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Despite a high rate of concurrent mathematical difficulties among children with dyslexia, we still have limited information regarding the prevalence and severity of mathematical deficits in this population. To address this gap, we developed a comprehensive battery of cognitive tests, known as the UCSF Mathematical Cognition Battery (MCB), with the aim of identifying deficits in four distinct mathematical domains: number processing, arithmetical procedures, arithmetic facts retrieval, and geometrical abilities. The mathematical abilities of a cohort of 75 children referred to the UCSF Dyslexia Center with a diagnosis of dyslexia, along with 18 typically developing controls aged 7 to 16, were initially evaluated using a behavioral neurology approach. A team of professional clinicians classified the 75 children with dyslexia into five groups, based on parents and teachers reported symptoms and clinical history. These groups included children with no mathematical deficits and children with mathematical deficits in number processing, arithmetical procedures, arithmetic facts retrieval, or geometrical abilities. Subsequently, the children underwent evaluation using the MCB to determine concordance with the clinicians impressions. Additionally, neuropsychological and cognitive standardized tests were administered. Our study reveals that within a cohort of children with dyslexia, 66% exhibit mathematical deficits, and among those with mathematical deficits, there is heterogeneity in the nature of these deficits. If these findings are confirmed in larger samples, they can potentially pave the way for new diagnostic approaches, consistent subtype classification, and, ultimately personalized interventions.

Primary progressive aphasia (PPA) is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic (lvPPA), associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic (svPPA), associated with semantic deficits and anterior temporal lobe (ATL) atrophy; non-fluent (nfvPPA) associated with grammar and/or speech-motor deficits and inferior frontal gyrus (IFG) atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of "not-a-verb" responses and the highest number of semantically related nouns (production of baseball instead of throw to noun ball); in contrast, svPPA patients produced the highest percentage of "unrelated verb" responses and the highest number of light verbs (production of take instead of throw to noun ball). Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language.

Abstract The Irpinia Fault, also known as the Monte Marzano Fault System, located in the Southern Apennines (Italy), is one of the most seismically active structures in the Mediterranean. It is the source of the 1980, Ms 6.9, multi-segment rupture earthquake that caused significant damage and nearly 3,000 casualties. Paleoseismological surveys indicate that this structure has generated at least four Mw ~ 7 surface-rupturing earthquakes in the past 2 ka. This paper presents a comprehensive, high-resolution geophysical investigation focused on the southernmost fault segment of the Monte Marzano Fault System, i.e., the Pantano-Ripa Rossa Fault, outcropping within the Pantano di San Gregorio Magno intramontane basin. The project, named TEst Site IRpinia fAult (TESIRA), was supported by the University of Napoli Federico II to study the near-surface structure of this intra-basin fault splay that repeatedly ruptured co-seismically in the past thousands of years. Our imaging approach included 2D and 3D electrical and seismic surveys, gravimetry, 3D FullWaver electrical tomography, drone-borne GPR and magnetic surveys, and CO2 soil flux assessment across the surface rupture. This multidisciplinary investigation improved our understanding of the basin shallow structure, providing an image of a rather complex subsurface fault and basin geometry. Seismic data suggest that fault activity at the Pantano segment of MMFS is characterized by a near-surface cumulative displacement greater than previous estimations, calling into question earlier assumptions about the timing of its activation. Despite some challenges with our drone-mounted survey equipment, the integrated dataset provides a comprehensive and reliable image of the subsurface structure. This work demonstrates the utility of developing an integrated approach at high-resolution geophysical imaging and interpretation of fault zones with weak morphological expressions.

Motivation Pangenomes provide novel insights for population and quantitative genetics, genomics and breeding not available from studying a single reference genome. Instead, a species is better represented by a pangenome or collection of genomes. Unfortunately, managing and using pangenomes for genomically diverse species is computationally and practically challenging. We developed a trellis graph representation anchored to the reference genome that represents most pangenomes well and can be used to impute complete genomes from low density sequence or variant data. Results The Practical Haplotype Graph (PHG) is a pangenome pipeline, database (PostGRES & SQLite), data model (Java, Kotlin or R) and Breeding API (BrAPI) web service. The PHG has already been able to accurately represent diversity in four major crops including maize, one of the most genomically diverse species, with up to 1000-fold data compression. Using simulated data, we show that, at even 0.1× coverage, with appropriate reads and sequence alignment, imputation results in extremely accurate haplotype reconstruction. The PHG is a platform and environment for the understanding and application of genomic diversity. Availability and implementation All resources listed here are freely available. The PHG Docker used to generate the simulation results is https://hub.docker.com/ as maizegenetics/phg:0.0.27. PHG source code is at https://bitbucket.org/bucklerlab/practicalhaplotypegraph/src/master/. The code used for the analysis of simulated data is at https://bitbucket.org/bucklerlab/phg-manuscript/src/master/. The PHG database of NAM parent haplotypes is in the CyVerse data store (https://de.cyverse.org/de/) and named/iplant/home/shared/panzea/panGenome/PHG_db_maize/phg_v5Assemblies_20200608.db. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Whereas science fiction has no identity, no necessary conditions, no essence, and no timeless and universal attributes, we should not be able to recognize it. We do. Something must allow it. This article will show how recognition and learning outweigh contingent feature-based academic projects on science fiction as ends, thereby revealing the socio-cognitive frames that buttress such recognition and proposes that we consider semio-cognitive models to refine our understanding of the genre. To that end, this article shows how science fiction is a creative mode recognizable by its prototypes and the theories built thereon. Ultimately, this article promotes a means-based socio-cognitive understanding of science fiction where it is free, in a new way, from retrospective academic projects to define it by ends.

Introducción: La humanidad esta incrementado su esperanza de vida de manera manifiesta: 30 años desde 1950. Lo anterior implica un incremento notorio de los adultos mayores. Indagar acerca del bienestar de tal población se convierte en una necesidad mundial. En Colombia se espera que en la década del 2020 al 2030 se doble el número de adultos mayores, y desafortunadamente no en las mejores condiciones socioeconómicas. Por lo anterior se hace necesario promover investigaciones sobre los adultos mayores, extendiendo el rango más allá de lo biológico y abordando aspectos psicosociales en particular relacionados con el bienestar. Esta investigación eso pretende Objetivos: Estimar la relación entre la percepción de felicidad y los apoyos familiares, sociales e individuales de una población de adultos mayores en Bogotá, Colombia. Materiales y métodos: Tipo de estudio descriptivo de corte transversal. Población: 3.166 adultos de 60 o más años encuestados en Bogotá entre 2012 y 2018. Variables: Se aplicó encuesta autodiligenciada, se escogieron las variables ¿En el momento actual usted se siente? Feliz, normal o triste versus “sociodemográficas, estructura y función familiar, apoyos a través de ¿Cuándo tiene problemas sabe que puede contar? (casi siempre, a veces y casi nunca) de miembros familiares, apoyos sociales, y apoyos propios. Resultados: El 60% (n 1891) se sienten felices, y 12% (n 379) tristes. El 38% (n=1199) viven en hogares nucleares y 18% (n 76%) viven solos. El 76% (n= 1860) perciben una buena función familiar y 3% (n 260) perciben una disfunción familiar severa). La función familiar resulto ser la relación más poderosa (Buena función familiar severa versus disfunción familiar severa con OR de 15 (IC 95% 9,8-23,7). Un profesor como apoyo mostró OR de 4,7 (IC 95% 1,8-12,4), mama con OR 3,5 (IC 95% 1,5-8,6), organizaciones comunitarias OR 2,3 (IC 95% 1,3-4,1), hogar nuclear OR 2 (IC 95% 1,4-2,9). Conclusión: La buena función familiar es la relación más poderosa relacionada con la felicidad y relacionarse con un profesor aparece de forma prometedora.

A correction for the article "The phantom chorus: birdsong boosts human well-being in protected areas", is presented, which is published in the December 16, 2020, issue of the periodical.

State of the Art: Semantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition., Methodology: We selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery - Recognition, Naming, Semantic associations - pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task's performance were conducted with a Voxel-based morphometry approach using CAT12., Results: svPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces' recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with grey matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS)., Conclusion: Our results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Developments in mRNA/lipid nanoparticle (LNP) technology have advanced the fields of vaccinology and gene therapy, raising questions about immunogenicity. While some mRNA/LNPs generate an adjuvant-like environment in muscle tissue, other mRNA/LNPs are distinct in their capacity for multiple rounds of therapeutic delivery. We evaluate the adjuvancy of components of mRNA/LNPs by phenotyping cellular infiltrate at injection sites, tracking uptake by immune cells, and assessing the inflammatory state. Delivery of 9 common, but chemically distinct, LNPs to muscle revealed two classes of inflammatory gene expression programs: inflammatory (Class A) and noninflammatory (Class B). We find that intramuscular injection with Class A, but not Class B, empty LNPs (eLNPs) induce robust neutrophil infiltration into muscle within 2 h and a diverse myeloid population within 24 h. Single-cell RNA sequencing revealed SM-102-mediated expression of inflammatory chemokines by myeloid infiltrates within muscle 1 day after injection. Surprisingly, we found direct transfection of muscle infiltrating myeloid cells and splenocytes 24 h after intramuscular mRNA/LNP administration. Transfected myeloid cells within the muscle exhibit an activated phenotype 24 h after injection. Similarly, directly transfected splenic lymphocytes and dendritic cells (DCs) are differentially activated by Class A or Class B containing mRNA/LNP. Within the splenic DC compartment, type II conventional DCs (cDC2s) are directly transfected and activated by Class A mRNA/LNP. Together, we show that mRNA and LNPs work synergistically to provide the necessary innate immune stimuli required for effective vaccination. Importantly, this work provides a design framework for vaccines and therapeutics alike.

Cross-linguistic studies with healthy individuals are vital, as they can reveal typologically common and different patterns while providing tailored benchmarks for patient studies. Nevertheless, cross-linguistic differences in narrative speech production, particularly among speakers of languages belonging to distinct language families, have been inadequately investigated. Using a picture description task, we analyze cross-linguistic variations in connected speech production across three linguistically diverse groups of cognitively normal participants-English, Chinese (Mandarin and Cantonese), and Italian speakers. We extracted 28 linguistic features, encompassing phonological, lexico-semantic, morpho-syntactic, and discourse/pragmatic domains. We utilized a semi-automated approach with Computerized Language ANalysis (CLAN) to compare the frequency of production of various linguistic features across the three language groups. Our findings revealed distinct proportional differences in linguistic feature usage among English, Chinese, and Italian speakers. Specifically, we found a reduced production of prepositions, conjunctions, and pronouns, and increased adverb use in the Chinese-speakers compared to the other two languages. Furthermore, English participants produced a higher proportion of prepositions, while Italian speakers produced significantly more conjunctions and empty pauses than the other groups. These findings demonstrate that the frequency of specific linguistic phenomena varies across languages, even when using the same harmonized task. This underscores the critical need to develop linguistically tailored language assessment tools and to identify speech markers that are appropriate for aphasia patients across different languages., Competing Interests: Competing interests: None

Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors., (© 2024. The Author(s).)

Background and Objectives: Within frontotemporal dementia (FTD), the behavioral variant (bvFTD) characterized by frontal atrophy, and semantic behavioral variant (sbvFTD) characterized by right anterior temporal lobe (rATL) atrophy, present diagnostic challenges due to overlapping symptoms and neuroanatomy. Accurate differentiation is crucial for clinical trial inclusion targeting TDP-43 proteinopathies. This study investigated whether automated speech analysis can distinguish between FTD-related rATL and frontal atrophy, potentially offering a non-invasive diagnostic tool., Methods: In a cross-sectional design, we included 40 participants with FTD-related predominant frontal atrophy (n=16) or predominant rATL atrophy (n=24) and 22 healthy controls from the UCSF Memory and Aging Center. Using stepwise logistic regression and receiver operating characteristic (ROC) curve analysis, we analyzed 16 linguistic and acoustic features that were extracted automatically from audio-recorded picture description tasks. Neuroimaging data were analyzed using voxel-based morphometry to examine brain-behavior relationships of regional atrophy with the features selected in the regression models., Results: Logistic regression identified three features (content units, lexical frequency, familiarity) differentiating the overall FTD group from controls (AUC=.973), adjusted for age. Within the FTD group, five features (adpositions/total words ratio, arousal, syllable pause duration, restarts, words containing 'thing') differentiated frontal from rATL atrophy (AUC=.943). Neuroimaging analyses showed that semantic features (lexical frequency, content units, 'thing' words) were linked to bilateral inferior temporal lobe structures, speech and lexical features (syllable pause duration, adpositions/total words ratio) to bilateral inferior frontal gyri, and socio-emotional features (arousal) to areas known to mediate social cognition including the right insula and bilateral anterior temporal structures. As a composite score, this set of five features was uniquely associated with rATL atrophy., Discussion: Automated speech analysis effectively distinguished the overall FTD group from controls and differentiated between frontal and rATL atrophy. The neuroimaging findings for individual features highlight the neural basis of language impairments in these FTD variants, and when considered together, underscore the importance of utilizing features' combined power to identify impaired language patterns. Automated speech analysis could enhance early diagnosis and monitoring of FTD, offering a scalable, non-invasive alternative to traditional methods, particularly in resource-limited settings. Further research should aim to integrate automated speech analysis into multi-modal diagnostic frameworks.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11 C-labelled Pittsburgh Compound B-PET and structural MRI. 18 F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB 50-70 cerebellar grey reference and FDG 30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18 F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18 F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18 F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease., Competing Interests: Y.L., E.T., B.G., and G.W. report no conflict of interest relevant to this manuscript. J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415, SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC; Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Carlos Cruchaga, PhD, receives research support from Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is a member of the advisory board of Vivid Genetics, Halia Therapeutics and Adx Healthcare. G.S.D.’s research is supported by NIH (K23AG064029, U01AG057195 and U19AG032438), the Alzheimer’s Association and the Chan Zuckerberg Initiative. He serves as a consultant for Parabon NanoLabs, Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the clinical director of the Anti-NMDA Receptor Encephalitis Foundation, Inc. (Canada; uncompensated). He is the co-project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc., and Continuing Education, Inc. He owns stock in ANI Pharmaceuticals. R.J.B., MD, is the director and principal investigator of the DIAN and DIAN-TU-001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman-La Roche, Ltd. and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech, United Neuroscience. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). He has been an invited speaker and consultant for AC Immune, F. Hoffman La Roche, Ltd. and Janssen and a consultant for Amgen and Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01 AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE HealthCare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE HealthCare, Roche, Johnson & Johnson and Merck. He serves as an associate editor for JAMA Neurology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Morphosyntactic assessments are important for characterizing individuals with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA). Yet, standard tests are subject to examiner bias and often fail to differentiate between nfvPPA and logopenic variant PPA (lvPPA). Moreover, relevant neural signatures remain underexplored. Here, we leverage natural language processing tools to automatically capture morphosyntactic disturbances and their neuroanatomical correlates in 35 individuals with nfvPPA relative to 10 healthy controls (HC) and 26 individuals with lvPPA. Participants described a picture, and ensuing transcripts were analyzed via part-of-speech tagging to extract sentence-related features (e.g., subordinating and coordinating conjunctions), verbal-related features (e.g., tense markers), and nominal-related features (e.g., subjective and possessive pronouns). Gradient boosting machines were used to classify between groups using all features. We identified the most discriminant morphosyntactic marker via a feature importance algorithm and examined its neural correlates via voxel-based morphometry. Individuals with nfvPPA produced fewer morphosyntactic elements than the other two groups. Such features robustly discriminated them from both individuals with lvPPA and HCs with an AUC of .95 and .82, respectively. The most discriminatory feature corresponded to subordinating conjunctions was correlated with cortical atrophy within the left posterior inferior frontal gyrus across groups (p FWE  < .05). Automated morphosyntactic analysis can efficiently differentiate nfvPPA from lvPPA. Also, the most sensitive morphosyntactic markers correlate with a core atrophy region of nfvPPA. Our approach, thus, can contribute to a key challenge in PPA diagnosis., Competing Interests: Declaration of competing interest The authors report no disclosures relevant to the manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses., (© 2024. The Author(s).)

Background: Dementia care is challenging due to the divergent trajectories in disease progression and outcomes. Predictive models are needed to flag patients at risk of near-term mortality and identify factors contributing to mortality risk across different dementia types., Methods: Here, we developed machine-learning models predicting dementia patient mortality at four different survival thresholds using a dataset of 45,275 unique participants and 163,782 visit records from the U.S. National Alzheimer's Coordinating Center (NACC). We built multi-factorial XGBoost models using a small set of mortality predictors and conducted stratified analyses with dementiatype-specific models., Results: Our models achieved an area under the receiver operating characteristic curve (AUC-ROC) of over 0.82 utilizing nine parsimonious features for all 1-, 3-, 5-, and 10-year thresholds. The trained models mainly consisted of dementia-related predictors such as specific neuropsychological tests and were minimally affected by other age-related causes of death, e.g., stroke and cardiovascular conditions. Notably, stratified analyses revealed shared and distinct predictors of mortality across eight dementia types. Unsupervised clustering of mortality predictors grouped vascular dementia with depression and Lewy body dementia with frontotemporal lobar dementia., Conclusions: This study demonstrates the feasibility of flagging dementia patients at risk of mortality for personalized clinical management. Parsimonious machine-learning models can be used to predict dementia patient mortality with a limited set of clinical features, and dementiatype-specific models can be applied to heterogeneous dementia patient populations., (© 2024. The Author(s).)

Tau PET has enabled the visualization of paired helical filaments of 3 or 4 C-terminal repeat tau in Alzheimer disease (AD), but its ability to detect aggregated tau in frontotemporal lobar degeneration (FTLD) spectrum disorders is uncertain. We investigated 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3-b:4,5c']dipyridine ([ 18 F]PI-2620), a newer tracer with ex vivo evidence for binding to FTLD tau, in a convenience sample of patients with suspected FTLD and AD using a static acquisition protocol and parametric SUV ratio (SUVr) images. Methods: We analyzed [ 18 F]PI-2620 PET data from 65 patients with clinical diagnoses associated with AD or FTLD neuropathology; most (60/65) also had amyloid-β (Aβ) PET. Scans were acquired 30-60 min after injection; SUVr maps (reference, inferior cerebellar cortex) were created for the full acquisition and for 10-min truncated sliding windows (30-40, 35-45,…50-60 min). Age- and sex-adjusted z score maps were computed for each patient, relative to 23 Aβ-negative cognitively healthy controls (HC). Mean SUVr in the globus pallidus, substantia nigra, subthalamic nuclei, dentate nuclei, white matter, and temporal gray matter was extracted for the full and truncated windows. Results: Patients with suspected AD neuropathology (Aβ-positive patients with mild cognitive impairment or AD dementia) showed high-intensity temporoparietal cortex-predominant [ 18 F]PI-2620 binding. At the group level, patients with clinical diagnoses associated with FTLD (progressive supranuclear palsy with Richardson syndrome [PSP Richardson syndrome], corticobasal syndrome, and nonfluent-variant primary progressive aphasia) exhibited higher globus pallidus SUVr than did HCs; pallidal retention was highest in the PSP Richardson syndrome group, in whom SUVr was correlated with symptom severity (ρ = 0.53, P = 0.05). At the individual level, only half of PSP Richardson syndrome, corticobasal syndrome, and nonfluent-variant primary progressive aphasia patients had a pallidal SUVr above that of HCs. Temporal SUVr discriminated AD patients from HCs with high accuracy (area under the receiver operating characteristic curve, 0.94 [95% CI, 0.83-1.00]) for all time windows, whereas discrimination between patients with PSP Richardson syndrome and HCs using pallidal SUVr was fair regardless of time window (area under the receiver operating characteristic curve, 0.77 [95% CI, 0.61-0.92] at 30-40 min vs. 0.81 [95% CI, 0.66-0.96] at 50-60 min; P = 0.67). Conclusion: [ 18 F]PI-2620 SUVr shows an intense and consistent signal in AD but lower-intensity, heterogeneous, and rapidly decreasing binding in patients with suspected FTLD. Further work is needed to delineate the substrate of [ 18 F]PI-2620 binding and the usefulness of [ 18 F]PI2620 SUVr quantification outside the AD continuum., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t -tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline ( P = 0.006) and 46.1% versus 25.4% at last visit ( P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency ( P < 0.001), Trail Making Test Part B ( P < 0.001) and digit span ( P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points ( P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels ( P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design., Competing Interests: J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415 and SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. A.M.F., PhD, is the Biomarker Core Leader of the DIAN-TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC, Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. A.J.A., PhD, has served as a consultant for Biogen Inc and H. Lundbeck HS. J.H., PhD, is a paid consultant for F. Hoffmann-La Roche, Ltd., Takeda, and Lundbeck and is on the Data Safety and Monitoring Board for Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01-AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE Healthcare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE Healthcare, Roche, Johnson & Johnson and Merck. He serves as associate editor for JAMA Neurology. All other authors report no conflict of interest relevant to this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The accurate visualization and assessment of the complex cardiac and pulmonary structures in 3D is critical for the diagnosis and treatment of cardiovascular and respiratory disorders. Conventional 3D cardiac magnetic resonance imaging (MRI) techniques suffer from long acquisition times, motion artifacts, and limited spatiotemporal resolution. This study proposes a novel time-resolved 3D cardiopulmonary MRI reconstruction method based on spatial transformer networks (STNs) to reconstruct the 3D cardiopulmonary MRI acquired using 3D center-out radial ultra-short echo time (UTE) sequences. The proposed reconstruction method employed an STN-based deep learning framework, which used a combination of data-processing, grid generator, and sampler. The reconstructed 3D images were compared against the start-of-the-art time-resolved reconstruction method. The results showed that the proposed time-resolved 3D cardiopulmonary MRI reconstruction using STNs offers a robust and efficient approach to obtain high-quality images. This method effectively overcomes the limitations of conventional 3D cardiac MRI techniques and has the potential to improve the diagnosis and treatment planning of cardiopulmonary disorders.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The ability to identify and track T-cell receptor (TCR) sequences from patient samples is becoming central to the field of cancer research and immunotherapy. Tracking genetically engineered T cells expressing TCRs that target specific tumor antigens is important to determine the persistence of these cells and quantify tumor responses. The available high-throughput method to profile TCR repertoires is generally referred to as TCR sequencing (TCR-Seq). However, the available TCR-Seq data are limited compared with RNA sequencing (RNA-Seq). In this paper, we have benchmarked the ability of RNA-Seq-based methods to profile TCR repertoires by examining 19 bulk RNA-Seq samples across 4 cancer cohorts including both T-cell-rich and T-cell-poor tissue types. We have performed a comprehensive evaluation of the existing RNA-Seq-based repertoire profiling methods using targeted TCR-Seq as the gold standard. We also highlighted scenarios under which the RNA-Seq approach is suitable and can provide comparable accuracy to the TCR-Seq approach. Our results show that RNA-Seq-based methods are able to effectively capture the clonotypes and estimate the diversity of TCR repertoires, as well as provide relative frequencies of clonotypes in T-cell-rich tissues and low-diversity repertoires. However, RNA-Seq-based TCR profiling methods have limited power in T-cell-poor tissues, especially in highly diverse repertoires of T-cell-poor tissues. The results of our benchmarking provide an additional appealing argument to incorporate RNA-Seq into the immune repertoire screening of cancer patients as it offers broader knowledge into the transcriptomic changes that exceed the limited information provided by TCR-Seq., (Published by Oxford University Press 2023.)

The domestication of forest trees for a more sustainable fiber bioeconomy has long been hindered by the complexity and plasticity of lignin, a biopolymer in wood that is recalcitrant to chemical and enzymatic degradation. Here, we show that multiplex CRISPR editing enables precise woody feedstock design for combinatorial improvement of lignin composition and wood properties. By assessing every possible combination of 69,123 multigenic editing strategies for 21 lignin biosynthesis genes, we deduced seven different genome editing strategies targeting the concurrent alteration of up to six genes and produced 174 edited poplar variants. CRISPR editing increased the wood carbohydrate-to-lignin ratio up to 228% that of wild type, leading to more-efficient fiber pulping. The edited wood alleviates a major fiber-production bottleneck regardless of changes in tree growth rate and could bring unprecedented operational efficiencies, bioeconomic opportunities, and environmental benefits.

Purpose: To investigate motion compensated, self-supervised, model based deep learning (MBDL) as a method to reconstruct free breathing, 3D pulmonary UTE acquisitions., Theory and Methods: A self-supervised eXtra dimension MBDL architecture (XD-MBDL) was developed that combined respiratory states to reconstruct a single high-quality 3D image. Non-rigid motion fields were incorporated into this architecture by estimating motion fields from a lower resolution motion resolved (XD-GRASP) reconstruction. Motion compensated XD-MBDL was evaluated on lung UTE datasets with and without contrast and compared to constrained reconstructions and variants of self-supervised MBDL that do not account for dynamic respiratory states or leverage motion correction., Results: Images reconstructed using XD-MBDL demonstrate improved image quality as measured by apparent SNR (aSNR), contrast to noise ratio (CNR), and visual assessment relative to self-supervised MBDL approaches that do not account for dynamic respiratory states, XD-GRASP and a recently proposed motion compensated iterative reconstruction strategy (iMoCo). Additionally, XD-MBDL reduced reconstruction time relative to both XD-GRASP and iMoCo., Conclusion: A method was developed to allow self-supervised MBDL to combine multiple respiratory states to reconstruct a single image. This method was combined with graphics processing unit (GPU)-based image registration to further improve reconstruction quality. This approach showed promising results reconstructing a user-selected respiratory phase from free breathing 3D pulmonary UTE acquisitions., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective . Model based deep learning (MBDL) has been challenging to apply to the reconstruction of 3D non-Cartesian MRI due to GPU memory demand because the entire volume is needed for data-consistency steps embedded in the model. This requirement makes holding even a single unroll in GPU memory difficult meaning memory efficient techniques used to increase unroll number like gradient checkpointing and deep equilibrium learning will not work well for high spatial resolution 3D non-Cartesian reconstructions without modification. Here we develop a memory efficient method called block-wise learning that combines gradient checkpointing with patch-wise training to overcome this obstacle and allow for fast and high-quality 3D non-Cartesian reconstructions using MBDL. Approach . Block-wise learning applied to a single unroll decomposes the input volume into smaller patches, gradient checkpoints each patch, passes each patch iteratively through a neural network regularizer, and then rebuilds the full volume from these output patches for data-consistency. This method is applied across unrolls during training. Block-wise learning significantly reduces memory requirements by tying GPU memory for a single unroll to user selected patch size instead of the full volume. This algorithm was used to train a MBDL architecture to reconstruct highly undersampled, 1.25 mm isotropic, pulmonary magnetic resonance angiography volumes with matrix sizes varying from 300-450 × 200-300 × 300-450 on a single GPU. We compared block-wise learning reconstructions against L1 wavelet compressed reconstructions and proxy ground truth images. Main results . MBDL with block-wise learning significantly improved image quality relative to L1 wavelet compressed sensing while simultaneously reducing average reconstruction time 38x. Significance . Block-wise learning allows for MBDL to be applied to high spatial resolution, 3D non-Cartesian datasets with improved image quality and significant reductions in reconstruction time relative to traditional iterative methods., (Creative Commons Attribution license.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and difficult to treat cancers with tumors typically exhibiting high levels of chronic hypoxia. Hypoxia activates hypoxia-inducible factors (HIFs) that mediate cellular responses to adapt to low oxygen environments. Hypoxia also causes endoplasmic reticulum (ER) stress, increasing activating transcription factor 4 (ATF4), a master regulator of the unfolded protein response (UPR) pathway that mediates cellular response to ER stress. ATF4 is overexpressed in PDAC and is associated with poor prognoses. While ATF4 promotes cell proliferation and tumorigenesis, most studies have been conducted under normoxia or acute hypoxia. The functions of ATF4 in chronic hypoxia remain largely unexplored. Using siRNA knockdown experiments of healthy skin fibroblast cells WS1 and PDAC cell lines PANC-1 and Mia-PaCa2 to analyze mRNA and protein expression levels, a novel ATF4 function was identified, in which it decreases HIF2α mRNA and increases HIF1α mRNA in chronic hypoxia while having no effect in acute hypoxia. A scratch assay was used to show that ATF4 decreases cell migration in chronic hypoxia as opposed to the increase in cell migration ATF4 imparts in acute hypoxia. Colony formation assay and cell viability assay showed that ATF4 promotes colony formation and cell viability in both chronic and acute hypoxia. In addition to the differential response of ATF4 in chronic hypoxia compared with acute hypoxia, this is the first time ATF4 has been implicated in regulation of response to hypoxia via interaction with HIF proteins in PDAC.

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neurovascular 4D-Flow MRI has emerged as a powerful tool for comprehensive cerebrovascular hemodynamic characterization. Clinical studies in at risk populations such as aging adults indicate hemodynamic markers can be confounded by motion-induced bias. This study develops and characterizes a high fidelity 3D self-navigation approach for retrospective rigid motion correction of neurovascular 4D-Flow data. A 3D radial trajectory with pseudorandom ordering was combined with a multi-resolution low rank regularization approach to enable high spatiotemporal resolution self-navigators from extremely undersampled data. Phantom and volunteer experiments were performed at 3.0T to evaluate the ability to correct for different amounts of induced motions. In addition, the approach was applied to clinical-research exams from ongoing aging studies to characterize performance in the clinical setting. Simulations, phantom and volunteer experiments with motion correction produced images with increased vessel conspicuity, reduced image blurring, and decreased variability in quantitative measures. Clinical exams revealed significant changes in hemodynamic parameters including blood flow rates, flow pulsatility index, and lumen areas after motion correction in probed cerebral arteries (Flow: P<0.001 Lt ICA, P=0.002 Rt ICA, P=0.004 Lt MCA, P=0.004 Rt MCA; Area: P<0.001 Lt ICA, P<0.001 Rt ICA, P=0.004 Lt MCA, P=0.004 Rt MCA; flow pulsatility index: P=0.042 Rt ICA, P=0.002 Lt MCA). Motion induced bias can lead to significant overestimation of hemodynamic markers in cerebral arteries. The proposed method reduces measurement bias from rigid motion in neurovascular 4D-Flow MRI in challenging populations such as aging adults., Competing Interests: Declaration of Competing Interest S.C. Johnson serves on an advisory board for Roche Diagnostics for which he receives an honorarium and is principal investigator of an equipment grant from Roche. He receives research funding from Cerveau Technologies, (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Pollinators at high elevations face multiple threats from climate change including heat stress, failure to phenological match advancing flower resources and competitive pressure from range-expanding species of lower elevations. We conducted long-term multi-site surveys of alpine bumble bees to determine how phenology of range-stable and range-expanding species is responding to climate change. We ask whether bumble bee responses generate mismatches with floral resources, and whether these mismatches in turn promote community disruption and potential species replacement. In alpine environments of the central Rocky Mountains, range-stable and range-expanding bumble bees exhibit phenological mismatches with flowering host plants due to earlier flowering of preferred resources under warmer spring temperatures. However, workers of range-stable species are more canalised in their foraging schedules, exploiting a relatively narrow portion of the flowering season. Specifically, range-stable species show less variance in phenology in response to temporally and spatially changing conditions than range-expanding ones. Because flowering duration drives the seasonal abundance of floral resources at the landscape scale, we hypothesize that canalisation of phenology in alpine bumble bees could reduce their access to earlier or later season flowers. Warmer conditions are decreasing abundances of range-stable alpine bumble bees above the timberline, increasing abundance of range-expanding species, and facilitating a novel and more species-diverse bumble bee community. However, this trend is not explained by greater phenological mismatch of range-stable bees. Results suggest that conversion of historic habitats for cold-adapted alpine bumble bee species into refugia for more heat-tolerant congeners is disrupting bumble bee communities at high elevations, though the precise mechanisms accounting for these changes are not yet known. If warming continues, we predict that the transient increase in diversity due to colonization by historically low-elevation species will likely give way to declines of alpine bumble bees in the central Rocky Mountains., (© 2022 John Wiley & Sons Ltd.)

Objective. The aim of this mixed-methods study was to examine the effect of disabled backward navigation on computerized calculation examinations in multiple courses. Methods. Student performance on comprehensive pharmacy calculation examinations before and after implementation of disabled backward navigation were compared. Deidentified data from ExamSoft were used to determine median examination scores, passing rates, and time to completion for all three attempts given on comprehensive calculation exams held in a pharmacy calculations course (PharDSci 504) and in three applied patient care laboratory courses (Pharm 531, 541, and 551). An anonymous, voluntary student survey gathered student perceptions of disabled backward navigation. Qualitative data were evaluated for thematic findings. Results. The impact of disabled backward navigation on test scores and passing rates varied by course and test attempt. Students in Pharm 541 and 551 performed significantly worse on the initial test attempt after backward navigation was disabled compared to the previous year, with no significant differences in student performance seen on the retakes. Performance in PharDSci 504 and Pharm 531 followed the opposite pattern, with no significant difference in performance for the initial tests but significantly increased performance on the retakes. The amount of time spent on examinations either significantly decreased or remained the same. Student perceptions were generally consistent across all cohorts, with at least 74% agreeing that disabling backward navigation increased examination difficulty. Conclusion. Disabling backward navigation had a mixed effect on student examination performance. This may highlight how student behaviors change as backward navigation is disabled., (© 2022 American Association of Colleges of Pharmacy.)

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.