1,721,242 research outputs found
Perspectives Toward the Development of Quantitative Seed Amplification Assays for α-Synuclein
No full textTracking neurodegenerative diseases in biofluids: Combining pathology and pathophysiology markers is the way
No full textBiofluid biomarkers to track neurodegenerative diseases in vitam are urgently needed. Recent studies show that large-scale proteomic analyses based on the proximity extension assay may reveal novel biomarkers reflecting disease pathophysiology. Such biomarkers will likely express their maximal clinical value when used in combination with pathology-specific biomarkers
Sporadic Creutzfeldt–Jakob disease
No full textSporadic Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is generally regarded as a spontaneous neurodegenerative illness, arising either from a spontaneous PRNP somatic mutation or a stochastic PrP structural change. Alternatively, the possibility of an infection from animals or other source remains to be completely ruled out. Sporadic CJD is clinically characterized by rapidly progressive dementia with ataxia, myoclonus, or other neurologic signs and, neuropathologically, by the presence of aggregates of abnormal prion protein, spongiform change, neuronal loss, and gliosis. Despite these common features the disease shows a wide phenotypic variability which was recognized since its early descriptions. In the late 1990s the identification of key molecular determinants of phenotypic expression and the availability of a large series of neuropathologically verified cases led to the characterization of definite clinicopathologic and molecular disease subtypes and to an internationally recognized disease classification. By showing that these disease subtypes correspond to specific agent strain-host genotype combinations, recent transmission studies have confirmed the biologic basis of this classification. The introduction of brain magnetic resonance imaging techniques such as fluid-attenuated inversion recovery and diffusion-weighted imaging sequences and cerebrospinal fluid biomarker assays for the detection of brain-derived proteins as well as real-time quaking-induced conversion assay, allowing the specific detection of prions in accessible biologic fluids and tissues, has significantly contributed to the improved accuracy of the clinical diagnosis of sporadic CJD in recent years
Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease
No full textThe introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials
Rapidly Progressive Alzheimer’s Disease: Contributions to Clinical-Pathological Definition and Diagnosis
No full textRapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathological, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinical, pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathological data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group
History and state of the art of PrP-res “typing” in Creutzfeldt-Jakob disease
No full textMuch progress has been made in understanding the molecular basis of phenotypic variability in Creutzfeldt-Jakob disease (CJD) in the last ten years. The most significant advance was the discovery that the genotype at polymorphic codon 129 of PRNP and the “type” of the protease-resistant prion protein fragment, PrP-res, have a major influence on the disease phenotype in all forms of CJD, irrespective of their etiology. The most widely accepted CJD classification includes six clinico-pathological phenotypes and two major types of PrP-res, types 1 and 2, which can be distinguished on the basis of a ∼2 kDa difference in relative molecular mass of the protein fragment. However, alternative classifications of human PrP-res types distinguished three patterns of PrP-res molecular mass instead of two, thereby creating significant confusion in the field. Fortunately, progress has been recently made in clarifying these disparities. Most significant in this regard, has been the finding that pH variation among CJD brain homogenates in standard buffers influences the size of PrP-res. Thus, some of the PrP-res heterogeneity used to identify putative strain-specific PrP-res types simply represents a technical “artefact” related to the experimental conditions. On the other hand, recent data have also shown that PrP-res types 1 and 2 are heterogeneous biological species, which can be further distinguished into molecular subtypes that fit the current histopathological classification of sporadic CJD in 6 subtypes. Finally, novel truncated PrP-res fragments of smaller size than PrP-res types 1 and 2 have recently been identified in CJD. Although more studies are needed to fully characterize the presence, characteristics and biological significance of these peptides, preliminary results indicate that their search and characterization may be useful in the molecular diagnostics of CJD subtypes
Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies
Full text linkIntroduction: Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies.Area covered: This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed.Expert opinion: Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression
Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer's Disease with Emphasis on Atypical Disease Variants
No full textAccording to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0 sensitivity and 75.3, 92.1, and 75 specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1 sensitivity and 97.7 specificity overall, and 96.2 sensitivity and 95.5 specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD
Clinical Reasoning: Rapidly progressive dementia in a patient with HIV after an exotic journey
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Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt–Jakob disease in cell-protein misfolding cyclic amplification
No full textThere are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrP(Sc)) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes VV2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrP(Sc)-specific antibody not recognizing PrP(Sc) in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products
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