An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

INTRODUCTION: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time. METHODS: Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Cardicola beveridgei n. sp. (Digenea: Aporocotylidae) from the mangrove jack, Lutjanus argentimaculatus (Perciformes: Lutjanidae), and C. bullardi n. sp. from the Australian spotted mackerel, Scomberomorus munroi (Perciformes: Scombridae), from the northern Great Barrier Reef

Cardicola Short, 1953 is a genus of the Aporocotylidae Odhner, 1912 (Digenea), with 25 currently recognised species described from 32 species of Perciformes and Mugiliformes fishes around the world, including eight species from the Great Barrier Reef. Here, we describe two new species from this region, namely Cardicola beveridgei n. sp. from the ventricle and atrium of the mangrove jack, Lutjanus argentimaculatus (Forsskål) (Perciformes: Lutjanidae), and Cardicola bullardi n. sp. from the ventricle of the Australian spotted mackerel, Scomberomorus munroi Collette & Russo (Perciformes: Scombridae), from off Lizard Island, Queensland, Australia. These two new species are most easily distinguished from the 25 current members of Cardicola in having the combination of i) a spinous oral sucker, ii) an anteriorly intercaecal ovary, iii) a uterus that extends anteriorly from the oötype, iv) the number of spines per ventrolateral transverse row, and in v) body size and the length/width ratio, vi) the oesophagus and caecal length(s) relative to body total length, vii) the length of the posterior caeca relative to the anterior pair, viii) the testis length/width ratio and its total size relative to that of the body, ix) the postovarian field as a percentage of body length, and x) egg size. In addition, C. beveridgei n. sp. is further differentiated by possessing a female genital pore that opens anterodextral to the male pore while C. bullardi n. sp. differs further in possessing a testis that is almost entirely intercaecal and does not extend anteriorly to the level of the intestinal bifurcation. Employing genetic analysis of ITS2 rDNA sequence data, representing these species and a further 13 recognised and three putative species of Cardicola, we were able to unequivocally confirm these specimens as distinct (9–22% different over 420 nucleotide positions). Distance analysis of ITS2 showed that i) species of Cardicola from the Siganidae formed a monophyletic clade, to the exclusion of other Cardicola species reported from the Scombridae, Sparidae, Lutjanidae and Chaetodontidae, ii) a general phylogenetic isolation exists between the species of Cardicola reported from scombrid fishes, and iii) C. beveridgei n. sp. and Cardicola milleri Nolan & Cribb, 2006 from lutjanids and Cardicola chaetodontis Yamaguti, 1970 from chaetodontids are phylogenetically close, despite the evolutionary remoteness between the host groups and their highly disparate biology. Given the likelihood of many additional species being attributed to Cardicola, we predict that continued molecular analyses will indicate that this genus will prove to incorporate a series of radiations in association with particular fish taxa as well as evidence of host-switching. (Nucleotide sequences reported in this paper are available in the GenBank database under accession no. KF752497)

Dynamic cerebral autoregulation reproducibility is affected by physiological variability

Parameters describing dynamic cerebral autoregulation (DCA) have limited reproducibility. 59 In an international, multi-centre study, we evaluated the influence of multiple analytical 60 methods on the reproducibility of DCA. Fourteen participating centers analyzed repeated 61 measurements from 75 healthy subjects, consisting of five minutes of spontaneous 62 fluctuations in blood pressure (BP) and cerebral blood flow velocity (CBFv) signals, based on 63 their usual methods of analysis. DCA- methods were grouped into three broad categories, 64 depending on output types: 1. Transfer function analysis (TFA); 2. Autoregulation index 65 (ARI); and 3. correlation coefficient. Only TFA gain in the low frequency (LF) band showed 66 good reproducibility in approximately half of the estimates of gain, defined as an intraclass 67 correlation coefficient (ICC) of > 0.6. None of the other DCA metrics had good 68 reproducibility. For TFA-like and ARI-like methods, ICCs were lower than values obtained 69 with surrogate data (p<0.05). For TFA-like methods, ICCs were lower for the very low 70 frequency (VLF) band (gain 0.38 ± 0.057, phase 0.17 ± 0.13) than for LF band (gain 0.59 ± 71 0.078, phase 0.39 ± 0.11, p≤0.001 for both gain and phase). For ARI-like methods, the mean 72 ICC was 0.30 ± 0.12 and for the correlation methods 0.24 ± 0.23. Based on comparisons with 73 ICC estimates obtained from surrogate data, we conclude that physiological variability or 74 non-stationarity is likely to be the main reason for the poor reproducibility of DCA 75 parameters