Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics.

(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer's disease and related dementias (ADRD). This study identified potential mechanisms of the smoking-cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer's Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function.

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts.

Alzheimer's disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

Relationship of Cognitive and Social Engagement to Health and Psychological Outcomes in Community-Dwelling Older Adults.

BACKGROUND: Cognitive and social engagement is an important yet underdocumented aspect of older adult engagement and function. OBJECTIVE: The purpose of this study was to examine relationships between cognitive and social engagement and health and psychological outcomes in a cohort of community-dwelling older adults aged approximately 55-70 years. METHODS: Analysis of data from the Wisconsin Registry for Alzheimer's Prevention, a multiwave cohort study with 1,582 participants, using a 1:1 prospective case-control design to examine whether lower cognitive and social engagement at Visit 4 (baseline) is associated with worse health and psychological outcomes at Visit 5 (2 years after Visit 4). Wisconsin Registry for Alzheimer's Prevention participants were included in this study if they had complete data on cognitive and social engagement and self-rated health at both visits. RESULTS: After matching potential covariates using propensity scores, participants with low cognitive and social engagement (cases) at baseline continued to have significantly lower cognitive and social engagement than the controls (participants with high cognitive and social engagement at baseline) at Visit 5, and they had lower self-rated health and higher surgery rate. Depressive symptoms, cognitive status, and hospitalization at Visit 5 did not significantly differ between cases and controls. DISCUSSION: This study provides evidence supporting cognitive and social engagement as an important marker of early decline in activity engagement that may indicate a potential later decline in functional, psychological, and health outcomes.

Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer's Disease.

BACKGROUND: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer's disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. OBJECTIVE: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. METHODS: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. RESULTS: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. CONCLUSION: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

Measuring longitudinal cognition: Individual tests versus composites.

INTRODUCTION: Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aß). METHODS: Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aß modified cognitive trajectories. RESULTS: Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aß interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics. DISCUSSION: These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.

Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum.

BACKGROUND: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an "AD signature" composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). METHODS: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. RESULTS: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112-0.298) and A + T+ CU groups (Cliff's deltas = 0.212-0.731). CONCLUSIONS: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease.

Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

Screening for insulin resistance and cardiovascular risk in collegiate football linemen.

OBJECTIVE: To investigate the relationship between fitness, obesity, and the risk factors of type 2 diabetes and cardiovascular disease in obese-classified [by body mass index (BMI) > 30 kg/m] collegiate football linemen and male students of similar age and BMI. DESIGN: Cross-sectional observational study. SETTING: Institutional university based. PARTICIPANTS: Two groups of volunteer students. Thirty collegiate football linemen and 10 sedentary age-matched and size-matched peers. INDEPENDENT VARIABLE: Status as lineman or sedentary student. MAIN OUTCOME MEASURES: Height, weight, blood pressure, and body fat percent (BF%) were measured for each subject. Fasting blood draw was used to determine glucose, insulin, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. RESULTS: The athlete group had lower mean (SD) BF% [21.8 (3.89) vs control 27.1 (7.07); P = 0.01], despite no significant difference in age, weight, height, or BMI. The athlete group had lower systolic blood pressure [135.6 (13.29) mm Hg vs 148.1 (13.77); P = 0.015] and at-risk LDL (10% vs 40%; P = 0.05). The groups did not differ significantly in other measures. Body fat percent (before and after adjusting for BMI) was significantly correlated with every risk factor except glucose, whereas BMI was only significantly correlated with blood pressure and insulin. CONCLUSIONS: Collegiate football linemen with elevated BMI have select risk factors, particularly blood pressure and LDL cholesterol that improved over sedentary peers. However, concerning risk factor profiles of linemen warrant standard age-appropriate and size-appropriate screening for cardiovascular and metabolic disease. Body fat percent more strongly correlated with risk factors than with BMI and may be the stronger tool for estimating risk in this population.

Predictors of malignancy and recommended follow-up in patients with negative endoscopic ultrasound-guided fine-needle aspiration of suspected pancreatic lesions.

BACKGROUND: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can characterize and diagnose pancreatic lesions as malignant, but cannot definitively rule out the presence of malignancy. Outcome data regarding the length of follow-up in patients with negative or nondiagnostic EUS-FNA of pancreatic lesions are not well-established. OBJECTIVE: To determine the long-term outcome and provide follow-up guidance for patients with negative EUS-FNA diagnosis of suspected pancreatic lesions based on imaging predictors. METHODS: A retrospective review of patients undergoing EUS-FNA for suspected pancreatic lesions, but with negative or nondiagnostic FNA results was conducted at a tertiary care referral medical centre. Patient demographics, EUS imaging characteristics and follow-up data were examined. RESULTS: Seventeen of 55 patients (30.9%) with negative/nondiagnostic FNA were subsequently diagnosed with pancreatic malignancy. The risk of cancer was significantly higher for patients who had associated lymph nodes on EUS (P<0.001) and vascular involvement on EUS (P=0.001). The mean time to diagnosis in the group with falsenegative EUS-FNA diagnosis was 66 days. The true-negative EUSFNA patients were followed for a mean of 403 days after negative EUS-FNA results without the development of malignancy. CONCLUSION: For patients undergoing EUS-FNA for a suspected pancreatic lesion, a negative or nondiagnostic FNA does not provide conclusive evidence for the absence of cancer. Patients for whom vascular invasion and lymphadenopathy are detected on EUS are more likely to have a true malignant lesion and should be followed closely. When a patient has been monitored for six months or more with no cancer being diagnosed, there appears to be much less chance that a pancreatic malignancy is present.

Newborn screening for cystic fibrosis: parents' preferences regarding counseling at the time of infants' sweat test.

Newborn screening (NBS) protocols for cystic fibrosis (CF) are the first regional population-based programs to incorporate DNA analysis into their procedures. Research about these programs can inform policy and practice regarding how best to counsel families with abnormal NBS results. The grounded theory method guided interviews with 33 families whose infants had abnormal CF NBS results. A dimensional analysis of these interviews provided a theoretical framework describing parents' preferences regarding counseling during their infant's sweat test appointment. This framework describes the contexts and characteristics of the two main dimensions of parents' preferences: factual information and emotional support. Factual information included learning about the probability of a CF diagnosis, CF disease facts, sweat test procedure, and CF genetics. Social support consisted of offering parents a choice about the timing and amount of CF information, showing empathy for their distress, instilling hope, personalizing counseling, and providing hospitality. This framework also explains the consequences of counseling that matched versus mismatched parental preferences in these domains. Counseling that matched parents preferences reduced parents' distress while mismatched counseling tended to increase parents' worry about their infant.

Preventing early, prolonged vitamin E deficiency: an opportunity for better cognitive outcomes via early diagnosis through neonatal screening.

OBJECTIVE: To evaluate whether early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) and early vitamin E status are associated with cognitive function. STUDY DESIGN: We assessed cognitive function for 71 children without meconium ileus (ages 7.3-16.9 years) enrolled in the screened (S) or control (C) group of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, 2nd edition generated the cognitive skills index (CSI; mean = 100, SD = 16). Vitamin E deficiency at diagnosis was defined as plasma alpha-tocopherol (alpha-T) below 300 microg/dL (<300E). Primary analyses evaluated CSI scores across the 4 levels of group (S or C) by using alpha-T status (<300E or >300E) with analysis of covariance. RESULTS: After adjusting for covariates, CSI in the C<300E group was significantly lower than each of the other groups (C>300E, S<300E, and S>300E; P < .05). The highest proportion of CSI scores >84 occurred in the C<300E group (41%). Patients in this group also had the lowest mean head circumference z-scores at diagnosis. CONCLUSIONS: Our results show that prolonged alpha-T deficiency in infancy is associated with lower subsequent cognitive performance. Thus, diagnosis via NBS may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy.

Quality of life of children with cystic fibrosis.

OBJECTIVE: To review health-related quality of life (QOL) and associated issues and to describe a study investigating "Child Health Questionnaire" (CHQ) scores in relationship to newborn screening (NBS) for cystic fibrosis (CF) and markers of disease severity. METHODS: A total of 36 patients from 10-15.5 years old who were enrolled in the screened or control group of the Wisconsin CF Neonatal Screening Project completed the CHQ. Scale scores comprised the dependent variables. Independent variables included study group and measures of disease severity. Analyses included Fisher's exact, 2-sample Wilcoxon, and t tests. RESULTS: QOL did not differ significantly between the screened and control groups for any of the scales. None of the comparisons of CHQ scale scores across measures of disease severity were significant in this small sample, but the CHQ and power were limiting. CONCLUSIONS: Our results did not demonstrate a benefit of CF NBS on QOL; however, the CHQ may not be adequately sensitive to QOL in children with CF with disease severity comparable to our sample. The Cystic Fibrosis Questionnaire, a recently validated CF-specific QOL measure for pediatric samples, is likely to provide a more informative evaluation of the effects of CF NBS on patients' QOL.

Psychosocial risk associated with newborn screening for cystic fibrosis: parents' experience while awaiting the sweat-test appointment.

BACKGROUND: The psychosocial effects on parents of infants with abnormal results in cystic fibrosis (CF) newborn screening (NBS) that uses genetic testing remain unclear. METHODS: Twenty-eight individuals representing 14 families participated in grounded theory interviews approximately 6 months after their child's positive NBS results for CF. Participants also completed the Center for Epidemiologic Studies Depression Scales (CES-D) at their infant's sweat-test appointment (n = 51) and/or approximately 6 months after the sweat test (n = 35). RESULTS: Most parents experienced high levels of emotional distress during their wait for the sweat-test appointment (CES-D score, mean +/- SD: 16.5 +/- 6.7; 43.1% in the clinical range; median wait: 7 days; range: 3-35 days). CES-D scores of these parents were also significantly higher than those of comparison parents. Interviews showed that parental cognitive uncertainty and emotional distress were influenced by the parents' prior knowledge of NBS, CF, and their carrier status; parents' adjustment to their new baby; and the physicians' approach to informing parents. Parents' coping strategies involved requesting a sweat test as soon as possible, searching for information, assessing the infant's risk/health, seeking support, praying, or not talking with others. CONCLUSIONS: The waiting period from notification regarding positive NBS results to diagnostic test results can be psychologically distressing to parents, causing depressive symptoms that vary depending on their perceptions about the likelihood that their infant has CF. Implications for future research examining psychosocial interventions for NBS are discussed.

Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition.

OBJECTIVE: Patients who have cystic fibrosis (CF) and experience delayed diagnosis by traditional methods have greater nutritional insult compared with peers diagnosed via neonatal screening. The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. METHODS: Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, Second Edition was administered to generate the Cognitive Skills Index (CSI) and cognitive factor scores (Verbal, Nonverbal, and Memory). RESULTS: Cognitive scores in the overall study population were similar to normative data (CSI mean [standard deviation]: 102.5 [16.6]; 95% confidence interval: 99.1-105.9). The mean (standard deviation) CSI scores for the screened and control groups were 104.4 (14.4) and 99.8 (18.5), respectively. Significantly lower cognitive scores correlated with indicators of malnutrition and unfavorable family factors such as single parents, lower socioeconomic status, and less parental education. Our analyses revealed lower cognitive scores in patients with low plasma alpha-tocopherol (alpha-T) levels at diagnosis. In addition, patients in the control group who also had vitamin E deficiency at diagnosis (alpha-T < 300 microg/dl) showed significantly lower CSI scores in comparison with alpha-T-sufficient control subjects and both deficient and sufficient alpha-T subsets of screened patients. CONCLUSION: Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.