1,721,039 research outputs found
Perspectives Toward the Development of Quantitative Seed Amplification Assays for α-Synuclein
No full textInside the clinical evaluation of sleepiness: subjective and objective tools
No full textPurpose To critically review the available tools for evaluating excessive daytime sleepiness (EDS) in clinical practice. Methods Objective tests and subjective scales were divided into three groups in accordance with the different dimensions of sleepiness they measure, namely physiological, manifest, and introspective. Strengths, weaknesses, and limitations of each test have been analysed and discussed along with the available recommendations for their use in clinical practice. Results The majority of the tests developed for sleepiness evaluation do not have practical usefulness outside the research setting. The suboptimal correlation between different tests mainly depends on the different dimensions of sleepiness they analyse. Most importantly in-laboratory tests poorly correlate with sleepiness in real-life situations and, to date, none is able to predict the risk of injuries related to EDS, especially on an individual level. Conclusions There exists not the one best test to assess EDS, however, clinicians can choose a more specific test to address a specific diagnostic challenge on the individual level. The development of novel performance tests with low cost and easy to administer is advisable for both screening purposes and fitness for duty evaluations in populations at high risk of EDS-related injuries, for example professional drivers
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
Creutzfeldt-Jakob disease in a man surviving COVID-19. Disentangling a casual or causal association by neuropathology
No full textAbstract
Background Literature reporting the onset of Creutzfeldt-Jakob disease (CJD) immediately after COVID-19 infection has
strengthened a possible causal link between infection and neurodegeneration. Here, we report a novel case undergoing
detailed neuropathological assessment.
Case report Two months after he had contracted SARS-CoV-2 infection, a 54-year-old man manifested a subacute onset of ataxia, headache, anosmia, and hallucinations, followed by rapidly progressive cognitive decline.
Electroencephalography documented unspecific slowing with periodic polyphasic delta waves. Brain MRI showed
hyperintensities of basal ganglia and thalami on DWI/FLAIR. CSF tested positive for the 14-3-3 protein, and prion
seeding activity was demonstrated by the real-time quaking-induced conversion assay. The patient died 2 months
after the neurologic onset. The neuropathological examination confirmed the diagnosis of CJD and ruled out COVID19-related encephalitis.
Discussion To disentangle the link between COVID-19 infection and CJD, neuropathology is essential determining the
extent of changes related to both conditions. In our patient, we did not fnd any specifc abnormality related to COVID-19.
Our conclusion is in line with the current worldwide epidemiological data that do not show an increase in CJD cases since
the beginning of the COVID-19 pandemi
Immunotherapy of oneiric stupor in Morvan syndrome: Efficacy documented by actigraphy
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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
Cerebrospinal fluid biomarkers of neurodegeneration in narcolepsy type 1
Full text linkTo measure the levels of five neurodegenerative biomarkers in the cerebrospinal fluid (CSF) of patients with narcolepsy type 1 (NT1) with variable disease duration
Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings
Full text linkThe Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2)
Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
Full text linkCreutzfeldt-Jakob disease (CJD) is characterized by a broad phenotypic spectrum regarding symptoms, progression, and molecular features. Current sporadic CJD (sCJD) classification recognizes six main clinical-pathological phenotypes. This work investigates the molecular basis of the phenotypic heterogeneity of prion diseases through a multi-omics analysis of the two most common sCJD subtypes: MM1 and VV2. We performed DNA target sequencing on 118 genes on a cohort of 48 CJD patients and full exome RNA sequencing on post-mortem frontal cortex tissue on a subset of this cohort. DNA target sequencing identified multiple potential genetic contributors to the disease onset and phenotype, both in terms of coding, damaging-predicted variants, and enriched groups of SNPs in the whole cohort and the two subtypes. The results highlight a different functional impairment, with VV2 associated with higher impairment of the pathways related to dopamine secretion, regulation of calcium release and GABA signaling, showing some similarities with Parkinson’s disease both on a genomic and a transcriptomic level. MM1 showed a gene expression profile with several traits shared with different neurodegenerative, without an apparent distinctive characteristic or similarities with a specific disease. In addition, integrating genomic and transcriptomic data led to the discovery of several sites of ADAR-mediated RNA editing events, confirming and expanding previous findings in animal models. On the transcriptomic level, this work represents the first application of RNA sequencing on CJD human brain samples. Here, a good clusterization of the transcriptomic profiles of the two subtypes was achieved, together with the finding of several differently impaired pathways between the two subtypes. The results add to the understanding of the molecular features associated with sporadic CJD and its most common subtypes, revealing strain-specific genetic signatures and functional similarities between VV2 and Parkinson’s disease and providing preliminary evidence of RNA editing modifications in human sCJD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01483-9
Clinical Reasoning: Rapidly progressive dementia in a patient with HIV after an exotic journey
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