Derek L. Norton

Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer’s disease in late-middle-aged adults

Alzheimer’s disease (AD) is characterized by substantial neurodegeneration, including both cortical atrophy and loss of underlying white matter fiber tracts. Understanding longitudinal alterations to white matter may provide new insights into trajectories of brain change in both healthy aging and AD, and fluid biomarkers may be particularly useful in this effort. To examine this, 151 late-middle-aged participants enriched with risk for AD with at least one lumbar puncture and two diffusion tensor imaging (DTI) scans were selected for analysis from two large observational and longitudinally followed cohorts. Cerebrospinal fluid (CSF) was assayed for biomarkers of AD-specific pathology (phosphorylated-tau/Aβ42 ratio), axonal degeneration (neurofilament light chain protein, NFL), dendritic degeneration (neurogranin), and inflammation (chitinase-3-like protein 1, YKL-40). Linear mixed effects models were performed to test the hypothesis that biomarkers for AD, neurodegeneration, and inflammation, or two-year change in those biomarkers, would be associated with worse white matter health overall and/or progressively worsening white matter health over time. At baseline in the cingulum, phosphorylated-tau/Aβ42 was associated with higher mean diffusivity (MD) overall (intercept) and YKL-40 was associated with increases in MD over time. Two-year change in neurogranin was associated with higher mean diffusivity and lower fractional anisotropy overall (intercepts) across white matter in the entire brain and in the cingulum. These findings suggest that biomarkers for AD, neurodegeneration, and inflammation are potentially important indicators of declining white matter health in a cognitively healthy, late-middle-aged cohort.

Age-accelerated cognitive decline in asymptomatic adults with CSF β-amyloid

Objective Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of β-amyloid (Aβ) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile. Methods Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimers Prevention or Wisconsin Alzheimers Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for Aβ42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and hippocampal volume outcomes. Results Two hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were Aβ+ only (preclinical AD stage 1), 25 (8%) were Aβ+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline. Conclusion In an asymptomatic at-risk cohort, elevated CSF Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.

Associations between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer’s Disease

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimers disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimers Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.

Cognitive variability—A marker for incident MCI and AD: An analysis for the Alzheimer's Disease Neuroimaging Initiative

The potential of intra‐individual cognitive variability (IICV) to predict incident mild cognitive impairment (MCI) or Alzheimers disease (AD) was examined and compared to well‐established neuroimaging and genetic predictors.

Effectiveness of a Best Practice Advisory at Improving Hypertension Control

BACKGROUND Inadequately treated hypertension (HTN) leads to considerable morbidity and mortality. Despite many treatment options, blood pressure (BP) control is suboptimal. Missed opportunities due to the growing complexity of primary care office visits contribute. Electronic health records (EHRs) offer best practice alerts (BPA) tools to support clinicians in identifying poor BP control. BPAs have demonstrated effectiveness for other health outcomes. METHODS EHR data were collected for patients ≥18 years old seen for primary care office visits prior to, during, and after the BPA active period and used to identify patients for whom the BPA fired or would have fired during control periods. Logistic regression examined the association of BPA activation with follow-up BP check within 14-90 days and with BP control at follow-up, controlling for demographics and health conditions. RESULTS The BPA active period was associated with reduced patient follow-up; however, a number of covariates were predictive of increased follow-up: Black non-Hispanics, Hispanics, patients on the chronic kidney disease, HTN, or diabetes registries, as well as the morbidly obese, insurance status, and seasonal factors. For those who did follow-up, BPA activation was associated with improved BP control. CONCLUSIONS BPA activation was associated with worse patient follow-up but improved BP control. Some subgroups had significantly different rates of follow-up and BP control. This study did not have an experimental design as the BPA was a quality improvement initiative. These results highlight the critical importance of planning experimentally designed organizational initiatives to fully understand their impact.

TRANSFORMATION OF CSF BIOMARKER VALUES BETWEEN MEASUREMENT BATCHES

recovery relative to later denaturation (Mean (SD) CSF Ab142collection1⁄41061(476) pg/mL, CSF Ab1-42Aliquot1⁄4996(414) pg/ mL; vs. CSF Ab1-42Analysis1⁄4822(385) pg/mL, CSF Ab142LoBind1⁄4899(376) pg/mL (p<0.0002)). The Ab1-42/Ab1-40 ratio reduced recovery variability due to collection condition, and improved discrimination between control and dementia groups. The assay was stable for 2 years, but CSFAb peptide measurements and the Ab1-42/Ab1-40 ratio were not longitudinally stable for the study period. CSF Ab1-42 was stable for 15months (“Collection”,“Aliquot”) or 18months (“Analysis”). The Ab1-42/Ab1-40 ratio was stable for 8 months (“Collection”,“Aliquot”) and 11months (“Analysis”). Conclusions:When measured with a UP-RPLC-MS/ MS assay, earlier denaturation improved CSFAb peptide recovery. CSF Ab1-42, Ab1-40, Ab1-38, Ab1-34, and the Ab1-42/Ab1-40 ratio were not stable for the study period when samples were stored frozen. The Ab1-42/Ab1-40 ratio was useful for normalizing adsorption-related artifacts at baseline and for separating Dx groups, but was more sensitive to longitudinal instability. We recommend that UP-RPLC-MS/MS analysis of CSF Ab peptides from frozen samples occur within the cutoffs specified or close to the time of collection.

Hypertension and obesity moderate the relationship between β-amyloid and cognitive decline in midlife

This study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between β‐amyloid (Aβ) and longitudinal cognitive performance in late middle‐aged adults enriched for Alzheimers disease (AD) risk.

INCIDENT DEMENTIA IN NON-HISPANIC AFRICAN AMERICANS AND WHITES WITH MILD COGNITIVE IMPAIRMENT: CAN WE MAKE RACIAL COMPARISONS USING ALZHEIMER’S DISEASE CENTER DATA?

Model 1 .125 31.13** MFE-Total informants -.359 -5.58** -.53, -.25 Model 2 .134 17.31** MFE-Total informants -.341 -5.26** -.51, -.23 GDS -.115 -1.78 -.98, .05 Model 3 .399 47.63** MFE-Total informants -.227 -4.10** -.36, -.13 GDS -.10 -1.89 -.84, .02 Age -.528 -9.65** -.63, -.42 Model 4 .582 74.58** MFE-Total informants -.186 -4.02** -.3, -.10 GDS -.033 -.73 -.50, .23 Age -.324 -6.43** -.42, -.22 Years of schooling .487 9.62** .64, .98

TOBACCO EXPOSURE AND CESSATION IS ASSOCIATED WITH INCIDENT DEMENTIA AND NURSING HOME PLACEMENT

Background:It has been suggested that illiteracy and low level of education are risk factors for developing dementia, but also that bilingualism could function as a protective factor. In Peru, both conditions are very frequent. We observed a dementia prevalence of 6.85% in schooled subjects and 15.2% for illiterates; but there is still no data on how bilingualism modulates cognitive response in healthy illiterates, especially in executive function. Therefore, our objectivewas to compare performance of bilingual andmonolingual healthy elder illiterates in executive control tasks, controlling the influence of age and the type of work. Methods:We evaluated 56 healthy illiterate elderlies, 40 bilinguals (M 1⁄4 71.20, SD 1⁄4 5.94) and 16monolinguals (M1⁄4 75.25, SD1⁄4 10.28) with inhibitory control tasks (modified Stroop, see figure 1), response suppression (Go / No Go), cognitive flexibility (Hanoi tower) and working memory (forward and backward digits, WAIS III). Non-parametric contrast statistics (U Mann Whitney) and covariance analysis were used, where the fixed factors were bilingualism and type of work (elementary or instrumental) and age as a covariate. Results: We observed significant differences between number and symbol (Z 1⁄4 -3.38, p <.001) and interference (Z1⁄4 -2.61, p <.009) of the Stroop tasks; in both cases bilinguals score better than monolinguals (see figure 2). The analysis of covariance also showed a greater effect of bilingualism on the measures of inhibitory control (Numbers and symbols, F 1⁄4 8.085, p <.006 and interference, F 1⁄4 9.604, p <.003) than age and type of work. No significant differences were observed in the other components of executive control. Conclusions: a bilingual advantage is observed in inhibitory control tasks in healthy illiterate older adults, which is not associated with age or type of work. This advantage seems to be associated with the activation of executive control mechanisms formore complex tasks. These data show that bilingualism modulates the cognitive response and functions as a cognitive reserve factor; hence the importance of its promotion and empowerment. We recommend conducting epidemiological and follow-up studies in this population.

Characterizing the effects of sex, APOE ε4, and literacy on mid-life cognitive trajectories: Application of Information-Theoretic model-averaging and multi-model inference techniques to the Wisconsin Registry for Alzheimer's Prevention Study

Objective In this paper we apply Information-Theoretic (IT) model averaging to characterize a set of complex interactions in a longitudinal study on cognitive decline. Prior research has identified numerous genetic (including sex), education, health and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find models that best fit the observed data; these techniques risk interpretations that only the selected predictors are important. In reality, several models may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates); inference from traditional model selection approaches can lead to overly confident conclusions. Method Here we use longitudinal cognitive data from ~1550 late-middle aged adults the Wisconsin Registry for Alzheimer’s Prevention study to examine the effects of sex, Apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a model set with combinations of interactions among sex, APOE, literacy, and age. Results For a list-learning test, model-averaged results showed better performance for women vs men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an effect on cognitive performance in this age range (~40-70). Conclusions These results illustrate the utility of the IT approach and point to literacy as a potential modifier of decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work.