Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: a randomized, controlled clinical trial.

BACKGROUND: Evidence links lifestyle factors with Alzheimer's disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD. METHODS: A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer's Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher's exact test. Secondary outcomes included plasma Aß42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures. RESULTS: Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aß42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC (p= 0.001), CDR-SB (p= 0.032), and CDR Global (p= 0.037) tests and borderline significance in the ADAS-Cog test (p= 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aß42/40 ratio increased in the intervention group and decreased in the control group (p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aß42/40 ratio. The microbiome improved only in the intervention group (p <0.0001). CONCLUSIONS: Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD. TRIAL REGISTRATION: Approved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Biomarkers of neurodegeneration and neural injury as potential predictors for delirium.

OBJECTIVES: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk. METHODS: In a cohort of older adults who underwent elective surgery, delirium case-no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aß)42 , Aß40 , total (t)-Tau, phosphorylated (p)-Tau181 , neurofilament-light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme-linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays. RESULTS: Plasma GFAP correlated significantly with CSF GFAP and both plasma and CSF GFAP values were nearly two-fold higher in delirium cases. The median paired difference between delirium case and control without delirium for plasma GFAP was not significant (p = 0.074) but higher levels were associated with a greater risk for delirium (odds ratio 1.52, 95% confidence interval 0.85, 2.72 per standard deviation increase in plasma GFAP concentration) in this small study. No matched pair differences or associations with delirium were observed for NfL, p-Tau 181, Aß40 and Aß42 . CONCLUSIONS: These preliminary findings suggest that plasma GFAP, a marker of astroglial activation, may be worth further investigation as a predictive risk marker for delirium.

Successful aging after elective surgery II: Study cohort description.

BACKGROUND: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID-19 pandemic, and lay the foundation for future work using this cohort. METHODS: SAGES II is a prospective observational cohort study of community-dwelling adults age 65 and older undergoing major non-cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID-19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. RESULTS: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty-eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID-19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1-month follow-up; nearly 90% of enrolled participants completed interviews through 6-month follow-up. CONCLUSION: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers-including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource.

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non-Muscle-Invasive Bladder Cancer.

Importance: The BCG vaccine-used worldwide to prevent tuberculosis-confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non-muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses. Objective: To evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event. Design, Setting, and Participants: This cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023. Main Outcomes and Measures: The main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting. Results: In this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, -0.011; 95% CI, -0.019 to -0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, -0.056; 95% CI, -0.075 to -0.037). Conclusions and Relevance: In this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

SynthSR: A public AI tool to turn heterogeneous clinical brain scans into high-resolution T1-weighted images for 3D morphometry.

Every year, millions of brain magnetic resonance imaging (MRI) scans are acquired in hospitals across the world. These have the potential to revolutionize our understanding of many neurological diseases, but their morphometric analysis has not yet been possible due to their anisotropic resolution. We present an artificial intelligence technique, "SynthSR," that takes clinical brain MRI scans with any MR contrast (T1, T2, etc.), orientation (axial/coronal/sagittal), and resolution and turns them into high-resolution T1 scans that are usable by virtually all existing human neuroimaging tools. We present results on segmentation, registration, and atlasing of >10,000 scans of controls and patients with brain tumors, strokes, and Alzheimer's disease. SynthSR yields morphometric results that are very highly correlated with what one would have obtained with high-resolution T1 scans. SynthSR allows sample sizes that have the potential to overcome the power limitations of prospective research studies and shed new light on the healthy and diseased human brain.

Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan.

BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes ( P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels ( P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.

ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC. METHODS: We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [3H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 µl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [3H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF. RESULTS: We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aß. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.

Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study.

BACKGROUND: Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. METHODS: We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids. RESULTS: Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. CONCLUSIONS: In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

Association of Plasma Neurofilament Light with Postoperative Delirium.

OBJECTIVE: To examine the association of the plasma neuroaxonal injury markers neurofilament light (NfL), total tau, glial fibrillary acid protein, and ubiquitin carboxyl-terminal hydrolase L1 with delirium, delirium severity, and cognitive performance. METHODS: Delirium case-no delirium control (n = 108) pairs were matched by age, sex, surgery type, cognition, and vascular comorbidities. Biomarkers were measured in plasma collected preoperatively (PREOP), and 2 days (POD2) and 30 days postoperatively (PO1MO) using Simoa technology (Quanterix, Lexington, MA). The Confusion Assessment Method (CAM) and CAM-S (Severity) were used to measure delirium and delirium severity, respectively. Cognitive function was measured with General Cognitive Performance (GCP) scores. RESULTS: Delirium cases had higher NfL on POD2 and PO1MO (median matched pair difference = 16.2pg/ml and 13.6pg/ml, respectively; p < 0.05). Patients with PREOP and POD2 NfL in the highest quartile (Q4) had increased risk for incident delirium (adjusted odds ratio [OR] = 3.7 [95% confidence interval (CI) = 1.1-12.6] and 4.6 [95% CI = 1.2-18.2], respectively) and experienced more severe delirium, with sum CAM-S scores 7.8 points (95% CI = 1.6-14.0) and 9.3 points higher (95% CI = 3.2-15.5). At PO1MO, delirium cases had continued high NfL (adjusted OR = 9.7, 95% CI = 2.3-41.4), and those with Q4 NfL values showed a -2.3 point decline in GCP score (-2.3 points, 95% CI = -4.7 to -0.9). INTERPRETATION: Patients with the highest PREOP or POD2 NfL levels were more likely to develop delirium. Elevated NfL at PO1MO was associated with delirium and greater cognitive decline. These findings suggest NfL may be useful as a predictive biomarker for delirium risk and long-term cognitive decline, and once confirmed would provide pathophysiological evidence for neuroaxonal injury following delirium. ANN NEUROL 2020;88:984-994.

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 Inflammation after Surgery for Elders (RISE) study: Study design, procedures, and cohort profile.

INTRODUCTION: The Role of Inflammation after Surgery for Elders study correlates novel inflammatory markers measured in blood, cerebrospinal fluid (CSF) assays, and [11C]-PBR28 positron-emission tomography imaging. METHODS: This study involved a prospective cohort design with patients who underwent elective hip and knee arthroplasty under spinal anesthesia. Sixty-five adults participated with their family members. Inflammatory biomarker assays were measured preoperatively on day 1 and postoperatively at one month. RESULTS: On average, participants were 75 years old, and 72% were female. 54% underwent total knee arthroplasty, and 46% underwent total hip arthroplasty. The mean Modified Mini-Mental State (3MS) Examination score was 89.3; four patients (6%) scored ≤77 points. Plasma assays were completed in 63 (97%) participants, cerebrospinal fluid assays in 61 (94%), and PET imaging in 44 (68%). DISCUSSION: This complex study presents an innovative effort to correlate peripheral and central inflammatory biomarkers before and after major surgery in older adults. Strengths include collecting concurrent blood, cerebrospinal fluid, and positron-emission tomography with detailed clinical characterization of delirium, cognition, and functional status.

Insulin and adipokine signaling and their cross-regulation in postmortem human brain.

Aberrant insulin and adipokine signaling has been implicated in cognitive decline associated with both type 2 diabetes mellitus and neurodegenerative diseases. We established methods that reliably measure insulin, adiponectin and leptin signaling, and their crosstalk, in thawed postmortem mid-frontal cortical tissue from cognitively normal older subjects with a short postmortem interval. Insulin-evoked insulin receptor (IR) activation increases activated, tyrosine-phosphorylated IRß on tyrosine residues 960, 1150, and 1151, insulin receptor substrate-1 recruitment to IRß and phosphorylated RAC-α-serine/threonine-protein kinase. Adiponectin augments, but leptin inhibits, insulin signaling. Adiponectin activates adiponectin receptors to induce APPL1 binding to adiponectin receptor 1 and 2 and T-cadherin and downstream adenosine monophosphate-dependent protein kinase phosphorylation. Insulin inhibited adiponectin-induced signaling. In addition, leptin-induced leptin receptor (OB-R) signaling promotes Janus kinase 2 recruitment to OB-R and Janus kinase 2 and downstream signal transducer and activator of transcription 3 phosphorylation. Insulin enhanced leptin signaling. These data demonstrate insulin and adipokine signaling interactions in human brain. Future studies can use these methods to examine insulin, adiponectin, and leptin metabolic dysregulation in aging and disease states, such as type 2 diabetes and Alzheimer's disease-related dementias.

Consensus Approaches to Identify Incident Dementia in Cohort Studies: Systematic Review and Approach in the Successful Aging after Elective Surgery Study.

OBJECTIVES: To survey the current methods used to ascertain dementia and mild cognitive impairment (MCI) in longitudinal cohort studies, to categorize differences in approaches and to identify key components of expert panel methodology in current use. METHODS: We searched PubMed for the past 10 years, from March 6, 2007 to March 6, 2017 using a combination of controlled vocabulary and keyword terms to identify expert panel consensus methods used to diagnose MCI or dementia in large cohort studies written in English. From these results, we identified a framework for reporting standards and describe as an exemplar the clinical consensus procedure used in an ongoing study of elective surgery patients (the Successful Aging after Elective Surgery study). RESULTS: Thirty-one articles representing unique cohorts were included. Among published methods, membership of experts panel varied significantly. There was more similarity in what types of information was use to ascertain disease status. However, information describing the diagnostic decision process and resolution of disagreements was often lacking. CONCLUSIONS: Methods used for expert panel diagnosis of MCI and dementia in large cohort studies are widely variable, and there is a need for more standardized reporting of these approaches. By describing the procedure in which our expert panel achieved consensus diagnoses, we hope to encourage the development and publication of well-founded and reproducible methods for diagnosis of MCI and dementia in longitudinal studies.

High C-Reactive Protein Predicts Delirium Incidence, Duration, and Feature Severity After Major Noncardiac Surgery.

OBJECTIVES: To examine associations between the inflammatory marker C-reactive protein (CRP) measured preoperatively and on postoperative day 2 (POD2) and delirium incidence, duration, and feature severity. DESIGN: Prospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Adults aged 70 and older undergoing major noncardiac surgery (N = 560). MEASUREMENTS: Plasma CRP was measured using enzyme-linked immunosorbent assay. Delirium was assessed from Confusion Assessment Method (CAM) interviews and chart review. Delirium duration was measured according to number of hospital days with delirium. Delirium feature severity was defined as the sum of CAM-Severity (CAM-S) scores on all postoperative hospital days. Generalized linear models were used to examine independent associations between CRP (preoperatively and POD2 separately) and delirium incidence, duration, and feature severity; prolonged hospital length of stay (LOS, >5 days); and discharge disposition. RESULTS: Postoperative delirium occurred in 24% of participants, 12% had 2 or more delirium days, and the mean ± standard deviation sum CAM-S was 9.3 ± 11.4. After adjusting for age, sex, surgery type, anesthesia route, medical comorbidities, and postoperative infectious complications, participants with preoperative CRP of 3 mg/L or greater had a risk of delirium that was 1.5 times as great (95% confidence interval (CI) = 1.1-2.1) as that of those with CRP less than 3 mg/L, 0.4 more delirium days (P < .001), more-severe delirium (3.6 CAM-S points higher, P < .001), and a risk of prolonged LOS that was 1.4 times as great (95% CI = 1.1-1.8). Using POD2 CRP, participants in the highest quartile (≥235.73 mg/L) were 1.5 times as likely to develop delirium (95% CI = 1.0-2.4) as those in the lowest quartile (≤127.53 mg/L), had 0.2 more delirium days (P < .05), and had more severe delirium (4.5 CAM-S points higher, P < .001). CONCLUSION: High preoperative and POD2 CRP were independently associated with delirium incidence, duration, and feature severity. CRP may be useful to identify individuals who are at risk of developing delirium.

Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia.

Schizophrenia is a chronic debilitating neuropsychiatric disorder that affects about 1 % of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of the Research Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in the lipogenic pathway are suppressed. Moreover, we discovered that maturation of a master transcriptional regulator for lipid synthesis, sterol regulatory element binding protein-1 (SREBP1) is induced by neuronal activity, and is required for induction of the immediate early gene ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We found that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human patients with schizophrenia. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in dysbindin-1 knockout mice, and these deficits were restored by an atypical antipsychotic drug, clozapine. Together, results indicate an important role of dysbindin-1 in neuronal activity induced SREBP1 and ARC, which could be related to cognitive deficits in schizophrenia.

Higher C-Reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study.

BACKGROUND: Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation. METHODS: The Successful Aging after Elective Surgery study enrolled dementia-free adults ≥70 years old undergoing major scheduled noncardiac surgery (N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation-based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium. RESULTS: C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [p < .05], 0.29 mg/L, 1.56 mg/L [p < .01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [p < .05], 2.53 mg/L [p < .01]) and postoperative day 2 (MPD 71.97 mg/L [p < .01], 35.18 mg/L [p < .05], 63.76 mg/L [p < .01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, -0.66 mg/L, 1.10 mg/L). CONCLUSIONS: Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium.

Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology.

BACKGROUND: Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. OBJECTIVE: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. METHODS: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-ß load. RESULTS: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOEɛ4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-ß. CONCLUSIONS: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease.

INTRODUCTION: Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings. METHODS: Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease. RESULTS: 8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items. DISCUSSION: Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min.

Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study.

INTRODUCTION: The dynamic range of cerebrospinal fluid (CSF) amyloid ß (Aß1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. METHODS: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). RESULTS: Seven proteins were significantly associated with Aß1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. DISCUSSION: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.