Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline

Background: Alzheimer’s disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. Objective: This exploratory study aimed to define latent classes from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. Methods: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer’s Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. Results: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. Conclusions: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia: Design of the ADvance Randomized Controlled Trial

Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS off or DBS on groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned on for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer\u27s Disease Assessment Scale -- cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test€“retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up

Graphical methods for understanding changes in states: Understanding medication use pathways

Abstract Objectives As epidemiological studies become longer and larger, the field needs novel graphical methods to visualize complex longitudinal data. The aim of this study was to present the Slinkyplot, a longitudinal crosstabulation, to illustrate patterns of antidepressant use in a large prospective cohort of older adults with mild cognitive impairment. Methods Data from the National Alzheimer's Coordinating Center are used to track switches between different states and types of antidepressant use. A Slinkyplot is populated with rows representing the state of medication use at each timepoint and columns representing the state at each subsequent visit. Results The constructed Slinkyplots display the common practice of switching on and off different antidepressants over time, with citalopram, sertraline, and bupropion most commonly used followed by switching to another SSRI or SNRI as second‐line treatment. Conclusions Slinkyplots are an innovative graphical means of visualizing complex patterns of transitions between different states over time for large longitudinal studies

Neuronal-Derived EV Biomarkers Track Cognitive Decline in Alzheimer’s Disease

The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD

Association between allostatic load and health behaviours: a latent class approach

BACKGROUND: Allostatic load (AL) has been characterised in many ways throughout the literature; however, its relationship to health behaviours has only been studied in limited populations. We aimed to uncover qualitative patterns of biological indicators in AL and determine if those patterns were associated with certain health behaviours. METHODS: We conducted latent class analysis using biological indicators from a multiethnic population. We fit latent class regression of class on health behaviours (smoking, poor diet, physical activity and alcohol use) to measure the association between each latent class of AL and each health behaviour. RESULTS: Four classes, \u27Metabolic+Cholesterol, \u27Blood Pressure\u27, \u27Metabolic+Blood Pressure\u27 and \u27Low\u27, were found in the sample. Latent class regression showed that physical activity and alcohol use were significantly associated with the \u27Metabolic+Blood Pressure\u27 class. CONCLUSION: Less physical activity was required to improve AL than was previously found. Low to moderate alcohol use was beneficial for lower AL. Implications of the amount of physical activity necessary to lower AL is discussed

Effects of incentivizing viral suppression in previously incarcerated adults living with HIV

Background: The amount of HIV in a person’s blood can be suppressed to an undetectable level through antiretroviral therapy medications (ART). Adhering to an ART regimen can improve a person’s health and reduce HIV transmission. Despite these benefits, many people with HIV do not maintain the level of adherence required to achieve an undetectable viral load. This problem is particularly common among people who have been incarcerated. Objective: To determine effects of incentivizing viral suppression in previously incarcerated adults with HIV. Methods: Adults with HIV (N = 102) and detectable viral load (>200 copies/mL) were randomly assigned to a Usual Care or Incentive group. Usual Care participants did not earn incentives for viral suppression. Incentive participants earned incentives ($10/day maximum) for providing blood samples with a reduced or undetectable (<200 copies/mL) viral load. Assessments were conducted every 3 months. Results collected during the first year were aggregated and compared based on group assignment and incarceration history. Results: Previously incarcerated participants in the Incentive group provided more (OR: 2.9; CI: 1.3-6.8; p <.05) blood samples with an undetectable viral load (69%) than those in the Usual Care group (41%). Never-incarcerated participants in the Incentive group provided more (OR: 6.8; CI: 2.2-21.0; p <.01) blood samples with an undetectable viral load (78%) than those in the Usual Care group (36%). Effects of incentives did not differ by incarceration history. Conclusions: Incentivizing viral suppression can increase viral suppression (undetectable viral load) in people who have been incarcerated

Alzheimer's disease biomarkers as predictors of trajectories of depression and apathy in cognitively normal individuals, mild cognitive impairment,and Alzheimer's disease dementia

Objectives To examine trajectories of depression and apathy over a 5-year follow-up period in (prodromal) Alzheimer's disease (AD), and to relate these trajectories to AD biomarkers. Methods The trajectories of depression and apathy (measured with the Neuropsychiatric Inventory or its questionnaire) were separately modeled using growth mixture models for two cohorts (National Alzheimer's Coordinating Center, NACC, n = 22 760 and Alzheimer's Disease Neuroimaging Initiative, ADNI, n = 1 733). The trajectories in ADNI were associated with baseline CSF AD biomarkers (A beta(42,)t-tau, and p-tau) using bias-corrected multinomial logistic regression. Results Multiple classes were identified, with the largest classes having no symptoms over time. Lower A beta(42)and higher tau (ie, more AD pathology) was associated with increased probability of depression and apathy over time, compared to classes without symptoms. Lower A beta(42)(but not tau) was associated with a steep increase of apathy, whereas higher tau (but not A beta(42)) was associated with a steep decrease of apathy. Discussion The trajectories of depression and apathy in individuals on the AD spectrum are associated with AD biomarkers

Validation of a Wireless, Self-Application, Ambulatory Electroencephalographic Sleep Monitoring Device in Healthy Volunteers.

Study objectivesTo evaluate the validity of an ambulatory electroencephalographic (EEG) monitor for the estimation of sleep continuity and architecture in healthy adults.MethodsHealthy, good sleeping participants (n = 14) were fit with both an ambulatory EEG monitor (Sleep Profiler) and a full polysomnography (PSG) montage. EEG recordings were gathered from both devices on the same night, during which sleep was permitted uninterrupted for eight hours. The study was set in an inpatient clinical research suite. PSG and Sleep Profiler records were scored by a neurologist board certified in sleep medicine, blinded to record identification. Agreement between the scored PSG record, the physician-scored Sleep Profiler record, and the Sleep Profiler record scored by an automatic algorithm was evaluated for each sleep stage, with the PSG record serving as the reference.ResultsResults indicated strong percent agreement across stages. Kappa was strongest for Stage N3 and REM. Specificity was high for all stages; sensitivity was low for Wake and Stage N1, and high for Stage N2, Stage N3, and REM. Agreement indices improved for the manually scored Sleep Profiler record relative to the autoscore record.ConclusionsOverall, the Sleep Profiler yields an EEG record with comparable sleep architecture estimates to PSG. Future studies should evaluate agreement between devices with a clinical sample that has greater periods of wake in order to better understand utility of this device for estimating sleep continuity indices, such as sleep onset latency and wake after sleep onset