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Mobulid rays are medium‐ to large‐sized pelagic‐dwelling planktivorous elasmobranchs that are circumglobally distributed. Brazil has a high diversity of Mobula species, with five of the nine globally valid species and one additional putative new species.Brazil represents a substantial knowledge gap concerning the ecology, distribution and threats to mobulid rays. In global distribution analyses, several species have been underrepresented along the Brazilian coast.The dataset is composed of information from peer‐reviewed and grey literature, as well as data from scientific expeditions, citizen science collaboration, social media and local news.We found 6,450 records of manta and devil rays along the Brazilian coast, including Mobula tarapacana, Mobula mobular, Mobula thurstoni, Mobula hypostoma, Mobula birostris and the putative new species (Mobula cf. birostris).Our results revealed alarmingly high captures, such as 4.5 tons of M. hypostoma in a single fishery cruise and 809 individuals of Mobula spp. from a single fleet during one year in the Southeastern region.These findings evidence the fisheries' threats to mobulid species in Brazil and highlight previously unnoted species records, such as the occurrence of M. hypostoma on the entire Brazilian continental shelf, including estuaries and M. tarapacana in coastal regions.Integrative information on the occurrence, distribution, and threats to mobulid rays on local and global scales is crucial to supporting strategies for their effective management and conservation. [ABSTRACT FROM AUTHOR]

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid‐β plasma biomarker positivity was approximately half the rate in 300 non‐MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid‐β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453–459 [ABSTRACT FROM AUTHOR]

Objective: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). Methods: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross‐sectional data from the amyloid PET positive and negative groups. Results: The amyloid PET positive sub‐cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub‐cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15–19 years before estimated symptom onset for CSF Aβ42/Aβ40, plasma Aβ42/Aβ40, CSF pT217/T217, and amyloid PET; 12–14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP‐25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7–9 years before estimated symptom onset for CSF pT205/T205, CSF YKL‐40, hippocampal volumes, and cognitive measures. Interpretation: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951–965 [ABSTRACT FROM AUTHOR]

Background: Balancing the need to standardize cognitive measures with the need to evolve alongside advances in scientific knowledge is an inherent challenge for longitudinal studies of Alzheimer disease (AD). The Uniform Data Set (UDS) offers a solution for this in cognitive batteries and is implemented across Alzheimer Disease Research Centers (ADRCs). Using equipercentile equating, we combined data spanning two versions of the UDS and derived domain‐specific and general cognitive composites. We compared the relationships of these measures with common biomarkers of AD, as well as their statistical power to detect cognitive change in clinical trials. Method: Using longitudinal data from the Knight ADRC, domain‐specific cognitive composites were created using an exploratory factor analysis. The resulting four factors clustered episodic memory, semantic memory, working memory, and attention/processing speed tasks (Figure 1). We also computed a commonly‐used preclinical Alzheimer cognitive composite (PACC), an alternative Knight‐ADRC‐PACC, which did not include MMSE, and a global composite. Relationships between each cognitive composite and neuroimaging metrics of amyloid, tau, atrophy, and clinical symptoms, were compared cross‐sectionally and longitudinally (Figure 2). We also performed power analyses of all composites to calculate necessary sample sizes to observe a medium‐sized effect in a four‐year clinical trial. Result: Overall, general metrics of cognition slightly outperformed domain‐specific composites, although the working memory composite consistently reflected a poor relationship with AD biomarkers (Figure 2). Power analyses revealed that the global, Knight‐ADRC‐PACC, and attention/processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the ADCS‐PACC, required two to three times as many individuals (Figure 3). Conclusion: We found that data‐driven, domain‐specific, composites of cognitive performance can complement already‐established general cognitive composites, with the possible exception of the present working memory composite. In line with prior work, we highlight that attention and processing speed may be sensitive metrics of cognitive change in AD. The inclusion of the MMSE, such as in the ADCS‐PACC, may greatly reduce the sensitivity and statistical power of summary cognitive composites. Our results have important implications for the development of cognitive outcome metrics for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Triplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer's disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology. Method: Cross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of.001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired. Result: Significant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold.05) and right (threshold.005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of.772 and.830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of.786 for left (threshold.0005) and.770 for right (threshold.0005) hemispheres. Conclusion: CT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment. 1. Dincer (2020). NeuroImage: Clinical, 28, 102491. 2. Su (2019). Alzheimer's Dement, 11, 180‐190. [ABSTRACT FROM AUTHOR]

Background: Midlife obesity, as evidenced by high body mass index (BMI), is increasingly understood as a risk factor for development of Alzheimer's disease. Importantly, visceral fat, by producing adipokines, contributes to inflammation as well as insulin resistance, mechanisms involved in development of Alzheimer's disease. Herein, we aimed to assess association of white matter microstructure, measured by Diffusion tensor imaging (DTI), with obesity and abdominal adipose tissue composition at midlife. Method: A total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI. Insulin resistance status was assessed using Homeostatic Model Assessment for Insulin Resistance. Abdominal visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa) and VAT/SAT ratio was calculated. A diffusion spectrum imaging scheme with a total of 98 diffusion samplings and a voxel size of 2 mm was acquired. Using DSI studio (https://dsi‐studio.labsolver.org/), the diffusion data were reconstructed using generalized q‐sampling imaging and the tensor metrics were calculated. Fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, RD, respectively) for white matter tracts were compared across study groups using one‐way ANOVA. Multiple regression models with sex, age, and education as covariates were used to assess the association of BMI, VAT/SAT ratio, and HOMA‐IR with DTI metrics. Result: Our data showed that BMI was negatively associated with AD values in right inferior fronto‐occipital fasciculus, tapetum and forceps major of Corpus Callosum (CC), superior and middle cerebellar peduncle, and bilateral reticular tract. The negative association of BMI with AD values in tapetum of CC was significant only in women. Right reticular tract MD and superior cerebellar peduncle MD and RD values were also significantly associated with BMI. There were no significant associations between neither of diffusion metrics and VAT/SAT ratio or HOMA‐IR. Conclusion: Association of midlife obesity with lower axonal diffusivity, reflective of lower white matter integrity, with differential patterns in men and women especially in CC, is in line with previous findings in healthy individuals. Reduced axonal diffusivity in reticular and brain stem pathways could be indicative of early dysregulations observed in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Estimates of "brain‐predicted age" quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression. Method: We used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐β‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education. Result: DBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3). Conclusion: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation. [ABSTRACT FROM AUTHOR]

Background: Disease‐modifying therapies for Alzheimer's Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort. Method: Participants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI. Result: Our results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2). Conclusion: Our results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker. [ABSTRACT FROM AUTHOR]

Background: Staging Alzheimer's disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF) biomarkers. Method: We created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm in 426 participants covering the whole AD spectrum (Table 1) by evaluating CSF Ab42/40 and 5 CSF tau markers: the proportion of tau phosphorylated at three threonine residues (pT205/T205, pT217/T217, and pT231/T231), and the concentrations of microtubule‐binding region of tau at residue 243 [MTBR‐tau243] and total‐tau [mid‐domain containing T212‐221]). We investigated associations between CSF stages and cross‐sectional and longitudinal changes in amyloid and tau pathologies, neurodegeneration and cognition using linear regression models. ROC curves were used to identify the optimal stage for predicting positivity in imaging biomarkers and to separate AD vs non‐AD cognitive symptoms. We also tested the relative risk of progression from cognitively unimpaired or MCI to AD‐type dementia using Kaplan‐Meier curves and Cox‐proportional Hazard models. Creation of the model and cross‐sectional analyses were replicated in an independent cohort (n = 222, Table 1). Result: SuStaIn revealed that only one subtype was present and that five CSF biomarkers (ordered: Ab42/40, pT217/T217, pT205/T205, MTBR‐tau243, T212‐221) were sufficient to create an accurate disease staging model (Fig.1A‐B). Increasing stages (0‐5) were associated with increased abnormality in other AD‐related biomarkers (Fig.1C). In both cohorts, stage ≥2 accurately predicted amyloid‐PET positivity (AUC≥0.89), stage ≥4 predicted tau‐PET (AUC≥0.94) and neurodegeneration positivity (AUC≥0.81). In the main cohort, stage≥2 separated non‐AD from AD‐related cognitive impairment (AUC = 0.96). Longitudinal changes for several AD‐biomarkers by stages are presented in (Fig.2A). Higher stages (4‐5) at baseline were associated with higher hazard ratios (HR) of progressing to AD‐type dementia (CU&MCI: HR = 4.6[2.0,10.9], MCI: HR = 3.5[1.5,8.1], Fig.2B‐C). Conclusion: Our results suggest that the AD continuum can be accurately staged with a single CSF sample, which may be useful in the clinical setting for patient management but also as a tool in clinical trials for selection and monitoring of study participants. [ABSTRACT FROM AUTHOR]

Background: Resting‐state functional connectivity (RSFC) provides estimates of brain networks using fMRI. There are conflicting reports regarding the effects of amyloid‐ß (Aß) and tau on RSFC networks in cognitively normal participants. These inconsistencies might be explained by a recently‐proposed theoretical model that Aß and tau have an interactive effect on RSFC, marked first by hyper‐connectivity in association with Aß, then by hypo‐connectivity in association with tau. Although there is preliminary support for this model, independent validations and further characterizations of the effects of Aß and tau on RSFC are needed. Method: We analyzed RSFC, Aß PET, and tau PET data from the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal (Clinical Dementia Rating®: 0). RSFC was collected on two scanners in partly‐overlapping samples (PETMR N: 190, TRIO N: 149). RSFC data were processed with framewise censoring and global signal regression. RSFC networks were defined using 298 regions of interest. Aß was measured with PET PiB and AV‐45 tracers, which were harmonized using a Centiloid conversion. Tau was measured with a PET AV‐1451 tracer and was summarized in pre‐defined regions. Main effect and interaction relationships between Aß, tau PET, and RSFC were tested with linear regression models, controlling for age, sex, education, and head motion as covariates, with a false discovery rate correction. Result: We did not observe a bidirectional interaction effect in any of the hypothesized networks (default mode [DMN], salience [SAL], frontoparietal [FPN]). Aß was positively associated with RSFC, independent of tau, in the DMN and SAL, while tau was negatively associated with RSFC, independent of Aß, in the SAL only. Exploratory analyses of FC within and between all networks did not identify clear patterns of interactive biomarker effects, nor consistent patterns of main effect relationships within any of the other networks. Conclusion: These results do not support an interactive model of RSFC in preclinical AD. Inconsistencies with previous interactions may be driven by sample‐specific or methodological differences, or the low reliability of FC and brain‐behavior relationships. Prominent biomarker relationships in the DMN and SAL are consistent with regional overlap with Aß deposition in early AD. [ABSTRACT FROM AUTHOR]

According to Lima-Nascimento & al. (2019) and Zappi & al. (2011), 20 of those cacti species are endangered and 9 are critically endangered due to habitat fragmentation or the specific relationship between species and their habitats (Goettsch & al., 2015). In this work, the chromosome numbers of one species belonging to the genus I Malvastrum i , seven species from the genus I Sida i and two species from the genus I Sidastrum i were analyzed. Recordings of those chromosome numbers confirm the importance of polyploidy and dysploidy events in the chromosome evolution of the genus based on I x i = 7 and I x i = 8 as the suggested numbers of chromosomes for the genus (Aguilar & al., 2003). Chromosome numbers for I Anthurium i and I Philodendron i spp. (Araceae) occurring in Bahia, Brazil. Thus, chromosome counts of 18 BS cacti species are presented in Table 1. 1 Table Chromosome data of the studied Cactaceae species. [Extracted from the article]

The regenerative capacity of corneal endothelial cells (CECs) differs between species; in bigger mammals, CECs are arrested in a non‐proliferative state. Damage to these cells can compromise their function causing corneal opacity. Corneal transplantation is the current treatment for the recovery of clear eyesight, but the donor tissue demand is higher than the availability and there is a need to develop novel treatments. Interestingly, rabbit CECs retain a high proliferative profile and can repopulate the endothelium. There is a lack of fundamental knowledge to explain these differences. Gaining information on their transcriptomic variances could allow the identification of CEC proliferation drivers. In this study, human, sheep, and rabbit CECs are analyzed at the transcriptomic level. To understand the differences across each species, a pipeline for the analysis of pathways with different activities is generated. The results reveal that 52 pathways have different activity when comparing species with non‐proliferative CECs (human and sheep) to species with proliferative CECs (rabbit). The results show that Notch and TGF‐β pathways have increased activity in species with non‐proliferative CECs, which might be associated with their low proliferation. Overall, this study illustrates transcriptomic pathway‐level differences that can provide leads to develop novel therapies to regenerate the corneal endothelium. [ABSTRACT FROM AUTHOR]

This article, titled "The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart defects: a systematic review and meta-analysis," aims to determine the additional diagnostic value of prenatal exome sequencing (pES) compared to standard testing for fetuses with congenital heart defects (CHD). The study reviewed the literature from January 2010 to February 2023 and identified 1957 cases. The results showed that pES provided an increased diagnostic yield for all CHD, isolated CHD, and CHD associated with extracardiac malformations (ECMs) of 17.4%, 9.3%, and 35.9% respectively. The most common anomalies in fetuses with ECMs were gastrointestinal, central nervous system, and neck/skin anomalies. The study also identified the most common genetic syndrome and mode of inheritance. The authors concluded that the likelihood of a monogenic cause for CHD with extracardiac anomalies is high, but clinicians should consider the clinical utility of offering pES in selected cases. [Extracted from the article]

Background: The balance between production, clearance, and toxicity of Ab peptides is central to AD pathobiology. Though highly variable in terms of age of symptom onset (AAO), hundreds of pathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of AD (ADAD). PSEN1 forms the catalytic core of the γ‐secretase complex and thereby directly mediates the production of longer, aggregation‐prone Aβ peptides relative to shorter, non‐aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation‐specific differences in γ‐secretase function, as measured by a ratio of production of shorter vs. longer Aβ species. Methods: Aβ‐37, 38, 40, 42, and 43 production was quantified from 162 unique PSEN1 variants expressed in HEK293 cells engineered to lack endogenous wild‐type PSEN1/2 (Figure 1). Prediction of AAO was carried out in 107 PSEN1 variants (characterized by Liu et al, 2022) and then replicated with a set 55 unique PSEN1 variants represented in the Dominantly Inherited Alzheimer Network (DIAN; n = 190 corresponding variant carriers with detailed cognitive and biomarker data; Figure 2). Results: Mutation‐level variations in Aβ production, including a novel composite representing γ‐secretase function (lower score = less g‐processivity), from the cellular model were highly predictive of actual AAO across the 162 mutants examined (Non‐DIAN variants [N = 107]: r = 0.71, p <2.2e‐16; DIAN variants [N = 55]: r = 0.61, p = 6.10e‐07). Our cell‐based γ‐secretase function composite was strongly associated with cerebral PiB‐PET β‐amyloid burden (B[SE] = ‐0.03[0.01], p = 4.06e‐07), MRI gray matter volume (B[SE] = 44.22[6.4], p = 5.15e‐01), cerebrospinal fluid Aβ42/40 (B[SE] = 6.3e‐04[1.5e‐04], p = 4.46e‐05) and phosphorylated tau‐217 (B[SE] = ‐0.01[0.002], p = 1.98e‐05), Clinical Dementia Rating®‐ Sum of Boxes (B[SE] = ‐0.07[0.02], p = 4.86e‐05), and Mini‐Mental State Exam (B[SE] = 0.11[.03], p = 2.17e‐04). Conclusions: Biochemical variations in γ‐secretase function across PSEN1 pathogenic variants broadly predicted the cross‐sectional clinical, cognitive, and biomarker course of ADAD, including AAO. These findings elucidate the critical link between γ‐secretase function, Aβ production, and severity of AD. The novel approach designed here also represents a tool to account for heterogeneity in ADAD clinical trials and to assess the pathogenicity of PSEN1 variants of unknown significance or with limited family history. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden. Method: CSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1). Result: Combining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids). Conclusion: CSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures. [ABSTRACT FROM AUTHOR]

Background: Obesity and adiposity at midlife, evidenced by high body mass index (BMI), are increasingly understood as a risk factor for Alzheimer's disease (AD). Importantly, visceral fat is known to be associated with insulin resistance and proinflammatory state, the mechanisms involved in AD pathology. Herein, we aimed to assess the association between brain MRI volumes as well as amyloid and tau uptake with obesity, insulin resistance, and abdominal adipose tissue in cognitively normal midlife population. Method: A total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI, as well as amyloid and tau PET scan. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) > 1.9 was used as a measure of insulin resistance. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi‐automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas. Dynamic amyloid imaging was performed with a bolus injection of ∼15 mCi of [11C]PiB, followed by a 60‐min scan. A single intravenous bolus of between 7.2‐10.8 mCi of AV‐1451 was administered. Data from the 30‐60 minute, and 80‐100 minute post‐injection window for PiB and AV‐1451 were used for the analysis, respectively. The association of brain volumes and PiB and AV‐1451 SUVRs within the default mode network areas with BMI and VAT/SAT ratio were assessed using linear regression models. Result: We observed lower right entorhinal white matter volumes in obese participants with insulin resistance compared to metabolically normal non‐obese group (p = 0.004), without any significant difference in PiB or AV‐1451 SUVRs. Regression models with sex, age and education as covariates showed a significant positive association between VAT/SAT ratio and left precuneus white matter PiB SUVRs (R2 = 0.31, p = 0.005), but no significant associations with AV‐1451 SUVRs. Conclusion: In our midlife obese sample with insulin resistance, there were lower right entorhinal white matter volume, which is involved in relaying information to the hippocampus. We also demonstrate higher early amyloid pathology in AD‐signature areas such as the precuneus in mid‐life persons with high VAT/SAT ratio, a marker of visceral obesity. [ABSTRACT FROM AUTHOR]

Background: Studies suggest distinct differences in the development, presentation and longitudinal progression of Alzheimer's Disease (AD) between women and men. However, most of these sex‐specific differences have been explored in symptomatic stages of sporadic AD. We investigated cross‐sectional sex differences in clinical‐cognitive assessments as well as fluid and imaging biomarkers in the spectrum of dominantly inherited AD (DIAD). Method: 319 DIAD mutation carriers of the Dominantly Inherited Alzheimer Network‐Observational study (DIAN‐OBS) were included in the analysis and, according to Clinical Dementia Rating® (CDR®) scores, classified as presymptomatic (CDR = 0, 66,1%) or symptomatic (CDR>0). All participants underwent clinical and neuropsychological assessment; lumbar puncture, structural MRI and 11C‐PiB‐PET imaging for amyloid‐β detection were conducted. Mann‐Whitney‐U‐test, Fisher's Exact and linear mixed models with fixed effects for sex, estimated age of onset (EYO) and their interaction, a random effect for family, and years of education and CDR Sum of Boxes as covariates (where appropriate) were used to explore cross‐sectional sex differences. Result: Demographics showed no significant sex differences in presymptomatic (pMC, 56.4% women, p>0.05) or symptomatic mutation carriers (sMC, 52,7% women, p>0.05). In pMC, men showed a worse performance on the Digit Symbol test (p<0.01, Fig.1) than women, and, in interaction with EYO, a better performance in immediate (p<0.05) and delayed (p<0.05) prose recall. In contrast, sMC men performed better on the Animal Naming test (p<0.05), but, in interaction with EYO, worse on the Digit Span forward (p<0.01). CSF analysis did not indicate sex‐related differences in Aβ42/Aβ40‐Ratio, phosphorylated Tau‐181 or total Tau levels (all p>0.05) in either group. In pMC men, PET imaging revealed significantly less tracer binding in the medial orbitofrontal cortex, the frontal pole and the rostral & caudal anterior cingulate in interaction with EYO (all p<0.05, Fig. 2). Furthermore, MRI volume analysis showed a significant reduction in the amygdala in women compared to men (p<0.01) in sMC. Conclusion: We report preliminary results suggesting cross‐sectional sex differences in presymptomatic and symptomatic DIAD mutation carriers regarding episodic, verbal and working memory; processing speed; as well as differential patterns of PiB‐PET burden within cerebral areas related to emotion, decision making and cognitive flexibility. [ABSTRACT FROM AUTHOR]

Background: Imaging transcriptomics is a rapidly developing field that combines neuroimaging with genomics to study mechanisms that influence the organization and activity of the nervous system. Using whole‐brain microarray mRNA expression data from the Allen Human Brain Atlas (AHBA), we examined spatial gradients of gene expression in the brain. We then related these gradients to known spatial patterns of brain function. Method: We mapped regional mRNA expression data from more than 21,000 genes to the 200‐parcel Schaeffer atlas. Principle components analysis (PCA) was used to reduce the dimensionality of the data to ten principle components (PCs). This was done for all genes for the whole brain (WBExp) as well as those specific to Alzheimer Disease (ADExp). We additionally mapped eight other properties: functional connectivity gradients (Fig. 2A), myelin, cortical thickness, cerebral blood volume, cerebral blood flow, glucose consumption, and evolutionary expansion (Fig. 2B) to this atlas to explore their relationships with genetic patterns. Region weights from the PCs were predicted from these eight maps. Result: The majority of variance for both WBExp (Fig. 1A & 1C) and ADExp (Fig. 1B & 1D) expression was explained by three PCs. Functional connectivity gradients one (β = ‐0.38, β = 0.14), two (β = 0.33, β = ‐0.45), and five (β = ‐0.44, β = 0.32) were moderately related to the first PC of WBExp (Fig. 3A) and ADExp (Fig. 3C) expression patterns (p < 0.05), respectively. Cortical thickness (β = ‐0.32, β = 0.19), cerebral brain volume (β = 0.10, β = ‐0.13), cerebral blood flow (β = 0.42, β = ‐0.52), and evolutionary expansion (β = 0.08, β = ‐0.20) were additionally moderately related to the the WBExp PC1 (Fig. 3B, p < 0.05) and the ADExp PC1 (Fig. 3D, p < 0.05), respectively. Conclusion: Our results highlighted that gradients in genetic expressions are related to functional gradients seen using rs‐fMRI as well as biological properties such as cortical thickness, cerebral blood volume, cerebral blood flow, and evolutionary expansion. These findings shed light on mechanisms that influence the structure and function of the brain. Understanding the relationship between genetic patterns and these properties can give insight into healthy and diseased‐brain states such as Alzheimer disease. [ABSTRACT FROM AUTHOR]

Background: The Centiloid (CL) project was developed to harmonise the quantification of Aβ‐PET scans to a unified scale. The CL neocortical mask was defined using 11C‐PiB, overlooking potential differences in regional distribution among Aβ tracers. We created a universal mask using an independent dataset of 5 Aβ tracers, and investigated its impact on inter‐tracer agreement, tracer variability and group separation. Method: Using data from the ADOPIC study (AIBL, ADNI and OASIS3), age‐matched pairs of mild Alzheimer's disease (AD) (MMSE = 20‐24;CL>25) and healthy controls (MMSE> = 28;CDR = 0;CL<15) were selected: 18F‐Florbetapir (FBP:147 pairs), 18F ‐Florbetaben (FBB:22 pairs), 18F ‐Flutemetamol (FLT:10 pairs), 18F ‐NAV (NAV:42 pairs), 11C‐PiB (PIB:63 pairs). The PET images were smoothed to a uniform 8mm resolution to reduce the influence of different scanner sharpness on the derived masks. The images were then spatially normalised using the SPM CL pipeline and transformed into SUVR (whole cerebellum). For each tracer, the mean AD‐HC difference image was computed and mirrored. The threshold for each difference image was optimised to maximise the overlap with the standard CL mask. The Universal mask was defined as the intersection of all 5 masks. It was then used to recalibrate each tracer into Centiloids. The Universal mask and associated transforms were evaluated on the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement and variance in the young controls (YC). They were also evaluated on the baseline ADOPIC dataset (N = 3565) with the effect‐size between HC/AD and HC/MCI. Result: The overlap between each tracer specific mask was high (mean Dice = 0.82). The Universal mask was 26% smaller than the Standard one, but the overlap was high (Dice = 0.74). The Universal mask led to a small reduction in the variance of the YC in most tracers (‐3.4%) and a small increase in the R2 between each of the 11C‐PiB/18F‐tracer pairs (+0.24%). In ADOPIC, it led to a higher effect‐size between HC/AD (1.43 vs 1.42) and HC/MCI (0.71 vs 0.70). Conclusion: The universal CL mask led to an increase in inter‐tracer agreement and group separation. Those increases were however relatively small indicating that the existing standard CL mask is suitable for the quantification of all Aβ tracers. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients. Method: The Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate. Result: As an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer's disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered "Appropriate" to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered "Appropriate" to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD. Conclusion: The updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) blood tests are needed to aid in the evaluation of dementia, but the performance of these tests should be evaluated in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the participant acceptability and validity (relative to amyloid PET) of a plasma amyloid‐β 42/40 test in a diverse, community‐based sample of older adults, and explore the impact of important factors (age, race, education, cognition, APOE genotype, and medical conditions) on the blood test's performance. Method: SEABIRD measured plasma amyloid‐β 42/40 in a diverse population of older adults in the Saint Louis, Missouri, USA area. Participants completed a blood collection, cognitive screening (AD8® dementia screening interview and Montreal Cognitive Assessment [MoCA]), and a survey about their study experience and perceptions of the blood test. A subset of participants completed additional blood collection for reproducibility, amyloid PET and MRI for validation of the blood test, and the Clinical Dementia Rating® (CDR) for validation of the cognitive screening measures. Result: Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2% (Table 1). Compared to the general population, SEABIRD participants were more likely to be female, aged 70‐79 years, and highly educated. They were less likely to report high cholesterol, diabetes, kidney disease, and stroke, and more likely to report depression. The receiver operating characteristic area under the curve for distinguishing cognitively unimpaired (CDR = 0) from cognitively impaired (CDR>0) individuals was 0.72 for the informant‐rated AD8, 0.46 for the self‐rated AD8, 0.70 for the MoCA, and 0.79 for the AD8/MoCA composite (Table 2). Survey results indicated that the blood test was well accepted (Figure 1), but it was perceived more positively by white and highly educated individuals. Conclusion: A study of an AD blood test achieved rapid enrollment, broader diversity than typical AD cohorts, and high rates of participation. These results suggest that an AD blood test could be used for screening in a diverse clinical population. [ABSTRACT FROM AUTHOR]

In this article, we presented an asymptotic streamline diffusion finite element method (SDFEM) for singularly perturbed convection–diffusion‐type differential difference equations. Using the asymptotic expansion approximation, the differential difference equations are converted into nondelay differential equations. A SDFEM is applied to the modified equation. Further, we proved that the method gives an almost second‐order convergence in maximum norm, in L2‐norm whereas first‐order convergence in H1‐norm. Numerical results are presented to validate the theoretical results. [ABSTRACT FROM AUTHOR]

Objective: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR‐tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR‐tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. Methods: Cross‐sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non‐carriers had sequential characterization of N‐terminal/mid‐domain phosphorylated tau (p‐tau) followed by MTBR‐tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. Results: CSF MTBR‐tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR‐tau species were associated with amyloid pathology and CSF p‐tau; whereas the "core" MTBR‐tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. Interpretation: Changes in CSF soluble MTBR‐tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R‐specific MTBR‐tau (border) to the NFT (core) MTBR‐tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR‐tau species in the CSF may serve as a marker of tau‐related disease progression and target engagement of anti‐tau therapeutics. ANN NEUROL 2023;93:1158–1172 [ABSTRACT FROM AUTHOR]

Single atoms and nanoclusters of Fe, Ni, Co, Cu, and Mn are systematically designed and embedded in a well‐defined C1N1‐type material that has internal cavities of ≈0.6 nm based on four N atoms. These N atoms serve as perfect anchoring points for the nucleation of small nanoclusters of different metal natures through the creation of metal‐nitrogen (TM‐N4) bonds. After pyrolysis at 800 °C, TM@CNx‐type structures are obtained, where TM is the transition metal and x < 1. Fe@CNx and Co@CNx are the most promising for oxygen reduction reaction and hydrogen evolution reaction, respectively, with a Pt‐like performance, and Ni@CNx is the most active for oxygen evolution reaction (OER) with an EOER of 1.59 V versus RHE, far outperforming the commercial IrO2 (EOER = 1.72 V). This systematic and benchmarking study can serve as a basis for the future design of advanced multi‐functional electrocatalysts by modulating and combining the metallic nature of nanoclusters and single atoms. [ABSTRACT FROM AUTHOR]

Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET. Methods: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation–mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled. Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids). Discussion: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging. Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD. [ABSTRACT FROM AUTHOR]

Background: Variants in the apolipoprotein E (APOE) gene represent the greatest genetic risk factor for Alzheimer disease (AD). Carriers of the ε4 allele have an increased risk of developing AD pathology and a lower age of symptom onset. While prior work has focused on the sporadic form of AD, little is known about how the ε4 allele impacts AD‐specific pathology in autosomal dominant AD (ADAD). Method: 430 participants from the Charles and Joanne F. Knight Alzheimer Disease Research Center and 276 ADAD mutation‐carriers from the Dominantly Inherited Alzheimer Network, were included in these analyses. Participants were classified as ε4‐positive or ‐negative, and further grouped using Clinical Dementia Rating® (CDR®) scores as cognitively impaired or –unimpaired (Table 1). All participants completed magnetic resonance imaging (MRI), beta‐amyloid positron emission tomography (Ab‐PET), and cognitive testing within a 12‐month period. Result: Using regression models, we replicated prior work demonstrating that the ε4 allele is associated with an increase in AD pathology measured by Ab‐PET and MRI in a sporadic AD cohort. Furthermore, the ε4 allele was also associated with a decline in cognitive performance. Follow‐up pairwise comparisons revealed that within the sporadic‐AD cohort, the influence of the ε4 allele was most pronounced in individuals who were cognitively impaired. In contrast, in a cohort of individuals possessing autosomal dominant mutations, the ε4 allele was not associated with increases in pathology measured by Ab‐PET and MRI, nor was it associated with a decrease in cognition (Table 1; Figure 1). Conclusion: We present quantitative evidence that the APOE‐ ε4 allele differentially impacts the pathology and cognitive outcomes of sporadic‐ and autosomal dominant AD. In those with sporadic AD, possession of at least one copy of the ε4 allele is associated with increased amyloid deposition and cortical thinning, as well as decreased cognition, particularly in individuals who are cognitively impaired. However, in ADAD mutation‐carriers, these same patterns are not evident. We propose that this is due to the overwhelming influence of the autosomal dominant genetic mutations that drive this unique and rare form of AD. [ABSTRACT FROM AUTHOR]

Background: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Binding of 18F‐Flortaucipir (FTP) has qualitatively been noted in the skull. We investigate the characteristics of this off‐target signal, as well as its impact on regional PET analyses. Method: FTP tau PET, 18F‐Florbetapir (FBP) amyloid PET, head CT, and T1‐weighted MR images were acquired for 313 cognitively unimpaired and impaired older participants. A subset (n=152) also received a 11C‐PiB PET scan. Another subset (n=14) received longitudinal FTP scans. MR images were segmented into ROIs using FreeSurfer and a skull ROI for each participant was defined from the head CT after removing non‐skull bone and tissue. Standard uptake value ratios (SUVRs) were calculated for all ROIs. Skull binding was correlated across FTP, FBP, and PiB to determine if binding is radioisotope specific. Longitudinal persistence of FTP skull signal was tested in the subset with longitudinal data. Finally, participants were grouped by amyloid positivity based on FBP and linear models controlling for age and sex predicted regional non‐partial volume corrected (non‐PVC) and PVC SUVR from skull SUVR to assess the regional impact of skull signal. Result: FTP skull binding was significantly correlated with both FBP (ρ=0.48, p<0.001, Figure 1A) and PiB (ρ=0.34, p<0.001, Figure 1B), suggesting the binding is not due to tracer defluorination. In the longitudinal subset, baseline SUVR was significantly correlated with follow‐up SUVR (Figure 2). Higher skull SUVR resulted in erroneously elevated regional SUVRs for areas in the frontal, parietal, and temporal lobes in amyloid negative individuals. After applying PVC, only medial temporal, inferior parietal, and lateral occipital continued to show significant positive relationships with skull SUVR (Figure 3). Decreased skull bone density was significantly related to higher skull SUVR in women but not men (see Figure 4). Conclusion: Skull signal from FTP is a stable, subject‐specific phenomenon that can persist across longitudinal visits and tracers. This off‐target signal can potentially bias quantitative PET measurements in AD tauopathy regions in amyloid negative but not positive individuals even after PVC is applied. The bone binding was overwhelmingly driven by women, suggesting at least some proportion of previously observed sex effects may be driven by bone uptake. [ABSTRACT FROM AUTHOR]

Background: Renal transplant recipients (RTRs) are at increased risk of developing skin cancer; however, the role of immunosuppression is not yet fully understood. In this study, we evaluated the immunohistochemical changes in the skin of RTRs under three different immunosuppression regimens: mTOR inhibitors (mTORi), sirolimus or everolimus, mycophenolic acid (MPA) precursors such as mycophenolate sodium or mofetil, or azathioprine (AZA). Methods: We evaluated biopsies of sun‐exposed and sun‐protected skin for immunohistochemical quantification of B lymphocytes (CD20+), T lymphocytes (CD3+, CD4+, and CD8+), and Langerhans cells (LCs) (CD1a+) in 30 RTRs and 10 healthy controls. The RTRs were divided into three groups: mTORi (n = 10), MPA (n = 10), and AZA (n = 10). Results: No differences were observed in the number of B lymphocytes. However, a significant decrease in the number of T lymphocytes and LCs was observed in both sun‐protected and sun‐exposed skin in the AZA and MPA groups, although to a lesser degree in the latter group. The skin of the mTORi group did not differ from that of the control group in terms of the number of B and T lymphocytes and LCs. Conclusions: Patients treated with mTORi exhibit preserved cellular elements related to cutaneous immune surveillance. The use of AZA induced a greater degree of skin immunosuppression than in the control group, as demonstrated by the decrease in T lymphocytes and LCs. [ABSTRACT FROM AUTHOR]

Introduction: Multiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy. Method: A Residual Inception Encoder‐Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound‐B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10‐fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects. Results: Significantly stronger between‐tracer correlations (P <.001) were observed after harmonization for both global amyloid burden indices and voxel‐wise measurements in the training cohort and the external testing cohort. Discussion: We proposed and validated a novel encoder‐decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers. [ABSTRACT FROM AUTHOR]

The article "EP10.09: Assessing human fetuses undergoing acute pain: validation of the fetal-7 scale" presents the validation of a fetal pain scoring system called the Fetal-7 scale. The study involved two steps: internal consistency, inter- and intrarater reliability, and sensitivity and specificity analysis. The results showed high internal consistency and reliability of the Fetal-7 scale, with a sensitivity of 100% and specificity of 94.4% in differentiating between healthy fetuses at rest and those experiencing acute pain. The authors suggest that the Fetal-7 scale can be a valuable tool in assessing acute pain-related behavior in third trimester fetuses and guiding analgesic procedures after fetal surgery. Further research is needed to explore postoperative pain in fetuses and its effects after birth. [Extracted from the article]

Background: Alzheimer's disease (AD), the most common form of dementia, is a complex polygenic disease with genetic, cellular, pathologic, and clinical heterogeneity. Recently, significant attempts have been made for identifying AD biomarkers for reliably tracking disease progression in its early asymptomatic stages. To this end, amyloid PET imaging has provided useful information tracking accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Previous investigations have conducted genetic association studies of CSF Aβ42, both continuously as well as using a threshold for amyloid positivity, and identified novel genes and loci potentially contributing to the preclinical stage in AD. In a recent case‐control based study using amyloid PET as a quantitative trait, Raghavan et al., identified a novel locus for amyloidosis within RBFOX1 gene in 4,314 participants, however, further investigations are needed to replicate and expand on these findings. Method: In order to investigate the underlying genetic basis for brain amyloidosis in AD, we systematically analyzed the largest collection of amyloid imaging data (N = 6,320), across multiple ethnicities from multicenter cohorts (ADRC, A4, DIAN, ADNI, ADNIDOD, UPitt, and HABS) as a quantitative trait to identify the functional variants and genes driving the association of AD. Furthermore, we have conducted diagnosis‐, gender‐, and APOE‐stratified analyses to investigate the effect of these variables on the brain amyloidosis. Result: Preliminary results found a strong APOE signal in chr19 (min P = 1e‐185) and a genome‐wide significant hit (P = 2e‐08) in the chromosome 7 (potentially, associated to TMEM106B gene) warranting further investigation (Fig. 1). Moreover, some suggestive signals were detected in chr10 (P = 1e‐07) and chr12 (P = 5e‐07). Consistent with previous finding, we found RBFOX1 to be associated with increased amyloid burden (β = 0.07), however, the signal was only nominally significant (P = 0.03). Additional analyses including multi‐ancestry meta‐analysis using FHS, AIBL, and EISAI cohorts and post‐GWAS analyses are ongoing. Conclusion: The identification of pre‐clinical AD‐specific molecular signatures and pathways will enable the characterization of appropriate therapeutic targets for the prevention and/or treatment of AD. Results generated from our investigation will further serve to generate prediction models for amyloid positivity and Mendelian Randomization (MR) analyses. [ABSTRACT FROM AUTHOR]

Background: Smartphone‐based ecological momentary assessments (EMA) have the potential to capture subtle changes in cognition associated with preclinical Alzheimer disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on EMA principles and administers brief tests of associative memory, processing speed, and working memory ∼4 times per day over 7 consecutive days. Participants perform these 7‐day cycles every ∼6 months, longitudinally. ARC was designed to be performed unsupervised, on participants' personal devices, and in their everyday environments in order to increase accessibility, testing, and reliability. Method: We evaluated the reliability, validity, and feasibility of ARC in a large, well‐characterized sample of cognitively normal older adults (ages 65‐97) and individuals with very mild dementia (ages 61‐88). Participants completed at least one 7‐day cycle of ARC testing along with conventional cognitive assessments. Most participants also had cerebrospinal fluid, amyloid and tau PET, and structural MRI data available. The reliability, validity, and feasibility of ARC as an unsupervised, high‐frequency cognitive assessment tool using participants' personal smartphones was tested by examining (1) between‐subjects and test‐retest reliability, (2) correlations with age, conventional cognitive measures, and AD‐related biomarkers, and (3) adherence and attrition rates of older adults with varying technology familiarity. Result: First, ARC tasks demonstrated good reliability such that between‐person reliability across the 7‐day cycle and test‐retest reliabilities at 6‐month and 1‐year follow‐ups all exceeded intraclass correlations of 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures. Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, high adherence rates and low attrition rates indicated that ARC was feasible and, to some extent, enjoyable, for older adult participants. Conclusion: Ultimately, these results suggest that ARC is a reliable and valid measure of cognition in older adults at risk for AD and is a feasible tool for assessing subtle cognitive changes associated with the earliest stages of AD. [ABSTRACT FROM AUTHOR]

Background: Caloric restriction (CR) improves neuronal stress resistance in animals and improves cognitive performance in older adults (1‐3). Neuroinflammation is an increasingly recognized mechanism relevant to Alzheimer disease (AD). We investigated the effect of a 12‐week CR diet on imaging markers of dementia and neuroinflammation in midlife individuals with multiple sclerosis (MS), a prototype neuroinflammatory disease. Methods: In a single‐blind randomized controlled trial, 10 participants with MS (8 women and 2 men, age: 45.5±10.67 and education: 16.4±2.5 years) were recruited from the Washington University John L. Trotter MS Center and randomly assigned to participate in either a 12‐week CR or control group on their regular diet. Participants fasted 2 days a week and during those days eating no more than 500 calories. Participants underwent MRI scanning at the time of recruitment and at the end of the 12‐week program. Volumetric analyses were conducted through FreeSurfer 7.1.1 (4), relative regional cerebral blood flow (rCBF) was obtained through ASL‐MRICloud (5), and hindered and restricted diffusion fractions (HF and RF) were calculated through the diffusion basis spectrum imaging (DBSI), representing tissue edema and inflammatory cell infiltration respectively Results: Six participants were obese, two were overweight and two had normal weight with an average BMI of 30.3±5.48 kg/m2 across participants. Following 12‐weeks of CR, participants showed an increase in normalized hippocampal volume (p:0.02) compared to those on regular diet. CR also resulted in improved cortical thickness in the bilateral medial orbitofrontal cortices compared to the control group (p:0.014). An average increase in relative perfusion (rCBF) in the bilateral inferior temporal gyri (p:0.02, & p:0.004) and bilateral fusiform gyri (p:0.008 & p:0.002) was observed in participants undergoing CR compared to those on a regular diet at the end of 12‐weeks (Figure 1 and 2). Being on a CR diet was associated with reduced HF and RF in the bilateral inferior longitudinal fasciculi (p:0.04 & p:0.002) indicating reduced edema and cellularity (6). Conclusion: CR is associated with alterations in brain's structure and function in terms of improved volumetric measurements, regional perfusion and reduced tissue inflammation, and hence implicated as a neuroprotective intervention in midlife persons. [ABSTRACT FROM AUTHOR]

Nirmatrelvir coadministered with ritonavir is highly efficacious in reducing the risk of coronavirus disease 2019 (COVID‐19) adverse outcomes among patients at increased risk of progression to severe disease, including patients with chronic kidney disease. Because nirmatrelvir is eliminated by the kidneys when given with ritonavir, this phase I study evaluated the effects of renal impairment on pharmacokinetics, safety, and tolerability of nirmatrelvir/ritonavir. Participants with normal renal function (n = 10) or mild, moderate, or severe renal impairment (n = 8 each) were administered a single 100‐mg nirmatrelvir dose with 100 mg ritonavir given 12 hours before, together with and 12 and 24 hours after the nirmatrelvir dose. Systemic nirmatrelvir exposure increased with increasing renal impairment, with mild, moderate, and severe renal impairment groups having respective adjusted geometric mean ratio areas under the plasma concentration‐time profile from time 0 extrapolated to infinite time of 124%, 187%, and 304% vs. the normal renal function group. Corresponding ratios for maximum plasma concentration were 130%, 138%, and 148%. Apparent clearance was positively correlated with estimated glomerular filtration rate, and geometric mean renal clearance values were particularly lower for the moderate (47% decrease) and severe (80% decrease) renal impairment groups vs. the normal renal function group. Nirmatrelvir/ritonavir exhibited an acceptable safety profile; treatment‐related adverse events were mild in severity, and there were no significant findings regarding laboratory measurements, vital signs, or electrocardiogram assessments. These findings led to a dose reduction recommendation for nirmatrelvir/ritonavir in patients with moderate renal impairment (150/100 mg nirmatrelvir/ritonavir instead of 300/100 mg twice daily for 5 days). NCT04909853. [ABSTRACT FROM AUTHOR]

Against the background of a long history of acceptance of transmigration from various parts of the world and interethnic marriages being embraced, political agendas that prevailed following the independence of Malaysia culminated in a society with increasing ethnic polarisation impacting on social cohesion and reports of aversion to interethnic marriages. This study is aimed at exploring the perspectives of people who have lived through the different socio‐political changes impacting on the social fabric. Using an exploratory cross‐sectional qualitative design, 36 participants from the three main ethnic groups, across three generations (Baby Boomers, Generation Xers, and Millennials) were interviewed to explore their views on interethnic marriages in Peninsular Malaysia. Iterative questioning was adopted to enhance reliability of data, which were processed by thematic analysis. Although each of the generational groups had different lived experiences, the findings indicate commonalities identified in terms of two main themes, i.e., challenges and facilitators. The predominant perception is the challenge of religion conversion required by non‐Muslims in relationships with Muslims. The issue of ethnicity did not arise as of concern amongst the different ethnic groups from this urban sample. Of significance is the heightened ethno‐religionist consciousness with implications on social cohesion for community relations and nation building. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that the optimal ischemia time (IT) threshold in pediatric heart transplantation (PHT) is up to 4 h, independent of other donor organ factors. The purpose of this study was to examine the relationship between IT and donor left ventricular ejection fraction (LVEF) and study their impact on PHT outcomes. Methods: This is a retrospective cohort study of PHT (<18 years) identified in UNOS between January 2000 and March 2020. Post‐transplantation survival analysis of patients receiving donor hearts with IT<4, 4–6, and >6 h was performed using Kaplan–Meier curves. Cohort was divided according to donor LVEF median value, and survival was analyzed. Cox regression was performed. Results: Median LVEF was 65% in the study cohort (6669 PHT). Overall, IT>6 h was associated with worse survival compared to <4 h regardless of donor LVEF. For allografts with LVEF < 65%, IT = 4–6 h was associated with worse survival compared with IT < 4 h (p =.006) but had similar survival compared with IT > 6 h (p =.315). For allografts with LVEF ≥ 65%, IT = 4–6 h had similar survival compared with <4 h (p =.175) but improved survival compared with >6 h (p =.003). After adjusting for donor and recipient variables, Cox regression showed that IT = 4–6 h was not associated with increased mortality for LVEF ≥ 65%. Conclusions: The IT threshold of 4 h does not apply to all allografts. Recipients of hearts with LVEF≥65% can tolerate an IT up to 6 h without any detriment to survival. Routine acceptance of these donor hearts could mitigate longer waiting times and poor donor availability for many candidates. [ABSTRACT FROM AUTHOR]

Little is known about dietary adequacy, for young Ugandan children, or context‐specific food choices to improve it. This study estimated the percentage of breastfed 12–23‐month‐old rural Eastern Ugandan children (n = 114) at risk of inadequate intakes of 12 nutrients; and identified realistic food choices for improving it. In this cross‐sectional survey, dietary (weighed food records), anthropometric and socioeconomic data were collected. The percentages of children at risk of inadequate nutrient intakes were estimated, assuming 541 g/day of breast milk was consumed. The median nutrient densities of their complementary feeding diets were also compared with desired levels. Linear programming analyses were used to identify 'problem nutrients' (where requirements will be difficult to meet given dietary practices) and model food choices to improve dietary adequacy. Overall, 21.2% of children were stunted and 3.8% were wasted. A high percentage (>45%) of children were at risk of inadequate intakes, for nine of the 12 nutrients assessed, and dietary nutrient densities were below desired levels for seven of the 12 nutrients. Iron, calcium, thiamine and niacin were 'problem nutrients'. Through careful selection of foods, modelling indicates that population level dietary adequacy can be achieved for eight of the 12 nutrients modelled. These choices include cows' milk, legumes, green leafy vegetables, sweet potatoes and fruits. Overall results suggest these high percentages of children at risk of inadequate nutrient intakes can be reduced through behaviour change interventions, although additional interventions may be required to ensure population‐level dietary adequacy for iron, thiamine and niacin. Key messages: Dietary adequacy, for breastfed 12–23‐month‐old rural Eastern Ugandan children, is poor with over 45% of children at risk of inadequate intakes of nine micronutrients.Inadequate intakes of micronutrients likely contribute to growth faltering in this population where 21% of children are stunted but less than 4% are wasted.Dietary adequacy can be improved through careful selection of nutrient‐dense foods, including cows' milk, legumes, green leafy vegetables, sweet potatoes, and fruits.A food‐based approach alone, however, will not reduce the percentage of children at risk of inadequate intakes to low levels, for iron, thiamine and perhaps niacin, indicating alternative interventions are required. [ABSTRACT FROM AUTHOR]

Objective: To assess the incidence of testicular cancer in trans women (male sex assigned at birth, female gender identity) using gender‐affirming hormonal treatment. Patients and Methods: Data of trans women starting hormonal treatment at our gender identity clinic between 1972 and 2017 were linked to the national pathology database to obtain testicular cancer diagnoses. The standardised incidence ratio (SIR) was calculated using the number of observed testicular cancer cases in our cohort and the number of expected cases based on age‐specific Dutch incidence rates. Subgroup analyses were performed in testicular tissues sent for histopathological analysis at the time of bilateral orchidectomy, and when follow‐up exceeded 5 years. Results: The cohort consisted of 3026 trans women with a median follow‐up time of 2.3 interquartile range (IQR) (1.6–3.7) years. Two testicular cancer cases were identified whilst 2.4 cases were expected (SIR 0.8, 95% confidence interval 0.1–2.8). In addition, one testicular cancer case was encountered in an orchidectomy specimen (0.1%). In the 523 trans women with a follow‐up time of >5 years (median [IQR] 8.9 [6.4–13.9] years), no testicular cancer was observed. Conclusion: Testicular cancer risk in trans women is similar to the risk in cis men. The testicular cancer cases occurred within the first 5 years after commencing hormonal treatment, and the percentage of cases encountered at the time of bilateral orchidectomy was low. As no testicular cancer was observed in trans women with a long follow‐up period, long‐term hormonal treatment does not seem to increase testicular cancer risk. [ABSTRACT FROM AUTHOR]

Increasing prevalence of infections caused by antimicrobial‐resistant gram‐negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime‐avibactam is a novel β‐lactam β‐lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra‐abdominal infection, and complicated urinary tract infection or hospital‐acquired ventilator‐associated pneumonia (adults only in the United States) caused by susceptible gram‐negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000–500 mg by 2‐hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime‐avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime‐avibactam pediatric dosage regimens (all by 2‐hour IV infusion) of 50–12.5 mg/kg (maximum 2,000–500 mg) q8h for those ≥6 months to 18 years old, and 40–10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Background: Plaque psoriasis is a common, chronic and relapsing inflammatory skin disease clinically characterized by erythema and scaling desquamation. As over 90% of psoriasis patients benefit from topical therapies, local treatments continue to play an eminent role in management strategies. One such topical treatment is the fixed dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP). Objectives: Pooled analysis of two different phase 3 clinical trails to compare superiority regarding efficacy, safety and quality of life (QoL) between CAL/BDP PAD‐cream and CAL/BDP TS. Methods: The data from two phase 3, multicentre, randomized, investigator‐blind, active and vehicle‐controlled trials enrolling patients with psoriasis were pooled and analysed. Investigational products included a CAL/BDP cream based on PAD™ Technology (PAD‐cream) designed for high skin penetration and increased patient preference, an active control (marketed CAL/BDP topical suspension/gel, in the following abbreviated as CAL/BDP TS) and cream vehicle, which were applied once daily for 8 weeks. Results: Efficacy and safety of the novel CAL/BDP PAD‐cream formulation for the topical treatment of psoriasis demonstrated superiority for all efficacy end points after 8 weeks of treatment. PGA treatment success for CAL/BDP PAD‐cream (43.2%) was greater than CAL/BDP TS (31.9%; P < 0.0001), the mean per cent reduction in mPASI for CAL/BDP PAD‐cream was 64.6% compared to 56.4% for CAL/BDP TS (P < 0.0001) and DLQI 0/1 was obtained by 43.8% in the CAL/BDP PAD‐cream group versus 34.2% in the CAL/BDP TS group (P = 0.0005). There was no adverse drug reaction reported with a frequency of >1%, associated with the CAL/BDP PAD‐cream. Conclusions: The novel fixed dose combination CAL/BDP PAD‐cream offers greater efficacy, superior patient QoL and equivalent favourable safety for the topical treatment of psoriasis, in comparison to the currently available topical suspension/gel. [ABSTRACT FROM AUTHOR]

Background: The Centiloid (CL) project was developed to harmonise the quantification of Amyloid PET scans to a unified scale. The neocortical mask used for quantification was obtained using a private dataset of 19 mild AD patient and 25 older controls imaged using 11C‐PiB. The mean difference SUVR images were smoothed, subtracted and thresholded at 1.05 SUVR. While this threshold was chosen to maximise areas of specific Amyloid binding while avoiding areas of non‐specific binding, it was not evaluated in terms of agreement between different tracers or group separation. In this study, we created a new mask using an independent dataset of 11C‐PiB images, and investigated its impact on inter‐tracer agreement, tracer variability and group separation. Method: Using the AIBL and OASIS databases, 63 mild AD (MMSE=20‐24;CL>20) and 63 Healthy controls (MMSE>=28;CDR=0;CL<20) matched based on age and gender, were selected. Their 11C‐PiB images were spatially normalised using the SPM CL pipeline and transformed into SUVR using the whole cerebellum. A mean AD‐HC difference image was computed and thresholds of [0.6‐1.2] SUVR were explored. The resulting masks were evaluated in the 5 Amyloid tracers using the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement, variance in the young controls (YC) and YC‐AD effect‐size (ES). The recalibrated CL were evaluated on the AIBL dataset with the ES on the HC‐AD and HC‐MCI using baseline and rate of change (CL/yr). Result: Using a higher threshold resulted in a smaller neocortical mask, better targeting regions of high Amyloid update. In the GAAIN dataset, the smaller masks led to higher R2 for each 11C‐PiB/18F‐Tracer pairs and higher YC‐AD ES. They also led to a lower variance in the YC for all tracers except for Flutemetamol. In AIBL, while it increased the ES at baseline, it decreased in the HC‐MCI when using CL/yr. Conclusion: While using a smaller neocortical mask improved inter‐tracer agreement and reduced variance in YC, the results in AIBL indicate that it might not be as sensitive to detect early changes as highlighted with poorer HC‐MCI ES. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated. Methods: Data from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t). Results: Gaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall's t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR >0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3). Conclusions: Neuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation, an intrinsic immune response of the nervous system, is important in an early phase of Alzheimer Disease (AD) pathogenesis. However, it is largely unclear how neuroinflammation promotes the clinical progression of AD. Extracellular water edema (ECW) from Neuro‐inflammation imaging (NII), a diffusion‐based MRI approach for neuroinflammation, has been utilized to asses white matter (WM) neuroinflammation in AD. This study aims to investigate the relationship between WM neuroinflammation and longitudinal cognitive changes in AD. Method: This study included 286 participants who were enrolled in ongoing research at the Knight ADRC at Washington University in Saint Louis. The CSF levels of Aβ42/Aβ40 and ptau181 measured with the automated Lumipulse platform were used to categorize participants as being positive or negative amyloid (A) and tau (T), respectively (Table 1). As measures of cognitive performance, the Knight ADRC Preclinical Alzheimer Cognitive Composite (Knight ADRC‐PACC) and a Global composite score were employed for each individual. The rates of change of cognitive measures were calculated for each individual. The NII was acquired with a multi‐b value scheme (bmax =1400s/mm2 and 25 directions). The total WM neuroinflammation (NII‐ECW) was obtained using TBSS (http://www.fmrib.ox.ac.uk/fsl) based WM skeleton. Randomise in FSL was utilized to examine voxel‐wise relationships between NII‐ECW and the rate of change of cognitive measures. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed for comparing continuous and categorical variables of the participants' demographics, respectively. The group differences of NII‐ECW were tested using one‐way ANOVA. All statistical tests were conducted in R (R Core Team, 2020). Age, sex, and APOE ε4 carrier status were adjusted as covariates. Result: Table 1 summarizes demographic data. When compared to the A‐T‐ group, the A+T+CDR0 and A+T+CDR0.5 groups had higher NII‐ECW (Figure 1). When the A+T+CDR1 group was compared to the other groups, there was no group difference in NII‐ECW. There were substantial negative associations between the NII‐ECW and the rates of change of cognitive measures in the widespread WM regions (Figure 2). Conclusion: Our data suggest that neuroinflammation increases early in preclinical AD and decreases later in the disease. Furthermore, baseline neuroinflammation as measured by NII‐ECW predicts cognitive decline in AD. [ABSTRACT FROM AUTHOR]

Background: Estimates of "brain‐predicted age" quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior studies have typically modeled brain‐predicted age with volumetric magnetic resonance imaging (MRI), but other modalities, including resting‐state functional connectivity (FC) and multimodal MRI, have more recently been explored. In the present study, we tested the sensitivity of brain‐age predictions derived from volumetric, FC, and multimodal MRI to group differences in AD status and individual differences in cognition. Method: We trained three Gaussian process regression models to predict age from (1) FC, (2) regional brain volumes, and (3) multimodal MRI (FC+volumetric) in 493 control participants (cognitively normal, amyloid‐negative [A‐], 18‐89 years old). We applied the trained models to independent samples staged by the presence or absence of amyloid (A+/A‐) and tau (T+/T‐) using PET (Centiloid) and CSF (amyloid β‐42/40 ratio, phosphorylated tau 181): 122 A‐T‐, 62 A+T‐, 62 A+T+, as well as 154 symptomatic AD participants. Global cognition was assessed using an established composite of cognitive tests across multiple domains. Result: All models successfully predicted age in the control training set, with the multimodal model (mean absolute error [MAE]=5.3 years) outperforming the unimodal volumetric (MAE=6.0 years) and FC models (MAE=8.3 years) (Figure 1). In all three models, the brain age gap (BAG) was significantly elevated in symptomatic AD compared to cognitively normal controls. In the FC and multimodal models, the BAG was significantly reduced in A+T+ participants compared to T‐ controls (Figure 2). In symptomatic AD, lower global cognitive composite scores were associated with elevated volumetric and multimodal BAGs (Figure 3). Conclusion: Both FC and volumetric estimates of brain age are sensitive to symptomatic AD, consistent with previous reports. Additionally, FC‐based brain age may exhibit a biphasic response to preclinical AD pathology while volumetric brain age may be sensitive to cognitive decline in the symptomatic stage. Multimodal estimates of brain age capture each of these modality‐specific relationships, and further, improve sensitivity to healthy age differences. Hence, multimodal neuroimaging models may be useful in staging early symptomatic and preclinical AD. [ABSTRACT FROM AUTHOR]

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies.Dose‐dependent treatment effects were observed in some biomarkers.No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), patients and caregivers often report a pattern of increasing cognitive and behavioral difficulties in evening hours, known colloquially as "sundowning." Here, we describe the first known attempt to capture circadian fluctuations in cognition in humans at risk for AD using a novel smartphone assessment that samples cognition rapidly and repeatedly over a 7‐day period. We hypothesized that cognitive sundowning would manifest among individuals with abnormal AD biomarkers, even in preclinical stages of AD. Methods: Older adults (N=168, Ages 61‐94 years) were asked to complete 4 brief smartphone‐based testing sessions per day for 7 consecutive days at quasi random intervals throughout the day, from morning until evening. Tests included associate memory, processing speed, and visual working memory tasks (Figure 1). Cerebrospinal fluid biomarkers for beta amyloid (Ab42) and phosphorylated tau181 (ptau) were collected within ∼3 years of smartphone tests. Scores from morning hours (range ∼5am – 12pm) were averaged for comparison with averaged scores from evening hours (after 12pm). Mixed effect models evaluated time of day effects by CSF biomarker status and clinical status. Results: Participant characteristics are provided in Table 1. Models with terms for age, gender, education, APOE e4 status, and Clinical Dementia Rating™ Sum of Boxes tested the interaction between time of day and CSF ptau/Ab42 ratio in predicting cognition (Figure 2). Compared to those with normal biomarkers, participants with abnormal CSF ptau/Aβ42 ratio had worse associate memory (p=0.03) and processing speed performance (p=0.026) in evening hours. On processing speed, participants with abnormal ptau/Aβ42 ratios were slower by an average of 700ms in the evening compared to those with normal ptau/Aβ42 ratios tested in morning hours. When models were run in cognitively normal participants only, a similar pattern was observed, confirming the hypothesis that increasing loads of AD pathology result in worse cognitive performance in evening hours prior to symptom onset. Conclusion: Our results provide the first known evidence of cognitive sundowning in preclinical and early symptomatic AD and suggest that time of day is an important consideration for studies of cognition in AD populations. [ABSTRACT FROM AUTHOR]