Blood biomarkers for cognitive decline and clinical progression in a Mexican American cohort

Introduction: The clinical translation of biofluid markers for dementia requires validation in diverse cohorts. The study goal was to evaluate if blood biomarkers reflecting diverse pathophysiological processes predict disease progression in Mexican American adults. Methods: Mexican American adults (n = 745), 50 years of age and older, completed annual assessments over a mean of 4 years. Serum collected at baseline was assayed for total tau, neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation 14 (sCD14), and chitinase‐3‐like protein 1 (YKL‐40). Results: Higher GFAP and NFL were associated with global cognitive decline. Only GFAP was associated with increased incident dementia risk (hazard ratio: 1.611 (95% confidence interval: 1.204‐2.155)) and inclusion of additional biomarkers did not improve model fit. Discussion: Among a panel of six blood biomarkers previously associated with neurodegenerative disease, only GFAP predicted incident dementia in our cohort. The findings suggest that blood GFAP levels may aid dementia‐risk prediction among Mexican American adults

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Prognosis of "pre-heart failure" clinical phenotypes.

BACKGROUND:Heart failure (HF) is a clinical syndrome where diagnostic certainty varies. The prognosis of individuals with some clinical features of HF, but without the fully overt syndrome, is unclear. Therefore, we sought to evaluate their natural history. METHODS AND RESULTS:Between 1990 and 2009, all suspected HF cases in the Framingham Heart Study were adjudicated into 3 groups reflecting varying diagnostic certainty: definite (meeting HF diagnostic criteria; n = 479), possible (meeting HF criteria but with an alternative explanation for findings; n = 135), and probable (insufficient criteria for definite HF; n = 121) HF. Age-and-sex-matched individuals (n = 1112) without HF or cardiovascular disease (CVD) were controls. Using multivariable-adjusted Cox regression, we compared the possible/probable HF groups with controls regarding risk of incident definite HF, coronary heart disease (CHD), other CVD or death; and with definite HF regarding risk of latter three outcomes. During follow-up (mean 8.6 years), ~90% of individuals with possible, probable and definite HF experienced CVD events or died. Compared with controls, those with possible or probable HF experienced higher hazards for definite HF, CHD, other CVD and death (hazards ratios [HR] 1.35-9.31; p<0.05). The possible/probable groups did not differ from the definite HF group for risk of any outcome. Compared with the possible HF group, the probable HF group had a higher propensity for definite HF (HR 1.64, with a higher proportion of ischemic HF) but lower risk of death (HR 0.69). CONCLUSIONS:Individuals meeting partial criteria for HF are at a substantial risk for progression to HF, CVD, and mortality

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort*

IntroductionWe investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort.MethodsA total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI).ResultsHigher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P &lt; .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures.DiscussionOur findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging

BackgroundAlzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.ObjectiveTo identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.MethodsWeighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).ResultsTwo proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.ConclusionsProteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia

Acute kidney injury in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Anxiety sensitivity as a transdiagnostic risk factor for trajectories of adverse posttraumatic neuropsychiatric sequelae in the AURORA study

Anxiety sensitivity, or fear of anxious arousal, is cross-sectionally associated with a wide array of adverse posttraumatic neuropsychiatric sequelae, including symptoms of posttraumatic stress disorder, depression, anxiety, sleep disturbance, pain, and somatization. The current study utilizes a large-scale, multi-site, prospective study of trauma survivors presenting to emergency departments. Hypotheses tested whether elevated anxiety sensitivity in the immediate posttrauma period is associated with more severe and persistent trajectories of common adverse posttraumatic neuropsychiatric sequelae in the eight weeks posttrauma. Participants from the AURORA study (n = 2,269 recruited from 23 emergency departments) completed self-report assessments over eight weeks posttrauma. Associations between heightened anxiety sensitivity and more severe and/or persistent trajectories of trauma-related symptoms identified by growth mixture modeling were analyzed. Anxiety sensitivity assessed two weeks posttrauma was associated with severe and/or persistent posttraumatic stress, depression, anxiety, sleep disturbance, pain, and somatic symptoms in the eight weeks posttrauma. Effect sizes were in the small to medium range in multivariate models accounting for various demographic, trauma-related, pre-trauma mental health-related, and personality-related factors. Anxiety sensitivity may be a useful transdiagnostic risk factor in the immediate posttraumatic period identifying individuals at risk for the development of adverse posttraumatic neuropsychiatric sequelae. Further, considering anxiety sensitivity is malleable via brief intervention, it could be a useful secondary prevention target. Future research should continue to evaluate associations between anxiety sensitivity and trauma-related pathology