Amgen (Belgium)

OBJECTIVE: To evaluate persistence with anti-tumor necrosis factor (TNF) therapy and predictors of discontinuation in patients with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from RADIUS 1, a 5-year observational registry of patients with RA, to determine time to first- and second-course discontinuation of etanercept, infliximab, and adalimumab. First-course therapy was defined as first exposure to anti-TNF therapy, and second-course therapy was defined as exposure to anti-TNF therapy after the first discontinuation. Kaplan-Meier survival analysis was used to assess persistence, log-rank tests were used to compare therapies, and Cox proportional hazards models were used to assess potential predictors of treatment discontinuation. RESULTS: This analysis included 2418 patients. Mean persistence rates were similar among treatments [first-course: etanercept, 51%; infliximab, 48%; adalimumab, 48% (followup was 54 weeks for etanercept and infliximab and 42 weeks for adalimumab); second-course: 56%, 50%, 46%, respectively (followup was 36 weeks for etanercept and infliximab and 30 weeks for adalimumab)]. Discontinuations of first-course therapy due to ineffectiveness were similar among treatments (etanercept, 19%; infliximab, 19%; adalimumab, 20%) and discontinuations due to adverse events were significantly (p = 0.0006) lower for etanercept than for infliximab (etanercept, 14%; infliximab, 22%; adalimumab, 17%). Predictors from univariable analysis of first- or second-course therapy discontinuation included increased comorbidities (etanercept), female sex (infliximab), Clinical Disease Activity Index > 22 (infliximab), and a Stanford Health Assessment Questionnaire score > 0.5 (adalimumab). CONCLUSION: In this population, first- and second-course persistence was similar among anti-TNF therapies. First-course discontinuation due to adverse events was lower with etanercept compared with infliximab.

OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of no prophylaxis, primary prophylaxis (PP), or secondary prophylaxis (SP) with granulocyte colony-stimulating factors (G-CSFs), i.e., pegfilgrastim, lipegfilgrastim, filgrastim (6- and 11-day), or lenograstim (6- and 11-day), to reduce the incidence of febrile neutropenia (FN) in patients with stage II breast cancer receiving TC (docetaxel, cyclophosphamide) and in patients with non-Hodgkin lymphoma (NHL) receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) over a lifetime horizon from a Belgian payer perspective. METHODS: A Markov cycle tree tracked FN events during chemotherapy (3-week cycles) and long-term survival (1-year cycles). Model inputs, including the efficacy of each strategy, risk of reduced relative dose intensity (RDI), and the impact of RDI on mortality, utilities, and costs (in €; 2014 values) were estimated from public sources and the published literature. Incremental cost-effectiveness ratios (ICERs) were assessed for each strategy for costs per FN event avoided, life-year (LY) saved, and quality-adjusted LY (QALY) saved. LYs and QALYs saved were discounted at 1.5% annually. Deterministic and probabilistic sensitivity analyses (DSAs and PSAs) were conducted. RESULTS: Base-case ICERs for PP with pegfilgrastim relative to SP with pegfilgrastim were €15,500 per QALY and €14,800 per LY saved for stage II breast cancer and €7800 per QALY and €6900 per LY saved for NHL; other comparators were either more expensive and less effective than PP or SP with pegfilgrastim or had lower costs but higher ICERs (relative to SP with pegfilgrastim) than PP with pegfilgrastim. Results of the DSA for breast cancer and NHL comparing PP and SP with pegfilgrastim indicate that the model results were most sensitive to the cycle 1 risk of FN, the proportion of FN events requiring hospitalization, the relative risk of FN in cycles ≥2 versus cycle 1, no history of FN, and the mortality hazard ratio for RDI (<90% vs ≥90% [for NHL]). In the PSAs for stage II breast cancer and NHL, the probabilities that PP with pegfilgrastim was cost effective or dominant versus all other prophylaxis strategies at a €30,000/QALY willingness-to-pay threshold were 52% (other strategies ≤24%) and 58% (other strategies ≤24%), respectively. CONCLUSION: From a Belgian payer perspective, PP with pegfilgrastim appears cost effective compared to other prophylaxis strategies in patients with stage II breast cancer or NHL at a €30,000/QALY threshold.

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.

LBA8284 Background: Chemotherapy-induced anemia (CIA) often results in debilitating fatigue that can be alleviated with erythropoietic agents, epoetin alfa and darbepoetin alfa (DA). The ability to administer DA on a Q3W schedule to synchronize with the majority of chemotherapy regimens is of particular interest to clinicians and patients. The objective of this study is to evaluate and compare the efficacy and safety of Q3W with once-weekly (QW) DA using a non-inferiority approach. This is the largest study to date to examine efficacy of DA in the treatment of CIA using a fixed dose with extended dosing. Methods: This is a randomized, double-blind, active-controlled, phase 3 trial in 160 centers across Europe. Eligibility include age ≥18 years, anemia (hemoglobin [Hb] <11g/dL), and nonmyeloid malignancy with ≥12 weeks (wks) of planned chemotherapy. Patients (pts) were randomized 1:1 to either 2.25mcg/kg QW or 500mcg Q3W DA, stratified by tumor type, screening Hb (<10 or ≥10g/dL) and region. Pts in the Q3W treatment arm received QW placebo to maintain the double-blind nature and to avoid bias in treatment decisions. Pts were treated up to 16 wks. The primary endpoint is the incidence of transfusions from wk 5 to end of treatment period (EOTP). Other clinically meaningful endpoints include change in Hb, change in FACT-Fatigue scores and achievement of Hb ≥11g/dL from wk 5 to EOTP in the absence of transfusions. Analyses will be based on data from pts who received ≥1 dose of study medication. Kaplan-Meier estimates, adjusted for stratification factors, for each treatment arm will be compared using log-rank test. For the primary endpoint, a two-sided 95% confidence interval (CI) for the difference (Q3W-QW) in transfusion rates will be calculated. If the upper limit of the CI is ≤12.5% (based on previous studies of DA 2.25mcg/kg), then non-inferiority of the Q3W regimen to the QW regimen will be concluded. Two-sided 95% CI will also be calculated for the difference in mean Hb change of the treatment groups adjusting for stratification and baseline factors. Results: Final transfusion incidence rates on 705 pts will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly Amgen Amgen, Eli Lilly

Biomarker analysis for colorectal cancer has been shown to be reliable in Europe with 97% of samples tested by EQA participants to be correctly classified. This study focuses on errors during the annual EQA assessment. The aim was to explore the causes and actions related to the observed errors and to provide feedback and assess any improvement between 2016 and 2017. An electronic survey was sent to all laboratories with minimum one genotyping error or technical failure on ten tumor samples. A workshop was organized based on 2016 survey responses. Improvement of performance in 2017 was assessed for returning participants (n = 76), survey respondents (n = 13) and workshop participants (n = 4). Survey respondents and workshop participants improved in terms of (maximum) analysis score, successful participation, and genotyping errors compared to all returning participants. In 2016, mostly pre- and post-analytical errors (both 25%) were observed caused by unsuitability of the tumor tissue for molecular analysis. In 2017, most errors were due to analytical problems (50.0%) caused by methodological problems. The most common actions taken (n = 58) were protocol revisions (34.5%) and staff training (15.5%). In 24.1% of issues identified no action was performed. Corrective actions were linked to an improved performance, especially if performed by the pathologist. Although biomarker testing has improved over time, error occurrence at different phases stresses the need for quality improvement throughout the test process. Participation to quality improvement projects and a close collaboration with the pathologist can have a positive influence on performance.

BACKGROUND: Several studies have demonstrated negative effects of directional microphone configurations on left-right and front-back (FB) sound localization. New processing schemes, such as frequency-dependent directionality and front focus with wireless ear-to-ear communication in recent, commercial hearing aids may preserve the binaural cues necessary for left-right localization and may introduce useful spectral cues necessary for FB disambiguation. PURPOSE: In this study, two hearing aids with different processing schemes, which were both designed to preserve the ability to localize sounds in the horizontal plane (left-right and FB), were compared. RESEARCH DESIGN: We compared horizontal (left-right and FB) sound localization performance of hearing aid users fitted with two types of behind-the-ear (BTE) devices. The first type of BTE device had four different programs that provided (1) no directionality, (2-3) symmetric frequency-dependent directionality, and (4) an asymmetric configuration. The second pair of BTE devices was evaluated in its omnidirectional setting. This setting automatically activates a soft forward-oriented directional scheme that mimics the pinna effect. Also, wireless communication between the hearing aids was present in this configuration (5). A broadband stimulus was used as a target signal. The directional hearing abilities of the listeners were also evaluated without hearing aids as a reference. STUDY SAMPLE: A total of 12 listeners with moderate to severe hearing loss participated in this study. All were experienced hearing-aid users. As a reference, 11 listeners with normal hearing participated. DATA COLLECTION AND ANALYSIS: The participants were positioned in a 13-speaker array (left-right, -90°/+90°) or 7-speaker array (FB, 0-180°) and were asked to report the number of the loudspeaker located the closest to where the sound was perceived. The root mean square error was calculated for the left-right experiment, and the percentage of FB errors was used as a FB performance measure. RESULTS were analyzed with repeated-measures analysis of variance. RESULTS: For the left-right localization task, no significant differences could be proven between the unaided condition and both partial directional schemes and the omnidirectional scheme. The soft forward-oriented system and the asymmetric system did show a detrimental effect compared with the unaided condition. On average, localization was worst when users used the asymmetric condition. Analysis of the results of the FB experiment showed good performance, similar to unaided, with both the partial directional systems and the asymmetric configuration. Significantly worse performance was found with the omnidirectional and the omnidirectional soft forward-oriented BTE systems compared with the other hearing-aid systems. CONCLUSIONS: Bilaterally fitted partial directional systems preserve (part of) the binaural cues necessary for left-right localization and introduce, preserve, or enhance useful spectral cues that allow FB disambiguation. Omnidirectional systems, although good for left-right localization, do not provide the user with enough spectral information for an optimal FB localization performance.

INTRODUCTION: This study aimed to better understand panitumumab use in real-life clinical practice in first- and second-line treatment of metastatic colorectal cancer in five European countries. METHODS: This is a combined analysis of two observational, non-interventional prospective cohort studies, one of which was conducted in Germany and France, the other in Bulgaria, Czech Republic, and Hungary. The studies observed patients with wild-type [Kirsten] rat sarcoma viral oncogene homolog ([K]RAS/RAS) metastatic colorectal cancer (mCRC), who had been treated with panitumumab in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in the first line or with panitumumab combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the second line following fluoropyrimidine-based chemotherapy. The planned duration of observation was 12 months from the first dose of panitumumab. RESULTS: A total of 332 patients treated with panitumumab + FOLFOX in the first line and 94 patients treated with panitumumab + FOLFIRI in the second line were analyzed. The median number of panitumumab infusions was 10.0 in first-line FOLFOX patients and 11.5 in second-line FOLFIRI patients; the median duration of panitumumab exposure was 5.7 and 6.9 months, respectively. The unadjusted overall response rate (complete or partial response) in patients with available post-baseline response assessment (n = 290) was 51.7% in first-line FOLFOX and 44.9% in second-line FOLFIRI patients. In the first-line setting, resectability was achieved in 9.3%. Reported hospitalizations were mostly cancer-related visits such as scheduled anticancer treatment administrations, tumor assessment visits, or interventions. The majority of adverse drug reactions were skin disorders, with 75.3% in first-line FOLFOX patients and 72.3% in second-line FOLFIRI patients. CONCLUSION: Overall, the study results show that treatment patterns, clinical efficacy, and the safety profile of panitumumab in routine clinical practice were comparable to those in randomized controlled trials. The relatively low skin toxicity rate could be attributed to increasing experience in managing panitumumab-associated rash and some degree of underreporting. FUNDING: Amgen.

Abstract Background Traditional quantitative cut‐offs for amyloid PET positivity have been defined to discriminate Alzheimer’s dementia (AD) subjects from elderly Aβ‐negative non‐demented controls. Currently, observational and interventional studies focus on earlier stages of Aβ deposition, where established cut‐offs might not be appropriate. Here, we review recent developments on early pathology identification, and provide supporting evidence from three cohorts for the establishment of a “gray‐zone” of amyloid burden. Method Data from three cohorts of cognitively unimpaired individuals were included, namely ALFA+ (n=357), FACEHBI (n=228) and the AMYPAD Prognostic Study (n=122). PET scans ([ 18 F]flutemetamol and [ 18 F]florbetaben) were analyzed in Centiloid (CL) units. Gaussian Mixture Modelling was used to fit two/three Gaussians to the global CL values, and the cut‐off for early pathology detection was defined as two standard deviations above the mean of the left Gaussian. Then, the data was merged to derived a joint cut‐off. Finally, these data‐driven cut‐offs were compared to previously established thresholds in the context defining a range of CL values where pathology is emerging. Result GMM identified a cut‐off of CL=11 for FACEHBI, CL=14 for ALFA+, CL=17 for AMYPAD and CL=11 for the cohorts combined (Figure 1). Similarly, Salvadó et al identified two cut‐offs based on a direct comparison with established CSF Aβ42 thresholds: CL=12 to rule out‐amyloid pathology and CL=29 to denote established pathology. With a different approach, the FACEHBI working group finds CL=13 as an early threshold defined based on young healthy controls, and CL=36 as an established cut‐off to separate healthy elderly from Aβ‐positive AD‐dementia subjects. In AMYPAD, where a more comprehensive sampling of the AD continuum is present, fitting 3 Gaussians through the data allows the identification of two data‐driven cut‐offs: CL=13 and CL=29. Conclusion A number of recent and current reports converge to the utility of two cut‐offs for amyloid PET abnormality, an early cut‐off around CL=11‐17 where pathology may be emerging, and a second around CL=29‐36 where amyloid burden levels greatly correspond to neuropathology findings. Together, these create a gray‐zone of CL values pre‐AD dementia levels of amyloid burden, which can improve the detection of emerging pathology in observational and secondary prevention trials.

Background: Chemotherapy plays an important role in the treatment of early breast cancer (EBC). Granulocyte-colony stimulating factors (G-CSF) can reduce the risk of febrile neutropenia as primary prophylaxis (PP) or secondary prophylaxis (SP). The BRONS study investigated the incidence of serious neutropenic events (SNE) and G-CSF use in a Belgian population of EBC patients treated with myelosuppressive polychemotherapy.Methods: Conducted in 2011, this study was a prospective, multicentre, observational trial involving 260 patients. The primary endpoint was the incidence of SNE defined as either febrile neutropenia (FN) or prolonged severe neutropenia (PSN; neutrophil count ≤0.5 × 10⁹ for at least five days). Secondary endpoints included a description of the chemotherapeutic regimens prescribed and G-CSF use.Results: Nine percent of patients were treated with a dose-dense regimen (DD) and 91% received classical chemotherapy (CC). PP with G-CSF (PPG) was given to 20% of patients (100% in DD and 11% in CC). Eighteen percent of patients presented a SNE (4% in DD and 20% in CC) of which 15% were FN and 3% PSN. SNE occurrence was 8% in the PPG subgroup and 21% in the no-PPG subgroup. In the DD subgroup, all patients received PPG and no FN was reported. Twenty six adverse events related to G-CSF were reported in 8.2% of patients and two of these were classified as severe.Conclusion: This observational study highlights the high incidence of SNE with CC regimens in patients who do not receive PPG. It also confirms the safe profile of DD regimens with G-CSF support.

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PURPOSE: The study aim was to describe the management strategies used for severe infusion-related reactions (SIRs) and understand the impact of such events in oncology day hospitals in France, Germany, Spain, and the UK. METHODS: The study was based on qualitative telephone interviews and quantitative self-completion questionnaires and asked healthcare professionals about the impact of SIRs and consequent actions taken. RESULTS: The procedures to prevent and manage SIRs were similar across countries and settings. In all countries, they were part of a larger risk-assessment and adverse events-prevention process. Preventive measures included patient history, risk assessment, pre-medication, and close monitoring of high-risk patients. The management procedures comprised stopping the infusion, triggering of the emergency chain, administering corticosteroids ± antihistamines, and hospitalization if necessary. The recalled SIRs had important consequences to affected patients, healthcare providers, and hospital organizational plans. All affected patients needed to be monitored closely for a prolonged time, thus blocking hospital beds. 44% of patients needed to be hospitalized, 17% needed resuscitation, and one patient died of cardiac arrest immediately after the start of the infusion. Importantly, 82% of patients were not re-challenged with the presumedly SIR-causing regimen or re-challenged in a later line. CONCLUSION: SIRs are unpredictable in nature, may have an extremely rapid onset, and are potentially fatal. Such events have a profound impact on the affected and surrounding patients, the care team and the organizational plan of the day-hospitals. Specific tools to reliably identify high-risk patients and predict the occurrence of events are needed.

In Belgium, the calcimimetic cinacalcet is initially reimbursed for < or = 4 months in dialysis patients with secondary hyperparathyroidism (SHPT) and intact parathyroid hormone (iPTH) > or = 800 pg/mL, or iPTH 300-800 pg/ mL and Ca x P > 55 mg 2/dL2 despite > or = 6 months' optimal treatment with vitamin D sterols and/or phosphate binders. The Belgian, multicentre, observational study ECHO-B evaluated cinacalcet in such patients. Patients who began cinacalcet treatment after March 1, 2007 were eligible. Data were collected retro/prospectively from 6 months before until 16 months after starting cinacalcet (whether or not cinacalcet was continued). Median iPTH was markedly elevated (816 [IQR 551-991] pg/mL) at baseline (the time of starting cinacalcet), but decreased continuously over the course of the study, reaching a value of 414 pg/mL (IQR 240-641; median change -41%) at 4 months, 335 pg/mL (IQR 159-616; -60%) at 12 months and 250 pg/mL (IQR 172-436; -64%) at 16 months. Reductions in serum calcium (-7%) and phosphorus (-13%) were already (near) maximal at 4 months. The primary outcome (iPTH 150-300 pg/mL and/or a > or = 30% reduction within 4 months of starting cinacalcet; criterion for continued reimbursement in Belgium) was achieved in 65/81 patients (80%; 95% CI 72-89%). Results show that in dialysis patients with SHPT in real-life clinical practice, mineral metabolism improves after starting cinacalcet: our study findings suggest that PTH levels may continue decreasing after 12 months' treatment in this setting.

OBJECTIVES: To quantify hospitalizations and costs among adults with Philadelphia-negative relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) who received current salvage chemotherapies in Belgium. METHODS: A retrospective chart review identified patients aged ≥18 years and hospitalized between 2005 and 2015 for Ph-negative R/R B-cell ALL. Data were collected from the index date (first diagnosis of R/R ALL) until death or loss to follow-up. The salvage chemotherapy period was defined as the first chemotherapy hospitalization after the index date to the earliest of death, loss to follow-up, last chemotherapy dose plus 30 days, or initiation of hematological stem cell transplantation (HSCT). The primary endpoint was the percent of time in the hospital during the salvage chemotherapy period. Hospitalization costs were reported from the public health care payer perspective. RESULTS: Nineteen patients were included, with median age of 37 years. The average proportion of time patients spent in the hospital during the salvage chemotherapy period was 50.5%. From the index date to death, patients received a mean of 1.8 lines of chemotherapy, most commonly hyper-CVAD (31%). There was a mean of 5.5 inpatient hospitalizations and 40.1 outpatient visits with 40.8 outpatient lab tests. Mean costs per patient were €79,973 for hospitalization (excluding HSCT), €26,337 for HSCT, €21,007 for chemotherapy drugs, and €6,341 for outpatient management, resulting in a total cost from the payer's perspective of €133,965 per patient. CONCLUSION: Adults with Ph-negative R/R ALL spend half the time receiving salvage chemotherapy in the hospital. Their treatment is associated with large reimbursement costs in Belgium.

Laboratories require customized feedback on improving biomarker testing practices. A workshop was organized for laboratories that participated in a European external quality assessment scheme to resolve issues related to the estimation of neoplastic cell percentage and tissue quality for RAS testing for colorectal cancer. An interactive course about tissue quality took place to stress the importance of the pre-analytical phase. During a microscopic session, five H&E stained tumor tissue slides were discussed and neoplastic cell percentages estimated. Participants included 4 pathologists, 3 molecular biologists, a technologist and a clinical geneticist from 7 laboratories. In six laboratories, tumor contents are checked routinely by visual estimation by the pathologist. The average difference between the lowest and highest estimation was 22%. During the workshop the importance of the pre-analytical phase was stressed and feedback was provided. Such initiatives can contribute in improving biomarker testing standards in Europe

Abstract Background Parkinson’s disease (PD) is the second‐most common neurodegenerative disorder that affects 2–3% of the population ≥ 65 years of age and may belong to cognitive deficits and dementia in 50% of cases. Disease with Lewy Bodies (DLB) is emerging as another important cause of dementia in pathological aging. PD and DLB are both due to intra‐neuronal Lewy bodies and are characterized not only by motor dysfunctions but also cognitive and/or psychiatric symptoms. An open issue is the extent to which these diseases are distinct entities. In this respect, here we compared cortical sources of resting state eyes‐closed electroencephalographic (rsEEG) rhythms in PD and DLB patients as a function of global cognitive status. Method Clinical and rsEEG rhythms in demographic matched PD (N = 93), DLB (N = 46), Alzheimer’s disease dementia (AD, N= 70) and healthy elderly (Nold, N = 60) subjects were available from an international archive. Pathological groups were matched as cognitive status. Individual alpha frequency peak was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were considered. The eLORETA freeware estimated rsEEG cortical sources. Result Compared to the Nold subjects, the AD, DLB, and PD patients showed higher widespread delta source activities and lower posterior alpha source activities. Specifically, posterior alpha source activities were more abnormal in the AD than the DLB and PD groups, while widespread delta source activities were more abnormal in the PD and DLB than the AD group. As main novel results, in relation to the DLB and PD patients with low cognitive deficits and the control groups (Nold, AD), those with high cognitive deficits were characterized by higher parietoccipital delta source activities (DLB, Figure 1) and widespread alpha sources activities (PD, Figure 2). Conclusion These novel results suggest that in DLB and PD patients resting in the quiet wakefulness, abnormalities in cortical neural synchronization at delta and alpha frequencies are differently related to cognitive status despite the essence of alpha‐synucleinopathy.

Secondary objectives will include assessment of demographic and tumor characteristics, treatment compliance and switching, DFS, OS, safety parameters, additional QoL parameters, and hormone levels (estrone, estradiol, and follicle-stimulating hormone) as a measure of Ovarian Function Suppression (OFS).These parameters will allow researchers to investigate possible relationships between disease characteristics, treatment selection and clinical outcomes, with a focus on factors predicting treatment switching, suboptimal OFS and clinically significant changes in QoL.Results: The study is ongoing, with completion projected for July 2024.Interim analyses are planned for 2023 and 2024.Conclusion(s): This study will provide useful real-world information regarding QoL changes and clinical management of patients treated with OFS.The results generated will also provide insights into factors influencing treatment selection, with potential implications for treatment adherence and outcome optimization.

Abstract Background Previous evidence has shown that Alzheimer’s disease (AD) patients exhibited an increased risk of overt epileptic seizures or subclinical, non‐convulsive, epileptiform‐like electroencephalographic (EEG) signatures (i.e., spike‐sharp wave discharges, giant spikes, etc.) due to temporal and frontal lobe dysfunctions and aberrant cortical neural synchronization. In the present study, cortical sources of resting state eyes‐closed EEG (rsEEG) rhythms were estimated in patients with amnesic mild cognitive impairment due to AD (ADMCI), using normal elderly (Nold) and AD patients with dementia (ADD) as controls. The hypothesis was that rsEEG sources may be more abnormal in ADMCI with than without epileptiform‐like EEG signatures. Method Clinical and rsEEG data in 35 ADD, 50 ADMCI, and 35 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini Mental State Evaluation (MMSE) score was matched between the ADMCI with and without epileptiform‐like EEG signatures (i.e., spike‐sharp wave discharges, giant spikes, etc.). No subject had received a clinical diagnosis of epilepsy. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Result Frontal and temporal delta source activities were more abnormal in the ADMCI patients with epileptiform‐like EEG signatures (N = 13; 26%; ADMCI‐ELES) and ADD than the control ADMCI patients (N= 37; ADMCI‐noELES; Figure 1). This effect may not depend on sleep onset or epileptiform‐like EEG signatures as “biological artifacts” in the EEG signal, because of the present source analysis was performed from rsEEG epochs free from those signatures. Conclusion The present findings suggest that in MCI patients, AD neuropathology may derange neurophysiological low‐frequency (i.e. delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance, and such derangement may be more pronounced in frontal and temporal cortical regions in ADMCI patients characterized by epileptiform EEG signatures. Future investigations should cross‐validate the present findings by a longitudinal prospective study testing. We predict that ADMCI patients with those delta source and epileptiform‐like EEG signatures may develop a fast disease progression.

Abstract Background The aim of this study was to identify DNA methylation signatures that were associated with 15 CSF biomarker measures of Alzheimer’s disease (AD) or neurodegeneration. Method We profiled DNA methylation in 886 blood samples from the EMIF‐AD study using the Illumina EPIC array, identifying differentially methylated loci, and regions consisting of multiple adjacent differentially methylated sites. Results We identified Bonferroni‐significant differences in DNA methylation with respect to CSF t‐tau Z‐score (five loci), Aβ42 levels (one loci), YKL‐40 levels (six loci) and NFL (seven loci). Significant differentially methylated regions were identified in 13 of the 15 analyses, with overlapping regions featuring in multiple CSF measures( MX2, RHOH, ANKMY1, ZFP57 ) analyses, which was unsurprising given the high correlation between measures. Interestingly, we identified several regions that overlapped between the tau and amyloid ( ZBTB22 ), tau and NFL ( S100A13 ), NFL and neurogranin ( SORD ), and neurogranin and amyloid ( STRA6 ) regional analyses. Conclusion In this blood‐based epigenome‐wide association study of AD‐relevant CSF biomarkers we identified several interesting genomic loci and regions.

Abstract Background We previously described three spatio‐temporal subtypes of amyloid accumulation trajectories, measured with PET (Collij et al., 2022). APOE4 carriers tended to have initial amyloid deposition in frontal regions compared to those showing initial deposition in parietal and occipital regions, suggesting different underlying disease mechanisms. Here, we investigated the relationship between global and regional amyloid burden and Alzheimer’s disease polygenic risk scores (AD‐PRS). Method AD‐PRS were calculated for 458 non‐demented individuals participating in EPAD and AMYPAD, based on 85 identified risk loci, including and excluding the two major APOE variants (Bellenguez et al., 2022). After exclusion of APOE , the remaining 83 risk loci were functionally annotated and classified into six pathway sets (annotation tool as defined in Tesi et al., (2020)): path‐PRSimmune‐activation, path‐PRSsignal‐transduction, path‐PRSinflammatory‐response, path‐PRSmigration, path‐PRSamyloid‐production, path‐PRSclearance. 18F‐Florbetaben or 18F‐Flutemetamol PET were acquired and quantified using the Centiloid pipeline to obtain global and regional (frontal, precuneus, lateral parietal, lateral temporal, occipital) amyloid burden (Klunk et al., 2015). Linear models assessed the association between amyloid burden and each (path‐)PRS, corrected for age, sex, and PET‐tracer. Result Participants were 67.5±7.03 years of age, 57.6% female, and 109 were considered amyloid‐positive (CL&gt;21). Global amyloid burden was highly associated with AD‐PRS APOE and, to a lesser extent, AD‐PRS noAPOE (β = 14.75, p &lt;5.9e‐15 and β = 7.99, p = 0.03, respectively, Figure 1 ). Similar results were obtained for regional burden ( Table 1 ). After exclusion of APOE , both path‐PRSmigration (β = 51.92, p = 0.02) and path‐PRSclearance (β = 39.87, p = 0.02) were significantly associated with global amyloid burden, where path‐PRSclearance showed the strongest association with amyloid burden across all regions (frontal: β = 38.96, p = 0.009; precuneus: β = 50.11, p = 0.006; lateral parietal: β = 44.10, p = 0.003; lateral temporal: β = 26.59, p = 0.04; occipital: β = 17.17, p = 0.049). Path‐PRSmigration and Path‐PRSamyloid‐production were significantly associated with only the precuneus (β = 58.15, p = 0.02; β = 19.03, p = 0.04, respectively) and lateral parietal cortex (β = 47.12, p = 0.02; β = 16.41, p = 0.03, respectively). Conclusion Results illustrate that genetic predisposition beyond APOE is associated with global and regional amyloid burden. Path‐PRS results implicate clearance mechanisms in early disease pathogenesis, though strongest with the precuneus and lateral parietal cortex, which are early amyloid‐accumulating regions. Since AD‐PRS were associated with longitudinal changes in amyloid (Luckett et al., 2022), we aim to further investigate the association of path‐PRS with longitudinal amyloid within EPAD and AMYPAD.

Abstract Background Brain amyloid‐β (Aβ) is the pathological hallmark of Alzheimer’s disease (AD). In logistic disease models, Aβ accumulation is a sigmoid function of time‐since‐disease‐onset (TSDO) ( figure 1 ). Previous positron emission tomography (PET)‐based models vary accumulation onset(t50) and duration(r) globally; capacity(K) and baseline(NS) regionally (Whittington2018). We confirm existing approaches and propose a more powerful ICA‐based approach to quantify disease severity and estimate TSDO. Method We used 1071 18F‐florbetapir standard uptake value ratio (SUVR) images from the ADNI‐2 study (adni.loni.usc.edu/data‐samples/data‐types/pet). Images were mapped into MNI space. Averages were extracted using the Harvard‐Oxford brain‐atlas. Whole‐brain tracer‐specific sigmoid parameters (Jack2013) obtained from the literature were used to estimate TSDO. Of 16 models of regional Aβ accumulation (each of the 4 regional sigmoid parameters varied either regionally or globally), the optimal Bayesian information criterion was found with global t50 and r, and regional NS and K ( figure 1 ) with global values r = 6.16y and t50 = 4.10y. Linearised maps of NS and K were obtained by regressing the SUVR maps onto the global sigmoid. We also estimated these maps as independent components, using a 2‐component ICA on the SUVR maps. Both outcomes were used to quantify Aβ accumulation from SUVR images as weighting factors of the accumulation map. We compared the weights from the logistic model and the ICA model in ADNI, using effect size measured with Hedges' g between cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (EMCI/MCI/LMCI) and AD groups. We compared 3 longitudinal visits (N = 112) in the OASIS‐3 study (see www.oasis‐brains.org) with both methods, global SUVR and Centiloid (Klunk2015) using 11C‐PiB PET SUVR images. Result Maps of accumulation capacity from both models had spatial correlation of 0.86 ( figure 2 ); baseline maps had spatial correlation of 0.95. Hedges' g between ADNI groups was 2.25 for K, and 2.42 for ICA (1.46 for global SUVR). In OASIS‐3, Hedges' g between visits was 1.24 for K, 1.46 for ICA (global SUVR 0.15, Centiloid 0.4). Conclusion We demonstrate that linear accumulation models can be used to quantify brain Aβ with PET; maps obtained by ICA yield larger effect sizes than the logistic method for differentiating groups and measuring changes between visits.