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AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability>0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability>0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.Methods248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50‐69, 70‐79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).ResultsSession completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p =.69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).ConclusionsThough the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.

AbstractIntroductionAlzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F‐flortaucipir‐positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA‐binding protein 43 (TDP‐43) was contributing to this volume‐uptake mismatch.MethodsSeventy‐seven participants with flortaucipir‐PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP‐43 pathology assessments. Bivariate‐response linear regression estimated the effect of age and TDP‐43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices.ResultsOlder participants had lower hippocampal volumes and overall flortaucipir uptake. TDP‐43‐immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP‐43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP‐43‐positives, reflecting the increasing TDP‐43 pathology frequency with age.DiscussionTDP‐43 pathology is a relevant contributor driving the volume‐uptake mismatch in older AD participants.Highlights TDP‐43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP‐43 pathology effect is seen in old age due to its increasing frequency. TDP‐43 pathology is a relevant driver of the volume‐uptake mismatch in old AD patients.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by pathological accumulation of scar tissue in the lung parenchyma. Many of the processes that are implicated in fibrosis, such as matrix deposition also occur following pneumonectomy (PNX). However, fibrosis does not occur. Since fibroblasts are the major cell type responsible for extracellular matrix production, we hypothesized that comparing their responses to PNX and bleomycin (BLM) would unveil key differences in the role they play during regulated and fibrotic lung growth. Methods RNA-sequencing was performed on flow cytometry-sorted fibroblasts from mouse lungs 14 days after bleomycin challenge, PNX, or sham. Pathway and transcription factor binding motif enrichment analysis were performed to characterize RNA-sequencing data. Normal human lung fibroblasts (NHLFs) were used as a cell culture model to validate targets. Results RNA-sequencing analysis revealed similar biological processes to be involved in both responses, including signaling by transforming growth factor-β (TGF-β1) and tumor necrosis factor-α. Transcription factor binding motif enrichment predicted erythroid transformation specific (ETS) superfamily members to play a key role in the response to BLM, whereas nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) were predicted to orchestrate much of the response to PNX. Itpkc, encoding inositol triphosphate kinase C, was a gene uniquely up-regulated by PNX and a likely AP-1 target. ITPKC overexpression in NHLFs antagonized the fibrotic effect of TGF-β1. RNA-sequencing analysis of primary NHLFs overexpressing ITPKC further supported its role in repressing collagen production and predicted it as an activator of canonical NF-κB signaling. ITPKC overexpression showed considerable overlap with the innate immune signaling seen following PNX. Conclusion Taken together, our RNA-sequencing analysis suggests that during post-PNX lung growth, AP-1 activates ITPKC to promote canonical NF-κB signaling to prevent fibrogenesis. Future studies to understand this lack of ITPKC induction during fibrotic injury may identify attractive therapeutic targets.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 14 months. GBMs are challenging to treat due to their heterogeneous nature. It has also been seen that these tumors have sex differences in their cellular subtypes as well as imaging. Radiomics has the potential to provide a non-invasive, spatial understanding of genetic and epigenetic diversity in these complex tumors and to aid in treatment planning. We have an ongoing study to obtain image-localized biopsies from GBM patients, allowing us to complete radiomic analysis and make connections between immunohistochemistry (IHC) and magnetic resonance imaging (MRI) features. We sought to determine if the patterns on imaging were correlated with underlying tumor biology. We focused on immunohistochemistry (IHC) markers of key features of tumor biology including SOX2 for stem-like tumor cells, CD68 for immune response and Ki67 for proliferation kinetics. Our study included 38 patients with a total of 99 biopsies (bxs): 27 males with 77 bxs and 11 females with 22 bxs. Biopsies were sectioned and stained for the SOX2, CD68, and KI67 markers. We computed 18 first-order radiomic features at each biopsy location for patients’ multimodal MRIs: T1W, T1Gd, T2W, FLAIR, apparent diffusion coefficient, diffusion weighted imaging (DWI) and susceptibility weighted imaging. We then performed correlation analysis between each radiomic feature and marker abundance for each IHC stain. Overall, we found sex-distinct patterns connecting imaging with these IHC markers. For example, amongst female patients, DWI held more prominent correlations with SOX2 than in males. Whereas there were more correlations between CD68 IHC abundance and T1Gd imaging features in males compared to females. Taken together, the overall patterns connecting locoregional imaging features to these IHC markers showed sex-distinct patterns suggesting the potential for sex to be an important biological variable when interpreting the biology underlying imaging changes.

AbstractRadioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease