756 research outputs found
Cerebrospinal Fluid and Blood Neurofilament Light Chain Protein in Prion Disease and Other Rapidly Progressive Dementias: Current State of the Art
No full textRapidly progressive dementia (RPD) is an umbrella term referring to several conditions causing a rapid neurological deterioration associated with cognitive decline and short disease duration. They comprise Creutzfeldt–Jakob disease (CJD), the archetypal RPD, rapidly progressive variants of the most common neurodegenerative dementias (NDs), and potentially treatable conditions such as infectious or autoimmune encephalitis and cerebrovascular disease. Given the significant clinical and, sometimes, neuroradiological overlap between these different disorders, biofluid markers also contribute significantly to the differential diagnosis. Among them, the neurofilament light chain protein (NfL) has attracted growing attention in recent years as a biofluid marker of neurodegeneration due to its sensitivity to axonal damage and the reliability of its measurement in both cerebrospinal fluid (CSF) and blood. Here, we summarize current knowledge regarding biological and clinical implications of NfL evaluation in biofluids across RPDs, emphasizing CJD, and other prion diseases. In the latter, NfL demonstrated a good diagnostic and prognostic accuracy and a potential value as a marker of proximity to clinical onset in pre-symptomatic PRNP mutation carriers. Similarly, in Alzheimer’s disease and other NDs, higher NfL concentrations seem to predict a faster disease progression. While increasing evidence indicates a potential clinical value of NfL in monitoring cerebrovascular disease, the association between NfL and prediction of outcome and/or disease activity in autoimmune encephalitis and infectious diseases has only been investigated in few cohorts and deserves confirmatory studies. In the era of precision medicine and evolving therapeutic options, CSF and blood NfL might aid the diagnostic and prognostic assessment of RPDs and the stratification and management of patients according to disease progression in clinical trials
Andare per parchi artistici
No full textNel nostro paese è possibile visitare alcune notevoli collezioni di arte ambientale. Si tratta di cosiddetti parchi-museo, che raccolgono opere di artisti ambientali italiani e stranieri. La caratteristica di molti, e di tutti i principali, è quella di contenere opere site-specific e quindi di instaurare un dialogo produttivo col paesaggio in cui si inseriscono. Parlare dei parchi-museo significa quindi parlare anche di alcuni luoghi di elezione del paesaggio italiano e della identità del nostro paese. Ogni parco offre l’occasione per incontrare le opere di artisti importanti dell’Environmental art, da Giuseppe Penone a Niki De Saint Phalle, da Richard Serra a Dani Karavan, e molti altri. Il volume si apre con un tuffo nel passato, il Sacro Bosco di Bomarzo, che ha ovviamente un’origine del tutto diversa ma può servire a raccordare il discorso contemporaneo ad un luogo allestito secoli fa, caratterizzato anch’esso dal dialogo tra le sculture e le architetture e il paesaggio, e si chiude con il Grande Cretto di Burri a Gibellina Vecchia, l’installazione ambientale di maggiori dimensioni In Italia e una delle più celebri
Molecular pathology, classification, and diagnosis of sporadic human prion disease variants.
No full textHuman prion diseases are a unique group of transmissible neurodegenerative diseases that occur as sporadic, familial or acquired disorders and show a wide range of phenotypic variation. The latter has been attributed to the existence of distinct strains of the agent or prion, and the genetic background of the host, namely the primary sequence of the gene encoding the prion protein, which is the site of mutations and polymorphisms. The characterization of distinct isoforms of the abnormal prion protein in the brain of affected patients, which has been shown to correlate with the disease phenotype, has recently led to the concept of molecular strain typing, in which the different prion protein isoforms or "types", possibly enciphering the strain variability in their conformation, may serve as surrogate markers for individual prion strains. In sporadic Creutzfeldt-Jakob disease, the most common human prion disease, there are at least six distinct clinico-pathological disease phenotypes that largely correlate at a molecular level with two prion protein types with distinctive physicochemical properties and the genotype at the methionine/valine polymorphic codon 129 in the prion protein gene. Recent results of transmission studies indicate that five prion strains with distinctive biological properties can be isolated from these six disease variants. It has also been shown that about a third of sporadic cases show a mixed phenotype and the co-occurrence of prion protein types. The origin of prion strains and their co-occurrence as well as the mechanisms underlying the strain-specific neuronal targeting remain largely unexplained and their understanding constitute, together with the development of successful therapies and more sensitive and specific clinical biomarkers, the major challenges that this disease poses for the future
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
No full textSix subtypes of sporadic Creutzfeldt-Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrPSc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrPSc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrPSc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrPSc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co-occurrence of pathological variants sharing PrPSc type 2. In contrast, molecular typing best detected the concurrent PrPSc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt-Jakob disease
Understanding prion strains: Evidence from studies of the disease forms affecting humans
No full textPrion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective
Sicilian Protected Areas Among Tourist Exploitation and Environmental Guardianship
No full textThis report pursues the objective to define the connection that ties exploitation of the environment quality in the protected areas and the opportunities of economic and tourist development. Sicilian protected areas involve a territory full of an extraordinary variety and concentration of historical, artistic and environmental resources, so that they represent one of the main tourist attractions of the Island. Unfortunately, the Sicilian protected areas system shows serious backwardnesses, so that the prevailing image is one of wide zones in state of abandonment and degrade. It needs to start a process of investments and programmes in order to realize an integration between both the basical aims of environmental safeguard and the promotion of sustainable touristic and economic activities. The report presents a brief description of protected areas’ features, as long as considering protected territories as an instrument of local economic and social development. The second part of the paper is focused on the main features of the Sicilian protected areas system, in order to highlight the matters concerning the tourist-recreational exploitation of the protected territories in a sustainable viewpoint.
Elevated plasma p-tau181 levels unrelated to Alzheimer's disease pathology in amyotrophic lateral sclerosis
No full textBackground: Phosphorylated-tau181 (p-tau181), a specific marker of Alzheimer's disease (AD) pathology, was found elevated in plasma but not in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). We expanded these findings in a larger patient cohort, exploring clinical/electrophysiological associations, prognostic value and longitudinal trajectories of the biomarker. Methods: We obtained baseline plasma samples from 148 ALS, 12 spinal muscular atrophy (SMA), and 88 AD patients, and 60 healthy controls. Baseline CSF and longitudinal plasma samples were from 130 and 39 patients with ALS. CSF AD markers were measured with the Lumipulse platform, and plasma p-tau181 with SiMoA.
Results: Patients with ALS showed higher plasma p-tau181 levels than controls (p<0.001) and lower than AD participants (p=0.02). SMA patients had higher levels than controls (p=0.03). In patients with ALS, CSF p-tau and plasma p-tau181 did not correlate (p=0.37). Plasma p-tau181 significantly increased with the number of regions showing clinical/neurophysiological lower motor neurons (LMN) signs (p=0.007) and correlated with the degree of denervation in the lumbosacral area (r=0.51, p<0.0001). Plasma p-tau181 levels were higher in classic and LMN-predominant than in bulbar phenotype (p=0.004 and p=0.006). Multivariate Cox regression confirmed plasma p-tau181 as an independent prognostic factor in ALS (HR 1.90, 95% CI 1.25 to 2.90, p=0.003). Longitudinal analysis showed a significant rise in plasma p-tau181 values over time, especially in fast progressors.
Conclusions: Plasma p-tau181 is elevated in patients with ALS, independently from CSF levels, and is firmly associated with LMN dysfunction. The finding indicates that p-tau181 of putative peripheral origin might represent a confounding factor in using plasma p-tau181 for AD pathology screening, which deserves further investigation
Monthly Intramuscular Neridronate for the Treatment of Postmenopausal Osteoporosis: Results of a 6-Year Prospective Italian Study
No full textPurpose. Oral bisphosphonates (BPs) are the most commonly used medications for osteoporosis (OP), but their poor gastrointestinal (GI) absorption and tolerance hamper compliance. Intramuscular (IM) neridronate (NE), an amino-BP, is an easy-to-administer, effective, and safe alternative to oral BPs. We assessed the 6-year effects of monthly IM NE on bone mineral density (BMD) and bone turnover biomarkers (BMs) in postmenopausal OP. Methods. This single-center, prospective study enrolled postmenopausal osteoporotic outpatients with gastric intolerance to BPs (based on Tuscany Region's law GRT n. 836 20/10/2008). They received 25mg IM NE once a month (with vitamin D and calcium if necessary) for 6 years. BMD was evaluated at lumbar spine (L1-L4), femoral neck (FN), and total femur (TF) at baseline (BL) and every 12 months afterwards. At BL, month 3, and every 12 months after BL, total and ionized calcium, vitamin D, parathyroid hormone 1-84, bone alkaline phosphatase (BALP), osteocalcin, and N- and C-terminal telopeptides were assayed. Results. Overall, 60 women (mean age: 62.3 +/- 7.5 years) received monthly IM NE for 6 years, with vitamin D and calcium supplementation in 81.3% of cases. Compared to BL, BMD increased significantly already after 1 year at all sites (4.5 +/- 0.9% for L1-L4, 4.5 +/- 0.8% for TF, and 2.1 +/- 0.6% for FN, P0.05), and the changes were maintained over time, whereas FN further improved up to year 3 and remained stable afterwards (P0.05). All BMs, except for total calcium and BALP, progressively decreased over time (P0.05). No fractures and significant adverse events were reported. Conclusion. The monthly administration of IM NE represents a manageable and effective option, in terms of BMD and bone BM improvement, for the long-term treatment of postmenopausal OP women with gastric intolerance to BPs. This trial is registered with ClinicalTrials.gov Identifier: NCT03699150
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