Citations

AbstractBackgroundCharacterizing stress can inform our understanding of direct and indirect pathways impacting mental and physical health outcomes, including age‐related cognitive decline. Chronic stress has been strongly associated with increased risk for cognitive decline, and hair cortisol concentration (HCC) has emerged as a viable neuroendocrine biomarker for its quantification. Cognitive appraisal of stress (CAS) provides key insight into the cognitive framework for responding to a given stressor. We implemented a multi‐pronged approach to evaluate chronic stress and examined its relation to cognition in older adults.MethodParticipants were 22 cognitively normal individuals (x̄ MMSE = 29.33, 0.92; x̄ age: 67.3 ± 8.8 years old, 17.0 ± 2.9 years of education, 54.5% female, 92.6% Non‐Hispanic White). Participants completed the Stress and Adversity Inventory (STRAIN) assessing lifetime stressor exposure and the Primary and Secondary Cognitive Appraisal Scale (PSCAS). HCC was used as a neuroendocrine biomarker of chronic stress. A brief cognitive battery assessing episodic memory and executive functions (Digit Span, HVLT‐R, Trail Making Test, Letter Fluency) and mood/anxiety measures were completed. To correct for skewness, log‐transformed HCC values were used for Pearson and partial correlation analyses controlling for age and education.ResultLifetime stressor exposure and CAS were not significantly related to cognitive performance (all ps > 0.05). There was a marginally significant association between HCC and executive functions (r = ‐0.41, p = 0.08). Total lifetime stressor count, chronicity, and severity were unrelated to symptoms of depression and anxiety (all ps > 0.05). Although lifetime stressor exposure and mood were not significantly related to HCC, higher HCC was associated with higher perceived control of stress (r = 0.45, p = 0.03).ConclusionHCC may be more sensitive to CAS rather than to objective stressor exposure. This highlights the potential of interventions targeted at improving coping in those with chronic stress. Results are preliminary, and the present study will explore impact of social and structural determinants of health on chronic stressor exposure, appraisal, and cognition.

AbstractBackgroundPlasma biomarker development is of increasing interest due to improved accessibility compared to established diagnostic modalities for Alzheimer’s disease (AD). However, current plasma biomarker candidates have not been tested comprehensively in diverse populations, and these markers represent only a fraction of pathways perturbed in AD. Therefore, there is a need to identify novel plasma biomarkers that account for both disease heterogeneity and patient diversity. This study seeks to address these knowledge gaps through untargeted plasma biomarker discovery in African Americans (AA), an underrepresented group in AD research despite having a higher risk of developing AD compared to non‐Hispanic Whites.MethodsUntargeted proteomics were performed using the SomaScan 7k assay on plasma samples from AA study participants clinically diagnosed as AD (n=142) or cognitively unimpaired (CU, n=144). Linear regression models adjusted for age, sex, and batch were implemented to identify differentially expressed proteins (DEPs). APOE was additionally adjusted for in a sensitivity analysis. DEPs with the lowest q‐values were selected as predictors in a receiver operating characteristic (ROC) analysis to assess their accuracy to discriminate AD versus CU individuals.ResultsA total of 153 DEPs were identified (q<0.05) when adjusting for age, sex, and batch, and 100 DEPs were identified when additionally adjusting for APOE. Of the 66 proteins overlapping between these models, SERPINA3, C7, IGFBP‐2, DKK3, SMOC1, and ACES had the lowest q‐values and were included in a ROC model adjusted for age, sex, and APOE. That model classified AD versus CU with an area under the curve (AUC) of 0.87 (95%CI: 0.83‐0.91), a 10.4% improvement over the base model including age, sex, and APOE (AUC=0.78; 95%CI: 0.72‐0.83). Despite the unbiased selection of proteins included in the ROC model, all selected proteins have been associated with AD and implicated in related functional pathways such as neuroinflammation, synaptic function, and insulin signaling.ConclusionThis preliminary plasma biomarker panel demonstrates the potential diagnostic capabilities of biomarker discovery through untargeted proteomics. Future directions include validation of findings in external datasets, concomitant assessment of p‐tau217, and evaluation of machine learning models to define the optimal diagnostic and predictive set of plasma protein biomarkers for AD in AA.

AbstractBackgroundRecent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.MethodWe assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐ß (Aß) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score =1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.ResultCI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)ConclusionOur study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.

AbstractBackgroundRecent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.MethodWe assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score ≥1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.ResultCI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)ConclusionOur study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.

AbstractBackgroundFew normative data for computerized measures administered in unsupervised remote environments are available. We aimed to determine what variables to include in normative models for remote self‐administered assessments, develop normative data for measures administered through Mayo Test Drive (MTD, a multi‐device remote cognitive assessment platform) and evaluate application of norms.Method1240 adults ages 33‐100 (96% White) from the Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center met normative sample inclusion criteria that included a concordant Cognitively Unimpaired (CU) diagnosis (3 independent raters all diagnosed CU) and CDR = 0 (see Table 1 for sample characteristics). Raw test scores were converted to normalized scaled scores. We derived regression‐based normative data that adjusted for age, age2, sex and education (base model); alternative models are also provided (age+age2+sex; age+ age2). We evaluated whether additional model terms beyond the base model were needed using an a priori cut‐off of 1% variance improvement in adjusted R2 over and above the base model. We examined rates of low test performance defined as performance below ‐1 SD in independent validation samples (n = 167 concordant CU, n = 64 mild cognitive impairment (MCI), n = 14 dementia). Rates are considered significantly different than expected when 95% confidence intervals (CIs) do not include the expected 14.7% base rate frequency.ResultNo additional potential model terms met our a priori cut‐off for inclusion beyond the base model (see Table 2), including other quadratic and cubic terms or interactions, device type, response input type, potential session interference, and national area deprivation index (ADI available in subset; N = 776). Application of norms showed expected rates of low test performance among CU participants (95% CI includes expected base rate) and significantly greater than expected rates of low test performance for all variables in MCI (e.g., 62.5% for composite) and dementia (e.g., 71.4% for composite; see Table 3).ConclusionTypical normative models appear appropriate for remote self‐administered measures and are sensitive to cognitive impairment. Device type and response input did not explain enough variance to warrant inclusion in normative models but are important for individual level interpretation. Future work will improve representation of individuals from under‐represented groups.

Abstract Background While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples for monitoring biomarker discovery, including anatomical location and post-surgical changes, remains unknown. Methods Aptamer-based proteomics was performed on 147 CSF samples from 74 patients; 71 of whom had grade 2–4 astrocytomas or grade 2–3 oligodendrogliomas. This included pre- versus post-resection intracranial CSF samples obtained at early (1–16 days; n = 20 patients) or delayed (86–153 days; n = 11 patients) time points for patients with glioma. Paired lumbar versus intracranial glioma CSF samples were also obtained (n = 14 patients). Results Significant differences were identified in the CSF proteome between lumbar, subarachnoid, and ventricular CSF in patients with gliomas. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome, with distinct sets of proteins present at different time points since resection. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies, such as bevacizumab and immunotherapies. Conclusions The intracranial glioma CSF proteome serves as a rich and dynamic reservoir of potential biomarkers that can be used to evaluate the effects of resection and other therapies over time. All data within this study, including detailed individual clinical annotations, are shared as a resource for the neuro-oncology community to collectively address these unanswered questions and further understand glioma biology through CSF proteomics.

Abstract Purpose: Current methods for glioma response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using longitudinal intracranial cerebrospinal fluid (CSF) from patients with gliomas. Experimental Design: Adults with gliomas underwent longitudinal intracranial CSF collection via Ommaya reservoirs or ventriculoperitoneal shunts. Cell-free DNA (cfDNA) was extracted and analyzed using PredicineCARE for cancer variant profiling and/or PredicineSCORE for low-pass whole-genome sequencing. Results: Five patients (two females and three males; median age, 40 years; range, 32–64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n = 4) or ventriculoperitoneal shunts (n = 1). In total, 47 CSF samples were obtained (median volume, 4.00 mL; 0.5–5 mL). Forty-one samples (87.2%) yielded sufficient cfDNA for testing. Patient-specific tumor-associated variant allelic frequencies (VAF), and thus tumor fraction, decreased in pre- versus postchemoradiation samples, including through pseudoprogression. These also increased with radiographic progression in three patients, although identifying the time of definitive disease progression from MRIs was a significant limitation. In two patients with isocitrate dehydrogenase (IDH)–mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate levels (0.64× and 0.62×, respectively, for the first patient and 0.01× and 0.07× for the other patient), although D-2-hydroxyglutarate and IDH1 VAF were not concordant in one patient thereafter. Moreover, the copy-number burden decreased below the limit of quantification during treatment and increased above the limit at progression. Conclusions: Longitudinal intracranial CSF cfDNA can be obtained in patients with gliomas during their disease course. However, before deploying this technique, numerous questions and challenges should be answered.

Introduction: The Mindfulness-Based Stress Reduction program for breast cancer survivors (MBSR [BCs]) is a stress-reducing program designed to increase cognitive functioning through four meditational practices. This randomized clinical trial aimed to determine if improvements in cognitive functioning and perceived cognitive abilities achieved from the MBSR(BC) were mediated through increased mindfulness, decreased rumination, and decreased perceived stress. Methods: Breast cancer survivors (BCSs) who met inclusion criteria of stage I, II, or III BC and received either chemotherapy (CT) or both CT and radiation were randomized to either the 6-week MBSR(BC), or Breast Cancer Education Support (BCES) program, or to a usual care (UC) regimen. Analysis of covariance was first implemented to identify potential mediators, followed by a formal mediational analysis to evaluate the effects of MBSR(BC) on 6-, 12-, and 26-week outcomes. Results: After consent, 212 BCS were randomized to MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31). The mean age was 56.5 and the majority of the BCS, 73.1%, were White and non-Hispanic. Results showed increases in “observing” as part of mindfulness as a potential mediator of MBSR(BC) effects on impairments on quality of life and logical memory at 6 months relative to UC. No mediation effects were identified for outcomes measured at 6 or 12 weeks and also when MBSR(BC) was compared with the BCES program. Discussion: These results partially supported our hypothesis that improvement in cognitive functioning would occur through increased mindfulness. Although few mediating relationships were identified, results showed a relationship between mindfulness and cognitive functioning. Both mediating relationships occurred through increases in “observing,” a subconcept of “mindfulness,” when compared to the MBSR(BC) with UC at 6 months. This study shows that mediators may help “optimize” clinical therapeutic treatment effects, thus contributing to the advancement of science. Trial Registration: ClinicalTrials.gov, www.ClinicalTrials.gov . Registration Number: NCT02786797.

Background: Reporting the 50 most cited manuscripts on virtual surgical planning (VSP) for craniofacial surgery, thereby providing a comprehensive review of landmark papers. Methods: The Web of Science Citation Index was used to identify the 50 most cited manuscripts on VSP in craniofacial surgery. These were classified by level of evidence, type of study, topic of interest, and anatomic site. Results: The mean number of citations was 126.3 ± SD 51.7. Twenty were clinical papers: 9 reviews, and 21 workflow or technology. The most common level of evidence (LoE) was 4 ( n = 12), followed by 3 ( n = 6), 2 ( n = 1), and 5 ( n = 1). Thirty-nine of 50 articles focused on the maxillomandibular area of the face, 5 zygomatic, 5 orbit, 2 cranial vault, and 1 nasal ethmoid bone. The majority of articles (37 of 50) were on orthognathic surgery, 11 facial reconstruction, 2 calvarium reconstruction or craniosynostosis, and 2 free flap procedures. Year of publication ranged from 2000 to 2019; 34 articles were published in craniomaxillofacial journals. Conclusion: VSP is a relatively new technology and most highly cited articles on this topic pertain to workflow, technology, and protocols, as these are necessary for its integration into clinical practice. In our list, VSP was most used in orthognathic surgery; however, due to the potential increased efficiency and accuracy, it is being explored in other areas of craniofacial surgery such as facial reconstruction and craniosynostosis. Accordingly, we expect to see increasingly widespread usage of VSP in other areas of surgery, which could potentially lead to highly cited papers.