Statin use moderates APOE's and CRP's associations with dementia and is associated with lesser dementia severity in ε4 carriers.

INTRODUCTION: We tested the effect of statins on C-reactive protein (CRP) and apolipoprotein E (APOE)'s associations with dementia severity. METHODS: A total of 1725 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) were assigned from 12-month follow-up data into the following groups: (1) ε4 (-)/statin (-), (2) ε4 (-)/statin (+), (3) ε4 (+)/statin (-), and (4) ε4 (+)/statin (+). Dementia severity was assessed by a δ homolog: "dHABS." A mediation model was stratified on statin use and moderation effects tested by a chi-square difference. RESULTS: Plasma CRP level decreased with ε4 allelic dose. Statins had no effect on the dHABS d-score in non-carriers but were associated with better scores in carriers. Treated carriers did not have more severe dementia than non-carriers. Statin use moderated the mutual adjusted effects of APOE and CRP. CRP was not a mediator of APOE's effect. DISCUSSION: Statins may provide a protective effect on the dementia severity of ε4 carriers. HIGHLIGHTS: δ is a dementia-specific phenotype related to general intelligence "g" and is assessed via a "d-score." Apolipoprotein E (APOE) and plasma C-reactive protein (CRP) are independently associated with δ. Plasma CRP decreases with ε4 allelic dose. Statins were associated with better (less demented) d-scores in ε4 carriers but had no effect in non-ε4 carriers. Treated ε4 carriers did not have more severe dementia than non-carriers. Statin use moderated the effects of APOE and CRP on δ. CRP was not a mediator of APOE's effect on δ.

Physiological mediators of prenatal environmental influences in autism spectrum disorder.

Recent research has pointed to the importance of the prenatal environment in the etiology of autism spectrum disorder (ASD) but the biological mechanisms which mitigate these environmental factors are not clear. Mitochondrial metabolism abnormalities, inflammation and oxidative stress as common physiological disturbances associated with ASD. Network analysis of the scientific literature identified several leading prenatal environmental factors associated with ASD, particularly air pollution, pesticides, the microbiome and epigenetics. These leading prenatal environmental factors were found to be most associated with inflammation, followed by oxidative stress and mitochondrial dysfunction. Other prenatal factors associated with ASD not identified by the network analysis were also found to be significantly associated with these common physiological disturbances. A better understanding of the biological mechanism which mediate the effect of prenatal environmental factors can lead to insights of how ASD develops and the development of targeted therapeutics to prevent ASD from occuring.

Prenatal air pollution influences neurodevelopment and behavior in autism spectrum disorder by modulating mitochondrial physiology.

We investigate the role of the mitochondrion, an organelle highly sensitive to environmental agents, in the influence of prenatal air pollution exposure on neurodevelopment and behavior in 96 children with autism spectrum disorder (ASD) [45 with neurodevelopmental regression (NDR); 76% Male; mean (SD) age 10 y 9 m (3 y 9 m)]. Mitochondrial function was assessed using the Seahorse XFe96 in fresh peripheral blood mononuclear cells. Second and third trimester average and maximal daily exposure to fine air particulate matter of diameter ≤2.5 µm (PM2.5) was obtained from the Environmental Protection Agency's Air Quality System. Neurodevelopment was measured using the Vineland Adaptive Behavior Scale 2nd edition and behavior was assessed using the Aberrant Behavior Checklist and Social Responsiveness Scale. Prenatal PM2.5 exposure influenced mitochondrial respiration during childhood, but this relationship was different for those with (r = 0.25-0.40) and without (r = -0.07 to -0.19) NDR. Mediation analysis found that mitochondrial respiration linked to energy production accounted for 25% (SD = 2%) and 10% (SD = 2%) of the effect of average prenatal PM2.5 exposure on neurodevelopment and behavioral symptoms, respectively. Structural equation models estimated that PM2.5 and mitochondrial respiration accounted for 34% (SD = 4%) and 36% (SD = 3%) of the effect on neurodevelopment, respectively, and that behavior was indirectly influenced by mitochondrial respiration through neurodevelopment but directly influenced by prenatal PM2.5. Our results suggest that prenatal exposure to PM2.5 disrupts neurodevelopment and behavior through complex mechanisms, including long-term changes in mitochondrial respiration and that patterns of early development need to be considered when studying the influence of environmental agents on neurodevelopmental outcomes.

Community Health Workers as Trust Builders and Healers: A Cohort Study in Primary Care.

PURPOSE: Improving patients' self-care for chronic disease is often elusive in the context of social deprivation. We evaluated whether a practice-integrated community health worker (CHW) intervention could encourage effective long-term self-management of type 2 diabetes mellitus (T2DM). METHODS: This cohort study, in a safety-net primary care practice, enrolled patients with uncontrolled T2DM and psychosocial risk factors. Patients were identified through a practice diabetes registry or by clinicians' referrals. The CHWs engaged patients in trust building and sensemaking to understand their social context, identify goals, navigate health care, and connect to community resources. Primary outcome was progress through 3 prospectively defined stages of self-care: outreach (meeting face-to-face); stabilization (collaborating to address patients' life circumstances); and self-care generativity (achieving self-care competencies). Secondary outcomes were change in hemoglobin A1c (HbA1c) and need for urgent care, emergency department, or hospital visits. RESULTS: Of 986 participating patients, 27% remained in outreach, 41% progressed to stabilization, and 33% achieved self-care generativity. Repeated measures ANOVA demonstrates an overall decline in HbA1c, without group differences, through the 4th HbA1c measurement (mean follow-up 703 days). Beginning at the 5th HbA1c measurement (mean 859 days), the self-care generativity group achieved greater declines in HbA1c, which widened through the 10th measurement (mean 1,365 days) to an average of 8.5% compared with an average of 8.8% in the outreach group and 9.0% in the stabilization group (P = .003). Rates of emergency department and hospital visits were lower in the self-care generativity group. CONCLUSIONS: Practice-linked CHWs can sustainably engage vulnerable patients, helping them advance self-management goals in the context of formidable social disadvantage.

δ scores predict multiple neuropsychiatric symptoms.

OBJECTIVES: Dementia severity is strongly related to Spearman's general intelligence factor "g", via the latent dementia phenotype "δ" and is distinct from domain-specific cognitive impairments arising from disease-specific regional pathologies. It is an empiric question whether behavioral and psychological symptoms of dementia (BPSD) are associated with δ or with domain-specific constructs. METHODS: A recently developed δ homolog ("dDx") was tested as a predictor of 1 year prospective BPSD in n = 723 Mexican-American and non-Hispanic White participants in the Texas Alzheimer's Research and Care Consortium (TARCC). The informant-rated frequencies of 12 BPSD were rated by the neuropsychiatric inventory (NPI-Q). Baseline BPSD, demographic features, selected biomarkers, and treatment exposure to acetylcholinesterase inhibitors were used as covariates. Composite scores derived from orthogonal latent measures of domain-specific memory (MEM) and executive function (EF) were also tested as predictors. RESULTS: "Functionally salient cognitive impairment (FSCI)" that is, categorical "dementia" as diagnosed by dDx was associated with increased prospective frequency of 11/12 BPSD, independently of baseline behavior and covariates. Age, depressive symptoms, and EF were associated with individual BPSD. MEM was not associated with any. Dementia severity, as measured by dDx, was also associated with a prospective increase in total NPI-Q scores. CONCLUSION: δ is associated non-specifically with multiple BPSD. This suggests the existence of a dementia-specific behavioral profile, arising from insults to general intelligence, and unrelated to disease-specific regional pathology(ies).

Tooth Fairy Study- The South Texas Oral Health Network Collaboration.

PURPOSE: This study's purpose was to examine the processes and the potential for dental practitioners to address environmental health exposure risks to their patients through dental practice-based research participation. To explore this, the South Texas Oral Health Network (STOHN) initiated a collaboration with The Tooth Fairy National Study investigating toxicants stored in deciduous teeth as a potential neurodevelopmental risk factor. BACKGROUND: Neurodevelopmental disorders (ND), like Autism Spectrum Disorder (ASD), affect 1 in 68 live births. Evidence suggests that environmental chemicals may play a role in ASD risk and/or etiology by acting independently or through interactions with genetic vulnerabilities. Provider awareness of environmental exposure risk during pregnancy and early childhood in South Texas is low. Therefore, it is important to increase provider knowledge and awareness to enable greater communication with patients. STOHN serves as a conduit reaching large numbers of patients. This study also engaged practitioners in an ongoing national study with minimal impact on their practice. METHODS: The goal was to enroll twenty parents with children via ten dental practitioners. STOHN pediatric and general practitioners were recruited for the study. Practitioners were contacted by phone and in person. Upon completion of Human Subject Protection training, each practitioner participated in a study training taught by a public health educator in the department of Family and Community Medicine at University of Texas Health Science Center in San Antonio (UTHSCSA). Training topics included NDs, environmental health exposures, patient engagement, survey administration, and how to collect donated teeth. This collaboration allowed STOHN to gather control teeth as well as demographic and health information for the Tooth Fairy Study repository for future analyses. Participants received a thank you card from the Tooth Fairy and participating providers were highlighted in the monthly STOHN newsletter. EVALUATION RESULTS: Evaluation was threefold: Practitioner enrollment and retention; practitioner confidence in educating their patients about potential environmental risk exposures and completed surveys with donated teeth. CONCLUSION: The interdisciplinary collaboration between dental practitioners and medical researchers through STOHN provided an opportunity to increase practitioner knowledge and awareness of a novel health concern, while also raising their confidence and willingness to educate their patients about potential environmental exposure risks. UTHSCSA IRB Protocol # HSC20170132E.

Service and Education: The Association Between Workload, Patient Complexity, and Teaching on Internal Medicine Inpatient Services.

BACKGROUND: Attending rounds remain the primary venue for formal teaching and learning at academic medical centers. Little is known about the effect of increasing clinical demands on teaching during attending rounds. OBJECTIVE: To explore the relationships among teaching time, teaching topics, clinical workload, and patient complexity variables. DESIGN: Observational study of medicine teaching teams from September 2008 through August 2014. Teams at two large teaching hospitals associated with a single medical school were observed for periods of 2 to 4 weeks. PARTICIPANTS: Twelve medicine teaching teams consisting of one attending, one second- or third-year resident, two to three interns, and two to three medical students. MAIN MEASURES: The study examined relationships between patient complexity (comorbidities, complications) and clinical workload variables (census, turnover) with educational measures. Teams were clustered based on clinical workload and patient complexity. Educational measures of interest were time spent teaching and number of teaching topics. Data were analyzed both at the daily observation level and across a given patient's admission. KEY RESULTS: We observed 12 teams, 1994 discussions (approximately 373 h of rounds) of 563 patients over 244 observation days. Teams clustered into three groups: low patient complexity/high clinical workload, average patient complexity/low clinical workload, and high patient complexity/high clinical workload. Modest associations for team, patient complexity, and clinical workload variables were noted with total time spent teaching (9.1% of the variance in time spent teaching during a patient's admission; F[8,549] = 6.90, p < 0.001) and number of teaching topics (16% of the variance in the total number of teaching topics during a patient's admission; F[8,548] = 14.18, p < 0.001). CONCLUSIONS: Clinical workload and patient complexity characteristics among teams were only modestly associated with total teaching time and teaching topics.

Construction of a Potential Telephone Assessment of Dementia Prevalence and Severity.

The "δ" (for "dementia") is a latent dementia phenotype that can be constructed by a unique confirmatory bifactor model in a structural equation model framework. Because it is derived from Spearman's general intelligence factor, "g," δ can be constructed from any cognitive battery. This may allow for accurate dementia case-finding by telephone and in the absence of expert clinical evaluation or review. The authors constructed a new δ homolog in a large ethnically diverse convenience sample: the Texas Alzheimer's Research and Care Consortium, comprising 2,016 participants (Alzheimer's disease [AD], N=920; mild cognitive impairment, N=277; normal controls, N=819). A δ composite ("dTEL") was extracted from informant-rated Instrumental Activities of Daily Living and a brief battery of verbal cognitive measures. The entire battery was engineered to be administered over the telephone. dTEL's model had excellent fit. dTEL correlated strongly with dementia severity, as measured by the Clinical Dementia Rating "sum of boxes" scale (r=0.78, p<0.001). The dTEL composite's area under the receiver operating characteristic curve for the discrimination between control subjects and AD patients was 0.97 (95% CI=0.964-0.975). This was superior to all dTEL indicators. Therefore, the authors have demonstrated that a δ homolog composite constructed entirely from verbal measures is strongly associated with dementia severity, can accurately diagnose dementia, and outperforms all observed measures from which it is constructed. Future studies are required to assess dTEL's performance relative to evaluation by expert clinicians when obtained by lay psychometricians over the telephone.

Practical Opportunities for Healthy Diet and Physical Activity: Relationship to Intentions, Behaviors, and Body Mass Index.

PURPOSE: Current strategies for improving diet and activity patterns focus on encouraging patients to make better choices, but they meet with limited success. Because the choices people make depend on the choices they have, we examined how practical opportunities for diet and physical activity shape behavioral intentions and achieved behaviors. METHODS: Participants included 746 adults who visited 8 large primary care practices in the Residency Research Network of Texas in 2012. We used structural equation models to confirm factor structures for a previously validated measure of practical opportunities, and then modeled achieved diet (Starting the Conversation - Diet questionnaire), physical activity (International Physical Activity Questionnaire), and BMI as a function of opportunities (classified as either resources or conversion factors that influence use of resources), behavioral intentions, and demographic covariates. RESULTS: In path models, resources (P <.001) and conversion factors (P = .005) predicted behavioral intentions for activity. Conversion factors (P <.001), but not resources, predicted diet intentions. Both activity resources (P = .01) and conversion factors (P <.001) were positively associated with weekly activity minutes. Diet conversion factors (P <.001), but not diet resources (P = .08), were positively associated with diet quality. The same patterns were observed for body mass index (BMI). Socioeconomic gradients in resources and conversion factors were evident. CONCLUSIONS: Individuals' feasible opportunities for healthy diet and activity have clinically meaningful associations with intentions, achieved behaviors, and BMI. Assessing opportunities as part of health behavior management could lead to more effective, efficient, and compassionate interventions.

Neuropsychiatric symptoms in community-dwelling Mexican-Americans: results from the Hispanic Established Population for Epidemiological Study of the Elderly (HEPESE) study.

OBJECTIVE: The Neuropsychiatric Inventory (NPI) is a well-established measure of psychopathology and frequently used in dementia studies. Little is known about its psychometric characteristics at a population level, particularly among Hispanics. We report the frequency of NPI symptoms in a community-dwelling older Mexican-American (MA) population cohort and the degree of symptom-related distress experienced by participant informants. METHODS: Participants were 1079 MA age 80 years and over residing in five southwestern states who were administered the NPI as part of wave-7 of the Hispanic Established Population for Epidemiological Study of the Elderly (HEPESE) conducted from 2010 to 2011. RESULTS: Nine hundred twenty-five informants rated NPI domains. Prevalence of neuropsychiatric symptoms (NPS) varied by symptom domain and ranged from agitation/aggression (32%) to euphoria/elation (5%). The overall rate of behavioral disturbances was 62.7%. On the other hand, 37.3% of informants reported no NPS. A significant fraction of the informants reported distress from the mood disorder cluster of the scale. CONCLUSIONS: A large percentage (>60%) of community-dwelling older MA have one or more informant-reported NPS. These symptoms have diagnostic, prognostic, and therapeutic implications. Although neuropsychiatric disorders may be the initial clinical manifestation of dementia and often appear before cognitive alterations, the high frequency of these symptoms in the HEPESE cohort may reflect a high prevalence of these disorders among community-dwelling MA. The pattern we observed also suggests relatively advanced stages of dementia.

Latent variables may be useful in pain's assessment.

BACKGROUND: Unobserved "latent" variables have the potential to minimize "measurement error" inherent to any single clinical assessment or categorical diagnosis. OBJECTIVES: To demonstrate the potential utility of latent variable constructs in pain's assessment. DESIGN: We created two latent variables representing depressive symptom-related pain (Pd) and its residual, "somatic" pain (Ps), from survey questions. SETTING: The Hispanic Established Population for Epidemiological Studies in the Elderly (H-EPESE) project, a longitudinal population-based cohort study. PARTICIPANTS: Community dwelling elderly Mexican-Americans in five Southwestern U.S. states. The data were collected in the 7th HEPESE wave in 2010 (N = 1,078). MEASUREMENTS: Self-reported pain, Center for Epidemiological Studies Depression Scale (CES-D) scores, bedside cognitive performance measures, and informant-rated measures of basic and instrumental Activities of Daily Living. RESULTS: The model showed excellent fit [χ2 = 20.37, DF = 12; p = 0.06; Comparative fit index (CFI) = 0.998; Root mean statistical error assessment (RMSEA) = 0.025]. Ps was most strongly indicated by self-reported pain-related physician visits (r = 0.48, p ≤0.001). Pd was most strongly indicated by self-reported pain-related sleep disturbances (r = 0.65, p <0.001). Both Pd and Ps were significantly independently associated with chronic pain (> one month), regional pain and pain summed across selected regions. Pd alone was significantly independently associated with self-rated health, life satisfaction, self-reported falls, Life-space, nursing home placement, the use of opiates, and a variety of sleep related disturbances. Ps was associated with the use of NSAIDS. Neither construct was associated with declaration of a resuscitation preference, mode of resuscitation preference declaration, or with opting for a "Do Not Resuscitate" (DNR) order. CONCLUSION: This analysis illustrates the potential of latent variables to parse observed data into "unbiased" constructs with unique predictive profiles. The latent constructs, by definition, are devoid of measurement error that affects any subset of their indicators. Future studies could use such phenotypes as outcome measures in clinical pain management trials or associate them with potential biomarkers using powerful parametric statistical methods.

Towards an aging-specific cognitive phenotype: the freedom house study.

UNLABELLED: BACKGROUND/STUDY CONTEXT: The authors have previously reported latent growth curve (LGC) models of 3-year change in multiple cognitive measures among successfully aging volunteers. In this analysis, the authors apply growth mixture modeling (GMM) to demonstrate homogeneous subsets among them with discriminable trajectories. Only one trajectory class can be interpreted as the effect of Aging Proper. The goal of the study was to describe an aging-specific cognitive phenotype (ASCP). METHODS: Five hundred forty-seven noninstitutionalized septuagenarian and octogenarian volunteers, residing in a comprehensive care retirement community, were assessed longitudinally on a comprehensive battery of brief psychometric measures. RESULTS: All variables held more than one latent class. Members of an a priori defined "Aging Proper" class were highly concordant across measures, and allowed the aging-specific cognitive phenotype (ASCP) to be examined. The ASCP was characterized by simultaneous decline in visuospatial function, coupled with improving verbal fluency. The ASCP was not associated with decline in memory task performance. CONCLUSIONS: Previously reported age-related declines in memory are more likely to represent the effects of comorbid disease and not aging per se. The ASCP is more consistent with earlier "Right Hemisphere" models of aging and could provide clues to the mechanisms underlying true aging-related cognitive changes.

An Exploratory Investigation of Organic Chemicals Detected in Baby Teeth: Differences in Children with and without Autism.

Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disorder characterized by deficits in language, communication, and social function with an estimated prevalence rate of between 1 in 30 and 44 U.S. births. Gene/environment (G × E) interactions are widely regarded as the most probable explanation for idiopathic ASD, especially because some genes are selectively targeted by various environmental xenobiotics. Because deciduous teeth are a likely biomarker of in utero exposure, the present study investigated if the quantity of chemicals found in deciduous teeth differs between children with and without ASD. Twenty-two deciduous teeth from children with ASD and 20 teeth from typically developed children were prepared and analyzed using THE Two-Dimensional Gas Chromatography Time-of-Flight Mass Spectrometer (GC × GC-TOF MS) with ChromaTOF version 23H2 software and Agilent 7890 gas chromatograph. The autism sample had significantly more chemicals in their teeth than the typical developing sample (99.4 vs. 80.7, respectively) (p < 0.0001). The majority of chemicals were identified as phthalates, plasticizers, pesticides, preservatives, or intermediary solvents used in the production of fragranced personal care or cleaning products or flavoring agents in foods. The known toxic analytes reported in this study are likely biomarkers of developmental exposure. Why there were greater concentrations of toxic chemicals in the teeth that came from children with ASD is unclear. A further understanding of the cavalcade of multiple biological system interactions (Interactome) could help with future efforts to reduce risks. Notwithstanding, the avoidance of pesticides, plastics, and scented personal care products may be warranted under the precautionary principle rule.

INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.

IMPORTANCE: Dementia is an "overdetermined" syndrome. Few individuals are demented by any single biomarker, while several may independently explain small fractions of dementia severity. It may be advantageous to identify individuals afflicted by a specific biomarker to guide individualized treatment. OBJECTIVE: We aim to validate a psychometric classifier to identify persons adversely impacted by inflammation and replicate it in a second cohort. DESIGN: Secondary analyses of data collected by the Texas Alzheimer's Research and Care Consortium (TARCC) (N = 3497) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1737). SETTING: Two large, well-characterized multi-center convenience samples. PARTICIPANTS: Volunteers with normal cognition (NC), Mild Cognitive Impairment (MCI) or clinical "Alzheimer's Disease (AD)". EXPOSURE: Participants were assigned to "Afflicted" or "Resilient" classes on the basis of a psychometric classifier derived by confirmatory factor analysis. MAIN OUTCOME(S) AND MEASURE(S): The groups were contrasted on multiple assessments and biomarkers. The groups were also contrasted regarding 4-year prospective conversions to "AD" from non-demented baseline diagnoses (controls and MCI). The Afflicted groups were predicted to have adverse levels of inflammation-related blood-based biomarkers, greater dementia severity and greater risk of prospective conversion. RESULTS: In ADNI /plasma, 47.1% of subjects were assigned to the Afflicted class. 44.6% of TARCC's subjects were afflicted, 49.5% of non-Hispanic Whites (NHW) and 37.2% of Mexican Americans (MA). There was greater dementia severity in the Afflicted class [by ANOVA: ADNI /F(1) = 686.99, p <0.001; TARCC /F(1) = 1544.01, p <0.001]. "INFLAMMATION" factor composite scores were significantly higher (adverse) in Afflicted subjects [by ANOVA in ADNI /plasma F(1) = 1642.64, p <0.001 and in TARCC /serum F(1) = 3059.96, p <0.001]. Afflicted cases were more likely to convert to AD in the next four years [by Cox's F, ADNI /plasma: F (252, 268) = 3.74 p < 0.001; TARCC /serum: F (160, 134) = 3.03, p < 0.001 (in TARCC's entire sample), F (110, 90) = 4.92, p <0.001 in NHW, and F(50, 44) = 2.13, p = 0.006 in MA]. The proportions converting were similar among afflicted NHW in both cohorts /biofluids but MA exhibited a lower risk (7% in TARCC /serum at 48 months). CONCLUSIONS AND RELEVANCE: Our inflammation-specific psychometric classifier selects individuals with pre-specified biomarker profiles and predicts conversion to "AD" across cohorts, biofluids, and ethnicities. This algorithm might be applied to any dementia-related biomarker making the psychometric estimation of individual biomarker effects feasible without biomarker assessment. Our approach also distinguishes individuals resilient to individual biomarker effects allowing for more accurate prediction and precision intervention.

Assessing Chemical Intolerance in Parents Predicts the Risk of Autism and ADHD in Their Children.

BACKGROUND: We sought to replicate our 2015 findings linking chemical intolerance in parents with the risk of their children developing autism and/or ADHD. Drawing upon our 2021 discovery of a strong association between chemical intolerance and mast cells, we propose an explanation for this link. METHODS: In a population-based survey of U.S. adults, we used the internationally validated Quick Environmental Exposure and Sensitivity Inventory (QEESI) to assess symptom severity and chemical intolerance. Parents were asked how many of their biological children had been diagnosed with autism and/or ADHD. RESULTS: Parents with chemical intolerance scores in the top versus bottom tenth percentile had 5.7 times the risk of reporting a child with autism and 2.1 times for ADHD. CONCLUSIONS: High chemical intolerance scores among parents of children with autism, coupled with our 2021 discovery of mast cell activation as a plausible biomechanism for chemical intolerance, suggest that (1) the QEESI can identify individuals at increased risk, (2) environmental counseling may reduce personal exposures and risk, and (3) the global rise in autism and ADHD may be due to fossil-fuel-derived and biogenic toxicants epigenetically "turning on" or "turning off" critical mast cell genes that can be transmitted transgenerationally. It is important to note that this study was observational in nature; as such, further research is needed using controlled trials to confirm causality and explore the proposed mechanism.

Reply to Ayoub-Charette et al. Lack of Biological Plausibility and Major Methodological Issues Cast Doubt on the Association between Aspartame and Autism. Comment on "Fowler et al. Daily Early-Life Exposures to Diet Soda and Aspartame Are Associated with Autism in Males: A Case-Control Study. Nutrients 2023, 15, 3772".

Thank you for the opportunity to respond to the concerns raised by Ayoub-Charette et al [...].

Alzheimer's disease pathology does not mediate the association between depressive symptoms and subsequent cognitive decline.

BACKGROUND: Depressive symptoms in nondemented individuals appear to hasten the progression from mild cognitive impairment to clinical Alzheimer's disease (AD) and double the risk of incident AD. However, the mechanism(s) by which depression might affect this risk has not been well established. The purpose of this analysis was to test the hypothesis that AD pathology mediates depression's apparent effect on the risk of dementia conversion using longitudinally collected psychometric testing and autopsy data from the Honolulu-Asia Aging Study. METHODS: Latent factor variables representing AD, cortical Lewy body (CLB), and ischemic neuropathology were tested as potential mediators of the association between the Center for Epidemiological Studies depression scale (CES-D) score and the 10-year prospective rate of cognitive decline, adjusted for baseline cognition, age, education, total number of medications, and brain weight at autopsy. RESULTS: CES-D scores, neurofibrillary tangle counts, CLB counts, and ischemic lesions each made significant independent contributions to cognitive decline. However, CES-D scores were not significantly associated with any pathological variable; thus the pathological variables were not mediators of the effect of CES-D scores on cognitive decline. CONCLUSIONS: Subsyndromal depressive symptoms are significantly associated with subsequent cognitive decline. Although the effect is relatively modest, it is stronger than that of amyloid-related neuropathologies and independent of that of neurofibrillary tangles, cortical Lewy bodies, and ischemic lesions. Our results argue against the role of AD-related neuropathology as a mediator of depression's effect on cognitive decline, but cannot rule out a significant mediation effect in a subset of cases, perhaps with more severe baseline depressive symptoms.

Multiple Adipokines Predict Dementia Severity as Measured by δ: Replication Across Biofluids and Cohorts.

BACKGROUND: We have explored dementia's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. OBJECTIVE: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). METHODS: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., "Adipokines". We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype "δ" in structural equation models (SEM). Significant factor loadings and Adipokines' association with δ were replicated across biofluids in the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ's variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer's disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. CONCLUSION: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs.

The effects of CNS atrophy and ICVD on tests of executive function and functional status are mediated by intelligence.

Background: Impairments in executive function (EF) are often attributed to ischemic cerebrovascular disease (ICVD) and frontal circuit pathology. However, EF can be distinguished from general intelligence and the latter is likely to manifest in "executive" measures. We aimed to distinguish the effects of imaging biomarkers on these constructs. Methods: We tested neuroimaging biomarkers as independent predictors of observed 12 month-prospective cognitive performance by a Multiple Indicators Multiple Causes (MIMIC) model in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N ≅ 1750). Results: ICVD was associated with ''Organization" (ORG) and "Planning" (PLAN) domain scores from the test of Every Day Cognition. Left anterior cingulate (LAC) atrophy was independently associated with Trail-Making part B and Animal Naming. The MIMIC model had excellent fit and tests additional latent variables i.e., EF and dEF (a latent δ homolog derived from Spearman's general intelligence factor, g). Only dEF was associated with instrumental activities of daily living (IADL). ICVD and LAC were both associated with observed executive measures through dEF. ICVD was independently associated with those same measures through EF. Conclusions: Observed EF is independently determined by multiple factors. The effects of EF-associated MRI biomarkers can be related to disability and dementia only via their effects on g. Because g /δ are unlikely to be located within the frontal lobes, the dementia-specific variance in executive measures may have little to do with either frontal structure or function. Conversely, domain-specific variance in EF may have little to do with either IADL-impairment or dementia.

Determination of safe levels of persistent organic pollutants in toxicology and epidemiology.

We reviewed published manuscripts from toxicology and epidemiology reporting harmful health effects and doses of persistent organic pollutants (POPs), published between 2000 and 2021. We found 42 in vitro, 32 in vivo, and 74 epidemiological studies and abstracted the dose associated with harm in a common Molar unit. We hypothesized that the dose associated with harm would vary between animal and human studies. To test this hypothesis, for each of several POPs, we assessed the significance of variation in the dose associated with a harmful effect [categorized as non-thyroid endocrine (NTE), developmental neurotoxicity (DNT), and Thyroid] with study type (in vitro, in vivo, and Epidemiology) using a linear model after adjustment for basis (lipid weight, wet weight). We created a Calculated Safety Factor (CSF) defined as the toxicology dose divided by epidemiology dose needed to exhibit significant harm. Significant differences were found between study types ranging from <1 to 5.0 orders of magnitude in the dose associated with harm. Our CSFs in lipid weight varied from 12.4 (95% confidence interval (CI) 3.3, 47) for NTE effects in Epidemiology relative to in vivo studies to 6,244 (95% CI 2510, 15530) for DNT effects in Epidemiology relative to in vitro in wet weight representing 12.4 to 6.2 thousand-fold more sensitivity in people relative to animals, and mechanistic models, respectively. In lipid weight, all CSF 95% CI lower bounds across effect categories were less than 6.5. CIs for CSFs ranged from less than one to four orders of magnitude for in vivo, and two to five orders of magnitude for in vitro vs. Epidemiology. A global CSF for all Epidemiology vs. all Toxicology was 104.6 (95% CI 72 to 152), significant at p<0.001.