CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab.

INTRODUCTION: We assessed the use of cerebrospinal fluid (CSF) biomarkers as an alternative to positron emission tomography (PET) for brain amyloid beta (Aß) pathology confirmation in the EMERGE and ENGAGE clinical trials. METHODS: EMERGE and ENGAGE were randomized, placebo-controlled, Phase 3 trials of aducanumab in participants with early Alzheimer's disease. Concordance between CSF biomarkers (Aß42, Aß40, phosphorylated tau 181, and total tau) and amyloid PET status (visual read) at screening was examined. RESULTS: Robust concordance between CSF biomarkers and amyloid PET visual status was observed (for Aß42/Aß40, AUC: 0.90; 95% CI: 0.83-0.97; p < 0.0001), confirming CSF biomarkers as a reliable alternative to amyloid PET in these studies. Compared with single CSF biomarkers, CSF biomarker ratios showed better agreement with amyloid PET visual reads, demonstrating high diagnostic accuracy. DISCUSSION: These analyses add to the growing body of evidence supporting CSF biomarkers as reliable alternatives to amyloid PET imaging for brain Aß pathology confirmation. HIGHLIGHTS: CSF biomarkers and amyloid PET concordance were assessed in Ph3 aducanumab trials. Robust concordance between CSF biomarkers and amyloid PET was observed. CSF biomarker ratios increased diagnostic accuracy over single CSF biomarkers. CSF Aß42/Aß40 demonstrated high concordance with amyloid PET. Results support CSF biomarker testing as a reliable alternative to amyloid PET.

Machine Learning to Develop and Internally Validate a Predictive Model for Post-operative Delirium in a Prospective, Observational Clinical Cohort Study of Older Surgical Patients.

BACKGROUND: Our objective was to assess the performance of machine learning methods to predict post-operative delirium using a prospective clinical cohort. METHODS: We analyzed data from an observational cohort study of 560 older adults (≥ 70 years) without dementia undergoing major elective non-cardiac surgery. Post-operative delirium was determined by the Confusion Assessment Method supplemented by a medical chart review (N = 134, 24%). Five machine learning algorithms and a standard stepwise logistic regression model were developed in a training sample (80% of participants) and evaluated in the remaining hold-out testing sample. We evaluated three overlapping feature sets, restricted to variables that are readily available or minimally burdensome to collect in clinical settings, including interview and medical record data. A large feature set included 71 potential predictors. A smaller set of 18 features was selected by an expert panel using a consensus process, and this smaller feature set was considered with and without a measure of pre-operative mental status. RESULTS: The area under the receiver operating characteristic curve (AUC) was higher in the large feature set conditions (range of AUC, 0.62-0.71 across algorithms) versus the selected feature set conditions (AUC range, 0.53-0.57). The restricted feature set with mental status had intermediate AUC values (range, 0.53-0.68). In the full feature set condition, algorithms such as gradient boosting, cross-validated logistic regression, and neural network (AUC = 0.71, 95% CI 0.58-0.83) were comparable with a model developed using traditional stepwise logistic regression (AUC = 0.69, 95% CI 0.57-0.82). Calibration for all models and feature sets was poor. CONCLUSIONS: We developed machine learning prediction models for post-operative delirium that performed better than chance and are comparable with traditional stepwise logistic regression. Delirium proved to be a phenotype that was difficult to predict with appreciable accuracy.

Education differentially contributes to cognitive reserve across racial/ethnic groups.

INTRODUCTION: We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity. METHODS: A total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups. RESULTS: Higher educational attainment attenuated the negative impact of WMH burden on memory (ß = -0.03; 99% CI: -0.071, -0.002) and language decline (ß = -0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics. DISCUSSION: Educational attainment does not contribute to CR similarly across racial/ethnic groups.

Postoperative Delirium and Postoperative Cognitive Dysfunction: Overlap and Divergence.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. METHODS: This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method-based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. RESULTS: One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07-1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72-1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71-2.09). CONCLUSIONS: Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Correction for retest effects across repeated measures of cognitive functioning: a longitudinal cohort study of postoperative delirium.

BACKGROUND: Few studies have compared methods to correct for retest effects or practice effects in settings where an acute event could influence test performance, such as major surgery. Our goal in this study was to evaluate the use of different methods to correct for the effects of practice or retest on repeated test administration in the context of an observational study of older adults undergoing elective surgery. METHODS: In a cohort of older surgical patients (N = 560) and a non-surgical comparison group (N = 118), we compared changes on repeated cognitive testing using a summary measure of general cognitive performance (GCP) between patients who developed post-operative delirium and those who did not. Surgical patients were evaluated pre-operatively and at 1, 2, 6, 12, and 18 months following surgery. Inferences from linear mixed effects models using four approaches were compared: 1) no retest correction, 2) mean-difference correction, 3) predicted-difference correction, and 4) model-based correction. RESULTS: Using Approaches 1 or 4, which use uncorrected data, both surgical groups appeared to improve or remain stable after surgery. In contrast, Approaches 2 and 3, which dissociate retest and surgery effects by using retest-adjusted GCP scores, revealed an acute decline in performance in both surgical groups followed by a recovery to baseline. Relative differences between delirium groups were generally consistent across all approaches: the delirium group showed greater short- and longer-term decline compared to the group without delirium, although differences were attenuated after 2 months. Standard errors and model fit were also highly consistent across approaches. CONCLUSION: All four approaches would lead to nearly identical inferences regarding relative mean differences between groups experiencing a key post-operative outcome (delirium) but produced qualitatively different impressions of absolute performance differences following surgery. Each of the four retest correction approaches analyzed in this study has strengths and weakness that should be evaluated in the context of future studies. Retest correction is critical for interpretation of absolute cognitive performance measured over time and, consequently, for advancing our understanding of the effects of exposures such as surgery, hospitalization, acute illness, and delirium.

Clinical outcomes in older surgical patients with mild cognitive impairment.

INTRODUCTION: Older adults, including those with mild cognitive impairment (MCI), are increasingly undergoing surgery. METHODS: Relative risks (RRs) of MCI alone or with delirium on adverse outcomes were estimated in an ongoing prospective, observational cohort study of 560 nondemented adults aged ≥70 years. RESULTS: MCI (n = 61, 11%) was associated with increased RR of delirium (RR = 1.9, P < .001) and delirium severity (RR = 4.6, P < .001). Delirium alone (n = 107), but not MCI alone (n = 34), was associated with multiple adverse outcomes including more major postoperative complication(s) (RR = 2.5, P = .002) and longer length of stay (RR = 2.2, P < .001). Patients with concurrent MCI and delirium (n = 27) were more often discharged to a postacute facility (RR = 1.4, P < .001) and had synergistically increased risk for new impairments in cognitive functioning (RR = 3.6, P < .001). DISCUSSION: MCI is associated with increased risk of delirium incidence and severity. Patients with delirium and MCI have synergistically elevated risk of developing new difficulties in cognitively demanding tasks.

Longitudinal Assessment of Self- and Informant-Subjective Cognitive Complaints in a Sample of Healthy Late-Middle Aged Adults Enriched with a Family History of Alzheimer's Disease.

OBJECTIVES: The purpose of this study was to investigate the longitudinal trajectory of self- and informant-subjective cognitive complaints (SCC), and to determine if SCC predict longitudinal changes in objective measures (OM) of cognitive function. METHODS: The study included healthy and cognitively normal late middle-aged adults enriched with a family history of AD who were evaluated at up to three visits over a 4-year period. At each visit (Visit 1-3), self- and informant-SCC and OM were evaluated. Linear mixed models were used to determine if the longitudinal rate of change of self- and informant-SCC were associated with demographic variables, depressive symptoms, family history (FH), and apolipoprotein epsilon 4 (APOE4) status. The same modeling approach was used to examine the effect of Visit 1 SCC on longitudinal cognitive change after controlling for the same variables. RESULTS: At Visit 1, more self-SCC were associated with fewer years of education and more depressive symptoms. SCC were also associated with poorer performance on cognitive measures, such that more self-SCC at Visit 1 were associated with poorer performance on memory and executive functioning measures at Visit 1, while more informant-SCC were associated with faster rate of longitudinal decline on a measure of episodic learning and memory. FH and APOE4 status were not associated with SCC. DISCUSSION: Self- and informant-SCC showed an association with OM, albeit over different time frames in our late middle-aged sample. Additional longitudinal follow-up will likely assist in further clarifying these relationships as our sample ages and more pronounced cognitive changes eventually emerge. (JINS, 2017, 23, 617-626).

Biomarker clusters are differentially associated with longitudinal cognitive decline in late midlife.

The ability to detect preclinical Alzheimer's disease is of great importance, as this stage of the Alzheimer's continuum is believed to provide a key window for intervention and prevention. As Alzheimer's disease is characterized by multiple pathological changes, a biomarker panel reflecting co-occurring pathology will likely be most useful for early detection. Towards this end, 175 late middle-aged participants (mean age 55.9 ± 5.7 years at first cognitive assessment, 70% female) were recruited from two longitudinally followed cohorts to undergo magnetic resonance imaging and lumbar puncture. Cluster analysis was used to group individuals based on biomarkers of amyloid pathology (cerebrospinal fluid amyloid-ß42/amyloid-ß40 assay levels), magnetic resonance imaging-derived measures of neurodegeneration/atrophy (cerebrospinal fluid-to-brain volume ratio, and hippocampal volume), neurofibrillary tangles (cerebrospinal fluid phosphorylated tau181 assay levels), and a brain-based marker of vascular risk (total white matter hyperintensity lesion volume). Four biomarker clusters emerged consistent with preclinical features of (i) Alzheimer's disease; (ii) mixed Alzheimer's disease and vascular aetiology; (iii) suspected non-Alzheimer's disease aetiology; and (iv) healthy ageing. Cognitive decline was then analysed between clusters using longitudinal assessments of episodic memory, semantic memory, executive function, and global cognitive function with linear mixed effects modelling. Cluster 1 exhibited a higher intercept and greater rates of decline on tests of episodic memory. Cluster 2 had a lower intercept on a test of semantic memory and both Cluster 2 and Cluster 3 had steeper rates of decline on a test of global cognition. Additional analyses on Cluster 3, which had the smallest hippocampal volume, suggest that its biomarker profile is more likely due to hippocampal vulnerability and not to detectable specific volume loss exceeding the rate of normal ageing. Our results demonstrate that pathology, as indicated by biomarkers, in a preclinical timeframe is related to patterns of longitudinal cognitive decline. Such biomarker patterns may be useful for identifying at-risk populations to recruit for clinical trials.

Beta-amyloid and cognitive decline in late middle age: Findings from the Wisconsin Registry for Alzheimer's Prevention study.

INTRODUCTION: The present study investigated the relationship between beta-amyloid (Aß) and cognition in a late middle-aged cohort at risk for Alzheimer's disease (AD). METHODS: One eighty-four participants (mean age = 60; 72% parental history of AD) completed a [C-11]Pittsburgh compound B positron emission tomography scan and serial cognitive evaluations. A global measure of Aß burden was calculated, and composite scores assessing learning, delayed memory, and executive functioning were computed. RESULTS: Higher Aß was associated with classification of psychometric mild cognitive impairment (MCI) at follow-up (P < .01). Linear mixed effects regression results indicated higher Aß was associated with greater rates of decline in delayed memory (P < .01) and executive functioning (P < .05). Apolipoprotein E (APOE) ε4 status moderated the relationship between Aß and cognitive trajectories (P values <.01). DISCUSSION: In individuals at risk for AD, greater Aß in late middle age is associated with increased likelihood of MCI at follow-up and steeper rates of cognitive decline.

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.

In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Tau positron emission tomography, cerebrospinal fluid and plasma biomarkers of neurodegeneration, and neurocognitive testing: an exploratory study of participants with myotonic dystrophy type 1.

OBJECTIVE: To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). METHODS: We recruited twelve participants with DM1 and, for comparison, two participants with Alzheimer's Disease (AD). Participants underwent cognitive screening and social cognition testing using the Dépistage Cognitif de Québec (DCQ), among other tests. Biomarkers included Tau PET with [18F]-AV-1451, CSF (Aß, Tau, phospho-Tau), and plasma (Aß, Tau, Nf-L, GFAP) studies. RESULTS: Of the twelve DM1 participants, seven completed the full protocol (Neurocognition 11/12; PET 7/12, CSF 9/12, plasma 12/12). Three DM1 participants were cognitively impaired (CI). On average, CI DM1 participants had lower scores on the DCQ compared to cognitively unimpaired (CU) DM1 participants (75.5/100 vs. 91.4/100) and were older (54 vs. 44 years old) but did not differ in years of education (11.3 vs. 11.1). The majority (6/7) of DM1 participants had no appreciable PET signal. Only one of the CI participants presented with elevated Tau PET SUVR in bilateral medial temporal lobes. This participant was the eldest and most cognitively impaired, and had the lowest CSF Aß 1-42 and the highest CSF Tau levels, all suggestive of co-existing AD. CSF Tau and phospho-Tau levels were higher in the 3 CI compared to CU DM1 participants, but with a mean value lower than that typically observed in AD. Nf-L and GFAP were elevated in most DM1 participants (9/11 and 8/11, respectively). Finally, CSF phospho-Tau was significantly correlated with plasma Nf-L concentrations. CONCLUSIONS AND RELEVANCE: We observed heterogenous cognitive and biomarker profiles in individuals with DM1. While some participants presented with abnormal PET and/or CSF Tau, these patterns were highly variable and only present in a small subset. Although DM1 may indeed represent a non-AD Tauopathy, the Tau-PET tracer used in this study was unable to detect an in vivo Tau DM1 signature in this small cohort. Interestingly, most DM1 participants presented with elevated plasma Nf-L and GFAP levels, suggestive of other, possibly related, central brain alterations which motivate further research. This pioneering study provides novel insights towards the potential relationship between biomarkers and neurocognitive deficits commonly seen in DM1.

Development and internal validation of a predictive model of cognitive decline 36 months following elective surgery.

INTRODUCTION: Our goal was to determine if features of surgical patients, easily obtained from the medical chart or brief interview, could be used to predict those likely to experience more rapid cognitive decline following surgery. METHODS: We analyzed data from an observational study of 560 older adults (≥70 years) without dementia undergoing major elective non-cardiac surgery. Cognitive decline was measured using change in a global composite over 2 to 36 months following surgery. Predictive features were identified as variables readily obtained from chart review or a brief patient assessment. We developed predictive models for cognitive decline (slope) and predicting dichotomized cognitive decline at a clinically determined cut. RESULTS: In a hold-out testing set, the regularized regression predictive model achieved a root mean squared error (RMSE) of 0.146 and a model r-square (R2 ) of .31. Prediction of "rapid" decliners as a group achieved an area under the curve (AUC) of .75. CONCLUSION: Some of our models could predict persons with increased risk for accelerated cognitive decline with greater accuracy than relying upon chance, and this result might be useful for stratification of surgical patients for inclusion in future clinical trials.

Older Patients with Alzheimer's Disease-Related Cortical Atrophy Who Develop Post-Operative Delirium May Be at Increased Risk of Long-Term Cognitive Decline After Surgery.

BACKGROUND: Older surgical patients with Alzheimer's disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. OBJECTIVE: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. METHODS: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months 1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2-36. RESULTS: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, ß = -0.030, 95% confidence interval [-0.060, -0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (ß = -0.100 [-0.192, -0.007]). CONCLUSION: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.

The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [11C]PBR28 binding and exploration of its link to post-operative delirium.

Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, [11C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [11C]PBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, [11C]PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and [11C]PBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between [11C]PBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between [11C]PBR28 binding and fluid inflammatory markers or post-operative delirium.

The role of education in a vascular pathway to episodic memory: brain maintenance or cognitive reserve?

Educational attainment is associated with cognition among older adults, but this association is complex and not well understood. While associated with better cognition among healthy adults, more education predicts faster decline in older adults with cognitive impairment. Education may influence cognitive functioning through mechanisms involving brain maintenance (BM: reduced age-related pathology) or cognitive reserve (CR: altered pathology-cognition association). We examined evidence for each mechanism by quantifying main and interaction effects of education within a well-studied pathway involving systolic blood pressure, white matter hyperintensities (WMH), and episodic memory in 2 samples without dementia at the baseline (total N = 1136). There were no effects of education on systolic blood pressure or WMH, suggesting a lack of evidence for BM. In the sample less likely to progress to dementia, education attenuated the effect of WMH on memory at the baseline. In the sample more likely to progress to dementia, education exacerbated this effect at the baseline. These moderations provide evidence for a CR mechanism and are consistent with previous findings of faster decline once CR is depleted.

Delirium Burden in Patients and Family Caregivers: Development and Testing of New Instruments.

BACKGROUND AND OBJECTIVES: Delirium creates distinct emotional distress in patients and family caregivers, yet there are limited tools to assess the experience. Our objective was to develop separate patient and family caregiver delirium burden instruments and to test their content and construct validity. RESEARCH DESIGN AND METHODS: Two hundred forty-seven patients and 213 family caregivers were selected from an ongoing prospective cohort of medical-surgical admissions aged ≥70 years old. New patient and family caregiver delirium burden instruments were developed and used to measure the subjective experiences of in-hospital delirium. Delirium and delirium severity were measured by the Confusion Assessment Method (CAM) and CAM-Severity (long form). RESULTS: Both Delirium Burden (DEL-B) instruments consist of eight questions and are measured on a 0 - 40 point scale. Final questions had good clarity and relevancy, as rated by the expert panel, and good internal consistency (Cronbach's α = .82-.86). In the cohort validation, Patient DEL-B (DEL-B-P) was 5.1 points higher and Family Caregiver DEL-B (DEL-B-C) was 5.8 points higher, on average, for patients who developed delirium compared to those who did not (p < .001). Test-retest reliability of DEL-B-C at baseline and 1 month was strong (correlation = .73). Delirium severity was mildly-moderately correlated with DEL-B-P (correlation = .34) and DEL-B-C (correlation = .26), suggesting contribution of other factors. DISCUSSION AND IMPLICATIONS: We created instruments to reliably measure and evaluate the burden of delirium for patients and their family caregivers. Although additional validation is indicated, these instruments provide a key first step toward measuring and improving the subjective experience of delirium for patients and their families.

Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis.

In addition to the development of beta amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) involves the loss of connecting structures including degeneration of myelinated axons and synaptic connections. However, the extent to which white matter tracts change longitudinally, particularly in the asymptomatic, preclinical stage of AD, remains poorly characterized. In this study we used a novel graph wavelet algorithm to determine the extent to which microstructural brain changes evolve in concert with the development of AD neuropathology as observed using CSF biomarkers. A total of 118 participants with at least two diffusion tensor imaging (DTI) scans and one lumbar puncture for CSF were selected from two observational and longitudinally followed cohorts. CSF was assayed for pathology specific to AD (Aß42 and phosphorylated-tau), neurodegeneration (total-tau), axonal degeneration (neurofilament light chain protein; NFL), and synaptic degeneration (neurogranin). Tractography was performed on DTI scans to obtain structural connectivity networks with 160 nodes where the nodes correspond to specific brain regions of interest (ROIs) and their connections were defined by DTI metrics (i.e., fractional anisotropy (FA) and mean diffusivity (MD)). For the analysis, we adopted a multi-resolution graph wavelet technique called Wavelet Connectivity Signature (WaCS) which derives higher order representations from DTI metrics at each brain connection. Our statistical analysis showed interactions between the CSF measures and the MRI time interval, such that elevated CSF biomarkers and longer time were associated with greater longitudinal changes in white matter microstructure (decreasing FA and increasing MD). Specifically, we detected a total of 17 fiber tracts whose WaCS representations showed an association between longitudinal decline in white matter microstructure and both CSF p-tau and neurogranin. While development of neurofibrillary tangles and synaptic degeneration are cortical phenomena, the results show that they are also associated with degeneration of underlying white matter tracts, a process which may eventually play a role in the development of cognitive decline and dementia.

The Caregiver Burden of Delirium in Older Adults With Alzheimer Disease and Related Disorders.

OBJECTIVES: To measure the burden of delirium in older adults with or without Alzheimer disease or related disorders (ADRDs). DESIGN: Prospective, observational cohort. SETTING: Inpatient hospital and study participants' homes. PARTICIPANTS: A subset (n = 267) of older medical and surgical patients and their caregivers enrolled in the Better Assessment of Illness study. MEASUREMENTS: Delirium burden was measured using the DEL-B instrument (range = 0-40, with higher scores indicating greater burden) in caregivers (DEL-B-C) and patients 1 month after hospitalization. Severity of cognitive impairment (Montreal Cognitive Assessment [MoCA]), delirium presence (Confusion Assessment Method [CAM]), and delirium severity (CAM-Severity [CAM-S]) were measured during hospitalization and at 1-month follow-up. ADRD diagnosis was determined by a clinical consensus process. RESULTS: For patients with (n = 56) and without (n = 211) ADRD, both DEL-B instruments had good internal consistency. DEL-B-C scores had a median (interquartile range) among caregivers of patients with and without ADRD of 9 (5-15) and 5 (1-11), respectively (P < .05). If the patient developed delirium, caregivers experienced greater burden (ß[delirium × ADRD] = -.29; P = .42), regardless of ADRD status. Further, caregiver burden was modestly correlated with patient MoCA scores (Spearman correlation coefficient, ρ = -0.18; P = .01). Patients with ADRD who developed delirium self-reported less burden than those without ADRD (ß[delirium × ADRD] = -.67; P = .044). As with caregivers, delirium burden was modestly correlated with patient MoCA score (ρ = -0.18; P = .005) and correlated with the CAM-S in patients without ADRD (ρ = 0.38; P < .001) but not for patients with ADRD (ρ = -0.07; P = .61). CONCLUSIONS: Delirium resulted in the same degree of increased caregiver burden regardless of whether a patient had ADRD, signifying delirium is equally stressful to caregivers, even among those with experience caring for someone with a chronic cognitive disorder. Delirium burden is only modestly associated with degree of cognitive impairment, suggesting that other aspects of delirium contribute to burden. J Am Geriatr Soc 67:2587-2592, 2019.