Effect of race on prediction of brain amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau, and neurofilament light

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups. METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals

Predicting continuous amyloid PET values with CSF and plasma Aβ42/Aβ40

INTRODUCTION: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer\u27s disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET. METHODS: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled. RESULTS: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids). DISCUSSION: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging. HIGHLIGHTS: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD

Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light

OBJECTIVE: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231) and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups. METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status and cognitive status. Each participant underwent blood and cerebrospinal fluid (CSF) collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively. RESULTS: There were 76 matched pairs of AA and NHW participants (n=152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers and 91% were cognitively normal. AA were less likely than NHW to have brain amyloidosis by CSF Aβ42/Aβ40 (22% versus 43% positive, p = 0.003). The Receiver Operating Characteristic Area Under the Curve (ROC AUC) of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% confidence intervals [CI] 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231 or Nfl, AA had a lower probability of CSF Aβ42/Aβ40 positivity (Odds Ratio [OR] 0.31 [95% CI 0.13-0.73], OR 0.30 [0.13-0.71]) and OR 0.27 [0.12-0.64], respectively. Models of amyloid PET status yielded similar findings. CONCLUSIONS: Models predicting brain amyloidosis using a high performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA

Traumatic Brain Injury Intensive Evaluation and Treatment Program: Protocol for a Partnered Evaluation Initiative Mixed Methods Study

BackgroundThe traumatic brain injury (TBI) Intensive Evaluation and Treatment Program (IETP) is an innovative modality for delivering evidence-based treatments in a residential, inpatient format to special operational forces service members and veterans with mild TBI. IETPs provide bundled evidence-based assessment, treatment, referral, and case management in concordance with the existing guidelines for mild TBI and commonly co-occurring comorbidities. To date, there has been no formal characterization or evaluation of the IETP to understand the determinants of implementation across the system of care. The goal of our partnered evaluation initiative (PEI) with an operational partner, the Physical Medicine and Rehabilitation National Program Office, is to facilitate the full implementation of the IETP across all 5 Veterans Health Administration TBI–Centers of Excellence (TBI-COE) and to inform minimum standards while supporting the unique characteristics of each site. ObjectiveThis IETP partnered evaluation will describe each of the 5 TBI-COE IETP services and state of implementation to identify opportunities for adaptation and scale, characterize the relationship between patient characteristics and clinical services received, evaluate the outcomes for participants in the IETP, and inform ongoing implementation and knowledge translation efforts to support IETP expansion. In alignment with the goals of the protocol, ineffective treatment components will be targeted for deimplementation. MethodsA 3-year concurrent mixed methods evaluation using a participatory approach in collaboration with the operational partner and TBI-COE site leadership will be conducted. Qualitative observations, semistructured focus groups, and interviewing methods will be used to describe IETP, stakeholder experiences and needs, and suggestions for IETP implementation. Quantitative methods will include primary data collection from patients in the IETP at each site to characterize long-term outcomes and patient satisfaction with treatment and secondary data collection to quantitatively characterize patient-level and care system–level data. Finally, data sets will be triangulated to share data findings with partners to inform ongoing implementation efforts. ResultsData collection began in December 2021 and is currently ongoing. The results and deliverables will inform IETP characterization, evaluation, implementation, and knowledge translation. ConclusionsThe results of this evaluation seek to provide an understanding of the determinants affecting the implementation of IETPs. Service member, staff, and stakeholder insights will inform the state of implementation at each site, and quantitative measures will provide options for standardized outcome measures. This evaluation is expected to inform national Physical Medicine and Rehabilitation Office policies and processes and knowledge translation efforts to improve and expand the IETP. Future work may include cost evaluations and rigorous research, such as randomized controlled trials. International Registered Report Identifier (IRRID)DERR1-10.2196/4477

Empower Veterans Program (EVP): a chronic pain management program demonstrates positive outcomes among veterans

Abstract Background Chronic pain is a highly prevalent health condition among veterans. Traditional pharmacological interventions present unique challenges for chronic pain management including prescription opioid addiction and overdose. In alignment with the 2016 Comprehensive Addiction and Recovery Act and VA’s Stepped Care Model to meet veterans’ pain management needs, the Offices of Rural Health and Pain Management, Opioid Safety, and Prescription Drug Monitoring Program (PMOP) funded an enterprise-wide initiative to implement a Step 3 integrated tele-pain program: Empower Veterans Program (EVP). EVP provides veterans with chronic pain self-care skills using a whole health driven approach to pain management. Objectives The Comprehensive Addiction and Recovery Act prompted the strategic approach to offer non-pharmacological options to meet veterans’ pain management needs. EVP, a 10-week interdisciplinary group medical appointment, leverages Acceptance and Commitment Therapy, Mindful Movement, and Whole Health to provide veterans with chronic pain self-care skills. This evaluation was conducted to describe participant characteristics, graduation, and satisfaction rates; and assess pre-post patient-reported outcomes (PRO) associated with EVP participation. Methods A sample of 639 veterans enrolled in EVP between May, 2015 and December, 2017 provided data to conduct descriptive analyses to assess participant demographics, graduation, and satisfaction rates. PRO data were analyzed using a within-participants pre-post design, and linear mixed-effects models were used to examine pre-post changes in PRO. Results Of 639 participants, 444 (69.48%) graduated EVP. Participant median program satisfaction rating was 8.41 (Interquartile Range: 8.20–9.20). Results indicate pre-post EVP improvements (Bonferroni-adjusted p < .003) in the three primary pain outcomes (intensity, interference, catastrophizing), and 12 of 17 secondary outcomes, including physical, psychological, health-related quality of life (HRQoL), acceptance, and mindfulness measures. Discussion Data suggest that EVP has significant positive outcomes in pain, psychological, physical, HRQoL, acceptance, and mindfulness measures for veterans with chronic pain through non-pharmacological means. Future evaluations of intervention dosing effect and long-term effectiveness of the program is needed

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD

Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89-90% for Aβ PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments

Association of Elevated Amyloid and Tau Positron Emission Tomography Signal with Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment

Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.