The overlapping modular organization of human brain functional networks across the adult lifespan

Previous lifespan studies have demonstrated that the brain functional modular organization would change along with the adult lifespan. Yet, they assumed mutual exclusion among functional modules, ignoring convergent evidence for the existence of modular overlap. To reveal how age affects the overlapping functional modular organization, this study applied a detection algorithm requiring no prior knowledge of the resting-state fMRI data of a healthy cohort (N = 570, 18-88 years). Age-related regression analyses found a linear decrease in the overlapping modularity and the similarity of modular structure and overlapping node (i.e., region involved in multiple modules) distribution. The number of overlapping nodes increased with age, but the increment was distributed unevenly. In addition, across the adult lifespan and within each age group, the nodal overlapping probability consistently exhibited positive correlations with both functional gradient and flexibility. Further, we showed that the influence of age on memory-related cognitive performance might be explained by the change in the overlapping functional modular organization. Together, our results revealed age-related decreased segregation from the perspective of brain functional overlapping modular organization, providing new insight into the adult lifespan change in brain function and its influence on cognitive performance.

586. Immunogenicity of COVID-19 mRNA Vaccines in Patients with Lymphoid Malignancies

Background Patients with lymphoid malignancies are at high risk of severe COVID-19 disease and were not included in the phase 3 mRNA vaccine trials. Many patients with lymphoid malignancies receive immunosuppressive therapies, including B-cell depleting agents, that may negatively impact humoral response to vaccination. Methods We recruited patients with lymphoid malignancies and healthy participants who planned to receive two doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). Blood was drawn at baseline, prior to second dose of vaccine, and 28 days after last vaccination. Disease characteristics and therapies were extracted from patients’ electronic medical record. An ultrasensitive, single molecule array (Simoa) assay detected anti-Spike (S), anti-S1, anti-receptor binding domain (RBD), and anti-Nucleocapsid (N) IgG from plasma at each timepoint. Results 23 healthy participants and 37 patients with lymphoid malignancies were enrolled (Table 1). Low titers of anti-N (Fig 1A) demonstrate no prior exposure or acquisition of COVID-19 before vaccination or during the study. 37.8% of the lymphoid malignancy cohort responded to the vaccine, using an internally validated AEB cutoff of 1.07. A significantly higher magnitude of anti-S (p< 0.0001), anti-S1 (p< 0.0001) and anti-RBD (p< 0.0001) are present in the healthy as compared to lymphoid malignancy cohort at the second dose and day 28 post-series (Fig 1B, Fig 1C and Fig 1D). Anti-S IgG titers were compared between the healthy cohort, treatment naïve, and treatment experienced groups (Fig 2). The treatment naïve cohort had high titers by series completion which were not significantly different from the healthy cohort (p=0.2259), although the treatment experienced group had significantly decreased titers (p< 0.0001). Of the 20 patients who had received CD20 therapy, there was no clear correlation of anti-S IgG response with time from CD20 therapy, although most patients who received CD20 therapies within 12 months from the vaccine had no response (Figure 3). Table 1. Demographics Figure 1. Anti-N, Anti-S, Anti-S1, Anti-RBD and Anti-N Ig G for healthy v. lymphoid malignancy cohort The dotted line at 1.07 marks in an internally validated threshold to mark anti-S IgG response. The black bars denote median with 95% CI. Figure 2: Anti-S IgG for healthy v. treatment naïve v. treatment experienced The dotted line at 1.07 marks in an internally validated threshold to mark antibody response. The black bars denote median with 95% CI. Conclusion The vaccine-induced immune response was poor among treatment-experienced patients with lymphoid malignancies, especially among those who received CD20 therapies within 12 months. Figure 3. Months from CD20 therapy v. anti-S IgG titers The dotted line at 1.07 marks in an internally validated threshold to mark antibody response. Disclosures Jennifer Crombie, MD, AbbVie (Grant/Research Support)Bauer (Grant/Research Support)Karyopharm (Consultant)MorphoSys (Consultant) Philippe Armand, MD PhD, ADCT, Celgene, Morphosys, Daiichi, Miltenyi, Tessa, C4, Genmab, Enterome, Regeneron, Genentech, Epizyme, Astra Zeneca (Consultant, Sorry to put them all in, hope you can deconvolute for me)Affimed, Adaptive, BMS, Merck, Kite, IGM, Genentech (Research Grant or Support, Institutional research funding) David Walt, PhD, Quanterix Corporation (Board Member, Shareholder) Nicolas C. Issa, MD, AiCuris (Scientific Research Study Investigator)Astellas (Scientific Research Study Investigator)GSK (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

Does My Neck Make Me Clumsy? A Systematic Review of Clinical and Neurophysiological Studies in Humans

Introduction: Clumsiness has been described as a symptom associated with neck pain and injury. However, the actuality of this symptom in clinical practice is unclear. The aim of this investigation was to collect definitions and frequency of reports of clumsiness in clinical studies of neck pain/injury, identify objective measures of clumsiness and investigate the association between the neck and objective measures of clumsiness.Methods: Six electronic databases were systematically searched, records identified and assessed including a risk of bias. Heterogeneity in designs of studies prevented pooling of data, so qualitative analysis was undertaken.Results: Eighteen studies were retrieved and assessed; the overall quality of evidence was moderate to high. Eight were prospective cross-sectional studies comparing upper limb sensorimotor task performance and ten were case series involving a healthy cohort only. Clumsiness was defined as a deficit in coordination or impairment of upper limb kinesthesia. All but one of 18 studies found a deterioration in performing upper limb kinesthetic tasks including a healthy cohort where participants were exposed to a natural neck intervention that required the neck to function toward extreme limits.Conclusion: Alterations in neck sensory input occurring as a result of requiring the neck to operate near the end of its functional range in healthy people and in patients with neck pain/injury are associated with reductions in acuity of upper limb kinesthetic sense and deterioration in sensorimotor performance. Understanding the association between the neck and decreased accuracy of upper limb kinesthetic tasks provide pathways for treatment and rehabilitation strategies in managing clumsiness.

Early immunologic response to mRNA COVID-19 vaccine in patients receiving biologics and/or immunomodulators.

Patients with immune conditions and immune-modifying therapies were excluded from the Covid-19 vaccine trials. Studies have shown conflicting response to different vaccines in persons receiving immune suppressors or biologics. The aim of this study is to evaluate humoral and cellular response to Covid-19 vaccines in patients with Inflammatory Bowel Disease (IBD) using biologic and/or immunomodulatory (IMM) therapies. Methods: Participants are adults with IBD receiving biologics or IMM planning to receive a Covid 19 vaccine. Cellular immunity (CD4+ and CD8+ T cell levels) with flow cytometry are measured at baseline and 2 weeks after each vaccine dose. Humoral immunity (antibody titers and neutralizing capacity,VNT%) is analyzed by ELISA at baseline, 2 weeks after each dose, and 6 and 12 months after vaccine. We present the early results of the first 19 subjects. The study is approved by the IRB. Results: 19 subjects (18 in biologics and 1 in IMM) who received 2 doses of the Pfizer-BioNTech vaccine are included. Total IgG antibodies increased 21.13 times after the first dose and 90 times after the second dose. VTN% increased 11.92 times after the first dose and 53.79 times after the second dose. When compared with a healthy control cohort, total IgG antibodies and VTN% were lower in the subjects after the first dose. After the second dose, IgG antibodies increased but remained lower than controls, but VTN% were similar to controls. CD4 and CD8 mean levels had an upward trend after vaccination. Conclusions: Neutralizing capacity response to the vaccine in subjects was similar to a healthy cohort in spite of lower increases in total IgG antibodies. The CD4 and CD8 results observed may support the capacity to mount an effective cellular response in patients on biologics. Larger studies are needed to determine vaccine efficacy in these patients.

Genetics of severe hypercholesterolemia in the general population: Insights from the STANISLAS cohort

Background: Severe hypercholesterolemia (SH) is a common condition characterized by increased levels of total and low-density lipoprotein cholesterol (LDLc). Methods: The aim of this study is to screen for prevalence of hypercholesterolemia, perform heritability estimation of circulating lipoproteins and study the association between SH cases and surrogate cardiovascular disease markers among participants of STANISLAS cohort. Gene candidate analyses were utilized to investigate the association between lipid levels, SH and polymorphisms from the three commonly reported genes (APOB, LDLR and PCSK9). Results: Participants with SH (n=102; 6.9%) were older (58 vs. 51yr), had higher total cholesterol (290 vs. 209mg/dL), LDLc (206 vs. 136mg/dL) and triglycerides (114 vs. 88 mg/dL). Despite smoking less, they had carotid plaques more frequently (21.2 vs. 9.3%), higher cIMT (676 vs. 597µm), and had more frequent family history cardiovascular disease. The circulating lipid levels have an important heritability: LDLc 51.6%, HDLc 66.6%, total cholesterol 49.8%, and triglycerides 41.4%. The SNPs located in LDLR gene present the strongest association with LDLc levels: rs55997232, rs17242395, rs1010679, and rs11668477. Conclusion: In a healthy cohort, participants with SH had premature vascular damage. LDLc had an important component of heritability and SNPs linked to the LDLR gene presented a strong association with LDLc. These findings reinforce the need for an early identification and treatment of SH subjects, which is mostly polygenic.

443Factors associated with frailty in a relatively healthy community-dwelling older adults

Background Frailty is gaining importance as a predictor of disability and mortality in aged adults, and becoming frail poses a challenge for healthy aging. We investigated the prevalence and factors associated with pre-frail and frail status in a large study cohort of community-dwelling healthy older adults from Australia and the United States. Methods A total of 19,114 individuals (87% Australian and 56% women) aged 65 years or older enrolled in a primary prevention clinical trial were evaluated. Frailty status was classified using the modified Fried phenotype criteria comprising exhaustion, body mass index, grip strength, gait speed and physical activity. Prevalence and factors associated with frailty status (e.g., demographic characteristics and lifestyle factors) were reported using descriptive statistics along with a logistic regression model. Results At baseline, 39.0% (95% CI: 38.3, 39.7) of older trial participants were pre-frail and 2.2% (95% CI: 2.0, 2.4) were frail, respectively. Women were more likely to be frail (65.1% vs. 36.9%) and prefrail (58.0% vs. 42.0%) than men. Lower levels of education (<12 years), living alone, ethnic minorities, current smoking and past alcohol use were some of the factors which were common among frail or prefrail. Conclusions Despite being a relatively healthy cohort, more than one-third of the older trial participants were pre-frail, which was more prevalent among specific subgroups of individuals. This study emphasizes the high burden of the prefrailty status even among a healthy cohort of community-dwelling older people. Key messages The burden of prefrailty is high, even among a healthy cohort of older people in the communities.

Characterization of the Genitourinary Microbiome of 1,165 Middle-Aged and Elderly Healthy Individuals

Accumulated evidence shows that complex microbial communities resides in the healthy human urinary tract and can change in urological disorders. However, there lacks a comprehensive profiling of the genitourinary microbiota in healthy cohort. Here, we performed 16S rRNA gene sequencing of midstream urine specimens from 1,172 middle-aged and elderly healthy individuals. The core microbiota included 6 dominant genera (mean relative abundance >5%), including Prevotella, Streptococcus, Lactobacillus, Gardnerella, Escherichia-Shigella, and Veillonella, and 131 low-abundance genera (0.01–5%), displaying a distinct microbiome profiles to that of host-matched gut microbiota. The composition and diversity of genitourinary microbiome (GM) were distinct between genders and may fluctuate with ages. Several urotypes were identified by the stratification of microbiome profiles, which were mainly dominated by the six most predominant genera. The prevalence of urotypes was disparate between genders, and the male sample additionally harbored other urotypes dominated by Acinetobacter, Corynebacterium, Staphylococcus, or Sphingomonas. Peptoniphilus, Ezakiella, and Porphyromonas were co-occurred and co-abundant, and they may play crucial roles as keystone genera and be associated with increased microbial diversity. Our results delineated the microbial structure and diversity landscape of the GM in healthy middle-aged and elderly adults and provided insights into the influence of gender and age to it.

Developmental variation in testosterone:cortisol ratio alters cortical- and amygdala-based cognitive processes

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal–amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4–22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) covariance of the amygdala with CTh in visual and somatosensory areas. These brain parameters were in turn associated with lower verbal/executive function and higher spatial working memory. In sum, individual TC profiles may confer a particular brain phenotype and set of cognitive strengths and vulnerabilities, prior to adulthood.