1,721,023 research outputs found
Inflammation and oxidative damage in Alzheimer's disease : friend or foe?
No full textThe two major neuropathologic hallmarks of AD are extracellular Amyloid beta plaques and intracellular neurofibrillary tangles. A number of additional pathogenic mechanisms have been described, including inflammation and oxidative damage. Regarding inflammation, several cytokines and chemokines have been detected both immunohistochemically and in Cerebrospinal Fluid from patients. Some of them, including Tumor Necrosis Factor-alpha, Interferon-gamma-inducible Protein-10, Monocyte Chemotactic Protein-1 and Interleukin-8, are increased in AD and in Mild Cognitive Impairment, considered the prodromal stage of AD, suggesting that these modifications occur very early during the development of the disease, possibly explaining the failure of trials with anti-inflammatory agents in patients with severe AD. Further evidence suggests that cytokines and chemokines could play a role in other neurodegenerative disorders. These disorders are considered multifactorial diseases, and genetic factors influence pathological events and contribute to change the disease phenotype from patient to patient. Gene polymorphisms in crucial molecules, including cytokines, chemokines and molecules related to oxidative stress, may act as susceptibility factors, or may operate as regulatory factors, modulating the severity of pathogenic processes
Alzheimer's Disease : From Pathogenesis to Disease-Modifying Approaches
No full textThe two major neuropathologic hallmarks of AD are extracellular amyloid beta (A) plaques and intracellular neurofibrillary tangles (NFTs). A number of additional pathogenic mechanisms, possibly overlapping with A plaques and NFTs formation, have been described, including inflammation, oxidative damage, iron dysregulation, and alterations in cholesterol metabolism. In this review, all of these mechanisms will be discussed and treatments that are under development to interfere with these pathogenic steps will be presented. A primary goal of work in this area is identification of novel compounds that can block the course of the disease in early phases. For this reason they are currently termed "disease modifying" drugs. These drugs are designed to modify pathological steps leading to AD, thus acting on the evolution and progression of the disease. Some of these molecules are undergoing clinical testing whereas others are in preclinical phases of development. Several approaches have been considered, including mainly A beta deposition interference by anti-A aggregation agents, vaccination, gamma-secretase inhibition or selective A beta 42-lowering agents (SALAs), tau deposition interference by methyl thioninium chloride (MTC), and methods for reduction of inflammation and oxidative damage
RUOLO DELL’INFIAMMAZIONE E DEL DANNO OSSIDATIVO NELLA PATOGENESI DELLA MALATTIA DI ALZHEIMER E DELLA DEGENERAZIONE LOBARE FRONTOTEMPORALE
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Genetics and neurobiology of frontotemporal lobar degeneration
No full textFrontotemporal dementia (FTD) is characterised by brain intracellular deposition of abnormally phosphorylated tau protein, considered responsible for neuronal death. Several familial cases with different mutations in the tau encoding gene (MAPT), located on chromosome 17, have been described. Besides, in a Danish family, the genetic defect has been associated to chromosome 3. Although many FTD families exhibit known mutations, in some cases none of them occur. Recent findings demonstrate an increased intrathecal production of both pro- and anti-inflammatory cytokines in sporadic FTD patients. Besides, increased cerebrospinal fluid monocyte chemotactic protein-1 and interleukin-8 levels have been observed in FTD, whereas interferon-gamma-inducible protein-10 levels were similar to controls
Lack of Association between the GPR3 Gene and the Risk for Alzheimer's Disease
No full textAlzheimer's disease is the most frequent form of dementia and its incidence is rapidly increasing. Genetic factors are important determinants of the individual susceptibility to the disease and many efforts have been made to identify loci and markers involved. Recent finding describes the GPR3 gene as a modulator of β-amyloid production, suggesting that perturbation of its activity and function may contribute to the pathogenesis of AD. Furthermore, the gene is located at chromosome 1, in a region proposed as a susceptibility locus for the disease. We searched for nucleotide variations in the coding sequence and in the region 5 prime of it by dHPLC and analysed their distribution in a group of 104 AD patients and 109 age-matched controls. We identified 5 types of variation, two in the putative promoter region (g.27718954A>G and g.27719102A>T) and the others in exon 2 (c.51C>A, c.80C>G, and c.771C>T). All of them were equally represented in the two cohorts of the study, thus suggesting the absence of an association between GPR3 gene and AD in our population
Cerebrospinal fluid (CSF) tau and amyloid beta42 (A beta 42) protein abnormalities correlate with executive dysfunction in myotonic dystrophy type 1 (DM1) and type 2 (DM2)
No full textObjective: To correlate CSF tau (total, t-tau; phsophorylated, p-tau181) and A42 protein levels to neuropsychological profiles in DM1 and DM2.
Background: Preliminary data in patients with DM1 suggest that the Tau pathology in these patients may be different from Alzheimers disease.
Design/Methods: 33 patients with moderately severe DM1 (n = 23) and genetically-confirmed DM2 (n = 10) were subjected to neuromuscular and neuropsychological assessments. Results were compared to 16 age-, sex- and education-matched controls and to 29 frontotemporal (FTD) dementia patients. CSF t-tau, p-tau181 and A42 proteins were determined by using ELISA (Innogenetics, Belgium).
Results: (i) CSF levels of t-tau and p-tau181 proteins were increased in more than 3/4 of patients with DM1(t-tau: 378.2 pg/ml 289.6; p-tau181:58.3 pg/ml 36.9) and in 1/2 of DM2 (t-tau:272.5 pg/ml 179.5; p-tau181: 42.5 pg/ml 19), DM1 t-tau and p-tau181significantly higher than controls (p<0.05) but t-tau lower in DM1 compared to FTD (431.2 pg/ml 33.8, p = 0.01) and p-tau181 similar between DM1 and FTD (48.7 pg/ml 4.9); (iii) A42 levels were not significantly different in DM1 (941.3 pg/ml 328.3), DM2 (798pg/ml 258.3) and controls (901.88 pg/ml 250.4) and were similar to FTD (694.3 55.2); (iv) T-tau and p-tau181 levels correlated with frontal lobe test functions (TEA, p>0,05); (v) Significant inverse correlations were found between age at onset and t-tau in DM2 (r=-0.673, p < 0.05). (v) No correlation was found between disease duration, muscle strength scores, muscle disability and CTG or CCTG repeat size in DM1 and DM2.
Conclusions/Relevance: DM1 and DM2 are associated with a significant increase in CSF t- and p-tau levels along with normal A42 protein levels. The correlation to tests of frontal lobe function suggests these CSF biomarkers may play a role in the cognitive and behavioural profiles of DM1 and DM2. However, the usefulness for an attractive therapeutic target of cerebral involvement needs to be further addressed
A sporadic case of progressive non-fluent aphasia caused by a novel progranulin mutation
No full textNovel progranulin mutation in a sporadic case of frontotemporal dementia parkinsonism presentino with asymmetric rest tremor and cognitive decline
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