RESUMEN
BACKGROUND AND PURPOSE: Portugal has been identified as one of the countries with a high prevalence of LRRK2-G2019S, considered to be the most frequent known cause of familial and sporadic Parkinson's disease (PD). The aim of this study was to evaluate the prevalence of PD in Portugal using a door-to-door methodology. METHODS: A cross-sectional study was conducted in the Portuguese community-dwelling population; that is, elderly people living in the community on their own, aged ≥50 years and resident in mainland Portugal, in two phases: (i) a questionnaire was applied to screen potential cases of PD; and (ii) screened cases were evaluated by an expert in PD to confirm diagnosis. RESULTS: The adjusted prevalence of PD for the Portuguese community-dwelling population aged ≥50 years was 0.24%. The estimated total number of cases of PD for the Portuguese population is 180/100 000 inhabitants. CONCLUSIONS: The results of this study show that a geographical region with a high frequency of a causal mutation for PD does not automatically imply a high prevalence of patients with PD.
Asunto(s)
Enfermedad de Parkinson/epidemiología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Portugal/epidemiología , PrevalenciaRESUMEN
The survival of infantile-onset Pompe disease (IOPD) patients has improved dramatically since the introduction of enzyme replacement therapy (ERT) with a1glucosidase alfa. However, long-term IOPD survivors on ERT demonstrate motor deficits indicating that current therapy cannot completely prevent disease progression in skeletal muscle. We hypothesized that in IOPD, skeletal muscle endomysial stroma and capillaries would show consistent changes that could impede the movement of infused ERT from blood to muscle fibers. We retrospectively examined 9 skeletal muscle biopsies from 6 treated IOPD patients using light and electron microscopy. We found consistent ultrastructural endomysial stromal and capillary changes. The endomysial interstitium was expanded by lysosomal material, glycosomes/glycogen, cellular debris, and organelles, some exocytosed by viable muscle fibers and some released on fiber lysis. Endomysial scavenger cells phagocytosed this material. Mature fibrillary collagen was seen in the endomysium, and both muscle fibers and endomysial capillaries showed basal laminar reduplication and/or expansion. Capillary endothelial cells showed hypertrophy and degeneration, with narrowing of the vascular lumen. Ultrastructurally defined stromal and vascular changes likely constitute obstacles to movement of infused ERT from capillary lumen to muscle fiber sarcolemma, contributing to the incomplete efficacy of infused ERT in skeletal muscle. Our observations can inform approaches to overcoming these barriers to therapy.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , alfa-Glucosidasas/uso terapéutico , Estudios Retrospectivos , Capilares/patología , Células Endoteliales/patología , Músculo Esquelético/patología , AnticuerposRESUMEN
BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.
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Glucosilceramidasa/genética , Mutación , Enfermedad de Parkinson/genética , Anciano , Estudios de Casos y Controles , Genotipo , Humanos , Judíos/genética , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad RelativaRESUMEN
Previous studies show that APOE *4 carriers are at increased risk for ischemic stroke and intracerebral hemorrhage (ICH). The APOE *4 gene is also linked to increased incidence of cerebral amyloid angiopathy. It has been suggested that apolipoprotein E4 expression leads to increased vascular amyloid deposition, which may explain the increased incidence of ICH in APOE *4 carriers. Here we show a significant increase in ICH in apoE4 targeted replacement mice compared with apoE3 mice. In all, 89% of the vessels in the apoE4 mice that showed evidence for hemorrhage contained fibrillar amyloid beta based on thioflavine-S staining. Aged apoE4 mice contained predominantly vascular amyloid deposits in the frontal cortex and hippocampus, but also showed evidence for parenchymal amyloid deposits. Most of the parenchymal amyloid appeared diffuse in nature; however, a small fraction was thioflavine-S positive, indicating presence of fibrillar amyloid. Electron microscopy further revealed evidence for fibrillar deposits in the vessel walls of apoE4 mice, but not apoE3 mice. The apoE4 targeted replacement mice do not harbor any mutation in the amyloid precursor protein gene and, therefore, are similar to the majority of humans susceptible to cerebral amyloid angiopathy and ICH, where the APOE genetic polymorphism is the only known genetic risk factor.
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Apolipoproteína E4/fisiología , Angiopatía Amiloide Cerebral/genética , Arterias Cerebrales/patología , Hemorragia Cerebral/genética , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteína E3/genética , Apolipoproteína E3/fisiología , Apolipoproteína E4/genética , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Arterias Cerebrales/metabolismo , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/patología , Modelos Animales de Enfermedad , Marcación de Gen , Humanos , Ratones , Ratones Transgénicos , Proteínas Recombinantes de FusiónRESUMEN
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder showing predominant brainstem involvement, characterized by marked slowing of rapid eye movements (saccades), particularly along the vertical plane. While the contribution of the brainstem damage for the saccadic disturbance in PSP has been extensively studied, much less is known about its cortical and subcortical pathomechanisms. We measured reflexive (prosaccades) and voluntary (antisaccades) saccades in the vertical and horizontal plane in PSP patients (n=8) and controls (n=10) in an eye tracking study, followed by the measurement of blood oxygenation-level dependent (BOLD) activation (PSP, n=6; controls, n=10) during similar saccade paradigms. Behaviorally, PSP patients evidenced slower and lower amplitude prosaccades (horizontal and vertical) and lower amplitude antisaccades (vertical) than controls. Functionally, patients showed decreased frontostriatal BOLD activation during prosaccades (horizontal and vertical) and antisaccades (vertical), relative to controls. Additionally, PSP patients showed less default mode network (DMN) deactivation than controls for all types of saccades. Within groups, controls showed no BOLD differences between horizontal and vertical prosaccades while PSP patients demonstrated greater DMN deactivation during vertical prosaccades. Both groups evidenced greater DMN deactivation during vertical antisaccades when compared to their horizontal counterpart and patients further showed relative frontostriatal BOLD hypoactivity during vertical antisaccades. We found fMRI evidence of frontostriatal hypoactivity in PSP patients relative to controls, especially during vertical saccades. These new findings highlight the impact of cortical impairment in saccadic disturbance of PSP.
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Corteza Cerebral/fisiopatología , Movimientos Sacádicos/fisiología , Parálisis Supranuclear Progresiva/fisiopatología , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Medidas del Movimiento Ocular , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Oxígeno/sangre , Parálisis Supranuclear Progresiva/diagnóstico por imagenRESUMEN
Sensory deficits have been documented in Parkinson's disease, in particular within the visual domain. However, ageing factors related to the brain and to neural and non-neural ocular structures could explain some of the previously reported results, in particular the claimed impairment within the koniocellular pathway. This study addressed visual impairment attributable to the magno- (luminance), parvo- (red-green) and koniocellular (blue-yellow) pathways in a population of Parkinson's disease patients. To avoid potentially confounding factors, all subjects underwent a full neurophthalmological assessment which led to exclusion of subjects with increased intraocular pressure, diabetes even in the absence of retinopathy, and ocular abnormalities (from a total of 72 patients' eyes, 12 were excluded). Both parvo- and koniocellular pathways were studied by means of contrast sensitivity (CS) measurements along protan, tritan and deutan axes and also by fitting chromatic discrimination ellipses using eight measured contrast axes. Magnocellular function was assessed, using stimuli that induce a frequency doubling illusion, in 17 locations in the fovea and periphery. Achromatic (luminance modulation) thresholds were significantly higher in Parkinson's disease both in foveal and peripheral locations. A significant impairment was observed along protan and deutan axes, but only marginally along the tritan axis. These results were corroborated by a significant elongation of chromatic discrimination ellipses in our Parkinson's disease group. Correlation analysis showed that achromatic and chromatic CS measures were independent, which implies that multiple visual pathways are affected independently in Parkinson's disease. Magnocellular impairment was significantly correlated with age and disease stage, in contrast to the measured chromatic deficits. We conclude that in Parkinson's disease, independent damage occurs in the early magno- and parvocellular pathways. Furthermore, traditional koniocellular probing strategies in Parkinson's disease may be confounded by ageing factors, which may reconcile the previously reported controversial findings concerning chromatic impairment in Parkinson's disease.
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Enfermedad de Parkinson/fisiopatología , Trastornos de la Visión/fisiopatología , Envejecimiento/fisiología , Percepción de Color/fisiología , Sensibilidad de Contraste/fisiología , Femenino , Fóvea Central/patología , Fóvea Central/fisiopatología , Humanos , Ilusiones/fisiología , Masculino , Persona de Mediana Edad , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/patología , Estimulación Luminosa/métodos , Psicofísica , Retina/patología , Retina/fisiopatología , Umbral Sensorial/fisiología , Trastornos de la Visión/etiología , Trastornos de la Visión/patología , Percepción Visual/fisiologíaRESUMEN
Saccadic behaviour ranges from reflexive (e.g., prosaccade) to goal oriented voluntary movements (e.g., antisaccade). Behavioural asymmetries between vertical and horizontal saccades have been described both in normal individuals (greater delay of vertical prosaccades) and in disease states such as Parkinson's disease (PD) (prosaccades are short and antisaccades are delayed, especially in the vertical plane, possibly due to a frontostriatal deficit). Importantly, the cortical mechanisms for the generation of vertical saccades are largely unknown, both in health and disease, when compared with their horizontal counterpart. Moreover, studies exploring saccadic neural correlates and putative compensatory mechanisms at a functional level in PD are scarce. We investigated horizontal and vertical prosaccades and antisaccades in an eye tracking paradigm in 19 PD patients off medication and 22 healthy controls, followed by a block-design functional Magnetic Resonance Imaging (fMRI) study, consisting of two runs (prosaccade, antisaccade) of 6 blocks each (3 vertical, 3 horizontal). While saccade metrics were not significantly different between groups, PD showed left frontal underactivation during horizontal prosaccades and right parietal overactivation during horizontal and vertical prosaccades and horizontal antisaccades. Moreover, controls showed greater deactivation of the default-mode network (DMN) during antisaccades. Vertical prosaccades were associated with greater right frontal and cerebellar activity in controls, and cuneus hypoactivity in PD. Vertical antisaccades were associated with greater DMN deactivation in both groups and left frontal hypoactivity in PD. Putative functional compensatory changes in the right parietal cortex in PD patients may help to keep saccadic behaviour at the same level as the healthy controls. We provide first time evidence showing that functional cortical asymmetries between vertical and horizontal saccades occur distinctively in PD patients and healthy controls.
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Encéfalo/fisiopatología , Medidas del Movimiento Ocular , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Movimientos Sacádicos , Anciano , Mapeo Encefálico , Femenino , Lóbulo Frontal/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiopatología , Lóbulo Parietal/fisiopatología , Desempeño PsicomotorRESUMEN
We model the cytoskeleton as a fractal network by identifying each segment with a simple Kelvin-Voigt element with a well defined equilibrium length. The final structure retains the elastic characteristics of a solid or a gel, which may support stress, without relaxing. By considering a very simple regular self-similar structure of segments in series and in parallel, in one, two, or three dimensions, we are able to express the viscoelasticity of the network as an effective generalized Kelvin-Voigt model with a power law spectrum of retardation times Lâ¼τ(α). We relate the parameter α with the fractal dimension of the gel. In some regimes (0<α<1), we recover the weak power law behaviors of the elastic and viscous moduli with the angular frequencies G'â¼G"â¼w(α) that occur in a variety of soft materials, including living cells. In other regimes, we find different power laws for G' and G".
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Citoesqueleto , Fractales , ReologíaRESUMEN
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are implicated in autosomal dominant familial and sporadic Parkinson's disease (sPD). Given its relative frequency in PD and its putative function in several cellular pathways that are known to be impaired in the disease, we wanted to tackle LRRK2 physiological role and to address its potential as a PD therapeutic target. We investigated the impact of pharmacological inhibition of LRRK2 kinase activity in control and PD cell function. We provide evidence that physiologically LRRK2, through its kinase activity, regulates mitochondrial fission events and facilitates autophagic degradation by modulating lysosomal cellular localization. Upon LRRK2 inhibition, normal fission decreases, leading to the elongation of mitochondrial network which contributes to a poor degradation of deficient mitochondria. Moreover, LRRK2 inhibition promotes lysosomal perinuclear clustering, through Rab7 that further hinders autophagosomes degradation. These events induce a decrease in the autophagic flow, which contributed directly to a decreased proteolytic degradation of damaged mitochondria. These data resembled the results observed in sPD cells. Interestingly, the LRRK2 kinase activity is increased in sPD cells, and despite its inhibition recovers mitochondrial cellular localization, it did not improve microtubule network-dependent trafficking. Our results provide novel insights into the multiple mechanisms that dictate the association between LRRK2 and mitophagy in sPD, and contribute with new findings that could have important therapeutic implications.
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Autofagia/fisiología , Mitocondrias/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Fosforilación , Transporte de Proteínas , ProteolisisRESUMEN
BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.
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Proteínas del Tejido Nervioso/genética , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido , Adenina/metabolismo , Adulto , Anciano , Alelos , Brasil , Citosina/metabolismo , Femenino , Guanina/metabolismo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Reacción en Cadena de la Polimerasa , PortugalRESUMEN
Os autores apresentam os resultados do tratamento em 11 pacientes com aneurismas múltiplos. A conduta utilizada foi o tratamento cirúrgico de todos os aneurismas diagnosticados: em 8 pacientes a cirurgia total foi possível em um estágio e, apenas 3 pacientes necessitaram de uma segunda cirurgia para a clipagem dos aneurismas nao abordados na primeira cirurgia. Os autores sugerem a adoçao de uma conduta cirúrgica mais radical no tratamento dos aneurismas múltiplos.