Visit-to-visit blood pressure variability is associated with intrinsic capacity decline: Results from the MAPT Study.

BACKGROUND: The effectiveness of the body physiological regulatory mechanisms declines in late life, and increased Blood Pressure Variability (BPV) may represent an alteration in cardiovascular homeostatic patterns. Intrinsic Capacity (IC) has been proposed by the World Health Organization as a marker of healthy aging, based on individual's functional abilities and intended at preserving successful aging. We aimed to investigate the association of visit-to-visit BPV with IC decline in a population of community-dwelling older adults. METHODS: The study population consisted of 1407 community-dwelling participants aged ≥70 years from the MAPT study evaluated during the 5-year follow-up. Systolic BPV (SBPV) and diastolic BPV (DBPV) were determined through six indicators. Cognition, psychology, locomotion and vitality constituted the four IC domains assessed. Total IC Z-score resulted from the sum of the four domains Z-scores divided by 4. The incidence of domain impairment over time was also assessed. RESULTS: Higher SBPV was significantly associated with poorer IC Z-scores in all linear mixed models [1-SD increase of CV%: ß(SE)=-0.010(0.001), p < 0.01]. Similar results were observed for DBPV [1-SD increase of CV%: ß(SE)=-0.003(0.001), p = 0.02]. Incident IC impairment was significantly higher in participants with greater SBPV, [HR=1.16 (95 % CI, 1.01-1.33), p = 0.03], while greater DBPV did not show a higher risk of incident IC impairment. CONCLUSIONS: Greater BPV is associated with IC decline over time. Our findings support BP instability as a presumable index of altered cardiovascular homeostatic mechanism, suggesting that BPV might be a clinical marker of aging and addressable risk factor for promoting healthy aging.

Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early-stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age-dependent DCM. METHODS: Here, we used hiPSC-CMs from DMD patients selected by Speckle-tracking echocardiography and canine DMD cardiac biopsies to assess key early-stage Duchenne DCM features. RESULTS: Dystrophin deficiency was associated with RyR2 remodelling and SR Ca2+ leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P < 0.01), which led to early-stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03 ± 0.75 for HC vs. 13.67 ± 5.49 for DMD, P < 0.05) and p16 (1.86 ± 0.83 for HC vs. 10.71 ± 3.00 for DMD, P < 0.01) in DMD hiPSC-CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC-CMs. We observed cardiac hypocontractility in DMD hiPSC-CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65 ± 0.06 µm for DMD vs. 2.26 ± 0.08 µm for DMD + S107, P < 0.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis. CONCLUSIONS: We identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca2+ leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD-associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2-mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD-induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.

Longitudinal Associations Between ATPase Inhibitory Factor 1, Growth Differentiation Factor-15, and Nutritional Status in Older Adults From the MAPT Study.

BACKGROUND: Weight and appetite regulation have been associated with the expression and secretion of ATPase inhibitory factor 1 (IF1) and growth differentiation factor-15 (GDF-15), 2 potential biomarkers for age-related mitochondrial dysfunction. The aim was to explore the associations between these biomarkers and nutritional variables in the Multidomain Alzheimer Preventive Trial study. METHODS: IF1 and GDF-15 plasma levels were quantified at 1-year follow-up. The nutritional status was measured using the Mini Nutritional Assessment (MNA) score variation between baseline and 1- and 2-year visits; appetite loss was extracted from the MNA. Bodyweight was measured every 6 months until the third year and then yearly until the fifth year of follow-up, and weight loss was established if the loss was greater than 5% or 10% within the past 6 or 12 months, respectively. Bidirectional associations of IF1 and GDF-15 levels with malnutrition, appetite, and weight loss were examined. The interactions between individual IF1 and GDF-15 with sex were explored. RESULTS: Four hundred and forty-eight participants had MNA data and 1 045 had weight loss data. All the associations between IF1 levels and the MNA score, appetite loss, and weight loss were nonsignificant. Higher GDF-15 levels were cross-sectionally associated with appetite loss at the first year of follow-up, and the GDF-15 highest quartile was associated with nearly 80% higher risks of weight loss over 4 years. Interactions between IF1 and GDF-15 levels, and between these 2 markers and sex were not significantly associated with the outcomes. CONCLUSIONS: GDF-15 plasma levels were related to key malnutrition criteria.

Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function.

Doxorubicin (Dox) is an effective anticancer molecule, but its clinical efficacy is limited by strong cardiotoxic side effects. Lysosomal dysfunction has recently been proposed as a new mechanism of Dox-induced cardiomyopathy. However, to date, there is a paucity of therapeutic approaches capable of restoring lysosomal acidification and function in the heart. Methods: We designed novel poly(lactic-co-glycolic acid) (PLGA)-grafted silica nanoparticles (NPs) and investigated their therapeutic potential in the primary prevention of Dox cardiotoxicity in cardiomyocytes and mice. Results: We showed that NPs-PLGA internalized rapidly in cardiomyocytes and accumulated inside the lysosomes. Mechanistically, NPs-PLGA restored lysosomal acidification in the presence of doxorubicin or bafilomycin A1, thereby improving lysosomal function and autophagic flux. Importantly, NPs-PLGA mitigated Dox-related mitochondrial dysfunction and oxidative stress, two main mechanisms of cardiotoxicity. In vivo, inhalation of NPs-PLGA led to effective and rapid targeting of the myocardium, which prevented Dox-induced adverse remodeling and cardiac dysfunction in mice. Conclusion: Our findings demonstrate a pivotal role for lysosomal dysfunction in Dox-induced cardiomyopathy and highlight for the first time that pulmonary-driven NPs-PLGA administration is a promising strategy against anthracycline cardiotoxicity.

Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.

Intrinsic capacity (IC), the composite of physical and mental capacities, declines with age at different rates and patterns between individuals. We aimed to investigate the association between longitudinal IC trajectories and plasma biomarkers of two hallmarks of aging-chronic inflammation and mitochondrial dysfunction-in older adults. From the Multidomain Alzheimer Preventive Trial (MAPT), we included 1271 community-dwelling older people (mean [SD] age = 76.0 [4.3] years) with IC data over four years. Group-based multi-trajectory modeling was performed to identify clusters of the participants with similar longitudinal patterns across four IC domains: cognition, locomotion, psychology, and vitality. Five IC multi-trajectory groups were determined: low in all domains (8.4%), low locomotion (24.6%), low psychological domain (16.7%), robust (i.e., high in all domains except vitality; 28.3%), and robust with high vitality (22.0%). Compared to the best trajectory group (i.e., robust with high vitality), elevated levels of plasma interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNFR-1), and growth differentiation factor-15 (GDF-15) were associated with a higher risk of belonging to the "low in all domains" group (IL-6: relative risk ratio (RRR) [95% CI] = 1.42 [1.07 - 1.88]; TNFR-1: RRR = 1.46 [1.09 - 1.96]; GDF-15: RRR = 1.99 [1.45 - 2.73]). Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group. GDF-15 outperformed other biomarkers by showing the strongest associations with IC trajectory groups. Our findings found that plasma biomarkers reflecting inflammation and mitochondrial impairment distinguished older people with multi-impaired IC trajectories from those with high-stable IC.

IPSC derived cardiac fibroblasts of DMD patients show compromised actin microfilaments, metabolic shift and pro-fibrotic phenotype.

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy caused by mutations in the dystrophin gene. We characterized which isoforms of dystrophin were expressed by human induced pluripotent stem cell (hiPSC)-derived cardiac fibroblasts obtained from control and DMD patients. Distinct dystrophin isoforms were observed; however, highest molecular weight isoform was absent in DMD patients carrying exon deletions or mutations in the dystrophin gene. The loss of the full-length dystrophin isoform in hiPSC-derived cardiac fibroblasts from DMD patients resulted in deficient formation of actin microfilaments and a metabolic switch from mitochondrial oxidation to glycolysis. The DMD hiPSC-derived cardiac fibroblasts exhibited a dysregulated mitochondria network and reduced mitochondrial respiration, with enhanced compensatory glycolysis to sustain cellular ATP production. This metabolic remodeling was associated with an exacerbated myofibroblast phenotype and increased fibroblast activation in response to pro fibrotic challenges. As cardiac fibrosis is a critical pathological feature of the DMD heart, the myofibroblast phenotype induced by the absence of dystrophin may contribute to deterioration in cardiac function. Our study highlights the relationship between cytoskeletal dynamics, metabolism of the cell and myofibroblast differentiation and provides a new mechanism by which inactivation of dystrophin in non-cardiomyocyte cells may increase the severity of cardiopathy.

Investigating three ways of measuring the intrinsic capacity domain of vitality: nutritional status, handgrip strength and ageing biomarkers.

BACKGROUND: Vitality is conceptually considered as the underlying capacity influencing other intrinsic capacity (IC) domains and being related to nutrition, physiological reserve and biological ageing. However, there is no consensus on its operationalisation. OBJECTIVE: To investigate the structure and magnitude of the association of vitality with other IC domains and functional difficulties using three operational definitions of vitality. METHODS: We included 1,389 older adults from the Multidomain Alzheimer Preventive Trial with data on Mini Nutritional Assessment (MNA), handgrip strength and plasma biomarkers (comprising inflammatory and mitochondrial markers). Using path analysis, we examined the effects of vitality on difficulties in basic and instrumental activities of daily living (ADL and IADL) exerted directly and indirectly through the mediation of other IC domains: cognition, locomotion, psychological, vision and hearing. We further explored the longitudinal association of vitality with IC domains, ADL and IADL over 4 years using linear mixed-effect regression. RESULTS: We observed significant indirect effects of vitality on IADL, mainly through cognitive, locomotor and psychological domains, regardless of the vitality measurement. Participants with higher vitality had fewer IADL difficulties at follow-up (MNA score: ß [95% CI] = -0.020 [-0.037, -0.003]; handgrip strength: -0.011 [-0.023, 0.000]; plasma biomarker-based index: -0.015 [-0.028, -0.002]). Vitality assessed with the plasma biomarker-based index predicted improved locomotion over time. CONCLUSION: Vitality was associated with disability primarily through the mediation of other IC domains. The three indicators examined are acceptable measurements of vitality; biomarkers might be more suitable for the early detection of locomotion decline.

Association between physical activity, growth differentiation factor 15 and bodyweight in older adults: A longitudinal mediation analysis.

BACKGROUND: Late-life aging is often associated with appetite reduction and weight loss. Physical activity (PA) may prevent these processes, but the molecular mechanisms involved remain elusive. The present study investigated the putative mediating aspect of growth differentiation factor 15 (GDF-15), a stress signalling protein involved in aging, exercise and appetite control, on the association between PA and late-life-associated weight loss. METHODS: One thousand eighty-three healthy adults (63.8% women) aged 70 years and over who participated in the Multidomain Alzheimer Preventive Trial were included. Bodyweight (kg) and PA levels (square root of metabolic equivalent of task-min/week) were assessed repeatedly from baseline to the 3-year visit, whereas plasma GDF-15 (pg/mL) was measured at the 1-year visit. Multiple linear regressions were performed to test the association between first-year mean PA level, 1-year visit GDF-15 concentration and subsequent bodyweight changes. Mediation analyses were used to investigate whether GDF-15 mediated the association between first-year mean PA levels and consecutive bodyweight changes. RESULTS: Multiple regression analyses demonstrated that higher first-year mean PA levels significantly predicted lower GDF-15 and bodyweight at 1 year (B = -2.22; SE = 0.79; P = 0.005). In addition, higher 1-year visit GDF-15 levels were associated with faster subsequent bodyweight loss (Time × GDF-15 interaction B = -0.0004; SE = 0.0001; P = 0.003). Mediation analyses confirmed that GDF-15 mediated the association between first-year mean PA levels and subsequent bodyweight changes (mediated effect ab = 0.0018; bootstrap SE = 0.001; P < 0.05) and revealed that mean PA had no direct effect on subsequent bodyweight changes (c' = 0.006; SE = 0.008; P > 0.05). CONCLUSIONS: This study suggests that GDF-15 may be one of the molecules mediating the link between PA and late-life weight loss, but mechanistic studies are necessary to further support the present findings.

Plasma inflammation-related biomarkers are associated with intrinsic capacity in community-dwelling older adults.

BACKGROUND: How inflammation relates to intrinsic capacity (IC), the composite of physical and mental capacities, remains undefined. Our study aimed to investigate the cross-sectional and longitudinal associations between plasma inflammation-related biomarkers and IC in older adults. METHODS: This secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) included 1238 community-dwelling older individuals with IC assessments from 12 to 60 months. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor receptor-1 (TNFR-1), monocyte chemoattractant protein-1 (MCP-1) and growth differentiation factor-15 (GDF-15) were measured at 12 months. IC was operationalized as a score ranging from 0 to 100, derived from four domains: cognition, Mini-Mental State Examination; locomotion, Short Physical Performance Battery; psychological, Geriatric Depression Scale; and vitality, handgrip strength. A five-domain IC score (plus sensory) was investigated in a subsample (n = 535) with a 1-year follow-up as an exploratory outcome. RESULTS: The mean age of the 1238 participants was 76.2 years (SD = 4.3); 63.7% were female. Their initial four-domain IC scores averaged 78.9 points (SD = 9.3), with a yearly decline of 1.17 points (95% CI = -1.30 to -1.05; P < 0.001). We observed significant associations of lower baseline IC with higher CRP, IL-6, TNFR-1 and GDF-15, after controlling age, sex, MAPT group allocation and educational level [CRP: adjusted ß (95% CI) = -1.56 (-2.64 to -0.48); P = 0.005; IL-6: adjusted ß = -3.16 (-4.82 to -1.50); P < 0.001; TNFR-1: adjusted ß = -6.86 (-10.25 to -3.47); P < 0.001; GDF-15: adjusted ß = -7.07 (-10.02 to -4.12); P < 0.001]. Higher TNFR-1, MCP-1 and GDF-15 were associated with faster decline in four-domain IC over 4 years [TNFR-1: adjusted ß (95% CI) = -1.28 (-2.29 to -0.27); P = 0.013; MCP-1: adjusted ß = -1.33 (-2.24 to -0.42); P = 0.004; GDF-15: adjusted ß = -1.42 (-2.26 to -0.58); P = 0.001]. None of the biomarkers was significantly associated with the five-domain IC decline. CONCLUSIONS: Inflammation was associated with lower IC in older adults. Among all plasma biomarkers, TNFR-1 and GDF-15 were consistently associated with IC at the cross-sectional and longitudinal levels.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability.

Most physiopathological mechanisms underlying blood pressure variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging" and the hallmark "mitochondrial dysfunction" due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine growth/differentiation factor 15 (GDF-15) and two inflammatory biomarkers, interleukin 6 (IL-6) and tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. The study population consisted of 1096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥ 70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: ß (SE) = 0.07 (0.04), p < 0.044, for coefficient of variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

Expression and Function of MAO A in Cardiac Cells by Means of Adenovirus-Mediated Gene Transfer.

Gene-transfer methods are useful to study the structural or functional roles of recombinant proteins in vitro. In particular, adenovirus-mediated gene transduction results in strong efficiency and high level of expression in primary cells such as cardiomyocytes, which are difficult to transfect with classical methods. Here, we describe a protocol that enables efficient expression of MAO A in both primary cells and cell lines. Following expression of recombinant MAO A, substrate-induced activation of the enzyme can be assessed by measuring production of reactive oxygen species and downstream signal transduction pathways in cells. This model allows to decipher the biological function of MAO A on metabolism, mitochondrial fitness, cell death/survival, and proliferation.

Monoamine Oxidase Inhibitors Prevent Glucose-Dependent Energy Production, Proliferation and Migration of Bladder Carcinoma Cells.

Bladder cancer is the 10th most common cancer in the world and has a high risk of recurrence and metastasis. In order to sustain high energetic needs, cancer cells undergo complex metabolic adaptations, such as a switch toward aerobic glycolysis, that can be exploited therapeutically. Reactive oxygen species (ROS) act as key regulators of cancer metabolic reprogramming and tumorigenesis, but the sources of ROS remain unidentified. Monoamine oxidases (MAOs) are mitochondrial enzymes that generate H2O2 during the breakdown of catecholamines and serotonin. These enzymes are particularly important in neurological disorders, but recently, a new link between MAOs and cancer has been uncovered, involving their production of ROS. At present, the putative role of MAOs in bladder cancer has never been evaluated. We observed that human urothelial tumor explants and the bladder cancer cell line AY27 expressed both MAO-A and MAO-B isoforms. Selective inhibition of MAO-A or MAO-B limited mitochondrial ROS accumulation, cell cycle progression and proliferation of bladder cancer cells, while only MAO-A inhibition prevented cell motility. To test whether ROS contributed to MAO-induced tumorigenesis, we used a mutated form of MAO-A which was unable to produce H2O2. Adenoviral transduction of the WT MAO-A stimulated the proliferation and migration of AY27 cells while the Lys305Met MAO-A mutant was inactive. This was consistent with the fact that the antioxidant Trolox strongly impaired proliferation and cell cycle progression. Most interestingly, AY27 cells were highly dependent on glucose metabolism to sustain their growth, and MAO inhibitors potently reduced glycolysis and oxidative phosphorylation, due to pyruvate depletion. Accordingly, MAO inhibitors decreased the expression of proteins involved in glucose transport (GLUT1) and transformation (HK2). In conclusion, urothelial cancer cells are characterized by a metabolic shift toward glucose-dependent metabolism, which is important for cell growth and is under the regulation of MAO-dependent oxidative stress.

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults.

We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aß] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73-80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4 years. In the models utilizing plasma Aß alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aß levels. Models incorporating Aß plus multiple plasma biomarkers performed similarly to models included Aß alone in predicting dementia and CDR progression. However, improving Aß model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aß, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted ß [95% CI], - 0.21 [- 0.35 to - 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aß models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aß pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance.

Plasma MCP-1 and changes on cognitive function in community-dwelling older adults.

BACKGROUND: Monocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma MCP-1 levels (alone and in combination with ß-amyloid deposition-Aß42/40) with overall and domain-specific cognitive evolution among older adults. METHODS: Secondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aß42/40 (lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1+)) were used, as well as a dichotomy of Aß42/40. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT - memory). RESULTS: Plasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1+ was associated with worse evolution in the CCS (4-year between-group difference: ß = -0.14, 95%CI = -0.26, -0.02) and the CDR sum of boxes (2-year: ß = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1+ was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aß42/40, MCP-1+ was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aß42/40× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables. CONCLUSIONS: Baseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aß42/40 to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aß42/40.

Interactions Between Weight Loss and Plasma Neurodegenerative Markers for Determining Cognitive Decline Among Community-Dwelling Older Adults.

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-ß 42/40 (Aß 42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial, mean age 76.8 years (SD = 4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onward by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test; Digit Symbol Substitution Test; 10 MMSE orientation items (MMSEO) and free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL + lower Aß 42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p < .0001) and MMSEO (p = .021), compared with non-WL + higher Aß 42/40. WL + higher NfL (>94.55 pg/mL, highest quartile) or progranulin (>38.4 ng/mL, 3 higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO, and composite score (all p < .03), compared with non-WL + lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs Q4) revealed higher cognitive decline among the WL + lower progranulin group compared with non-WL + lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aß 42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment. Clinical trial number: NCT00672685.

Prospective Associations of Plasma Growth Differentiation Factor 15 With Physical Performance and Cognitive Functions in Older Adults.

BACKGROUND: Growth differentiation factor 15 (GDF15) has been associated with several age-related disorders, but its associations with functional abilities in community-dwelling older adults are not well studied. METHODS: The study was a secondary analysis of 1 096 community-dwelling older adults (aged 69-94 years) recruited from the Multidomain Alzheimer's Preventive Trial. Plasma GDF15 was measured 1 year after participants' enrollment. Annual data of physical performance (grip strength and Short Physical Performance Battery [SPPB]) and global cognitive functions (Mini-Mental State Examination [MMSE] and a composite cognitive score) were measured for 4 years. Adjusted mixed-effects linear models were performed for cross-sectional and longitudinal association analyses. RESULTS: A higher GDF15 was cross-sectionally associated with a weaker grip strength (ß = -1.1E-03, 95% CI [-2.0E-03, -1.5E-04]), a lower SPPB score (ß = -3.1E-04, 95% CI [-5.4E-04, -9.0E-05]), and worse cognitive functions (ß = -2.4E-04, 95% CI [-3.3E-04, -1.6E-04] for composite cognitive score; ß = -4.0E-04, 95% CI [-6.4E-04, -1.6E-04] for MMSE). Participants with higher GDF15 demonstrated greater longitudinal declines in SPPB (ß = -1.0E-04, 95% CI [-1.7E-04, -2.0E-05]) and composite cognitive score (ß = -2.0E-05, 95% CI [-4.0E-05, -3.6E-06]). The optimal initial GDF15 cutoff values for identifying participants with minimal clinically significant decline after 1 year were 2 189 pg/mL for SPPB (AUC: 0.580) and 2 330 pg/mL for composite cognitive score (AUC: 0.587). CONCLUSIONS: Plasma GDF15 is cross-sectionally and longitudinally associated with lower-limb physical performance and global cognitive function in older adults. Circulating GDF15 alone has a limited capacity of discriminating older adults who will develop clinically significant functional declines. CLINICAL TRIAL REGISTRATION: NCT00672685.

Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload.

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Isolation of macrophage subpopulations showed that the LYVE-1 positive subset sustained in vitro and in vivo lymphangiogenesis through the expression of pro-lymphangiogenic factors. In contrast, the LYVE-1 negative macrophage subset strongly expressed MMP12 and decreased the endothelial LYVE-1 receptors in lymphatic endothelial cells, a feature of cardiac lymphatic remodeling in failing hearts. The treatment of mice with a CCR2 antagonist during pressure overload modified the proportion of macrophage subsets within the pathological heart and preserved lymphatic network from remodeling. This study reports unknown and differential functions of macrophage subpopulations in the regulation of cardiac lymphatic during pathological hypertrophy and may constitute a key mechanism underlying the progression of heart failure.

Low-energy electron beam sterilization of solid alginate and chitosan, and their polyelectrolyte complexes.

Polysaccharidic scaffolds hold great hope in regenerative medicine, however their sterilization still remains challenging since conventional methods are deleterious. Recently, electron beams (EB) have raised interest as emerging sterilization techniques. In this context, the aim of this work was to study the impact of EB irradiations on polysaccharidic macroporous scaffolds. The effects of continuous and pulsed low energy EB were examined on polysaccharidic or on polyelectrolyte complexes (PEC) scaffolds by SEC-MALLS, FTIR and EPR. Then the scaffolds' physicochemical properties: swelling, architecture and compressive modulus were investigated. Finally, sterility and in vitro biocompatibility of irradiated scaffolds were evaluated to validate the effectiveness of our approach. Continuous beam irradiations appear less deleterious on alginate and chitosan chains, but the use of a pulsed beam limits the time of irradiation and better preserve the architecture of PEC scaffolds. This work paves the way for low energy EB tailor-made sterilization of sensitive porous scaffolds.