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Introduction: The current study examined the contributions of comprehensive neuropsychological assessment and volumetric assessment of selected mesial temporal subregions on structural magnetic resonance imaging (MRI) to identify patients with amnestic mild cognitive impairment (aMCI) and mild probable Alzheimer's disease (AD) dementia in a memory clinic cohort., Methods: Comprehensive neuropsychological assessment and automated entorhinal, transentorhinal, and hippocampal volume measurements were conducted in 40 healthy controls, 38 patients with subjective memory symptoms, 16 patients with aMCI, 16 patients with mild probable AD dementia. Multinomial logistic regression was used to compare the neuropsychological and MRI measures., Results: Combining the neuropsychological and MRI measures improved group membership prediction over the MRI measures alone but did not improve group membership prediction over the neuropsychological measures alone., Conclusion: Comprehensive neuropsychological assessment was an important tool to evaluate cognitive impairment. The mesial temporal volumetric MRI measures contributed no diagnostic value over and above the determinations made through neuropsychological assessment., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Aquatic invertebrates provide important ecosystem services, including decomposition and nutrient cycling, and provide nutrition for birds, fish, amphibians, and bats. Thus, the effects of agricultural land management practices on aquatic invertebrates are relevant to farmers, wildlife biologists, and policymakers. Here, we used data on aquatic invertebrates (159 taxa, 73 to species, 75 to genus/family) collected in 40 wetlands in the Canadian prairies to test for direct and indirect relationships among land management types (perennial cover, organic, minimum tillage, conventional), landscape structure (cropland and wetland cover within the surrounding landscape), and water quality (total nutrient levels, turbidity) on species richness of invertebrates using structural equation modelling. Additionally, we assessed variation in community composition within and among wetlands in different land use management types using a direct gradient analysis and variance partitioning. The direct effects of land management type were not supported but we found strong supportive evidence that effects of land management on richness were significantly mediated through cropland cover, nutrient levels, and turbidity. After controlling for these indirect effects, aquatic invertebrate richness decreased along a gradient from the lowest to the highest farming intensity, i.e., richness decreased from perennial cover sites to organic to minimum tillage to conventional sites. Support was also found for negative effects of nutrient levels and turbidity on richness. We did not find significant support for differences in gamma diversity or a simple test (homogeneity of multivariate dispersions) of differences in turnover among land management types; however, land management had a significant effect in distance-based redundancy analysis. Taken together, these results suggest that focusing conservation efforts on reducing cropland erosion and nutrient inputs to wetlands and creating more permanent cover may be effective strategies for conserving richness of aquatic invertebrates in agricultural landscapes in this region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kirk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most suspected Creutzfeldt-Jakob disease (CJD) cases are eventually diagnosed with other disorders. We assessed the utility of investigating Alzheimer's disease (AD) biomarkers and neurofilament light (NfL) in patients when CJD is suspected. The study cohort consisted of cerebrospinal fluid (CSF) samples referred for CJD biomarker screening wherein amyloid beta 1-42 (Aβ1-42), phosphorylated tau 181 (p-tau181), and total tau (t-tau) could be assessed via Elecsys immunoassays ( n  = 419) and NfL via enzyme-linked immunosorbent assay (ELISA; n  = 161). In the non-CJD sub cohort ( n  = 371), 59% (219/371) had A+T- (abnormal Aβ1-42 only) and 21% (79/371) returned A+T+ (abnormal Aβ1-42 and p-tau181). In the 48 CJD subjects, a similar AD biomarker profile distribution was observed. To partially address the prevalence of likely pre-symptomatic AD, NfL was utilized to assess for neuronal damage. NfL was abnormal in 76% (25/33) of A+T- subjects 40 to 69 years of age, 80% (20/25) of whom had normal t-tau. This study reinforces AD as an important differential diagnosis of suspected CJD, highlighting that incorporating AD biomarkers and NfL at initial testing is worthwhile., Competing Interests: The authors of no conflicts of interest to report., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The current study compared the reliability of manual collateral sulcus depth and entorhinal and transentorhinal cortical volume measurements between native oriented MRI scans versus MRI scans realigned to the hippocampal long axis. Data included 10 participants with two serial 3.0T MRI scans from the Alzheimer's Disease Neuroimaging Initiative. Both collateral sulcus depth and entorhinal and transentorhinal cortical volume measurement reliability improved from the native to the hippocampal oriented scans. Standardizing scan orientation is important to optimize reliability of MRI-derived manual measurements of the entorhinal and transentorhinal cortices. In quantitative MRI studies, aligning scans to a common, normalized orientation is recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The current study aimed to validate entorhinal and transentorhinal cortical volumes measured by the automated segmentation tool Automatic Segmentation of Hippocampal Subfields (ASHS-T1). The study sample comprised 34 healthy controls (HCs), 37 individuals with amnestic mild cognitive impairment (aMCI), and 29 individuals with Alzheimer's disease (AD) dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Entorhinal and transentorhinal cortical volumes were assessed using ASHS-T1, manual segmentation, as well as a widely used automated segmentation tool, FreeSurfer v6.0.1. Mean differences, intraclass correlation coefficients, and Bland-Altman plots were computed. ASHS-T1 tended to underestimate entorhinal and transentorhinal cortical volumes relative to manual segmentation and FreeSurfer. There was variable consistency and low agreement between ASHS-T1 and manual segmentation volumes. There was low-to-moderate consistency and low agreement between ASHS-T1 and FreeSurfer volumes. There was a trend toward higher consistency and agreement for the entorhinal cortex in the aMCI and AD groups compared to the HC group. Despite the differences in volume measurements, ASHS-T1 was sensitive to entorhinal and transentorhinal cortical atrophy in both early and late disease stages. Based on the current study, ASHS-T1 appears to be a promising tool for automated entorhinal and transentorhinal cortical volume measurement in individuals with likely underlying AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs., Methods: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age., Results: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY., Conclusion: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity., (© 2022 Royal Australasian College of Physicians.)

Creutzfeldt-Jakob Disease Surveillance in Australia: Update to 31 December 2022: Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2022. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022., (© Commonwealth of Australia CC BY-NC-ND.)

Fibrosis-driven solid organ failure is a major world-wide health burden with few therapeutic options. Spiny mice (genus: Acomys) are terrestrial mammals that regenerate severe skin wounds without fibrotic scars to evade predators. Recent studies have shown that spiny mice also regenerate acute ischemic and traumatic injuries to kidney, heart, spinal cord, and skeletal muscle. A common feature of this evolved wound healing response is a lack of formation of fibrotic scar tissue that degrades organ function, inhibits regeneration, and leads to organ failure. Complex tissue regeneration is an extremely rare property among mammalian species. In this article, we discuss the evidence that Acomys represents an emerging model organism that offers a unique opportunity for the biomedical community to investigate and clinically translate molecular mechanisms of scarless wound healing and regeneration of organ function in a mammalian species., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Prion diseases are pathogenically linked to the normal cellular prion protein (PrP C ) misfolding into abnormal conformers (PrP Sc ), with PrP Sc accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletely resolved, including the level of pathophysiological overlap between neurotoxic and transmitting species of PrP Sc and the temporal profiles of their propagation. To further investigate the likely time of occurrence of significant levels of neurotoxic species during prion disease development, the well characterised in vivo M1000 murine model was employed. Following intracerebral inoculation, detailed serial cognitive and ethological testing at specified time points suggested subtle transition to early symptomatic disease from ∼50% of the overall disease course. In addition to observing a chronological order for impaired behaviours, different behavioural tests also showed distinctive profiles of evolving cognitive impairments with the Barnes maze demonstrating a relatively simple linear worsening of spatial learning and memory over an extended period while in contrast a conditioned fear memory paradigm previously untested in murine prion disease demonstrated more complex alterations during disease progression. These observations support the likely production of neurotoxic PrPSc from at least just prior to the mid-point of murine M1000 prion disease and illustrate the likely need to tailor the types of behavioural testing across the time course of disease progression for optimal detection of cognitive deficits., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The most frequently utilized biomarkers to support a pre-mortem clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) include concentrations of the 14-3-3 and total tau (T-tau) proteins, as well as the application of protein amplification techniques, such as the real time quaking-induced conversion (RT-QuIC) assay, in cerebrospinal fluid (CSF). Utilizing CSF from a cohort of neuropathologically confirmed (definite) sCJD ( n = 50) and non-CJD controls ( n = 48), we established the optimal cutpoints for the fully automated Roche Elecsys ® immunoassay for T-tau and the CircuLexTM 14-3-3 Gamma ELISA and compared these to T-tau protein measured using a commercially available assay (INNOTEST hTAU Ag) and 14-3-3 protein detection by western immunoblot (WB). These CSF specimens were also assessed for presence of misfolded prion protein using the RT-QuIC assay. T-tau showed similar diagnostic performance irrespective of the assay utilized, with ~90% sensitivity and specificity. The 14-3-3 protein detection by western blot (WB) has 87.5% sensitivity and 66.7% specificity. The 14-3-3 ELISA demonstrated 81.3% sensitivity and 84.4% specificity. RT-QuIC was the single best performing assay, with a sensitivity of 92.7% and 100% specificity. Our study indicates that a combination of all three CSF biomarkers increases sensitivity and offers the best chance of case detection pre-mortem. Only a single sCJD case in our cohort was negative across the three biomarkers, emphasizing the value of autopsy brain examination on all suspected CJD cases to ensure maximal case ascertainment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Senesi, Lewis, Varghese, Stehmann, McGlade, Doecke, Ellett, Sarros, Fowler, Masters, Li and Collins.)

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver and key therapeutic target for human cancers. Current therapies targeting HER2 are primarily based on overexpression of the wild-type form of HER2. However, kinase domain mutations have been identified that can increase the activity of HER2 even when expressed at basal levels. Using purified enzymes, we confirmed the hyperactivity of two HER2 mutants (D769Y and P780insGSP). To identify small molecule inhibitors against these cancer-associated variants, we used a combined approach consisting of biochemical testing, similarity-based searching, and in silico modeling. These approaches resulted in the identification of a candidate molecule that inhibits mutant forms of HER2 in vitro and in cell-based assays. Our structural model predicts that the compound takes advantage of water-mediated interactions in the HER2 kinase binding pocket., (© 2022 John Wiley & Sons Ltd.)

Agriculture is one of the largest threats to global biodiversity. However, most studies have focused only on the direct effects of agriculture on biodiversity, and few have addressed the indirect effects, potentially over or under-estimating the overall impacts of agriculture on biodiversity. The indirect effect is the response not to the agricultural cover types or operations per se , but instead, to the way that agriculture influences the extent and configuration of different types of natural land cover in the landscape. We used structural equation modelling (SEM) to evaluate the direct, indirect, and total effects of agriculture on species richness of three bird guilds: forest birds, shrub-edge birds, and open country birds. We found that forest bird richness was driven by the negative indirect effect of cropland via forest loss. Shrub-edge and open country bird richness increased with the amount of agriculture land covers; however, importantly, we found negative indirect effects of agriculture on both guilds via a reduction in more natural land covers. This latter result highlights how we would have over-estimated the positive effects of agriculture on shrub-edge and open country bird richness had we not measured both direct and indirect effects (i.e., the total effect size is less than the direct effect size). Overall, our results suggest that a bird-friendly agricultural landscape in our region would have forest that is configured to maximize forest edge, and a high proportion of perennial forage within the agricultural portion of the landscape., Supplementary Information: The online version contains supplementary material available at 10.1007/s10531-023-02559-1., Competing Interests: Competing InterestsThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: In Alzheimer's disease (AD), plasma amyloid beta (Aβ) 1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown., Methods: Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study., Results: The p-tau181/Aβ 1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ 1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ 1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes ( P < 0.0001)., Discussion: Plasma p-tau181/Aβ 1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials., Competing Interests: Eugeen Vanmechelen is cofounder and shareholder of ADx NeuroSciences. Erik Stoops is employee and shareholder of ADx NeuroSciences. Jeroen Vanbrabant, Nele Dewit, and Kimberley Mauroo are employees of ADx NeuroSciences. Paul Maruff is a full‐time employee of Cogstate Ltd. Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie; he is on the scientific advisory board for Cerveau Technologies; and consulted for Prothena, Eisai, Roche, and Biogen Australia. The other authors did not report any conflict of interest. Author disclosures are available in the supporting information, (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Automated magnetic resonance imaging (MRI) volumetry is a promising tool to evaluate regional brain volumes in dementia and especially Alzheimer's disease (AD)., Purpose: To compare automated methods and the gold standard manual segmentation in measuring regional brain volumes on MRI across healthy controls, patients with mild cognitive impairment, and patients with dementia due to AD., Study Type: Systematic review and meta-analysis., Data Sources: MEDLINE, Embase, and PsycINFO were searched through October 2021., Field Strength: 1.0 T, 1.5 T, or 3.0 T., Assessment: Two review authors independently identified studies for inclusion and extracted data. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2)., Statistical Tests: Standardized mean differences (SMD; Hedges' g) were pooled using random-effects meta-analysis with robust variance estimation. Subgroup analyses were undertaken to explore potential sources of heterogeneity. Sensitivity analyses were conducted to examine the impact of the within-study correlation between effect estimates on the meta-analysis results., Results: Seventeen studies provided sufficient data to evaluate the hippocampus, lateral ventricles, and parahippocampal gyrus. The pooled SMD for the hippocampus, lateral ventricles, and parahippocampal gyrus were 0.22 (95% CI -0.50 to 0.93), 0.12 (95% CI -0.13 to 0.37), and -0.48 (95% CI -1.37 to 0.41), respectively. For the hippocampal data, subgroup analyses suggested that the pooled SMD was invariant across clinical diagnosis and field strength. Subgroup analyses could not be conducted on the lateral ventricles data and the parahippocampal gyrus data due to insufficient data. The results were robust to the selected within-study correlation value., Data Conclusion: While automated methods are generally comparable to manual segmentation for measuring hippocampal, lateral ventricle, and parahippocampal gyrus volumes, wide 95% CIs and large heterogeneity suggest that there is substantial uncontrolled variance. Thus, automated methods may be used to measure these regions in patients with AD but should be used with caution., Evidence Level: 3 TECHNICAL EFFICACY: Stage 3., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: A diagnosis of variant Creutzfeldt-Jakob disease (vCJD), the zoonotic prion disease related to transmission of bovine spongiform encephalopathy, can carry enormous public health ramifications. Until recently, all vCJD clinical cases were confined to patients displaying methionine homozygosity (MM) at codon 129 of the prion protein gene ( PRNP ). The recent diagnosis of vCJD in a patient heterozygous (MV) at codon 129 reignited concerns regarding a second wave of vCJD cases, with the possibility of phenotypic divergence from MM vCJD and greater overlap with sporadic CJD (sCJD) molecular subtypes., Method and Results: We present a case of CJD with clinico-epidemiological and radiological characteristics creating initial concerns for vCJD. Thorough case evaluation, including data provided by genetic testing, autopsy and neuropathological histological analyses, provided a definitive diagnosis of the rare VV1 molecular subtype of sCJD., Conclusion: Distinguishing vCJD from sCJD is of vital public health importance and potentially more problematic with the development of non-MM vCJD cases. The patient described herein demonstrates that in addition to the clinico-epidemiological profile, combined supplementary pathological, biochemical and critical radiological analysis may be necessary for confident discrimination of sCJD, especially rare sub-types, from vCJD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Determining disease severity and predicting prognosis in younger onset-dementia (YOD) remains challenging. Whether CSF biomarkers neurofilament light (NfL), tau and amyloidβ 42 (Aβ42) can help provide such information has been underexplored., Methods: Patients with YOD and CSF analysis were identified. We compared baseline NfL, tau and Aβ42 concentrations with contemporaneous Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG) scores to assess their association with severity of cognitive impairment. Cognitive decline, as measured by longitudinal NUCOG assessment, was correlated against baseline biomarker levels to assess their utility in predicting the rate of cognitive decline., Results: 78 patients with YOD (mean age = 56 years, SD = 8) and CSF analysis were identified. Dementia types included Alzheimer's disease, behavioural variant frontotemporal dementia, dementia not-otherwise-specified and other. Tau was associated with contemporaneous memory dysfunction (r = -0.556, 95% CI:[-0.702,-0.393], p < .001). 21 patients had longitudinal cognitive assessment up to 82 months from CSF sampling. NfL was associated with the rate of executive function decline (r = 0.755, 95% CI:[0.259,0.937], p < .001). Aβ42 was associated with the rate of memory decline (r = -0.582, 95% CI:[-0.855,-0.274], p = .007) and rate of total NUCOG decline (r = -0.515, 95% CI: [-0.809, -0.227], p = .017)., Conclusion: CSF tau is related to contemporaneous memory impairment in YOD. NfL and Aβ42 levels are associated with the rate of executive function and memory decline, respectively, and may have a role in prognostication in YOD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice ( Acomys ) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)