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INTRODUCTION: We examined the relations of misfolded alpha synuclein (α‐synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER‐2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross‐sectional cerebrospinal fluid (CSF) α‐synuclein measurement from seed‐amplification assay as well as cross‐sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with α‐synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α‐synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α‐synuclein –negative participants in BioFINDER‐2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded α‐synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Highlights: Amyloid beta (Aβ), but not tau, was associated with alpha‐synuclein (α‐synuclein) positivity.Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status.α‐synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts. [ABSTRACT FROM AUTHOR]

The effect of preanalytical and analytical factors on the α-synuclein (α-syn) seed amplification assay's (SAA) performance has not been fully explored. Similarly, there is limited knowledge about the most suitable assay protocol and kinetic parameters for misfolded α-syn seed quantification. We studied the effect of centrifugation, repeated freeze-thaw cycles (up to seven), delayed freezing, detergent addition, and blood contamination on the performance of the cerebrospinal fluid (CSF) α-syn SAA real-time quaking-induced conversion (RT-QuIC). Moreover, we analysed the inter- and intra-plate variability, the recombinant protein batch effect, and the RT-QuIC parameters' variability when multiple samples were run in controlled conditions. Finally, we evaluated the assay potential of quantifying α-syn seed by assessing kinetic curves in serial CSF dilutions. Among tested preanalytical variables, a ≥0.01 % blood contamination and adding detergents significantly affected the RT-QuIC kinetic parameters and the number of positive replicates. Increasing the number of replicates improved result reproducibility. The number of positive replicates in serially diluted CSF samples improved discrimination between samples with high and low seeding activity, and the time to threshold (LAG) was the most reliable kinetic parameter in multiple experiment settings. Preanalytical variables affecting α-syn RT-QuIC performance are limited to blood contamination and detergent addition. The number of positive replicates and the LAG are the most reliable variables for quantifying α-syn seeding activity. Their consistent measurement in serial dilution experiments, especially when associated with an increased number of sample replicates, will help to develop the α-syn RT-QuIC assay further into a quantitative test. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients.CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers.Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants.LBP develops late in the disease course in ADAD.CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood‐based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. METHODS: We measured plasma brain‐derived tau (BD‐tau) and p‐tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt‐Jakob disease (CJD). RESULTS: Plasma BD‐tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p‐tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t‐tau with plasma BD‐tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p‐tau181 (r = 0.26, p = 0.04). The ratio BD‐tau/p‐tau181 performed equivalently to the CSF t‐tau/p‐tau181 ratio, differentiating AD from CJD (p < 0.0001). DISCUSSION: Plasma BD‐tau and p‐tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P‐tau significantly increased in AD but not in RPD. Plasma BD‐tau, like CSF t‐tau, increases according to neurodegeneration intensity. [ABSTRACT FROM AUTHOR]

In this report, we demonstrate that CD spectroscopy can be used as a tool to detect changes to DNA upon irradiation with UV light. We follow the spectroscopic response of DNA samples irradiated at selected exposure times with both CD and UV–Vis spectroscopy. We analyzed four different nucleic acids to evaluate the effect of the sequence on photodegradation. Only one polymer, calf thymus DNA, was a natural nucleic acid and contained all four nucleobases. The other three were synthetic polymers and contained only one type of base pair: poly (deoxyadenylic‐deoxythymidylic) acid [poly (dA‐dT)2] and poly (deoxyadenylic acid) · poly (deoxythymidylic acid) [poly (dA) · poly (dT)], which contained only adenine and thymine; poly (deoxyguanylic‐deoxycytidylic) acid [poly (dG‐dC)2], which contained only guanine and cytosine. CD and UV–Vis spectra showed sequence dependent changes. In particular, poly (dA) · poly (dT) undergoes changes more rapidly than the other sequences investigated. The CD spectrum of poly (dA) · poly (dT) gradually undergoes an inversion, suggesting a change in helicity, before disappearing due to the unfolding of the double strand. [ABSTRACT FROM AUTHOR]

Background: The introduction of the prion Real-Time Quaking-Induced Conversion assay (RT-QuIC) has led to a revision of the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD).Validation studies are needed for the amended criteria, especially for their diagnostic value in the clinical setting.Methods: We studied 1250 patients with suspected CJD referred for diagnosis to two Italian reference centres between 2010 and 2020. Focusing on the first diagnostic assessment, we compared the diagnostic value of the old and the amended criteria and that of different combinations of clinical variables and biomarker results.Results: The studied cohort comprised 850 participants with CJD (297 definite sCJD, 151 genetic CJD, 402 probable sCJD) and 400 with non-CJD (61 with neuropathology). At first clinical evaluation, the sensitivity of the old criteria (76.8%) was significantly lower than that of the amended criteria (97.8%) in the definite CJD cohort with no difference between definite and probable sCJD cases. Specificity was ~94% for both criteria against the non-CJD cohort (82.0% against definite non-CJD group). Cerebrospinal fluid (CSF) RT-QuIC was highly sensitive (93.9%) and fully specific against definite non-CJD patients. Limiting the criteria to a positive RT-QuIC or/and the combination of a clinical course compatible with possible CJD with a positive MRI (Q-CM criteria) provided higher diagnostic accuracy than both the old and amended criteria, overcoming the suboptimal specificity of ancillary test results (ie, CSF protein 14-3-3).Conclusions: CSF RT-QuIC is highly sensitive and specific for diagnosing CJD in vitam. The Q-CM criteria provide a high diagnostic value for CJD. [ABSTRACT FROM AUTHOR]