Citations

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

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

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

ABSTRACTBackgroundOlfactory neuroblastoma (ONB) is a rare sinonasal malignancy primarily treated with surgery. For tumors arising from the olfactory area, traditional treatment involves transcribriform resection of the anterior cranial fossa. Surgery can be performed with unilateral or bilateral resection depending on extent of involvement; however, there are currently no studies comparing outcomes between the two.MethodsProspective and retrospective data on primary ONB patients were collected from a multicenter registry involving eight academic sites. Propensity score matching (PSM) was used to create patient cohorts with similar baseline characteristics. Cox proportional hazards and Kaplan Meier analyses assessed overall survival (OS). Logistic regression assessed associations between extent of resection (unilateral versus bilateral) and tumor recurrence or postoperative cerebrospinal fluid (CSF) leak.ResultsA total of 187 ONB patients (47.6% female) with an average age of 53.6 ± 15.1 years were analyzed. Most tumors were unilateral (81.3%) and predominantly Kadish C (58.3%) or Hyams II (55.8%). Overall, 56.7% of patients underwent bilateral resection. Fifty‐four patients experienced tumor recurrence and nine had postoperative CSF leaks. Following PSM (n = 45/group), extent of resection was not associated with mortality (hazard ratio [HR] 1.73; p = 0.407) or OS (p = 0.400). There was no association between extent of resection and recurrence (odds ratio [OR] 0.90; p = 0.814) or postoperative CSF leak (OR 1.54; p = 0.647).ConclusionsFor ONB tumors where unilateral resection may be feasible and oncologically sound, the decision for unilateral versus bilateral resection showed no significant effect on survival, recurrence, or postoperative CSF leak. Oncologic outcomes may be comparable when resection is tailored to individual patient and tumor characteristics.

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

AbstractBackgroundThe association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.Method113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aβ‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aβ status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.ResultPPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aβ status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aβ status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aβ status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.ConclusionHarmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aβ status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.

Background Sinonasal mucosal melanoma has poor survival despite multimodality treatment. While the impact of immunotherapy (IT) on metastatic cutaneous melanoma is well-defined, there are relatively little data on sinonasal mucosal melanoma. Objective We sought to define immunotherapy outcomes in patients with sinonasal mucosal melanoma. Methods A retrospective cohort study evaluated patients treated with IT during their overall treatment strategy for SNMM. Patient demographics, treatment, and survival outcomes were recorded. Results 52 patients had IT treatment for SNMM from 2000 to 2022, with an average age of 69.1 ± 11.9 years. The most common treatment was surgery with radiation and IT ( n = 26, 50%). Most regimens consisted of a combination of Nivolumab and Ipilimumab ( n = 17, 32.7%) or pembrolizumab ( n = 14, 26.9%). 44.2% of patients experienced reported complications. Overall survival at 1-, 2-, and 5 years was 86.9%, 74.1%, and 39.1%, respectively. Conclusion Approximately half of patients will have a local response following immunotherapy, but it is rare to have improvement at metastatic locations. Further research within our group will assess optimal timing and markers that are predictive of response.

AbstractBackgroundThe association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.Method113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aß‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aß status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.ResultPPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aß status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aß status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aß status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.ConclusionHarmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aß status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.

AbstractBackgroundMany treatments targeting frontotemporal lobar degeneration (FTLD) are in the developmental pipeline, but the rarity of the disease, coupled with the behavioral and motor features of FTLD, make it challenging to identify sufficient trial participants who can attend frequent in‐person visits. Decentralized clinical trial designs with remote evaluations are attractive alternatives but require validated tools for symptom tracking. Our previous cross‐sectional analyses showed that cognitive tasks deployed via the ALLFTD Mobile App are reliable and sensitive to early stages of disease. The current study seeks to evaluate whether unsupervised smartphone cognitive tests are sensitive to longitudinal changes that occur with increasing FTLD disease stage.MethodThe study included 194 participants (mean baseline age 54.30, SD = 15.66; mean education = 16.52, SD = 2.31; 55.2% women) who were asymptomatic (Clinical Dementia Rating plus FTLD (CDR®+NACC‐FTLD) = 0 [n = 109; 43 carriers of FTLD‐associated genetic variants]), prodromal (CDR®+NACC‐FTLD = 0.5 [n = 39]), or symptomatic (CDR®+NACC‐FTLD>0.5 [n = 46]) at baseline. Participants completed ALLFTD Mobile App smartphone versions of Stroop, flanker, and 2‐back tasks, as well as an adaptive associative memory task, every six months for up to two years. Linear‐mixed effects models investigated the effect of disease severity on cognitive trajectories by testing the interaction of baseline CDR®+NACC‐FTLD box score and time on smartphone test scores. Analyses were repeated in the subsample of asymptomatic/prodromal CDR®+NACC‐FTLD<1) familial FTLD mutation carriers (C9orf72, n = 27; MAPT, n = 16). All models controlled for age, education, and sex.ResultGreater baseline disease severity was associated with lower cognitive scores across all tasks (β range: ‐0.28 to ‐0.13; p’s < 0.001), and faster rates of decline on the memory and 2‐back tasks (β range: ‐0.15 to ‐0.07; p’s<0.04). When the sample was restricted to asymptomatic and prodromal individuals (CDR®+NACC FTLD<1), greater baseline disease severity was still associated with lower scores across most tasks (β range: ‐0.48 to ‐0.27; p’s<0.002; 2‐back: β = ‐0.19, p = 0.26). When the sample was restricted to asymptomatic/prodromal mutation carriers, disease severity remained associated with the memory and flanker tasks (β range: ‐0.85 to ‐0.45; p’s<0.01).ConclusionThis study provides initial evidence that longitudinal smartphone‐based cognitive measurements capture the accelerated cognitive worsening that accompanies increasing disease progression in FTLD.