Changes in Cardiac Tone Regulation with Fatigue after Supra-Maximal Running Exercise

To investigate the effects of fatigue and metabolite accumulation on the postexercicse parasympathetic reactivation, 11 long-sprint runners performed on an outdoor track an exhaustive 400 m long sprint event and a 300 m with the same 400 m pacing strategy. Time constant of heart rate recovery (HRRτ), time (RMSSD), and frequency (HF, and LF) varying vagal-related heart rate variability indexes were assessed during the 7 min period immediately following exercise. Biochemical parameters (blood lactate, pH, PO2, PCO2, SaO2, and HCO3−) were measured at 1, 4 and 7 min after exercise. Time to perform 300 m was not significantly different between both running trials. HHRτ measured after the 400 m running exercise was longer compared to 300 m running bouts (183.7 ± 11.6 versus 132.1 ± 9.8 s, P < 0.01). Absolute power density in the LF and HF bands was also lower after 400 m compared to the 300 m trial (P < 0.05). No correlation was found between biochemical and cardiac recovery responses except for the PO2 values which were significantly correlated with HF levels measured 4 min after both bouts. Thus, it appears that fatigue rather than metabolic stresses occurring during a supramaximal exercise could explain the delayed postexercise parasympathetic reactivation in longer sprint runs

The effect of pre-exercise alkalosis on lactate/pH regulation and mitochondrial respiration following sprint-interval exercise in humans

Purpose: The purpose of this study was to evaluate the effect of pre-exercise alkalosis, induced via ingestion of sodium bicarbonate, on changes to lactate/pH regulatory proteins and mitochondrial function induced by a sprint-interval exercise session in humans.Methods: On two occasions separated by 1 week, eight active men performed a 3 × 30-s all-out cycling test, interspersed with 20 min of recovery, following either placebo (PLA) or sodium bicarbonate (BIC) ingestion.Results: Blood bicarbonate and pH were elevated at all time points after ingestion in BIC vs PLA (p &lt; 0.05). The protein content of monocarboxylate transporter 1 (MCT1) and basigin (CD147), at 6 h and 24 h post-exercise, and sodium/hydrogen exchanger 1 (NHE1) 24 h post-exercise, were significantly greater in BIC compared to PLA (p &lt; 0.05), whereas monocarboxylate transporter 4 (MCT4), sodium/bicarbonate cotransporter (NBC), and carbonic anhydrase isoform II (CAII) content was unchanged. These increases in protein content in BIC vs. PLA after acute sprint-interval exercise may be associated with altered physiological responses to exercise, such as the higher blood pH and bicarbonate concentration values, and lower exercise-induced oxidative stress observed during recovery (p &lt; 0.05). Additionally, mitochondrial respiration decreased after 24 h of recovery in the BIC condition only, with no changes in oxidative protein content in either condition.Conclusion: These data demonstrate that metabolic alkalosis induces post-exercise increases in several lactate/pH regulatory proteins, and reveal an unexpected role for acidosis in mitigating the loss of mitochondrial respiration caused by exercise in the short term

The effect of pre-exercise alkalosis on lactate/pH regulation and mitochondrial respiration following sprint-interval exercise in humans

Purpose: The purpose of this study was to evaluate the effect of pre-exercise alkalosis, induced via ingestion of sodium bicarbonate, on changes to lactate/pH regulatory proteins and mitochondrial function induced by a sprint-interval exercise session in humans. Methods: On two occasions separated by 1 week, eight active men performed a 3 × 30-s all-out cycling test, interspersed with 20 min of recovery, following either placebo (PLA) or sodium bicarbonate (BIC) ingestion. Results: Blood bicarbonate and pH were elevated at all time points after ingestion in BIC vs PLA (p < 0.05). The protein content of monocarboxylate transporter 1 (MCT1) and basigin (CD147), at 6 h and 24 h post-exercise, and sodium/hydrogen exchanger 1 (NHE1) 24 h post-exercise, were significantly greater in BIC compared to PLA (p < 0.05), whereas monocarboxylate transporter 4 (MCT4), sodium/bicarbonate cotransporter (NBC), and carbonic anhydrase isoform II (CAII) content was unchanged. These increases in protein content in BIC vs. PLA after acute sprint-interval exercise may be associated with altered physiological responses to exercise, such as the higher blood pH and bicarbonate concentration values, and lower exercise-induced oxidative stress observed during recovery (p < 0.05). Additionally, mitochondrial respiration decreased after 24 h of recovery in the BIC condition only, with no changes in oxidative protein content in either condition. Conclusion: These data demonstrate that metabolic alkalosis induces post-exercise increases in several lactate/pH regulatory proteins, and reveal an unexpected role for acidosis in mitigating the loss of mitochondrial respiration caused by exercise in the short term

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele