RESUMEN
OBJECTIVE: The aim of this systematic review (SR) was to gather all available epidemiological evidence on former participation in any type of sport, at a professional and varsity level, as a potential risk factor for neurodegenerative diseases (NDs) and neurocognitive disorders (NCDs). DESIGN: Systematic searches were performed on PubMed, the Cochrane databases, and the ISI Web of Knowledge databases. Included studies were assessed using the NOS checklist. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All epidemiological studies reporting data on the possible association between a clinical diagnosis of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND), dementia or mild cognitive impairment (MCI), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE) at any stage and with any clinical pattern and the former participation in any types of sport at a varsity and professional level were included. RESULTS: Data from the 17 included studies showed a higher frequency of NDs and NCDs in former soccer and American football players. Updating the previous SR confirmed a higher frequency of ALS/MND in former soccer players. Data reported a significantly higher risk of dementia/AD in former soccer players, and of MCI in former American football players. Results also showed a significantly higher risk of PD in former soccer and American football players, and a significantly higher risk of CTE in former boxers and American football players. This SR confirmed a higher risk of NDs and NCDs in former professional/varsity athletes. However, the pathological mechanisms underlying this association remain unclear, and further high-quality studies should be performed to clarify whether the association could be sport specific.
Asunto(s)
Esclerosis Amiotrófica Lateral , Encefalopatía Traumática Crónica , Disfunción Cognitiva , Demencia , Fútbol Americano , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Fútbol , Humanos , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/complicaciones , Atletas , Encefalopatía Traumática Crónica/epidemiología , Encefalopatía Traumática Crónica/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/complicaciones , Demencia/complicaciones , Enfermedades Neurodegenerativas/epidemiología , Enfermedades Neurodegenerativas/complicaciones , Enfermedad de Parkinson/complicacionesRESUMEN
OBJECTIVE: Alzheimer's disease (AD), the most common cause of dementia, typically shows a slow clinical progression over time. 'Rapidly progressive' AD, a variant of the disease characterized by an aggressive course, exhibits distinct clinical, biological, and neuropathological features. Here, we investigate neuropsychological predictors of rapid decline in a group of mild patients with AD. METHODS: One hundred fifty-three mild patients with AD admitted to a memory disorder clinic and followed for up to 3 years were included in this study. A comprehensive neuropsychological (NP) battery was performed at the time of enrollment. Patients were defined as 'rapidly progressive' if they exhibited a drop of 6 or more points on the Mini Mental State Examination (MMSE) between two consecutive annual visits. This event defined the main outcome in multiple analyses of variance and Cox proportional hazards models that investigated the impact of NP predictors. Categorical principal component analysis (CATPCA) was also employed in order to delineate clusters of NP tests and to test their effect on the outcome. RESULTS: Of 153 subjects, thirty-seven (24%) were classified as 'rapidly progressive'; those subjects showed younger age of symptoms onset compared to slow decliners (68 vs 71.5 years old). Baseline lower performance on a neuropsychological test of naming predicted a rapid decline over the follow-up (P = 0.001). Three clusters of NP were defined by CATPCA: (i) executive/language, (ii) visuospatial memory, and (iii) verbal memory. The executive/language component predicted a rapid decline over the follow-up (P = 0.016). CONCLUSION: Early executive/language impairment is highly predictive of a rapid progression of AD.
Asunto(s)
Enfermedad de Alzheimer/psicología , Pruebas Neuropsicológicas , Edad de Inicio , Anciano , Envejecimiento/psicología , Progresión de la Enfermedad , Función Ejecutiva , Femenino , Estudios de Seguimiento , Humanos , Lenguaje , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Valor Predictivo de las Pruebas , Análisis de SupervivenciaRESUMEN
An expanded hexanucleotide (GGGGCC) repeat in a non-coding promoter region of open reading frame 72 of chromosome 9 (C9ORF72) has been recently identified as a major cause of familial and sporadic frontotemporal lobar degeneration. We describe the clinical picture of a 64-year-old woman carrying the hexanucleotide repeat expansion, who developed a sporadic early-onset form of behavioral variant frontotemporal dementia characterized by the occurrence of uncommon behavioral manifestations such as binge eating disturbance and by a rapid worsening of cognitive abilities. Our report confirms previous studies asserting that C9ORF72 repeats may sustain heterogeneous clinical syndromes.
Asunto(s)
Bulimia/complicaciones , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/genética , Proteínas/genética , Encéfalo/patología , Bulimia/genética , Proteína C9orf72 , Cognición , Expansión de las Repeticiones de ADN , Femenino , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/psicología , Humanos , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
The aim of the present systematic review (SR) was to provide an overview of all published and unpublished clinical trials investigating the safety and efficacy of disease-modifying drugs targeting synaptic plasticity in dementia. Searches on CT.gov and EuCT identified 27 trials (4 phase-1, 1 phase-1/2, 18 phase-2, 1 phase-2/3, 1 phase-3, 1 phase-4, and 1 not reported). Twenty of them completed, and seven are currently active or enrolling. The structured bibliographic searches yielded 3585 records. A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. We used RoB tool for quality analysis of randomized studies. Efficacy was assessed as a primary outcome in all studies except one and the main scale used was ADAS-Cog (7 studies), MMSE and CDR (4 studies). Safety and tolerability were reported in eleven studies. The incidence of SAEs was similar between treatment and placebo. At the moment, only one molecule reached phase-3. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/terapia , Benzamidas , Brioestatinas , Humanos , Levetiracetam/uso terapéutico , Plasticidad Neuronal , Piperidinas , Piridinas , TiazolesRESUMEN
Branched-chain amino acids (BCAAs), valine, isoleucine, and leucine, are widely used among athletes as dietary integrators. Although the occurrence of untoward effects of BCCA supplementation, with particular regard to neurological disturbances, cannot be excluded, no specific studies have been performed so far. The aim of this work was to evaluate the effects of a diet enriched in BCAAs on the expression of oxidative stress pathway genes in the brain of C57Bl/6J mice. Animals were fed a standard or a BCAA diet for 95 days starting from postnatal day 21 until sacrifice. BCAA treatment, at doses comparable to human usage, significantly down-regulated the expression of some antioxidant genes, while up-regulating the expression of some oxygen transporters. In conclusion, it appears that BCAAs administered by diet could alter some specific oxidative stress pathways in the brain. Caution should thus be exercised in the widespread use of BCAAs as dietary integrators in sports practice.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Encéfalo/efectos de los fármacos , Dieta , Estrés Oxidativo/efectos de los fármacos , Esclerosis Amiotrófica Lateral/etiología , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Globinas/genética , Globinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Atención/fisiología , Trastornos del Conocimiento/genética , Función Ejecutiva/fisiología , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Cromosomas Humanos Par 21/genética , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , LinajeRESUMEN
Several lines of evidence suggest that the cholesterol content of neuronal membranes influences amyloid precursor protein (APP) processing; however, its role in transcriptional regulation of the cofactors for gamma-secretase, the key enzyme for the production of the Abeta peptide, is poorly understood. This study investigates whether the changes in cellular cholesterol metabolism modulate the expression of genes involved in the gamma-secretase complex function. The abundance of mRNA transcripts for presenilin 1 and 2 (PS1 and PS2), APP, and nicastrin were evaluated in neuroblastoma cells exposed either to serum-depleted medium or to low-density lipoproteins (LDL). Cholesterol esterification was markedly inhibited by mevinolin and U18666A, but was not significantly affected by any other of the tested treatments. gamma-Secretase genes and cofactors were not co-regulated and were not influenced by statin inhibition of cholesterol synthesis. Nicastrin and the APP isoforms showed constitutive expression. In the absence of exogenous lipids, cell PS1 and PS2 expression was induced by LDL and by lysosomal sequestration of cholesterol. However, a different pattern of induction of presenilin gene expression was observed in the latter condition, suggesting that lysosomal cholesterol levels are strong inducers of PS2 transcription. Taken together, these results indicate that lipid metabolism has a complex influence on gamma-secretase transcriptional pathways and, in particular, exogenous cholesterol and compartmentalization in neuroblastoma cells play a relevant role in regulating the transcription of presenilins, while modulation of the cholesterol biosynthesis pathway seems to exert a minor influence on the expression of gamma-secretase genes and cofactors.
Asunto(s)
Colesterol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Presenilina-1/genética , Presenilina-2/genética , Línea Celular Tumoral , Colesterol/metabolismo , Medio de Cultivo Libre de Suero , Humanos , Lípidos/biosíntesis , Lipoproteínas LDL/aislamiento & purificación , Lisosomas/metabolismo , Neuroblastoma , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética/efectos de los fármacosRESUMEN
Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Mutación , Anciano , Secretasas de la Proteína Precursora del Amiloide , Secuencia de Bases , Western Blotting , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Linaje , Polimorfismo Genético , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Perinatal hypoxic injury is the major cause of normal neural developmental alterations. Recent studies concerning animal models show that an hypoxic/ischaemic event triggers a process taking to a synaptic architecture reorganization which induces a transient change in the synaptic (synapsin 1, SNAP 25, APP) and neuronal (MAP2, N-CAM, GAP-43 and presenilins) protein expression. Here we review the post-translational modifications of some proteins after hypoxic-ischaemic events. A deeper study on synaptic proteins plasticity could give an important key for the understanding of the recovery mechanisms of the nervous system.
Asunto(s)
Hipoxia-Isquemia Encefálica/etiología , Proteínas del Tejido Nervioso/fisiología , Péptidos beta-Amiloides/fisiología , Modelos Animales de Enfermedad , Proteína GAP-43/fisiología , Humanos , Proteínas de la Membrana/fisiología , Proteínas Asociadas a Microtúbulos/fisiología , Moléculas de Adhesión de Célula Nerviosa/fisiología , Presenilina-1 , Presenilina-2 , Sinapsinas/fisiología , Proteína 25 Asociada a SinaptosomasRESUMEN
Fosinopril is distinguished from other ACE inhibitors by a pharmacokinetic pecularity in the sense that is can be metabolized either by liver or kidney. This was the rationale of the present research the aim of which was to verify if administered to patients with liver cirrhosis the drug was liable to alter global liver function and ability to metabolize drugs. Eight cirrhotic males, mean age 56 years, also suffering from high blood pressure, were studied. In these patients, liver and kidney function tests (BUN, creatinine blood level, serum and urinary electrolytes, creatinine clearance, calcium and phosphor blood level, transaminases, alkaline phosphatase prothrombin time, cholinesterase, gamma-glutamyl-transpeptidase) were carried out at baseline and after 30 days' fosinopril treatment (1 capsule every morning in the fasting state); in addition total functioning liver mass was assessed by the galactose test, and drug-metabolizing capacity by the antipyrine test. Treatment resulted in a significant improvement of pressure values in all patients (p < 0.01) and did not alter liver and kidney function parameters. Besides, no side effects were registered, especially no case of orthostatic hypotension. The antipyrine test was not influenced by fosinopril treatment. Therefore, short-term treatment with this ACE-inhibitor can be concluded to be effective and not to cause additional alterations of liver function in patients with liver cirrhosis.
Asunto(s)
Fosinopril/farmacología , Hipertensión/tratamiento farmacológico , Cirrosis Hepática/fisiopatología , Hígado/efectos de los fármacos , Hígado/fisiología , Fosinopril/uso terapéutico , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Cirrosis Hepática/complicaciones , Pruebas de Función Hepática , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Mutations of presenilin 2 gene are a rare cause of familial Alzheimer disease (AD). We describe an Italian family with hereditary dementia associated with a novel mutation in the presenilin 2 gene. METHODS: Clinical investigations of the diseased subjects; interviews with relatives; studies of medical records; pedigree analysis; and neuroradiologic, neuropathologic, and molecular genetic studies were carried out in the pedigree. RESULTS: Genetic analysis showed a novel PSEN2 A85V mutation present in the proband and in all analyzed affected members, in a subject presenting with an amnesic mild cognitive impairment, and in a young, still asymptomatic subject. The proband showed a clinical phenotype indicative of Lewy body dementia and the neuropathologic examination demonstrated the presence of unusually abundant and widespread cortical Lewy bodies in addition to the hallmark lesions of AD. Other affected members exhibited a clinical phenotype typical of AD. CONCLUSIONS: Our findings add complexity to the spectrum of atypical phenotypes associated with presenilin mutations and should then be taken into account when considering the nosography of neurodegenerative diseases. They also support previous data that specific mutations of genes associated with familial Alzheimer disease may influence the presence and extent of Lewy bodies.
Asunto(s)
Demencia/genética , Mutación Puntual , Presenilina-2/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Demencia/patología , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Presenilina-2/metabolismoRESUMEN
Glutathione (GSH) is a principal cellular scavenger of free radicals. Chronic alcohol abuse, as well as liver disease, induces a decrease of hepatic GSH. We evaluated the effect of GSH administration (2.4 g day-1 in saline i.v. for 15 days) on the concentration of GSH in plasma and erythrocytes and on liver function tests, including galactose and antipyrine tests. We studied 40 alcoholic cirrhotic patients: 22 treated with GSH (10 persistent alcohol abusers and 12 weaning from alcohol during the study) and 18 treated with saline only (8 persistent alcohol abusers and 10 abstainers). Treatment with GSH improved the concentration of GSH in plasma and erythrocytes only in abstainers from alcohol; it did not affect liver function tests or galactose clearance. Persistent alcohol consumption significantly prolonged antipyrine metabolism; GSH administration counteracted this effect.