Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

Importance: Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. // Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. // Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. // Main Outcomes and Measures: Amyloid-β plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer–tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Šídák tests. // Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer–containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. // Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Opportunities and challenges for a maturing science of consciousness

International audienc

Opportunities and challenges for a maturing science of consciousness

Scientific research on consciousness is critical to multiple scientific, clinical, and ethical issues. The growth of the field could also be beneficial to several areas including neurology and mental health research. To achieve this goal, we need to set funding priorities carefully and address problems such as job creation and potential media misrepresentation

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)

Mapping of the 17q21 locus.

<p><i>Top 3 panels:</i> P-values of association (−log₁₀ scale) with ovarian cancer risk for genotyped and imputed SNPs (1000 Genomes Project CEU), by chromosome position (b.37) at the 17q21 region, for <i>BRCA1</i>, <i>BRCA2</i> mutation carriers and combined. Results based on the kinship-adjusted score test statistic (1 d.f.). <i>Fourth panel:</i> Genes in the region spanning (43.4–44.9 Mb, b.37) and the location of the most significant genotyped SNPs (in red font) and imputed SNPs (in black font). <i>Bottom panel:</i> Pairwise r² values for genotyped SNPs on iCOG array in the 17q21 region covering positions (43.4–44.9 Mb, b.37).</p

Predicted breast and ovarian cancer absolute risks for <i>BRCA1</i> mutation carriers at the 5^th, 10^th, 90^th, and 95^th percentiles of the combined SNP profile distributions.

<p>The minimum, maximum and average risks are also shown. Predicted cancer risks are based on the associations of known breast or ovarian cancer susceptibility loci (identified through GWAS) with cancer risk for <i>BRCA1</i> mutation carriers and loci identified through the present study. Breast cancer risks based on the associations with: 1q32, 10q25.3, 19p13, 6q25.1, 12p11, <i>TOX3</i>, 2q35, <i>LSP1</i>, <i>RAD51L1</i> (based on HR and minor allele frequency estimates from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t001" target="_blank">Table 1</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t002" target="_blank">Table 2</a>, and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212.s016" target="_blank">Table S4</a>) and <i>TERT </i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Bojesen1" target="_blank">[31]</a>. Ovarian cancer risks based on the associations with: 9p22, 8q24, 3q25, 17q21, 19p13 (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t001" target="_blank">Table 1</a>) and 17q21.31, 4q32.3 (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen-1003212-t002" target="_blank">Table 2</a>). Only the top SNP from each region was chosen. Average breast and ovarian cancer risks were obtained from published data <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Antoniou10" target="_blank">[25]</a>. The methods for calculating the predicted risks have been described previously <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003212#pgen.1003212-Antoniou11" target="_blank">[28]</a>.</p

Study design for selection of the SNPs and genotyping of <i>BRCA1</i> samples.

<p>GWAS data from 2,727 <i>BRCA1</i> mutation carriers were analysed for associations with breast and ovarian cancer risk and 32,557 SNPs were selected for inclusion on the iCOGS array. A total of 11,705 <i>BRCA1</i> samples (after quality control (QC) checks) were genotyped on the 31,812 <i>BRCA1</i>-GWAS SNPs from the iCOGS array that passed QC. Of these samples, 2,387 had been genotyped at the SNP selection stage and are referred to as “stage 1” samples, whereas 9,318 samples were unique to the iCOGS study (“Stage 2” samples). Next, 17 SNPs that exhibited the most significant associations with breast and ovarian cancer were selected for genotyping in a third stage involving an additional 2,646 <i>BRCA1</i> samples (after QC).</p

Associations with SNPs at the novel 17q21 region with ovarian cancer risk for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers.

*<p>HRs estimated under the single disease risk model.</p