Citations

Abstract Aging‐related bone loss significantly impacts the growing elderly population globally, leading to debilitating conditions such as osteoporosis. Senescent osteocytes play a crucial role in the aging process of bone. This longitudinal study examines the impact of continuous local and paracrine exposure to senescence‐associated secretory phenotype (SASP) factors on biophysical and biomolecular markers in osteocytes. Significant cytoskeletal stiffening in irradiated (IR) osteocytes are found, accompanied by expansion of F‐actin areas and a decline in dendritic integrity. These changes, correlating with alterations in pro‐inflammatory cytokine levels and osteocyte‐specific gene expression, support the reliability of biophysical markers for identifying senescent osteocytes. Notably, local accumulation of SASP factors have a more pronounced impact on osteocyte biophysical properties than paracrine effects, suggesting that the interplay between local and paracrine exposure can substantially influence cellular aging. This study underscores the importance of osteocyte mechanical and morphological properties as biophysical markers of senescence, highlighting their time dependence and differential effects of local and paracrine SASP exposure. Collectively, the investigation into biophysical senescence markers offers unique and reliable functional hallmarks for the non‐invasive identification of senescent osteocytes, providing insights that can inform therapeutic strategies to mitigate aging‐related bone loss.

Background N-methyl-D-aspartate receptor antibody encephalitis (NMDAR-Ab-E) can have an onset during, after or prior to a pregnancy. In animal models, transplacental NMDAR immunoglobulin G transfer can affect neurodevelopment. In contrast, clinical reports of mothers affected by NMDAR-Ab-E typically are reassuring. We systematically reviewed maternal, infant and childhood clinical data pertaining to NMDAR-Ab-E with an onset before, during or after pregnancy and compared this to our single autoimmune neurology centre experience. Methods After pre-registration on PROSPERO (CRD42023408447), we searched PubMed and Scopus for NMDAR-Ab-E case reports/series with an onset before, during or after pregnancy (last search 19/10/2023). We extracted maternal, neonatal and childhood outcomes using an idealised checklist to derive summary statistics. Results After quality control, we identified 66 pregnancies in 61 women from 48 reports or series. 72% of women recovered with minimal or no neurological deficits, comparable to non-pregnancy-associated NMDAR-Ab-E. Likewise, 80% of pregnancies resulted in live births with a single neonatal death reported. Data on neonatal outcome measures were frequently unreported, and childhood follow-up was provided in only 60%. Our centre’s experience is consistent: 3/4 mothers recovered with no functional deficits and 7/8 children without evidence of compromise at a median follow-up of 2 years. Conclusions Current evidence does not overall suggest unfavourable maternal, fetal or childhood outcomes after NMDAR-Ab-E. However, the available sample is small, predominantly single case reports with modest follow-up, lacks standardisation, and data are often incomplete. Future approaches should address these caveats: developing multi-centre collaboration towards an international registry.

OBJECTIVE Stereotactic radiosurgery (SRS) is an effective treatment for refractory tremor. However, the lack of reliable patient-specific targeting biomarkers leads to varying outcomes. Although connectomic-based targeting is commonly used in deep brain stimulation, its application in SRS is limited. This study aimed to develop a new targeting approach by using patient-specific structural connectivity to improve outcomes after SRS. METHODS The authors performed a retrospective study of patients in a prospective trial for frameless virtual-cone SRS on a linear accelerator for essential tremor or tremor-dominant Parkinson disease. The primary endpoint was percentage improvement in Fahn-Tolosa-Marin tremor rating scale scores contralateral to the treatment side. Probabilistic tractography assessed connectivity from each thalamic voxel to the primary motor cortex (M1), primary sensory cortex (S1), and supplemental motor area/premotor cortex (SMA/PMC). Group-level comparisons were conducted to evaluate the relationship between the sweet spot for maximum contralateral tremor improvement and areas maximally connected to M1, S1, and SMA/PMC. Multiple regression analysis assessed the relationship between the lesion centerpoint coordinates and the maximally connected voxel to M1, S1, and SMA/PMC at the individual level. RESULTS The analysis included 27 patients with a mean follow-up of 17.9 ± 11.1 months. The sweet spot for maximal contralateral tremor improvement at the group level was in the region most connected to M1 cortex. Smaller y-distances (anterior-posterior) from the lesion center to the M1 maximally connected voxel significantly correlated with tremor improvement at the single-subject level (p < 0.001). However, the authors found no significant correlation between the lesion y-coordinate and the maximally connected voxel to SMA/PMC and S1, nor between the x-distances from the lesions to the SMA/PMC, M1, and S1 voxels (p > 0.07). CONCLUSIONS This study demonstrates that patient-specific connectivity between the treatment target and M1 correlates with treatment outcomes. The authors’ approach provides a practical targeting method for SRS thalamotomy for tremor.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Background: Cerebral microbleeds (CMBs) are associated with incident dementia, but the impact of specific CMB patterns is unclear. CMBs in lobar regions suggest cerebral amyloid angiopathy (CAA), which is sometimes accompanied by superficial siderosis (SS), while subcortical CMBs indicate hypertensive origins. This study investigates the association between CMB patterns and dementia risk in the community-based longitudinal Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: All ARIC-NCS participants with a 3T research MRI at visit 5 (2011-13; aged 67-90) without intracerebral hemorrhage or dementia were included. CMB and SS presence and location were coded from T2* GRE sequences. Individuals were classified into one of four patterns: no CMBs, only subcortical, mixed (lobar and/or SS + subcortical), and only lobar and/or SS. Incident dementia diagnoses were defined by cognitive testing (in-person and telephone), informant interviews, and hospital discharge codes or death certificates. Cox proportional-hazards models assessed the association between the presence, patterns, and frequency of CMBs (0,1,2,3+), presence of SS, and incident dementia from visit 5 through 2020. Model covariates included demographics, vascular risk factors, and imaging markers of small vessel disease. Results: Among 1609 participants, 364 had CMBs (Table 1). Participants with CMBs tended to be older and female compared to those without CMBs. Compared to individuals with no CMBs, presence of any CMBs was associated with an increased risk of dementia (Table 2). Compared to individuals without CMBs, individuals with only lobar CMBs and/or SS had an increased risk of incident dementia, as did individuals with mixed CMBs, but individuals with subcortical-only did not. Participants with ≥3 CMBs of any variant had an increased risk of incident dementia vs no CMBs. Although SS was infrequent, its presence (vs no SS) was associated with an elevated risk of dementia. Conclusion: CMBs, particularly in a mixed or lobar and/or SS-only pattern, are linked to an increased risk of incident dementia. The number of recurrent CMBs and any SS also showed an increased dementia risk. These data support that dementia risk is high in individuals with a CAA-type CMB pattern, but also emphasize that a mixed pattern, not typical of CAA alone, is associated with a high risk of dementia. Further studies should evaluate mechanisms by which these different patterns contribute to dementia.

Importance The emergency department (ED) offers an opportunity to initiate palliative care for older adults with serious, life-limiting illness. Objective To assess the effect of a multicomponent intervention to initiate palliative care in the ED on hospital admission, subsequent health care use, and survival in older adults with serious, life-limiting illness. Design, Setting, and Participants Cluster randomized, stepped-wedge, clinical trial including patients aged 66 years or older who visited 1 of 29 EDs across the US between May 1, 2018, and December 31, 2022, had 12 months of prior Medicare enrollment, and a Gagne comorbidity score greater than 6, representing a risk of short-term mortality greater than 30%. Nursing home patients were excluded. Intervention A multicomponent intervention (the Primary Palliative Care for Emergency Medicine intervention) included (1) evidence-based multidisciplinary education; (2) simulation-based workshops on serious illness communication; (3) clinical decision support; and (4) audit and feedback for ED clinical staff. Main Outcome and Measures The primary outcome was hospital admission. The secondary outcomes included subsequent health care use and survival at 6 months. Results There were 98 922 initial ED visits during the study period (median age, 77 years [IQR, 71-84 years]; 50% were female; 13% were Black and 78% were White; and the median Gagne comorbidity score was 8 [IQR, 7-10]). The rate of hospital admission was 64.4% during the preintervention period vs 61.3% during the postintervention period (absolute difference, −3.1% [95% CI, −3.7% to −2.5%]; adjusted odds ratio [OR], 1.03 [95% CI, 0.93 to 1.14]). There was no difference in the secondary outcomes before vs after the intervention. The rate of admission to an intensive care unit was 7.8% during the preintervention period vs 6.7% during the postintervention period (adjusted OR, 0.98 [95% CI, 0.83 to 1.15]). The rate of at least 1 revisit to the ED was 34.2% during the preintervention period vs 32.2% during the postintervention period (adjusted OR, 1.00 [95% CI, 0.91 to 1.09]). The rate of hospice use was 17.7% during the preintervention period vs 17.2% during the postintervention period (adjusted OR, 1.04 [95% CI, 0.93 to 1.16]). The rate of home health use was 42.0% during the preintervention period vs 38.1% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of at least 1 hospital readmission was 41.0% during the preintervention period vs 36.6% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of death was 28.1% during the preintervention period vs 28.7% during the postintervention period (adjusted OR, 1.07 [95% CI, 0.98 to 1.18]). Conclusions and Relevance This multicomponent intervention to initiate palliative care in the ED did not have an effect on hospital admission, subsequent health care use, or short-term mortality in older adults with serious, life-limiting illness. Trial Registration ClinicalTrials.gov Identifier: NCT03424109

Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.

AbstractBackgroundCerebral small vessel disease (cSVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although risk factors for cSVD have been identified, little is known about the biological processes and molecular mediators that influence cSVD development and progression.MethodsWithin the Atherosclerosis Risk in Communities (ARIC) study, we used SomaScan Multiplexed Proteomic technology to relate 4,877 plasma proteins to concurrently measured MRI‐defined cSVD characteristics, including WMHs, CMHs, and lacunar infarcts, in late‐life (n=1508; mean age: 76). Candidate protein associations with WMH volume were replicated in the Cardiovascular Health Study (n=765; mean age: 73) and Baltimore Longitudinal Study of Aging (n=902; mean age: 66). Cohort‐specific effect estimates were pooled using a fixed‐effect, inverse variance weighted meta‐analysis. Within 4228 non‐demented older adults in ARIC, we examined the association of WMH‐associated proteins with eight‐year dementia risk (641 incident dementia cases) using multivariate Cox proportional hazard models. All multivariate regression models were adjusted for demographic, kidney function, and cardiovascular risk variables.ResultsThis proteome‐wide analysis of older adults identified 13 WMH‐associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis (Figures 1a, 2a). Nine of these proteins replicated in one or more external cohort (Figures 1b, 2b) and two proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), remained associated with late‐life WMH volume when measured nearly two decades earlier during midlife (Figures 1c, 2c). Eight of the 13 WMH‐associated proteins were associated with lacunar infarcts, 6 with subcortical CMHs, and 4 with lobar CMHs (Figures 1d, 2d). Although none of the genes coding for WMH‐associated proteins have been nominated by WMH GWAS, 7 of these genes have been previously linked to cardiometabolic traits known to influence cSVD, such as blood pressure and cholesterol (Figures 1e, 2e). Finally, 11 candidate proteins were associated with incident dementia, underscoring their clinical relevance (Figures 1f, 2f).ConclusionsThis large‐scale proteomic analysis within longitudinal community‐based samples identified several plasma proteins, including OMG and NPTXR, as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

AbstractBackgroundBlood‐based biomarkers show promise as a noninvasive, inexpensive method for measuring Alzheimer’s disease pathology throughout the lifecourse. However, the predictive and classification accuracy of these biomarkers at different stages of the lifecourse and among diverse, community‐dwelling populations requires further investigation.MethodBetween 2014 and 2015, 329 dementia‐free participants from the Atherosclerosis Risk in Communities Study underwent brain magnetic resonance imaging (MRI) and florbetapir positron emission tomography (PET). Amyloid positivity was defined as a global cortex standardized uptake value ratio greater than 1.2. Stored plasma samples collected in midlife (1993‐95, mean age 58.5 years) and late‐life (2011‐13, mean age 76.2 years) from a subsample of 259 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 (p‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Unadjusted and covariate‐adjusted logistic regression models estimated the association between plasma biomarkers from midlife and late‐life and amyloid positivity in late‐life. Unadjusted receiver operating characteristic curves documented the classification accuracy of the plasma biomarkers separately and collectively.ResultThe sample (Table 1) included 151 women (58.1%), 105 Black participants (40.4%), and 136 (52.3%) participants with amyloid positivity. In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, assays measured in midlife were not associated with amyloid positivity in late‐life (Table 2). However, late‐life measurements of Aβ42/40, p‐Tau181, and GFAP and change per decade from midlife to late‐life in p‐Tau181 and GFAP were associated with greater odds of amyloid positivity. The greatest classification accuracy (Figure 1) was achieved by using all assays measured in midlife and late‐life (AUC = 0.754), although the accuracy when using only late‐life measures was comparable (AUC = 0.737).ConclusionLate‐life plasma biomarkers of Alzheimer's disease neuropathology and astrogliosis were associated with late‐life amyloid positivity, but midlife plasma biomarkers obtained 16 to 20 years earlier did not exhibit a statistically significant association. Additional longitudinal research is needed to determine whether changes in plasma biomarkers measured before an individual is classified as amyloid positive can be used to identify individuals at risk of developing Alzheimer's disease.