US Military Veteran Perspectives on Eating Disorder Screening, Diagnosis, and Treatment: A Qualitative Study.

OBJECTIVE: We aimed to explore US veteran perspectives on eating disorder screening, diagnosis, patient-provider conversations, and care in the Veterans Health Administration (VHA). METHOD: Rapid qualitative analysis of 30-45 min phone interviews with 16 (N = 16) veterans with an electronic health record ICD-10 eating disorder diagnosis, who received care at one of two VHA healthcare systems in Connecticut or California. Topics covered included: conversations with providers about eating disorder symptoms, diagnosis, and referral to treatment; feedback about an eating disorder screener, and; reflections on eating disorders among veterans and VHA's effort to address them. RESULTS: Most veterans reported difficulty understanding and defining the problems they were experiencing and self-diagnosed their eating disorder before discussing it with a provider. Treatment referrals were almost universally for being overweight rather than for an eating disorder, often leading veterans to feel misunderstood or marginalized. Overall, veterans were enthusiastic about the screener, preferred screening to be conducted by primary care providers, and noted that conversations needed to be non-stigmatizing. There was consensus that VHA is not doing enough to address this issue, that group support and therapy could be beneficial, and that resources needed to be centralized and accessible. DISCUSSION: For the most part, veterans felt that, at best, eating disorders and disordered eating are overlooked, and at worst, conflated with overweight. The majority of veterans got referred for weight loss or weight management services but would welcome the opportunity to be screened for, and referred to, eating disorder treatment.

Associations between posttraumatic stress disorder and eating disorder symptoms among women veterans.

Recent research suggests high rates of posttraumatic stress disorder (PTSD) and eating disorder (ED) comorbidity in women veterans. This study aims to expand the literature by examining associations between PTSD and ED diagnoses and symptoms in this population. We assessed probable PTSD diagnosis and symptom clusters (intrusion, avoidance, arousal and reactivity, and negative alterations in cognition and mood [NACM]), as well as probable Binge Eating Disorder (BED) diagnosis and ED subscales (dietary restraint, shape/weight overvaluation, and body dissatisfaction) in a sample of women veterans (N = 371). We investigated significance at the standard p < .05, and the Bonferroni-corrected p < .005 cut-off to adjust for experiment-wise error. Overall, we found that probable PTSD was associated with provisional BED (p < .001) using logistic regression at both cut-offs. Probable PTSD was associated with all ED subscales (all p's < 0.003) using linear regression models also at both cut-offs. Provisional BED was associated with NACM at p < .05 (p = .046), though it did not meet significance at our conservative cut-off. NACM was also associated with shape/weight overvaluation (p = .02) and a global ED score (p = .01) at p < .05, but not at our conservative cut-off; arousal was associated with shape/weight overvaluation (p = .04) and the global ED score (p = .02) at p < .05, but not at our conservative cut-off. Our findings may further guide how ED-related topics can be integrated in PTSD treatment for women veterans with comorbid PTSD and ED.

Validation of the EDDS-5 self-report survey against the SCID-5 diagnostic interview in US veterans.

The aim of our study was to validate the Eating Disorder Diagnostic Scale (EDDS-5) updated for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) with a diverse veteran population against a clinician-administered interview based on the Structured Clinical Interview for DSM-5 (SCID-5). Our sample included 343 veterans, 18-75 years, recruited April 2019 to December 2022 who completed the EDDS-5 as well as other eating disorder and mental health measures. A subsample of these veterans received clinical interviews (n = 166), which were used to validate the EDDS-5. We found that despite multiple proposed modifications, the EDDS-5 performed poorly at correctly identifying diverse veterans who were diagnosed as having eating disorders through clinician-administered interviews. The sensitivity was very low, indicating that using the EDDS-5 did not identify many true positives and may also over diagnose those without true eating disorders. The EDDS-5 may not be the best for screening or diagnostic purposes among diverse samples like veterans.

Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease.

BACKGROUND: Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance. RESEARCH QUESTION: Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease? STUDY DESIGN AND METHODS: In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance. RESULTS: Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%). INTERPRETATION: In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03038178; URL: www. CLINICALTRIALS: gov.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Specific Memory B Cells From Individuals With Diverse Disease Severities Recognize SARS-CoV-2 Variants of Concern.

The unprecedented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has called for substantial investigations into the capacity of the human immune system to protect against reinfection and keep pace with the evolution of SARS-CoV-2. We evaluated the magnitude and durability of the SARS-CoV-2-specific antibody responses against parental WA-1 SARS-CoV-2 receptor-binding domain (RBD) and a representative variant of concern (VoC) RBD using antibodies from 2 antibody compartments: long-lived plasma cell-derived plasma antibodies and antibodies encoded by SARS-CoV-2-specific memory B cells (MBCs). Thirty-five participants naturally infected with SARS-CoV-2 were evaluated; although only 25 of 35 participants had VoC RBD-reactive plasma antibodies, 34 of 35 (97%) participants had VoC RBD-reactive MBC-derived antibodies. Our finding that 97% of previously infected individuals have MBCs specific for variant RBDs provides reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to elicit immunity with the capacity to limit disease severity and transmission of VoCs as they arise and circulate.

The Annual Diagnostic Prevalence of Ankylosing Spondylitis and Axial Spondyloarthritis in the United States Using Medicare and MarketScan Databases.

OBJECTIVE: The objective of this study was to investigate the diagnostic prevalence of ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA) in the United States and examine treatment patterns for these diseases. METHODS: This retrospective observational cohort study drew from 2006-2014 data in the US Medicare Fee-for-Service and IBM MarketScan databases. AS and axSpA diagnoses were identified through International Classification of Diseases, Ninth Revision [ICD-9] codes. Diagnostic prevalence (per 10,000 patients) was calculated as patients with AS and axSpA with full insurance coverage in each calendar year divided by the total patients with full insurance coverage in the same year. Two diagnosis definitions were used: definition 1 (D1), one or more relevant ICD-9 codes from hospital claims or two or more relevant ICD-9 codes from outpatient claims; definition 2 (D2), one or more codes from hospital/outpatient claims. Primary analyses assessed annual AS and axSpA prevalence (D1); sensitivity analyses assessed annual (D2) and 2-year prevalence. Patterns in prevalence and treatment use were analyzed descriptively; no statistical tests were performed. RESULTS: An increase in AS prevalence (per 10,000 patients) was seen from 2006 to 2014 in primary analyses (Medicare: 2.12-3.60; MarketScan: 0.85-1.42) and sensitivity analyses. A similar trend occurred for axSpA (Medicare: 4.39-6.52; MarketScan: 1.33-2.21). For Medicare, the proportion of patients with AS (D1) using tumor necrosis factor α inhibitors (TNFis), conventional synthetic antirheumatic drugs (csARDs), nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and glucocorticoids remained relatively stable; for MarketScan, TNFi-treated patients increased (51.7% to 65.7%) and NSAID-treated patients decreased (63.5% to 55.7%). CONCLUSION: AS and axSpA prevalence may have increased in the United States between 2006 and 2014. Reasons are unknown, but this may be due to increased disease awareness, among other factors.

The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial.

BACKGROUND: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). OBJECTIVE: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). SETTING: Academic and community-based rheumatology, gastroenterology, and dermatology practices. PATIENTS: Adults aged 50 years or older receiving TNFis for any indication. INTERVENTION: Random assignment to ZVL versus placebo. MEASUREMENTS: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. RESULTS: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. LIMITATION: Potentially limited generalizability to patients receiving other types of immunomodulators. CONCLUSION: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. PRIMARY FUNDING SOURCE: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

Neutralization of SARS-CoV-2 variants by convalescent and BNT162b2 vaccinated serum.

SARS-CoV-2 and its variants continue to infect hundreds of thousands every day despite the rollout of effective vaccines. Therefore, it is essential to understand the levels of protection that these vaccines provide in the face of emerging variants. Here, we report two demographically balanced cohorts of BNT162b2 vaccine recipients and COVID-19 patients, from which we evaluate neutralizing antibody titers against SARS-CoV-2 as well as the B.1.1.7 (alpha) and B.1.351 (beta) variants. We show that both B.1.1.7 and B.1.351 are less well neutralized by serum from vaccinated individuals, and that B.1.351, but not B.1.1.7, is less well neutralized by convalescent serum. We also find that the levels of variant-specific anti-spike antibodies are proportional to neutralizing activities. Together, our results demonstrate the escape of the emerging SARS-CoV-2 variants from neutralization by serum antibodies, which may lead to reduced protection from re-infection or increased risk of vaccine breakthrough.

SARS-CoV-2 specific memory B-cells from individuals with diverse disease severities recognize SARS-CoV-2 variants of concern.

In this investigation we examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in the plasma, and peripheral memory B-cells along with their associated antibody profiles elicited after in vitro stimulation. We found that magnitude varied amongst individuals, but was the highest in hospitalized subjects. Variants of concern (VoC) -RBD-reactive antibodies were found in the plasma of 72% of samples in this investigation, and VoC-RBD-reactive memory B-cells were found in all but 1 subject at a single time-point. This finding, that VoC-RBD-reactive MBCs are present in the peripheral blood of all subjects including those that experienced asymptomatic or mild disease, provides a reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to limit disease severity and transmission of variants of concern as they continue to arise and circulate.

Neutralization of SARS-CoV-2 variants by convalescent and vaccinated serum.

We tested human sera from large, demographically balanced cohorts of BNT162b2 vaccine recipients (n=51) and COVID-19 patients (n=44) for neutralizing antibodies against SARS-CoV-2 variants B.1.1.7 and B.1.351. Although the effect is more pronounced in the vaccine cohort, both B.1.1.7 and B.1.351 show significantly reduced levels of neutralization by vaccinated and convalescent sera. Age is negatively correlated with neutralization in vaccinee, and levels of variant-specific RBD antibodies are proportional to neutralizing activities.

'Lady Windermere's counterpart? Pulmonary nontuberculous mycobacteria in men with bronchiectasis.

Pulmonary nontuberculous mycobacterial (NTM) disease occurs frequently in older women, and phenotypes of men with NTM disease are largely undescribed. We conducted a case-control study of 34 men with non-cystic fibrosis pulmonary NTM disease (cases), and three male and female control groups with or without NTM disease. Cases were median 71 years of age (range 30-94) and mostly non-Hispanic white (85.3%). These men had similarly low BMI as their female NTM patient counterparts, which was lower than both healthy men (p < 0.001) and bronchiectatic men without NTM (p = 0.06). Kyphoscoliosis was also more common in cases than healthy men (p= 0.007) or bronchiectatic men without NTM (p = 0.02). Our study was the first study to our knowledge to examine demographic features and phenotypes of men with NTM disease. Larger studies are needed to ascertain whether these phenotypes are characteristic of men with NTM disease.

In the Real World: Infections Associated with Biologic and Small Molecule Therapies in Psoriatic Arthritis and Psoriasis.

PURPOSE OF REVIEW: To summarize our most current understanding of the real world risk of infections associated with biologic and small molecule therapies in the setting of psoriatic disease. RECENT FINDINGS: Patients with psoriasis or psoriatic arthritis are at increased risk for infection from both their disease and some of their therapies. There is little real world data for biologic and small molecule therapies; however, ustekinumab and biologics inhibiting IL-17 or IL-23 appear to have reduced risk estimates compared to anti-TNF therapies. Apremilast seems to have little infectious signal with limited real world data, and for JAK inhibitors, limited real world data suggest a higher risk of herpes zoster. Recently approved targeted and small molecule therapies for psoriasis carry infectious risks for patients, although they appear to vary across mechanism of action. As these treatments become more widespread, and additional therapies are approved, it will be imperative to evaluate their safety in the context of real world data.

Mortality after Respiratory Isolation of Nontuberculous Mycobacteria. A Comparison of Patients Who Did and Did Not Meet Disease Criteria.

RATIONALE: The mortality of patients with respiratory tract isolates of nontuberculous mycobacteria (NTM) and their risk factors for death are not well described. OBJECTIVES: To determine age-adjusted mortality rates for patients with respiratory NTM isolates and their causes of death and to examine whether American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) diagnostic criteria identify those at higher risk of death after NTM isolation. METHODS: We linked vital records registries with a previously identified Oregon population-based cohort of patients with NTM respiratory isolation. We excluded patients with Mycobacterium gordonae (n = 33) and those who died (n = 21) at the time of first isolation. We calculated 5-year age-adjusted mortality rates. We used Kaplan-Meier and Cox proportional hazards analysis to examine the association of ATS/IDSA criteria and other risk factors with death. RESULTS: Of 368 subjects with respiratory NTM isolates in 2005-2006, 316 were included in the survival analysis. Most (84%) of their cultures isolated Mycobacterium avium complex. 35.1% died in the 5 years following respiratory isolation. Five-year age-adjusted mortality rates were slightly higher for those meeting (28.7/1,000) versus not meeting (23.4/1,000) ATS/IDSA criteria. In multivariate analysis, older age (adjusted hazard ratio [aHR], 1.06; 95% confidence interval [CI], 1.04-1.07) and lung cancer (aHR, 2.77; 95% CI, 1.51-5.07) were associated with an increased risk of death. A trend was noted between meeting ATS/IDSA criteria and subsequent death (aHR, 1.37; 95% CI, 0.95-1.97). Among cases, male sex, older age, and immunosuppressive therapy use were independent risk factors for death. CONCLUSIONS: In the State of Oregon, patients with NTM respiratory isolates have high mortality, regardless of whether they meet ATS/IDSA criteria for pulmonary NTM disease. Most patients die as a result of causes other than NTM infection.

Long-Term Outcomes in a Population-based Cohort with Respiratory Nontuberculous Mycobacteria Isolation.

RATIONALE: The natural history of nontuberculous mycobacteria (NTM) respiratory infection in the general population is poorly understood. OBJECTIVES: To describe the long-term clinical, microbiologic, and radiographic outcomes of patients with respiratory NTM isolates. METHODS: We previously identified a population-based cohort of patients with respiratory NTM isolation during 2005-2006 and categorized patients as cases or noncases using the American Thoracic Society/Infectious Diseases Society of America pulmonary NTM disease criteria at that time. During 2014-2015, we reviewed medical charts of patients alive on January 1, 2007. Outcomes of interest were the proportion of baseline noncases who later met case criteria and the proportions of patients with culture conversion or findings consistent with persistent disease at least 2-5 years and at least 5 years after first isolation. We defined disease persistence radiographically as infiltrate, nodules, or cavities and microbiologically as a positive respiratory mycobacterial culture. We used logistic regression to evaluate factors associated with evidence of persistence. RESULTS: The study included 172 patients (62% of 278 eligible); those not included either refused consent (n = 47) or were not located (n = 56). One hundred two (59%) included patients met case criteria at baseline. Mycobacterium avium complex was commonly isolated among baseline cases (n = 91 [89%]) and noncases (n = 52 [74%]). Overall, 57 (55%) baseline cases had died, as compared with 43 (61%) noncases (P = 0.47). Among baseline noncases, only four (5.7%) later met case criteria. Overall, 55 (54%) baseline cases and 6 (9%) noncases initiated NTM treatment. Among cases, cultures were converted in 25 (64.1%) treated versus 4 (40%) untreated patients (P = 0.04). Of 89 cases alive 2 years after isolation, 61 (69%) had additional radiography, and 35 (39%) had respiratory cultures. Of these individuals, 54 (89%) had radiographic evidence and 17 (49%) had microbiologic evidence of disease persistence. At 5 years after first isolation these figures were 36 (82%) and 13 (54%), respectively. Women were more likely to have persistent radiographic findings and microbiologic persistence, and patients with chronic obstructive pulmonary disease were less likely to have microbiologic persistence. CONCLUSIONS: In the general population, follow-up beyond 2 years of patients with respiratory NTM isolation is limited. Among those with additional evaluations, at least half of individuals have persistent positive cultures or radiographic findings consistent with NTM at least 2 years after isolation.

Social Support and Health Service Use in Depressed Adults: Findings From the National Health and Nutrition Examination Survey.

OBJECTIVE: We investigated the relationship between social support and health service use among men and women with depression. METHODS: Participants were 1379 adults with symptoms of depression (Patient Health Questionnaire-9 score ≥ 5) in the National Health and Nutrition Examination Survey. Using the framework of the Andersen Behavioral Model of Health Services Use, multivariable regression models used social support, stratified by depression severity, to estimate association with utilization of mental health and nonmental health services. Partial F-tests examined a priori interactions between social support and gender. RESULTS: Among those with adequate social support, odds of seeing a nonmental health provider were much higher when depression was moderate [Odds Ratio (OR): 2.6 (1.3-5.3)] or severe [OR: 3.2 (1.2-8.7)], compared to those lacking social support. Conversely, odds of mental health service use were 60% lower among those with moderate depression [OR: 0.4 (0.2-1.0)] when social support was adequate as opposed to inadequate. Social support was unrelated to service use when depression was mild. Gender moderated the relationship between social support and health service use among individuals with severe depression. CONCLUSIONS: Social support has opposite associations with mental and nonmental health service use among adults with clinically significant depression. This association is largely attributable to the effect of male gender on the relationship between social support and health service use.

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity.

Accumulation of amyloid beta-peptide (Abeta) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Abeta and the aldehyde-bearing cholesterol oxidation product 3-beta-hydroxy-5-oxo-5,6-secocholestan-6-al is known to increase Abeta amyloidogenicity. Here, we synthesized Abeta variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Abeta formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Abeta Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Abeta under identical conditions and at the same concentration. Our results show that Abeta modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Abeta.

Alzheimer's Abeta peptides containing an isostructural backbone mutation afford distinct aggregate morphologies but analogous cytotoxicity. Evidence for a common low-abundance toxic structure(s)?

Amyloid beta (Abeta) peptide amyloidogenesis, involving the formation of numerous distinct quaternary structures, appears to cause Alzheimer's disease. However, the precise identification of the toxic structure(s) and the neurotoxicity mechanism(s) remains elusive. Mutating the Abeta 1-40 Phe19-Phe20 backbone amide bond to an isostructural E-olefin bond enables formation of spherical aggregates to the exclusion of detectable amyloid fibrils. Herein, the fibrillization and toxicity of amide-to-ester mutants of Abeta 1-40 at the 19-20 position and surrounding backbone amide bonds are compared to the fibrillization and toxicity of the 19-20 E-olefin Abeta analogue and wild type Abeta. Whereas isostructural amide-to-E-olefin mutations eliminate both the H-bond donor and acceptor capabilities, isostructural amide-to-ester mutations eliminate the donor while retaining the ester carbonyl as a weakened acceptor. None of the amide-to-ester Abeta 1-40 mutants prevent fibrillization; in fact several exhibit hastened amyloidogenesis. The 18-19 amide-to-ester substitution is the only backbone mutation within the hydrophobic core region of the fibril (residues 17-21) that significantly slows fibrillization. Despite forming different morphologies, the 19-20 E-olefin mutant, the 18-19 amide-to-ester mutant, and WT Abeta 1-40 fibrils all exhibit similar toxicities when applied to PC12 cells at 18 h into the aggregation reactions, as assessed by MTT metabolic activity measurements. This result suggests that a common but low abundance aggregate morphology, that is accessible to these Abeta analogues, mediates toxicity, or that several different aggregate morphologies are similarly toxic.

The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation.

4-Hydroxynonenal (4-HNE), formed as a consequence of oxidative stress, exists at increased concentrations in Alzheimer's disease (AD) patients and is found in amyloid beta peptide (Abeta) plaques associated with AD. Although it remains an open question as to whether oxidative stress is a causative factor or a consequence of AD, we show here that 4-HNE, putatively resulting from the peroxidation of lipids, covalently modifies Abeta, triggering its aggregation. These Abeta modifications result from 1,4 conjugate addition and/or Schiff base formation, they occur at multiple locations on a single Abeta peptide, and they result in covalent cross-linking of Abeta peptides. The consequence of these reactions is that 4-HNE accelerates the formation of Abeta protofibrils while inhibiting the production of straight, mature fibrils. Recent studies implicating Abeta oligomers and protofibrils in the neurotoxic process that ultimately leads to AD suggest that the Abeta aggregates induced by 4-HNE may be important in the pathogenesis of AD. These results provide further incentive to understand the role of oxidative stress and small-molecule Abeta modifications in sporadic AD.