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ImportanceUnderstanding the relationship between patients’ clinical characteristics and outcomes is fundamental to medicine. When critically ill patients die after withdrawal of life-sustaining therapy (WLST), the inability to observe the potential for recovery with continued aggressive care could bias future clinical decisions and research.ObjectiveTo quantify the frequency with which experts consider patients who died after WLST following resuscitated cardiac arrest to have had recovery potential if life-sustaining therapy had been continued.Design, Setting, and ParticipantsThis prospective cohort study included comatose adult patients (aged ≥18 years) treated following resuscitation from cardiac arrest at a single academic medical center between January 1, 2010, and July 31, 2022. Patients with advanced directives limiting critical care or who experienced cardiac arrest of traumatic or neurologic etiology were excluded. An international cohort of experts in post-arrest care based on clinical experience and academic productivity was identified. Experts reviewed the cases between August 24, 2022, and February 11, 2024.ExposurePatients who died after WLST.Main Outcome and MeasuresThree or more experts independently estimated recovery potential for each patient had life-sustaining treatment been continued, using a 7-point numerical ordinal scale. In the primary analysis, which involved the patient cases with death after WLST, a 1% or greater estimated recovery potential was considered to be clinically meaningful. In secondary analyses, thresholds of 5% and 10% estimated recovery probability were explored.ResultsA total of 2391 patients (median [IQR] age, 59 [48-69] years; 1455 men [60.9%]) were included, of whom 714 (29.9%) survived to discharge. Cases of uncertain outcome (1431 patients [59.8%]) in which WLST preceded death were reviewed by 38 experts who rendered 4381 estimates of recovery potential. In 518 cases (36.2%; 95% CI, 33.7%-38.7%), all experts believed that recovery potential was less than 1% if life-sustaining therapies had been continued. In the remaining 913 cases (63.8%; 95% CI, 61.3%-66.3%), at least 1 expert believed that recovery potential was at least 1%. In 227 cases (15.9%; 95% CI, 14.0%-17.9%), all experts agreed that recovery potential was at least 1%, and in 686 cases (47.9%; 95% CI, 45.3%-50.6%), expert estimates differed at this threshold.Conclusions and RelevanceIn this cohort study of comatose patients resuscitated from cardiac arrest, most who died after WLST were considered by experts to have had recovery potential. These findings suggest that novel solutions to avoiding deaths based on biased prognostication or incomplete information are needed.

Limited scalability and restricted affordability impede the equitable deployment of curative models of care despite advances achieved with regenerative medicine therapeutics. Mitigating the risk of widening health disparities mandates actions that would improve the availability and accessibility of new classes of biotherapeutics. Namely, the use of Smart Manufacturing empowered by artificial intelligence to increase therapeutic production capacity while reducing cost is an emerging strategy central to the future of the regenerative care economy. Establishing an efficient and effective biomanufacturing ecosystem is essential to building regenerative pipelines into broadly available regenerative therapeutics options. This ecosystem must provide not only necessary cell environment controls and computer process power, but also the sensing technologies to feed critical process parameters to the algorithms in real-time. Here we outline key elements that are in development to support Smart Biomanufacturing, such as machine learning, advanced analytics, digital twins, and modular cytocentric production. The aim of integrating these technologies is to drive down costs, improve access to new regenerative medicine therapeutics, address regulatory science expectations, and in doing so, improve health equity.

Importance Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence in adults without AD indicates that females exhibit higher tau deposition than age-matched males, particularly in the setting of elevated β-amyloid (Aβ), but the evidence for sex differences in tau accumulation rates is inconclusive. Objective To examine whether female sex is associated with faster tau accumulation in the setting of high Aβ (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOE ε4 carrier status and tau accumulation. Data Sources This meta-analysis used data from 6 longitudinal aging and AD studies, including the Alzheimer’s Disease Neuroimaging Initiative, Berkeley Aging Cohort Study, BioFINDER 1, Harvard Aging Brain Study, Mayo Clinic Study of Aging, and Wisconsin Registry for Alzheimer Prevention. Longitudinal data were collected between November 2004 and May 2022. Study Selection Included studies required available longitudinal [ 18 F]flortaucipir or [ 18 F]-MK-6240 tau-PET scans, as well as baseline [ 11 C] Pittsburgh Compound B, [ 18 F]flutemetamol or [ 18 F]florbetapir Aβ-PET scans. Recruitment criteria varied across studies. Analyses began on August 7, 2023, and were completed on February 5, 2024. Data Extraction and Synthesis In each study, primary analyses extracted estimates for the sex (female or male) and the sex by baseline Aβ-PET status (high or low) association with longitudinal tau-PET using a series of mixed-effects models. Secondary mixed-effects models extracted the interaction estimate for the association of sex by APOE ε4 carrier status with longitudinal tau-PET. Study-specific estimates for each mixed-effects model were then pooled in a meta-analysis, and the global fixed effect (β) and total heterogeneity ( I 2 ) across studies were estimated. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures Seven tau-PET outcomes that showed cross-sectional sex differences were examined across temporal, parietal, and occipital lobes. Results Among 6 studies assessed, there were 1376 participants (761 [55%] female; mean [range] age at first tau scan, 71.9 [46-93] years; 401 participants [29%] with high baseline Aβ; 412 APOE ε4 carriers [30%]). Among individuals with high baseline Aβ, female sex was associated with faster tau accumulation localized to inferior temporal (β = −0.14; 95% CI, −0.22 to −0.06; P = .009) temporal fusiform (β = −0.13; 95% CI, −0.23 to −0.04; P = .02), and lateral occipital regions (β = −0.15; 95% CI, −0.24 to −0.06; P = .009) compared with male sex. Among APOE ε4 carriers, female sex was associated with faster inferior-temporal tau accumulation (β = −0.10; 95% CI, −0.16 to −0.03; P = .01). Conclusions and Relevance These findings suggest that sex differences in the pathological progression of AD call for sex-specific timing considerations when administrating anti-Aβ and anti-tau treatments.

Abstract Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA‐binding protein 43 (TDP‐43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP‐43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP‐43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP‐43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP‐43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic‐predominant age‐related TDP‐43 encephalopathy and pinpointing of the optimal timing for testing anti‐tau and anti‐TDP‐43 treatments in trials. Highlights Both tau and TAR DNA‐binding protein 43 (TDP‐43) pathology contribute to medial temporal lobe atrophy. There is a positive association between tau and TDP‐43 and potentially a synergism. It is unclear if tau and TDP‐43 have an additive or synergistic effect on atrophy. The relative timing of the tau and TDP‐43 effects on atrophy remains unclear. Clarifying the interplay between tau and TDP‐43 will help improve magnetic resonance imaging biomarkers.

AbstractObjectiveLimited evidence guides the optimal timing of treatment after the detection of tumor growth during the observation of sporadic vestibular schwannoma (VS). The current work aimed to inform the timing of radiosurgical intervention based on an analysis of patient outcomes among those who ultimately failed stereotactic radiosurgery (SRS) and underwent salvage microsurgery.Study DesignA historical cohort study.SettingSeven centers across the United States and Norway.MethodsAdults with sporadic VS who underwent salvage microsurgery following failed primary SRS were included. The primary outcome of interest was the association between tumor size at the time of primary SRS and the ability to achieve gross total resection (GTR) and maintain postoperative House–Brackmann (HB) facial nerve grade I at the last follow‐up after salvage microsurgery.ResultsAmong 96 patients, the median (interquartile range [IQR]) cerebellopontine angle (CPA) tumor size at primary SRS was 14.5 mm (10.0‐19.0). Each 1‐mm increase in CPA tumor size at the time of primary SRS was associated with a 13% increased likelihood of near‐total/subtotal resection or most recent postoperative HB grade >I (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.05‐1.21, P = .001), with an optimal tumor size threshold to distinguish this outcome of 12 mm of CPA extension (c‐index 0.73). Similarly, for each 1‐mm increase in CPA tumor size at the time of primary SRS, a 9% increase in any postoperative complication with salvage microsurgery was observed (OR 1.09, 95% CI 1.02‐1.15, P = .009).ConclusionCorroborated by size threshold surveillance data informing the timing of primary microsurgical resection, the current study suggests that VS outcomes are optimized when primary radiosurgical intervention is undertaken on growing tumors when they harbor 10–15 mm of cerebellopontine angle extension or less.

This cohort study conducted among Minnesota children diagnosed with adrenoleukodystrophy through newborn screening examines correlation of C26:0 lysophosphatidylcholine (C26LPC) with clinical phenotype over 5 years and recommends adjusting early childhood surveillance regimens in children with lower C26LPC levels.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

ABSTRACTOur objectives are to report on the outcomes of adrenal insufficiency (AI) and cerebral ALD (cALD) in children diagnosed with X‐linked adrenoleukodystrophy (ALD) identified by newborn screening (NBS) in Minnesota in the first 5 years following initiation of NBS in 02/2017. A retrospective chart review was conducted for children diagnosed with ALD via Minnesota NBS from 02/06/2017 through 02/06/2022. Data reviewed included newborn screening data, diagnostic very long chain fatty acid levels, ABCD1 molecular testing results, serial measurements of ACTH and cortisol, and serial brain MRI results. Thirty‐two boys and 11 girls were molecularly and/or biochemically confirmed to have ALD. Of these 32 boys, six (2–7 years; median age:18 months) developed AI. Two boys developed cALD and underwent stem cell transplantation, one of whom also has been diagnosed with AI. All the pathogenic/likely pathogenic variants detected during the first 5 years had initial C26:0 lysophosphatidylcholine (C26:0 lysoPC) values over 0.3 μmol/L at the time of newborn screening. The addition of ALD to NBS in Minnesota has allowed for early detection of asymptomatic AI in six young patients and asymptomatic cALD in two patients. Data from our study shows a positive correlation between high newborn screening LysoPC levels and variant pathogenicity.

AbstractBackgroundThe rapid development of blood‐based biomarkers (BBMs) has improved Alzheimer’s disease (AD) diagnostics with some tests now potentially suitable for clinical use. This aligns with the clinical availability of anti‐Aβ immunotherapies for early symptomatic AD, where BBMs can help address the increasing need for more rapid and early diagnosis. Clinical practice guidelines (CPG) can help guide healthcare professionals in incorporating BBMs into their clinical practice. The Alzheimer’s Association is collaborating with methodologists and a panel of 11 clinical and subject‐matter experts to develop a CPG for specialists, informed by a systematic review, on the use of BBMs for AD.MethodThe panel drafted several clinical questions prioritizing two questions on the use of BBMs in cognitively impaired or cognitively unimpaired individuals as the populations of immediate interest. Plasma p‐tau and Aβ biomarkers tests are index tests, and amyloid PET imaging, neuropathology, and CSF are reference standards. Experts in the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach are conducting a systematic review of the diagnostic accuracy of BBMs index tests by searching three databases (Pubmed, Embase, Cochrane Library) and will include assessments of the quality of collected evidence to inform the panel’s decision‐making process. Patients/caregivers and key external organizations will be engaged throughout.ResultThis session will cover preliminary evidence for answering the two clinical questions. At the time of abstract submission, the search strategy resulted in 880 titles/abstracts for the study selection process. Data abstraction, analysis, and evidence development are pending. Recommendations for answering clinical questions will be developed after July 2024, and all recommendations will be finalized and published by early 2025.ConclusionThe integration of BBMs into clinical care offers the potential to improve earlier and more accurate AD diagnosis for a broader patient population and expand access to new AD therapies. The development of evidence‐based CPGs is a critical step forward in optimizing and standardizing the clinical use of BBMs. As the field of AD diagnostics and treatment continues to evolve, this CPG on the use of BBMs for AD will expand and be regularly updated to include new target audiences/settings, patient populations, and associated evidence.

AbstractBackgroundMedial temporal lobe (MTL) atrophy is an early feature of multiple neurodegenerative diseases. In genetic frontotemporal lobar degeneration (FTLD, i.e. individuals carrying GRN, MAPT, or C9orf72 mutations), MTL atrophy can occur 10‐15 years before symptom onset. We aimed to better characterize MTL atrophy patterns in presymptomatic and symptomatic genetic FTLD using a multi‐atlas segmentation pipeline that allows precise measurement of MTL subregions.MethodParticipants included a diagnostically mixed sample of familial FTLD mutation carriers (MAPT: N=87; C9orf72: N=117; GRN: N=65) and 142 non‐carrier family member controls from the ALLFTD study cohort (Table 1). T1‐weighted MRIs were preprocessed using a multi‐atlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS]) to segment the amygdala, anterior and posterior hippocampus, and MTL cortices: entorhinal cortex (ERC), perirhinal cortex or Brodmann areas (BA) 35 and 36, and parahippocampal cortex (PHC). Following rigorous quality control and manual correction (Figure 1), we assessed bilateral volume differences in mutation carriers compared to controls, adjusted for age, sex, and total intracranial volume. Analyses were conducted separately for symptomatic (FTLD‐Clinical Dementia Rating Global Score&ge;0.5) and presymptomatic (Global Score=0) mutation carriers.ResultOut of 413 scans, 317 (76.8%) segmentations passed quality control while 94 (22.8%) needed some manual edits—this was more common in symptomatic than presymptomatic carriers (32% versus 15%, p=0.001). Three scans were excluded (<1%; 2 complete scans, 1 for selected subregions) due to insufficient landmark visibility in symptomatic GRN and MAPT carriers. In symptomatic carriers, all MTL subregions demonstrated reduced volume compared to controls, although MAPT carriers exhibited particularly marked atrophy, especially in anterior MTL subregions (Table 2; amygdala, ERC, BA35, hippocampus). Presymptomatic MAPT and C9orf72 carriers also exhibited significant atrophy of primarily anterior MTL cortices, while presymptomatic GRN carriers only exhibited significantly smaller ERC volume compared to controls.ConclusionMTL atrophy is present in genetic FTLD across mutation carriers, even at the presymptomatic stage. Anterior MTL subregions, which are also susceptible to neuropathologic accumulation in early Alzheimer’s disease and Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), tend to be more vulnerable than posterior subregions. Unsurprisingly, MAPT carriers show the greatest MTL atrophy compared to controls across groups.