Preliminary reference values for Alzheimer's disease plasma biomarkers in Congolese individuals with and without Alzheimer's disease.

Background: Western countries have provided reference values (RV) for Alzheimer's disease (AD) plasma biomarkers, but there are not available in Sub-Saharan African populations. Objective: We provide preliminary RV for AD and other plasma biomarkers including amyloid- ß (Aß42/40), phosphorylated tau-181 and 217 (p-tau181, p-tau217), neurofilament light (Nfl), glial fibrillary acidic protein (GFAP), interleukin 1b and 10 (IL-1b and IL-10) and tumor necrosis factor α (TNFα) in Congolese adults with and without dementia. Methods: 85 adults (40 healthy and 45 dementia) over 50 years old were included. Blood samples were provided for plasma AD biomarkers Aß42/40 and p-tau181, p-tau217; Nfl and GFAP; IL-1b and IL-10 and TNFα analyzed using SIMOA. Linear and logistic regressions were conducted to evaluate differences in biomarkers by age and gender and neurological status, and for the prediction of dementia status by each individual biomarker. RV were those that optimized sensitivity and specificity based on Youden's index. Results: In this sample of 85 adults, 40 (47%) had dementia, 38 (45.0%) were male, overall mean age was 73.2 (SD 7.6) years with 8.3 (5.4) years of education. There were no significant differences in age, gender, and education based on neurological status. Biomarker concentrations did not significantly differ by age except for p-tau181 and GFAP and did not differ by sex. Preliminary cutoffs of various plasma in pg/ml were 0.061 for Aß42/40, 4.50 for p-tau 181, 0.008 for p-tau 217, 36.5 for Nfl, 176 for GFAP, 1.16 for TNFa, 0.011 for IL-1b, and 0.38 for IL-10. All AUCs ranged between 0.64-0.74. P-tau 217 [0.74 (0.61, 0.86)] followed by GFAP [0.72 (0.61, 0.83), and Nfl [0.71 (0.60, 0.82)] had the highest AUC compared to other plasma biomarkers. Conclusions: This study provides RV which could be of preliminary utility to facilitate the screening, clinical diagnostic adjudication, classification, and prognosis of AD in Congolese adults.

Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

Alzheimer's pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer's disease (AD), and features of AD pathology like beta-amyloid (Aß) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer's neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. METHODS: We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aß[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aß[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aß[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aß[ +] or Aß[ -] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen's d > 0.50) were interpreted as potentially meaningful. RESULTS: Cognitively, within the TES group, Aß[ +] RHI/TES performed worse than Aß[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aß[ +] and Aß[ -] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aß[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aß[ -] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p's ≤ .004, d's > 1.0). CONCLUSIONS: Presence of Alzheimer's pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aß-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aß[ -] RHI/TES. Measuring well-validated Alzheimer's biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Presence of Preoperative Neurodegeneration Biofluid Markers in Patients with Postoperative Delirium.

BACKGROUND: The pathophysiology of delirium is incompletely understood, including what molecular pathways are involved in brain vulnerability to delirium. This study examined whether preoperative plasma neurodegeneration markers were elevated in patients who subsequently developed postoperative delirium through a retrospective case-control study. METHODS: Inclusion criteria were patients of 65 yr of age or older, undergoing elective noncardiac surgery with a hospital stay of 2 days or more. Concentrations of preoperative plasma P-Tau181, neurofilament light chain, amyloid ß1-42 (Aß42), and glial fibrillary acidic protein were measured with a digital immunoassay platform. The primary outcome was postoperative delirium measured by the Confusion Assessment Method. The study included propensity score matching by age and sex with nearest neighbor, such that each patient in the delirium group was matched by age and sex with a patient in the no-delirium group. RESULTS: The initial cohort consists of 189 patients with no delirium and 102 patients who developed postoperative delirium. Of 291 patients aged 72.5 ± 5.8 yr, 50.5% were women, and 102 (35%) developed postoperative delirium. The final cohort in the analysis consisted of a no-delirium group (n = 102) and a delirium group (n = 102) matched by age and sex using the propensity score method. Of the four biomarkers assayed, the median value for neurofilament light chain was 32.05 pg/ml for the delirium group versus 23.7 pg/ml in the no-delirium group. The distribution of biomarker values significantly differed between the delirium and no-delirium groups (P = 0.02 by the Kolmogorov-Smirnov test) with the largest cumulative probability difference appearing at the biomarker value of 32.05 pg/ml. CONCLUSIONS: These results suggest that patients who subsequently developed delirium are more likely to be experiencing clinically silent neurodegenerative changes before surgery, reflected by changes in plasma neurofilament light chain biomarker concentrations, which may identify individuals with a preoperative vulnerability to subsequent cognitive decline.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (ß = -0.17, p = .020), hemoglobin A1C (ß = -0.21, p = .016) and IL-6 (ß = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (ß = 0.20, p = .0015) and executive functioning (ß = 0.15, p = .012), but not memory performances (ß = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health.

Roles of physical activity and diet in cognitive aging: is more better?

Objective: To determine the synergistic effects of nutrition, specifically adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and physical activity on cognition and brain outcomes in a cross-sectional healthy aging cohort. Methods: A total of 132 adults (age range 52-91; Clinical Dementia Rating = 0) from the UCSF Brain Aging Project completed a 15-item MIND diet food frequency questionnaire and an 11-item self-report measure of weekly physical activity (Physical Activity Scale [PASE]). Cognitive outcomes included executive functioning, episodic memory, and language. Neuroimaging outcomes consisted of total grey matter volume and total white matter volume, adjusted for total intracranial volumes. All regression interaction models adjusted for age, sex, education, and a composite vascular burden score. Results: There was a significant interaction between PASE and MIND on executive functioning and total grey matter volume. Low levels of both related to disproportionately poorer cognitive and brain structural outcomes. Increasing levels of either, but not both, PASE or MIND related to better executive functioning and gray matter outcomes. For memory, language, and total white matter volume, the interaction between PASE and MIND showed the same directionality but did not reach statistical significance. Conclusions: Higher levels of physical activity associated with better executive functioning and gray matter volume, particularly when diet was poor. Similarly, higher levels of MIND diet adherence were associated with better brain and cognitive outcomes when physical activity was low. However, highest levels of physical activity and MIND diet together did not necessarily lead to disproportionately better cognitive and brain volume outcomes.

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy. OBJECTIVE: To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy. MATERIALS AND METHODS: A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality. RESULTS: The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2-79.8) compared to the ST alone group (19.1 months IQR 12.8-23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS. CONCLUSIONS: CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.

Dynamic autonomic nervous system states arise during emotions and manifest in basal physiology.

The outflow of the autonomic nervous system (ANS) is continuous and dynamic, but its functional organization is not well understood. Whether ANS patterns accompany emotions, or arise in basal physiology, remain unsettled questions in the field. Here, we searched for brief ANS patterns amidst continuous, multichannel physiological recordings in 45 healthy older adults. Participants completed an emotional reactivity task in which they viewed video clips that elicited a target emotion (awe, sadness, amusement, disgust, or nurturant love); each video clip was preceded by a pre-trial baseline period and followed by a post-trial recovery period. Participants also sat quietly for a separate 2-min resting period to assess basal physiology. Using principal components analysis and unsupervised clustering algorithms to reduce the second-by-second physiological data during the emotional reactivity task, we uncovered five ANS states. Each ANS state was characterized by a unique constellation of patterned physiological changes that differentiated among the trials of the emotional reactivity task. These ANS states emerged and dissipated over time, with each instance lasting several seconds on average. ANS states with similar structures were also detectable in the resting period but were intermittent and of smaller magnitude. Our results offer new insights into the functional organization of the ANS. By assembling short-lived, patterned changes, the ANS is equipped to generate a wide range of physiological states that accompany emotions and that contribute to the architecture of basal physiology.

Sex Differences in the Relationship between Perceived Stress and Cognitive Trajectories.

OBJECTIVE: Chronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults. DESIGN: Longitudinal observational study. SETTING: University research center. PARTICIPANTS: 274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits. MEASUREMENTS: Neurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers. RESULTS: The interaction between stress, sex, and time predicted executive functioning (ß = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women. CONCLUSION: Consistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.

Age-related brain atrophy is not a homogenous process: Different functional brain networks associate differentially with aging and blood factors.

Aging is characterized by a progressive loss of brain volume at an estimated rate of 5% per decade after age 40. While these morphometric changes, especially those affecting gray matter and atrophy of the temporal lobe, are predictors of cognitive performance, the strong association with aging obscures the potential parallel, but more specific role, of individual subject physiology. Here, we studied a cohort of 554 human subjects who were monitored using structural MRI scans and blood immune protein concentrations. Using machine learning, we derived a cytokine clock (CyClo), which predicted age with good accuracy (Mean Absolute Error = 6 y) based on the expression of a subset of immune proteins. These proteins included, among others, Placenta Growth Factor (PLGF) and Vascular Endothelial Growth Factor (VEGF), both involved in angiogenesis, the chemoattractant vascular cell adhesion molecule 1 (VCAM-1), the canonical inflammatory proteins interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the chemoattractant IP-10 (CXCL10), and eotaxin-1 (CCL11), previously involved in brain disorders. Age, sex, and the CyClo were independently associated with different functionally defined cortical networks in the brain. While age was mostly correlated with changes in the somatomotor system, sex was associated with variability in the frontoparietal, ventral attention, and visual networks. Significant canonical correlation was observed for the CyClo and the default mode, limbic, and dorsal attention networks, indicating that immune circulating proteins preferentially affect brain processes such as focused attention, emotion, memory, response to social stress, internal evaluation, and access to consciousness. Thus, we identified immune biomarkers of brain aging which could be potential therapeutic targets for the prevention of age-related cognitive decline.

Old plasma dilution reduces human biological age: a clinical study.

This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.

Longitudinal Trajectories of Memory Performance in Patients with Early-Stage Breast Cancer.

Background: While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods: We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results: Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion: Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients' experience of cognitive difficulties after treatment.

Interbatch Reliability of Blood-Based Cytokine and Chemokine Measurements in Community-Dwelling Older Adults: A Cross-Sectional Study.

Blood-based inflammatory markers hold considerable promise for diagnosis and prognostication of age-related neurodegenerative disease, though a paucity of research has empirically tested how reliably they can be measured across different experimental runs ("batches"). We quantified the interbatch reliability of 13 cytokines and chemokines in a cross-sectional study of 92 community-dwelling older adults (mean age = 74; 48% female). Plasma aliquots from the same blood draw were parallelly processed in 2 separate batches using the same analytic platform and procedures (high-performance electrochemiluminescence by Meso Scale Discovery). Interbatch correlations (Pearson's r) ranged from small and nonsignificant (r = .13 for macrophage inflammatory protein-1 alpha [MIP-1α]) to very large (r > .90 for interferon gamma [IFNγ], interleukin-10 [IL-10], interferon gamma-induced protein 10 [IP-10], MIP-1ß, thymus and activation-regulated chemokine [TARC]) with most markers falling somewhere in between (.67 ≤ r ≤ .90 for IL-6, tumor necrosis factor alpha [TNF-α], Eotaxin, Eotaxin-3, monocyte chemoattractant protein-1 [MCP-1], MCP-4, macrophage-derived chemokine [MDC]). All markers, except for IL-6 and MCP-4, showed significant differences in absolute values between batches, with discrepancies ranging in effect size (Cohen's d) from small to moderate (0.2 ≤ |d| ≤ 0.5 for IL-10, IP-10, MDC) to large or very large (0.68 ≤ |d| ≤ 1.5 for IFNγ, TNF-α, Eotaxin, Eotaxin-3, MCP-1, MIP-1α, MIP-1ß, TARC). Relatively consistent associations with external variables of interest (age, sex, systolic blood pressure, body mass index, cognition) were observed across batches. Taken together, our results suggest heterogeneity in measurement reliability of blood-based cytokines and chemokines, with some analytes outperforming others. Future work is needed to evaluate the generalizability of these findings while identifying potential sources of batch effect measurement error.

Enhanced Stress Resilience Training in Surgeons: Iterative Adaptation and Biopsychosocial Effects in 2 Small Randomized Trials.

OBJECTIVE: To determine the effects of ESRT (an iteratively adapted and tailored MBI) on perceived stress, executive cognitive function, psychosocial well-being (ie, burnout, mindfulness), and pro-inflammatory gene expression in surgical (ESRT-1) and mixed specialty (ESRT-2) PGY-1 volunteers. SUMMARY OF BACKGROUND AND DATA: Tailored MBIs have proven beneficial in multiple high-stress and high-performance populations. In surgeons, tailored MBIs have been shown to be feasible and potentially beneficial, but whether mindfulness-based cognitive training can improve perceived stress, executive function, well-being or physiological distress in surgical and nonsurgical trainees is unknown. METHODS: In 2 small single-institution randomized clinical trials, ESRT, a tailored mindfulness-based cognitive training program, was administered and iteratively adapted for first-year surgical (ESRT-1, 8 weekly, 2-hour classes, n = 44) and mixed specialty (ESRT-2, 6 weekly, 90-minute classes, n = 45) resident trainees. Primary and secondary outcomes were, respectively, perceived stress and executive function. Other prespecified outcomes were burnout (assessed via Maslach Burnout Inventory), mindfulness (assessed via Cognitive Affective Mindfulness Scale - Revised), and pro-inflammatory gene expression (assessed through the leukocyte transcriptome profile "conserved transcriptional response to adversity"). RESULTS: Neither version of ESRT appeared to affect perceived stress. Higher executive function and mindfulness scores were seen in ESRT-1, and lower emotional exhaustion and depersonalization scores in ESRT-2, at pre-/postintervention and/or 50-week follow-up (ESRT-1) or at 32-week follow-up (ESRT-2), compared to controls. Pooled analysis of both trials found ESRT-treated participants had reduced pro-inflammatory RNA expression compared to controls. CONCLUSIONS: This pilot work suggests ESRT can variably benefit executive function, burnout, and physiologic distress in PGY-1 trainees, with potential for tailoring to optimize effects.

Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease.

OBJECTIVE: To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically diagnosed Alzheimer disease syndromes (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses. METHODS: We measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression, and survival, and cortical thickness. RESULTS: Plasma NfL, but not plasma t-tau, discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology-confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone. CONCLUSION: Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance vs plasma t-tau in FTLD and AD.

Development and validation of the Uniform Data Set (v3.0) executive function composite score (UDS3-EF).

INTRODUCTION: Cognitive composite scores offer a means of precisely measuring executive functioning (EF). METHODS: We developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models. RESULTS: Final model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3-EF correlated most strongly with other EF tests (ßs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (ßs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (ß = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in UDS3-EF change (n = 286) was ≈40% of the next best measure (F-words; n = 714). CONCLUSIONS: The UDS3-EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests.

Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage.

BACKGROUND: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-ß (Aß) may shed light on astrocytic changes in aging and Alzheimer's disease (AD). OBJECTIVE: To examine associations between plasma GFAP and cortical Aß deposition in older adults across the typical aging-to-AD dementia spectrum. METHODS: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aß-PET burden. Aß-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aß-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aß-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aß-PET, and clinical severity. RESULTS: In both cohorts, plasma GFAP increased linearly with Aß-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aß-PET burden, the association between Aß and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aß-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aß-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aß-PET CLs with lower plasma GFAP. CONCLUSION: The relationship between astrocytic integrity and cortical Aß may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Screening for Lifetime History of Traumatic Brain Injury Among Older American and Irish Adults at Risk for Dementia: Development and Validation of a Web-Based Survey.

BACKGROUND: Traumatic brain injury (TBI) is an established risk factor for dementia but mechanisms are uncertain. Accurate TBI exposure classification is critical for cognitive aging research studies seeking to discover mechanisms and treatments of post-TBI dementia. Brief TBI screens, commonly used in epidemiological studies of cognitive aging, are insensitive, leading to exposure mis-classification. Comprehensive TBI interviews, while more sensitive, may be impractical. OBJECTIVE: We aimed to develop and validate a scalable, self-administered, comprehensive, web-based, TBI exposure survey for use in international cognitive aging research. METHODS: We adapted a gold-standard comprehensive TBI interview (the Ohio State University TBI Identification Method; OSU TBI-ID) into a self-administered web-based survey for older adults (Older Adult modification of the OSU TBI-ID; OA OSU TBI-ID). We assessed reliability of our web-based survey versus the gold-standard interview among 97 older adults with normal cognition and mild cognitive impairment (MCI). In addition, we assessed sensitivity of the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) brief TBI screen versus the interview among 70 older adults with normal cognition. RESULTS: Our OA OSU TBI-ID web-based survey had good to excellent reliability versus the interview (κ 0.66-0.73; ICCs 0.68-0.81) even among the sub-set with MCI (κ 0.74-0.88; ICCs 0.76-0.85), except for several age-at-injury variables. The NACC UDS brief TBI screen missed 50% of TBI exposures identified using the OSU TBI-ID interview. CONCLUSION: The OSU TBI-ID interview and web-based survey may facilitate more accurate TBI exposure classification in cognitive aging research thereby accelerating discovery of targetable mechanisms of post-TBI dementia.