[Cerebral amyloid angiopathy and dementias]. / Las amiloidosis cerebrales y las demencias.

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.

Las amiloidosis cerebrales y las demencias / Cerebral amyloid angiopathy and dementias

El depósito de amiloide en el cerebro produceenfermedades neurológicas caracterizadas pordemencia. Esos depósitos están constituidos porproteínas fibrilares con conformación â-planarcuyo origen es debido a mutaciones, infecciones oalteraciones exógenas. El tratamiento de lasamiloidosis cerebrales depende de la causa, y en elmomento actual se investiga la manipulación de lasíntesis de los péptidos responsables, susolubilización química o su extracción fuera del sistema nervioso

Cerebral amyloid angiopathy and dementiasAmyloid deposit in the brain causes neurologicaldiseases characterized by dementia. These depositsare constituted by fibrilar proteins with â-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

Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity.

Nitric oxide (NO) is a modulator of differentiation and survival of dopamine (DA) neurons. NO may play a role in the pathogenesis of Parkinson's disease (PD) since its levels are increased in parkinsonian brains and it can nitrosylate and alter the function of key proteins involved in the pathogenesis of PD. NO producing neurons are spared in parkinsonian brains suggesting that toxicity by NO can be compensated. Furthermore, the neurotoxic or neurotrophic effects of NO on DA neurons depend on the balance between NO levels and the intracellular levels of glutathione (GSH). We have investigated the effects of NO-donating agents on midbrain neuronal cultures from parkin-deficient mice. Parkin mutations are the most common genetic deficit observed in hereditary parkinsonism. These mice have abnormal DA release and metabolism, increased production of free radicals and a compensatory elevation of GSH. Cultures from parkin knockout (PK-KO) mice were more resistant than those of wild type (WT) to the neurotoxicity by NO, and the difference of susceptibility applied equally to DA, GABA and total number of neurons, and to astrocytes. NO-induced cell death was mainly apoptotic and could be reduced by caspase inhibitors. Cultures from PK-KO had greater levels of GSH than WT and, after treatment with NO, greater levels of S-nitrosoglutathione. The differences in susceptibility disappear when the synthesis of GSH is inhibited or the GSH chelated with diethyl maleate. Our data show that, contrary to the expectations, and related to the enhanced production of GSH in parkin knockout mice, parkin-deficient dopamine neurons are less susceptible to toxicity by NO.

Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline.

Parkinson's disease is a neurodegenerative disorder which is in most cases of unknown etiology. Mutations of the Park-2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK-KO) mice have abnormalities that resemble the clinical syndrome. We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK-KO and wild-type (WT) mice with rotenone (ROT). ROT (0.025-0.1 microm) produced a dose-dependent selective reduction of tyrosine hydroxylase-immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule-associated protein 2 in PK-KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone (Boc-D-FMK). PK-KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK-KO than in WT cultures. Indomethacin, a cyclo-oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT-induced apoptosis but did not change tyrosine hydroxylase-immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor N-nitro-L-arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal-regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT-naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK-KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK-KO mice were more susceptible than WT to ROT and the combined effects of Park-2 suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline.

Differential effects of l-DOPA on monoamine metabolism, cell survival and glutathione production in midbrain neuronal-enriched cultures from parkin knockout and wild-type mice.

l-DOPA is the most effective treatment for Parkinson's disease but in isolated neuronal cultures it is neurotoxic for dopamine (DA) neurones. Experiments in vivo and clinical studies have failed to show toxicity of l-DOPA in animals or patients but that does not exclude the possibility of a toxic effect of l-DOPA on patients with certain genetic risk factors. Mutations of the parkin gene are the most frequent cause of hereditary parkinsonism. Parkin null mice have a mild phenotype that could be modified by different neurotoxins. The aim of this study was to investigate whether the toxic effects of l-DOPA on DA neurones are amplified in parkin null mice. We have measured the effects of l-DOPA on cell viability, tyrosine hydroxylase (TH) expression, DA metabolism and glutathione levels of parkin knockout (PK-KO) midbrain cultures. Neuronal-enriched cultures from PK-KO mice have similar proportions of the different cell types with the exception of a significant increment of microglial cells. l-DOPA (400 microm for 24 h) reduced the number of TH-immunoreactive cells to 50% of baseline and increased twofold the percentage of apoptotic cells in cultures of wild-type (WT) animals. The PK-KO mice, however, are not only resistant to the l-DOPA-induced pro-apoptotic effects but they have an increased number of TH-immunoreactive neurones after treatment with l-DOPA, suggesting that l-DOPA is toxic for neurones of WT mice but not those of parkin null mice. MAPK and phosphatidylinositol-3 kinase signalling pathways are not involved in the differential l-DOPA effects in WT and PK-KO cultures. Intracellular levels of l-DOPA were not different in WT and parkin null mice but the intracellular and extracellular levels of DA and 3-4-dihydroxyphenylacetic acid, however, were significantly increased in parkin null animals. Furthermore, monoamine oxidase activity was significantly increased in parkin null mice, suggesting that these animals have an increased metabolism of DA. The levels of glutathione were further increased in parkin null mice than in controls both with and without treatment with l-DOPA, suggesting that a compensatory mechanism may protect DA neurones from neuronal death. This study opens new avenues for understanding the mechanisms of action of l-DOPA on DA neurones in patients with Park-2 mutations.

Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice.

Cinnarizine, a calcium antagonist that produces parkinsonism in humans, induces behavioural changes such as alopecia, buco-lingual dyskinesia and reduction of motor activity in female parkin knock out (PK-KO) mice but not in wild-type (WT) controls. PK-KO mice have high striatal dopamine levels and increased dopamine metabolism in spite of low reduced tyrosine hydroxylase protein. Cinnarizine, which blocks dopamine receptors and increases dopamine release, further increased dopamine metabolism. PK-KO mice increased GSH levels as a compensatory mechanism against enhanced free radical production related to acceleration of dopamine turnover. Neuronal markers, such as beta-tubulin slightly increased in PK-KO and furthermore with cinnarizine. Astroglial markers were decreased in PK-KO mice, and this effect was potentiated by cinnarizine, suggesting abnormal glia in these animals. Microglia was hyperactivated in PK-KO midbrain, suggesting inflammation in these animals. Proapoptotic proteins were increased by cinnarizine and, to a lesser extent, in PK-KO mice. Our data indicate that mutation of parkin is a risk factor for drug-induced parkinsonism.

[Prothrombotic factors in stroke]. / Factores protrombóticos en la enfermedad cerebrovascular isquémica.

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.

Factores protrombóticos en la enfermedad cerebrovascular isquémica / Prothrombotic factors in stroke

Introducción: Los polimorfismos del factor V Leiden y la protrombina 20210A son las mutaciones que con mayor frecuencia se asocian a la enfermedad trombótica venosa; sin embargo, su relación con la enfermedad cerebrovascular isquémica (ECVI) es dudosa. Este trabajo estudia la posible relación entre ambas entidades. Material y métodos: Se realizó un estudio de casos y controles en el que se incluyeron 312 pacientes de ECVI (73 menores de 60 años) y se compararon con las muestras de 204 donantes de sangre de la misma población demográfica. Los resultados se analizaron atendiendo a la edad de los pacientes y al tipo de ECVI (clasificación TOAST, 1993). Resultados: No se encontró asociación del factor V Leiden y la ECVI en la población general (odds ratio [OR]: 0,65; intervalo de confianza [IC] 95 por ciento: 0,18-2,27). El análisis por edades tampoco mostró asociación (menores de 60 años: OR: 1,12; IC 95 por ciento: 0,21-5,90; mayores de 60 años: OR: 0,50; IC 95 por ciento: 0,11-2,14). Respecto a la protrombina 20210A, la OR en menores de 60 años fue OR: 2,92; IC 95 por ciento: 0,71-11,92, lo que sugiere que este polimorfismo tiene una leve tendencia a asociarse con la ECVI. El análisis en el grupo total de enfermos no mostró asociación (OR: 2;0; IC 95 por ciento: 0,63-6,29), ni en el de mayores de 60 años (OR: 1,73; IC 95 por ciento: 0,51-5,83). En el estudio según el tipo de ECVI no se observaron diferencias en la distribución de ninguno de los polimorfismos estudiados. Conclusión: Este estudió sugiere que el polimorfismo de la protrombina 20210A podría estar implicado en la ECVI en sujetos menores de 60 años. Por otra parte, no se ha encontrado asociación entre el factor V Leiden y esta entidad (AU)

L-DOPA-induced excessive daytime sleepiness in PD: a placebo-controlled case with MSLT assessment.

A 74-year-old patient with idiopathic Parkinson's disease was evaluated for unintended sleep episodes that occurred after long-term treatment with 400 mg/day of L-dopa. Overnight sleep studies and multiple sleep latency testing were carried out under double-blind administration of either L-dopa or placebo. Mean sleep latency with L-dopa was 7 minutes, in contrast to a normal value of 19 minutes, 25 seconds with placebo. The authors' results suggest that L-dopa may cause daytime somnolence in some patients with Parkinson's disease.

[Disorders in gaze saccades in Huntington disease. Clinical correlations]. / Störung der Blicksakkaden bei der Huntington-Krankheit. Klinische Korrelationen.

Oculomotor abnormalities have long been recognized in Huntington's disease (HD). The precise correlation between them and other clinical findings has not yet been determined. Using videonystagmography, we studied reflexive, visually guided horizontal saccades in 32 patients with genetically confirmed HD: nine female and 23 male patients, including six with young onset HD (YOHD), 19 with adult onset HD (AOD), and seven with late onset HD (LOHD). Huntington's patients exhibited increased saccade latency (P < 0.05), decreased saccade velocity (P < 0.0005), and impaired saccade accuracy (P < 0.01). A significant difference between the different groups of patients could be determined, and YOHD was characterized by normal latency and decreased saccade velocity while LOHD showed increased saccade latency but normal velocity. Furthermore, we found a significant difference between the genetic data (length of CAG-repeats) and saccadic abnormalities, with higher repeat numbers corresponding to shorter latency and decreased velocity, as in YOHD. The study of saccade parameters might be useful as an objective method for testing the effectiveness of future therapies.

[Speed of ocular saccades in Huntington disease. Prospective study]. / Velocidad de las sacadas oculares en la enfermedad de Huntington. Estudio prospectivo.

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.

Velocidad de las sacadas oculares en la enfermedad de huntington. Estudio prospectivo / Speed of ocular saccades in Huntington's disease. Prospective study

FUNDAMENTO: Las perturbaciones oculomotoras son muy frecuentes en la enfermedad de Huntington (EH). Probablemente la caída de la velocidad sacádica es el hallazgo más característico desde el punto de vista neuroftalmológico. OBJETIVOS Y MÉTODOS: Estudiar prospectivamente la velocidad de las sacadas horizontales mediante videonistagmografía en 21 pacientes con EH confirmada genéticamente. Se realizó el mismo protocolo en la primera evaluación (tiempo 0) y en la de seguimiento (18,8 ñ 7,1 meses después). Se incluyó un grupo control de 15 individuos sin enfermedad neurológica. RESULTADOS: Los pacientes con EH presentaron una velocidad horizontal sacádica inferior a los controles, tanto para estímulo predecible como no predecible. Además, en el seguimiento manifestaron un deterioro significativo de la velocidad sacádica horizontal (p < 0,01; para estímulo predecible).Asimismo hubo correlación significativa entre la expansión de tripletes y la velocidad sacádica. CONCLUSIÓN: El estudio de la velocidad sacádica podría servir como método objetivo de seguimiento de la EH, especialmente en relación con el empleo de futuras terapias neuroprotectoras (AU)

Prevalencia de lesiones neuropatológicas de enfermedad de Alzheimer y de Parkison en individuos asintomáticos / Neuropathological changes of Alzheimer's and Parkinson diseases in asyntomatic individuals

Objetivos: Búsqueda de lesiones neuropatológicas características de la enfermedad de Alzheimer (EA) y de la enfermedad Parkinson (EP) en cerebros autopsiados de pacientes sin clínica neurológica. Pacientes y métodos: Del archivo del Banco de Tejidos para Investigación Neurológica se seleccionaron 60 casos sin historia de enfermedad neurológica de edades comprendidas entre 46 y 90 años. Sobre bloques fijados en formol e incluidos en parafina correspondientes a corteza cerebral (frontal, temporal, parieto-occipital), hipocampo (anterior y posterior) y mesencéfalo, se realizaron técnicas de hematoxifina-eosina; plata-metenamina modificada y Bieischowsky, en la corteza cerebral e hipocampos, para la determinación de lesiones de tipo EA; y técnicas de inmunohistoquírnica para el anticuerpo ubiquitina (Ub) para la detección de cuerpos de Lewy (CL) en la sustancia nigra. La cuantificación de las lesiones se realizó mediante los criterios del CERAD (Consortium to Establish a Registry for Aizbeimer Disease). Resultados: Se observaron lesiones de tipo Alzheimer, presencia de ovillos neurofibrilares (ONF), placas seniles, difusas y neuríticas. Atendiendo a la intensidad y distribución de las mismas se clasificaron en 'posibles EA' en el 13,3 por ciento (8 casos) y 'normales' en el 86,7 por ciento (52 casos),15 de los cuales no mostraron nigún tipo de lesión. En cuanto a las lesiones de EP; se observaron CL ubiquitina+ en 10 casos (17 por ciento), de los cuales 5 presentaron tanto CL como neuritas Ub+, mientras que en 17 casos (28 por ciento) sólo se observaron neuritas Ub+. Conclusiones: En el presente estudio se ha detectado una proporción significativa de pacientes sin clínica neurológica con lesiones características de EA o EP, según criterios diagnósticos de consenso, que sugieren la existencia de una fase preclínica prolongada en estas enfermedades neurodegenerativas. Un estudio más detallado de este subgrupo de individuos puede proporcionar claves patogénicas sobre las primeras fases del proceso neurodegenerativo (AU)

Genética de la enfermedad de Parkinson / Genetics and Parkinson disease

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Bradykinesia in Huntington's disease.

Huntington's disease (HD) is characterized by the presence of hyperkinesias, but bradykinesia is also present in most patients. We studied the motor performance of 18 patients with genetically proven HD (age, 38.5 +/- 10 y; clinical stage, 1.7 +/- 1.7; (CAG) triplet length, 49.2 +/- 6.8 triplets; all but three patients were free from neuroleptics) and compared with a control group (n = 18) and with a typical Parkinson's disease (PD) group (n = 20). Motor study included the four timed tests commonly used for PD: Pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). Tests were done at 9 AM. The PD group was studied in "off" condition, with no medication given for 12 hours. The HD group was slower than the controls on all tasks (all tests significant, p < 0.01, Mann-Whitney U test) and even slower than PD group (for FD, p < 0.05). A significant correlation was found between each test and clinical stage (for PS, r = 0.84; for FD, r = 0.75; for MTP, r = 087, and for WT, r = 0.77, Pearson). Severe bradykinesia was present in HD, and motor impairment is related to clinical stage.