones in culture but is the most effective drug for the treatment of Parkinson's disease, where it exhibits no clear toxicity. While glial cells surround and protect neurones in vivo, neurones are usually cultured in vitro in the absence of glia. We treated fetal midbrain rat neurones with L-DOPA, mesencephalic glia conditioned medium (CM) and L-DOPA + CM. L-DOPA reduced the number of tyrosine hydroxylase-positive (TH+) cells and [3H]DA uptake, and increased quinone levels. L-DOPA + CM restored [3H]DA uptake and quinone levels to normal, and increased the number of TH+ cells and terminals to 170% of control. CM greatly increased the number of TH+ cells and [3H]DA uptake. Mesencephalic glia therefore produced soluble factors which are neurotrophic for dopamine neurones, and which protect these neurones from the toxic effects of L-DOPA.

Occupational dystonia is a frequent clinical symptom in musicians and has been described as muscle spasms and hand cramps in pianists. Robert Schumann had a neurological impairment of his right hand that was not clinically diagnosed during his life and that impaired his career as pianist from his early 20s. This disturbance was characterized by pain and by rigidity of the fingers, which extended to other segments of his right upper extremity while he was performing and that increased with stress and improved with muscle relaxation. This disturbance produced a progressive impairment of his writing. We here hypothesize that Schumann's neurological problem was consistent with dystonia.

Abnormalities of striated muscle histology in patients with neuroacanthocytosis have been previously attributed to chronic denervation. This hypothesis is based in the presence of axonal peripheral neuropathy. In this 37-year-old patient clinical, biochemical and histologic data revealed a non specific primary myopathy. Other important findings were decreased levels of 5-hydroxy-indoleacetic acid (5-HILA) and homovanillic acid (HVA) in the CSF, cerebellar and basal ganglia atrophy seen in MRI and infertility of probable gonadal origin.

Levodopa, at concentrations of 0.25 x 10(-4) M or larger, is toxic for the human neuroblastoma cell NB69. Toxicity is associated with high levels of quinones, increased activity of complex II-III, and lack of changes of complex I of the mitochondrial respiratory chain. Deprenyl, which does not alter the production of quinones, has a partial protective effect. Tocopherol, 23 or 115 x 10(-6) M, lacks significant preventive effect on levodopa toxicity, but ascorbic acid, 10(-3) M, prevents levodopa toxicity and quinone formation. Deprenyl, 10(-4) M, provides additional protection in cultures treated with levodopa and ascorbic acid. Our results indicate that ascorbic acid and deprenyl prevent levodopa neurotoxicity by unrelated mechanisms. Both compounds should be considered as complementary drugs to test for slowing the progression of Parkinson's disease.

Parkinsonism is a well-known side effect of some calcium channel blockers (CCB). Its long-term evolution, however, is unknown. To clarify this issue, we performed a prospective follow-up study involving 32 patients diagnosed with CCB-induced parkinsonism. After the baseline examination, the CCB were discontinued and serial evaluations were carried out according to the same protocol. Despite a global improvement, cognitive and mood disturbances subsided slowly, and tremor persisted in most patients. After 18 months of CCB withdrawal, 44% of patients had depression, 88% had tremor, and 33% still had criteria for diagnosis of parkinsonism. During the survey, only three patients were found to be fully recovered. The improvement of some clinical symptoms was related to age: Patients younger than 73 years recovered better than older patients did. Our data indicate that CCB-induced parkinsonism is not the benign condition previously thought, and suggest an age-related prognosis of this entity.