Citations

Abstract Background Glial fibrillary acidic protein (GFAP) is a promising candidate blood‐based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease‐associated changes, its clinical correlates, and biofluid‐type dependency will influence its clinical utility. Methods We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ‐positive from Aβ‐negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion Our findings support a role for plasma GFAP as a clinical biomarker of Aβ‐related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Background: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. Methods: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. Results: MVP was associated with DMR absent/mild (ERO <20 mm 2 ) in 50%, moderate (ERO 20–40 mm 2 ) in 25%, and severe or higher (ERO ≥40 mm 2 ) in 25%, with mean ERO 24±24 mm 2 , regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%–90% range, 0–9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%–90% range, 4–11 versus 0–7) and mediocre correlation ( R 2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29–1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11–1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02–1.14]) or ≥1% (hazard ratio, 1.11 [1.08–1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10–1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10–1.16], all per 1-point increment with P <0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P <0.0001). Conclusions: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

AbstractBackgroundIn familial frontotemporal lobar degeneration (f‐FTLD), plasma levels of neurofilament light (NfL) are elevated at least two years prior to symptom onset and predict future clinical status. The Neurofilament Surveillance Project (NSP), an actively recruiting observational study, seeks to obtain higher resolution data of temporal changes in plasma NfL to better understand its clinical utility in f‐FTLD interventional trials. The NSP is a pre‐competitive collaboration sponsored by the Bluefield Project to Cure FTD and funded by biotechnology and pharmaceutical companies and nonprofit organizations.MethodParticipants must be members of families with disease‐causing mutations in C9orf72, MAPT or GRN and enrolled in the ALLFTD natural history study. Up to 335 participants, with roughly equal representation across mutation type, provide plasma quarterly for 3 years (4355 samples total) to enable the observation of peripheral NfL levels longitudinally during disease onset and progression. Plasma is collected by certified mobile research nurses during remote visits, and NfL is measured in batch at least every 6 months. NfL measurements from one plasma aliquot per draw will be correlated with annual assessments obtained in the ALLFTD study, including measures of disease severity (CDRÒ+NACC‐FTLD, CGI, etc.), cognitive function from the UDS Neuropsychology Battery, and volumetric MRI data. Additional plasma aliquots are reserved for future analyses of other biomarkers during the course of the study; another subset of aliquots is reserved to share with interested investigators after the study ends.ResultAs of 1/19/22, the NSP had enrolled 161 participants, including 62 from C9orf72 kindreds, 60 from MAPT kindreds, and 28 from GRN kindreds. One‐hundred forty‐five participants had completed their initial visit, and 109 had completed more than 3, and up to 5, quarterly blood draws. Enrollment and study visits are ongoing despite COVID‐related limitations.ConclusionThe quarterly blood sampling from this study, combined with annual comprehensive clinical assessments through the ALLFTD natural history study, will enable a more detailed understanding of when and how NfL levels change during phenoconversion and/or disease progression in f‐FTLD mutation carriers. These data will be especially informative in the context of the targeted investigational therapeutics for f‐FTLD now entering clinical trials.

AbstractBackgroundDyadic (self and study partner) subjective reports of an individual’s recent cognitive and functional decline are an efficient approach to facilitate identification of older adults with, and at risk for, Mild Cognitive Impairment (MCI). Such methods can be easily adapted for remote administration, but few studies have investigated the ability of remotely‐collected, unsupervised dyadic subjective reports to accurately detect MCI and cognitive decline.MethodsIn 289 older adults enrolled in the Brain health Registry (BHR), with clinically‐confirmed diagnoses of Cognitively‐unimpaired (CU) or MCI, we identified the optimal combination of remote measures to accurately distinguish CU from MCI. We then externally validated our predictive model in 217 participants enrolled in a separate cohort, Validation of Online Methods to Predict Cognitive Decline (eVAL). Predictors included Cogstate Brief Battery One Card Learning (OCL) accuracy; self‐ and study partner‐reported memory concern (SMCs); performance on online adaptations of Everyday Cognition Scale (ECog, self‐ and study partner‐report versions), Geriatric Depression Scale Short Form (GDS); family history of AD, age, gender, and education. We calculated 10‐fold cross validated area under the ROC curves (cvAUC), 95% confidence intervals (CI), and the percentage of participants correctly classified (accuracy) for all models. Likelihood ratio (LR) tests were used to compare model fits.ResultsIn the BHR cohort, models including dyad‐report ECog, family history of AD, GDS, and Cogstate OCL scores distinguished CU from MCI with the highest accuracy (cvAUC = 0.90; 95% CI = 0.83, 0.92; accuracy = 85.5%). Models excluding study partner‐report ECog distinguished diagnostic groups with moderate accuracy (cvAUC = 0.83; 95% CI = 0.78, 0.85; accuracy = 75.9%) When applied to the validation cohort, the optimal training model including dyadic report performed with moderate accuracy ( Table 2 ). In the validation cohort, inclusion of study partner (but not self) report SMC, in addition to dyadic‐report ECog, improved model fit (LR test p<0.01).ConclusionsRemotely‐collected dyadic subjective measures, along with other remote measures, accurately distinguish CU from MCI. Subjective cognitive and functional decline and concerns about memory problems independently contribute to diagnostic discrimination. Results support future utilization of remote dyadic subjective measures to efficiently identify older adults with MCI for prodromal AD clinical trials, and in clinical care settings.

Objective: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. Background: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. Methods: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. Results: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence (P<0.0001). Conclusions: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.