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Aims: In the search for blood‐based biomarkers of neurodegenerative diseases, we characterized the concentration of total prion protein (t‐PrP) in the plasma of neurodegenerative dementias. We aimed to assess its accuracy in this differential diagnostic context. Methods: Plasma t‐PrP was measured in 520 individuals including healthy controls (HC) and patients diagnosed with neurological disease control (ND), Alzheimer's disease (AD), sporadic Creutzfeldt‐Jakob disease (sCJD), frontotemporal dementia (FTD), Lewy body dementia (LBD) and vascular dementia (VaD). Additionally, t‐PrP was quantified in genetic prion diseases and iatrogenic CJD. The accuracy of t‐PrP discriminating the diagnostic groups was evaluated and correlated with demographic, genetic and clinical data in prion diseases. Markers of blood‐brain barrier impairment were investigated in sCJD brains. Results: Compared to HC and ND, elevated plasma t‐PrP concentrations were detected in sCJD, followed by FTD, AD, VaD and LBD. In sCJD, t‐PrP was associated neither with age nor sex, but with codon 129 PRNP genotype. Plasma t‐PrP concentrations correlated with cerebrospinal fluid (CSF) markers of neuro‐axonal damage, but not with CSF t‐PrP. In genetic prion diseases, plasma t‐PrP was elevated in all type of mutations investigated. In sCJD brain tissue, extravasation of immunoglobulin G and the presence of swollen astrocytic end‐feet around the vessels suggested leakage of blood‐brain barrier as a potential source of increased plasma t‐PrP. Conclusions: Plasma t‐PrP is elevated in prion diseases regardless of aetiology. This pilot study opens the possibility to consider plasma t‐PrP as a promising blood‐based biomarker in the diagnostic of prion disease. [ABSTRACT FROM AUTHOR]

Background: The shortage of available transplant organs has made it necessary to search for alternatives, one of which is xenotransplantation. However, the use of animal organs could face rejection from society and the personnel involved in its implementation., Objectives: (a) to analyze the attitudes of Veterinary Degree students in six Spanish Universities towards xenotransplantation; and (b) to determine the factors that affect its acceptance., Methods: Of the 2815 students surveyed in the degree program, 2683 valid surveys were obtained. Attitudes towards organ xenotransplantation were evaluated using a validated questionnaire of organ donation., Results: If xenotransplantation was confirmed as a clinical reality, 93% (n = 2493) of those surveyed would accept a xenotransplanted organ, whilst 7% would not. If the results of xenotransplantation were worse than those obtained with human donors and it entailed more risk, 12% (n = 318) would be in favor. 56% (n = 1497) of the students would accept a xenotransplantation provisionally pending the arrival of a human organ. Attitudes towards xenotransplantation were affected by the academic year in which a student was studying, with more favorable attitudes among students in the last year (88% in first year vs. 95% in fifth year; p < .001). More favorable attitudes are also observed depending on the attitude they have towards organ transplantation, with those students being more in favor of donating their organs when they die (94% vs. 88%; p < .001)., Conclusion: Veterinary students would have a very favorable attitude toward xenotransplantation if these animal organs functioned as well as human organs. Therefore, these students could play an important role in the future promotion of this technique., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biomarkers are becoming increasingly important for the differential diagnosis of neurodegenerative diseases. Previous observations indicated neurofilament light chain (NfL) as a potential blood-based biomarker for sporadic Creutzfeldt-Jakob disease (sCJD). Here, we investigated the stability, inter-assay/intra-assay variation and the regulation of NfL levels in CSF and plasma in a large cohort of sCJD patients by using a single-molecule array (SIMOA). We defined cutoffs for an accurate diagnosis and measured plasma NfL level in prion-infected mice models at different time points to identify the potential dynamics throughout the disease. Our analyses confirmed CSF and plasma NfL as stable and consistent marker for sCJD. Receiver operating characteristic (ROC) curve analysis showed an AUC of 0.92-0.93 to distinguish sCJD from control groups. Newly defined cutoffs revealed good diagnostic accuracies of CSF and plasma NfL, indicated by a sensitivity of 80-83.5% and a specificity of 87.4-91%. Studies on two humanized prion-infected mice lines (Tg340-PRNP 129MM and Tg361-PRNP 129VV) revealed increased plasma NfL levels in a late pre-clinical or very early clinical stage between 120-150 days post-inoculation. In conclusion, our work supports the potential use of CSF and plasma NfL as a very early biomarker in sCJD diagnostic with good diagnostic accuracies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Fatal familial insomnia is a rare hereditary prion disease associated with the D178N-129M PRNP mutation. Early diagnosis is difficult, because the clinical syndrome may overlap with affective disorders. In addition, most known cerebrospinal fluid biomarkers for prion diseases and magnetic resonance imaging do not show a good diagnostic accuracy for fatal familial insomnia. In this context, data on plasma biomarkers are scarce., Methods: We analyzed levels of neurofilament light chain, glial fibrillary acidic protein, chitinase-3-like protein 1, calcium-binding protein B, and total tau protein in six serial plasma samples from a patient with fatal familial insomnia. Subsequently, plasma neurofilament light chain was analyzed in n = 25 patients and n = 19 controls. The diagnostic accuracy and associations with disease stage and duration were explored., Results: Among all biomarker candidates in the case study, only neurofilament light chain levels showed a constant evolution and increased over time. They discriminated fatal familial insomnia from controls with an area under the curve of 0.992 (95% confidence interval [CI] = 0.974-1) in the case-control study. Higher concentrations were associated with methionine homozygosity at codon 129 PRNP (p = 0.006), shorter total disease duration (rho = -0.467, p = 0.019, 95% CI = -0.790 to -0.015), and shorter time from sampling to death (rho = -0.467, p = 0.019, 95% CI = -0.773 to -0.019)., Conclusions: Plasma neurofilament light chain may be a valuable minimally invasive diagnostic biomarker for fatal familial insomnia after clinical onset. Most important, stage-related increase and association with disease duration indicate potential as a prognostic marker and as a surrogate marker in clinical trials., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Biomarkers are increasingly recognized as tools in the diagnosis and prognosis of neurodegenerative diseases. No fluid biomarker for Parkinson’s disease (PD) has been established to date, but α-synuclein, a major component of Lewy bodies in PD and dementia with Lewy bodies (DLB), has become a promising candidate. Here, we investigated CSF α-synuclein in patients with PD (n = 28), PDD (n = 8), and DLB (n = 5), applying an electrochemiluminescence immunoassay. Median values were non-significantly (p = 0.430) higher in patients with PDD and DLB (287 pg/mL) than in PD (236 pg/mL). A group of n = 36 primarily non-demented patients with PD and PDD was clinically followed for up to two years. A higher baseline α-synuclein was associated with increases in Hoehn and Yahr classifications (p = 0.019) and Beck Depression Inventory scores (p < 0.001) as well as worse performance in Trail Making Test A (p = 0.017), Trail Making Test B (p = 0.043), and the Boston Naming Test (p = 0.002) at follow-up. Surprisingly, higher levels were associated with a better performance in semantic verbal fluency tests (p = 0.046). In summary, CSF α-synuclein may be a potential prognostic marker for disease progression, affective symptoms, and executive cognitive function in PD. Larger-scaled studies have to validate these findings and the discordant results for single cognitive tests in this exploratory investigation.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Lipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer's disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer's disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer's disease, differential diagnoses, other biomarkers, and clinical data., Methods: For this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer's disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer's disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28)., Results: Plasma Lipocalin-2 was significantly lower in Alzheimer's disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer's pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer's disease and healthy controls were 0.783 (95%CI: 0.712-0.855) in the study cohort and 0.766 (95%CI: 0.627-0.905) in the validation cohort. The area under the curve for Alzheimer's disease versus vascular dementia was 0.778 (95%CI: 0.667-0.890) in the study cohort. In Alzheimer's disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer's disease (p = 0.013)., Conclusions: Plasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer's disease and seems to be independent from currently employed biomarkers., (© 2022. The Author(s).)

Background: The cellular prion protein (PrP C ) is a membrane-bound, multifunctional protein mainly expressed in neuronal tissues. Recent studies indicate that the native trafficking of PrP C can be misused to internalize misfolded amyloid beta and α-synuclein (aSyn) oligomers., Objectives: We define PrP C 's role in internalizing misfolded aSyn in α-synucleinopathies and identify further involved proteins., Methods: We performed comprehensive behavioral studies on four transgenic mouse models (ThySyn and ThySynPrP00, TgM83 and TgMPrP00) at different ages. We developed PrP C -(over)-expressing cell models (cell line and primary cortical neurons), used confocal laser microscopy to perform colocalization studies, applied mass spectrometry to identify interactomes, and determined disassociation constants using surface plasmon resonance (SPR) spectroscopy., Results: Behavioral deficits (memory, anxiety, locomotion, etc.), reduced lifespans, and higher oligomeric aSyn levels were observed in PrP C -expressing mice (ThySyn and TgM83), but not in homologous Prnp ablated mice (ThySynPrP00 and TgMPrP00). PrP C colocalized with and facilitated aSyn (oligomeric and monomeric) internalization in our cell-based models. Glimepiride treatment of PrP C -overexpressing cells reduced aSyn internalization in a dose-dependent manner. SPR analysis showed that the binding affinity of PrP C to monomeric aSyn was lower than to oligomeric aSyn. Mass spectrometry-based proteomic studies identified clathrin in the immunoprecipitates of PrP C and aSyn. SPR was used to show that clathrin binds to recombinant PrP, but not aSyn. Experimental disruption of clathrin-coated vesicles significantly decreased aSyn internalization., Conclusion: PrP C 's native trafficking can be misused to internalize misfolded aSyn through a clathrin-based mechanism, which may facilitate the spreading of pathological aSyn. Disruption of aSyn-PrP C binding is, therefore, an appealing therapeutic target in α-synucleinopathies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)