bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Safety, Feasibility and Effect of the APOE Mimetic Peptide CN‐105 on Neuroinflammation and Delirium after Major Non‐cardiac/Non‐neurologic Surgery in Older Adults: Results from the Phase II, Triple Blind, Escalating Dose, MARBLE Randomized Clinical Trial
Authors: Berger Miles , Timko Noah J. , Boykin Piper C. , Emerson Jacqueline M. , Woldorff Marty G. , Wright Mary Cooter , Herbert J. Taylor , Moretti Eugene W. , Devinney Michael J. , Ryu David , VanDusen Keith W. , Bunning Thomas , Hsia Bethany J. , Browndyke Jeffrey N. , Blennow Kaj , Zetterberg Henrik , Laskowitz Daniel T. ,   the MARBLE Study Investigators
Published: January 2025

AbstractBackgroundAPOE4 leads to increased neuroinflammation, neurocognitive decline, increased risk of Alzheimer’s disease, and may be associated with increased delirium risk. However, the safety and feasibility of pharmacologic modulation of APOE to prevent neuroinflammation and postoperative delirium is unclear.MethodsWe performed a Phase II, triple blind, escalating dose, randomized controlled trial to determine the safety, feasibility, and efficacy of the APOE mimetic peptide CN‐105 for preventing postoperative neuroinflammation and delirium. We enrolled older adults (age ≥ 60 years) undergoing major non‐cardiac/non‐neurologic surgery with a planned overnight hospital stay. Patients were randomized 1:3 to placebo or intravenous CN‐105 (0.1, 0.5 or 1 mg/kg) starting within 1 hour before surgery and continuing every 6 hours (± 90 minutes) afterwards, until 13 doses were received or hospital discharge (whichever occurred first). The primary outcome was the number of Grade 2 or higher adverse events (AEs) among patients randomized to CN‐105 vs. placebo. Secondary outcomes included percent of drug doses administered within the correct time window, and postoperative delirium incidence and severity.Results203 patients were enrolled; 186 patients (mean [SD] age, 68.7 [5.3] years; 119 male) completed surgery on protocol (49 [26%] Placebo, 137 [74%] CN‐105; Figure 1). The groups were generally well‐matched (Table 1). Patients administered CN‐105 vs. placebo had less Grade 2 or higher AEs (median per patient [Q1, Q3] 1 [1, 3] vs. 2 [1, 5]; p = 0.025), and a lower rate of severe AEs (8.0% vs. 22.4%, p = 0.007; Table 2). The rate of doses administered within window was 95.3% (95% CI: 93.7%‐96.6%) for CN‐105‐treated patients and 93.8% (95% CI: 90.8%‐96.0%) for placebo‐treated patients. CN‐105 (vs. placebo) treated patients had a lower delirium incidence (19.3% vs 27.1%, relative risk = 0.71 [95% CI: 0.40‐1.27], p = 0.26), and lower median delirium severity (1 vs. 2; proportional odds ratio [95% CI] 0.66 [0.37, 1.20]; p = 0.178), though these effects were not statistically significant.ConclusionsCN‐105 is safe and feasible to administer to older non‐cardiac/non‐neurologic surgery patients, and led to fewer postoperative Grade 2 or higher AEs and severe AEs. The 95% CIs for the effects of CN‐105 included clinically relevant reductions in delirium incidence and severity.
PET Imaging of Microtubules in Cognitively Impaired and Normal Older Adults
Authors: Damuka Naresh , Miller Mack , Krizan Ivan , Bhoopal Bhuvanachandra , Orr Miranda E. , Gollepalli Krishna Kumar , Lockhart Samuel N. , Whitlow Christopher T , Mintz Akiva , Craft Suzanne , Sai Kiran K. Solingapuram 
Published: January 2025

AbstractBackgroundAlthough associated with early changes in Aβ and tau formations, microtubule (MT) destabilization has not yet been systematically evaluated as an early biomarker of neurodegeneration and a tool to quantify it in real‐time could provide information on these early changes in AD cascade. While current Aβ and tau PET approaches can characterize disease lesions, they fall short in capturing earlier molecular events. Our team development the first brain‐penetrant MT PET ligand, [11C]MPC‐6827. We evaluated its in vivo imaging efficacy in rodent and nonhuman primate models of AD, and subsequently conducted a first‐in‐human study. Here we show our preliminary MT‐PET and autoradiography data in cognitively impaired and age‐matched cognitively normal older adults and post‐mortem human brains respectively.MethodDynamic 1h brain PET imaging was conducted with [11C]MPC‐6827 in cognitively impaired (Aβ and tau PET positive) and cognitively normal (Aβ and tau PET negative) older adults (n = 5/group). MT‐PET uptake was correlated with [11C]PiB‐Aβ, and FTP‐tau SUVRs and fluid biomarker data. Autoradiography was performed in postmortem MCI/early AD (n = 3) and age‐matched cognitively normal adults (n = 2) brain tissues.Result[11C]MPC‐6827 uptake was higher in the frontal and prefrontal cortex, hippocampus, putamen, and pons of the cognitively impaired subjects than the controls. Uptake correlated positively with ptau181, [11C]PiB Aβ, and FTP‐tau SUVRs and inversely with their CSF Aβ42—validating its relevance to AD biomarkers. MT‐PET‐SUVRs positively correlated with calculated average PiB SUVRs (Pearson r = 0.667, p = 0.05) and with FTP SUVRs (r = 0.367, *
p = 0.047). Autoradiography uptake in AD prefrontal cortex and hippocampus was ∼39 and ∼43% (*p≤0.05) higher than that in control tissues.ConclusionOur [11C]MPC‐6827 human studies demonstrate (a) safety and feasibility; (b) robust brain uptake; (c) higher brain uptake in cognitively impaired subjects than in controls; (d) a highly positive correlation among PiB, and FTP uptakes; (e) autoradiography results may indicate not possibly of age confounding the imaging data. This study will be the first to image MT destabilization processes in AD. It will create a new understanding of MT‐based processes in the neurodegeneration cascade to optimize approaches of AD diagnosis and monitoring.
The Design of SPRINT MIND and SPRINT MIND 2020
Authors: Rapp Stephen R. , Supiano Mark A. 
Published: January 2025

AbstractBackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) included a specific aim on the effect of blood pressure lowering the risk of cognitive impairment (mild cognitive impairment (MCI) and dementia). Early termination of the trial and fewer than expected cases left the study under powered to detect cases of probable dementia, but the intervention reduced the risk for MCI and for a composite of MCI or probable dementia (PD). To increase the length of follow‐up and number of cases of probable dementia, two studies were funded: one from October 2017 through June 2018 and a second, the SPRINT MIND 2020 study, from December 2019 through December 2023.MethodIn the main trial, 9361 participants were randomized to either Intensive or Standard BP control, systolic BP < 120 or < 140 mmHg, respectively. For the cognitive aim, outcomes were adjudicated PD and MCI.ResultOf the 9361 participants in the SPRINT trial, 8563 completed one or more cognitive assessment, and 325 were adjudicated to have probable dementia at the end of the first extended follow‐up. The SPRINT MIND 2020 follow‐up ascertained an additional 216 cases of probable dementia. An additional 170 cases of mild cognitive impairment were also ascertained.ConclusionSPRINT MIND 2020 successfully extended follow‐up time for the SPRINT MIND study and increased the number of observed cognitive outcomes substantially enabling an analysis of legacy treatment effects.
The association of frailty with cognition outcomes in SPRINT‐MIND
Authors: Callahan Kathryn E. , Jaeger Byron C , Rapp Stephen R. , Pajewski Nicholas M. , Williamson Jeff D. 
Published: January 2025

AbstractBackgroundFrailty may moderate efficacy of interventions for Alzheimer’s disease (AD) and related dementias (ADRD), with higher efficacy at lower neuropathology burden in frailty. Using data from the Systolic Blood Pressure Intervention Trial (SPRINT) with extended post‐trial follow‐up, we assessed whether frailty moderated the effect of intensive blood pressure (BP) control and subsequent cognitive outcomes.MethodsPrimary outcomes were probable dementia (PD) and mild cognitive impairment (MCI). Intensive and standard BP control targeted systolic BP < 120 and < 140 mmHg, respectively. Frailty index (FI) was calculated using a deficit‐accumulation model. We tested for heterogeneity in the effect of intensive BP control among participants who were non‐frail (FI ≤ 0.10), pre‐frail (0.10 < FI ≤ 0.21), and frail (FI > 0.21) using Cox proportional hazards, accounting for differential baseline hazard by study site. Analyses were replicated in subgroups defined by age, sex, and race.ResultsOf the 9361 participants in the SPRINT trial, 8541 consented to follow‐up for PD/MCI and had calculable baseline FI. Over 54568 person‐years, 539 PD and 809 MCI events occurred. Participants categorized as non‐frail (N = 1412) were younger and more likely to be male versus pre‐frail (N = 4430) and frail (N = 2699) participants. Intensive versus standard BP control exhibited a heterogeneous effect for PD risk reduction (p = 0.03), with hazard ratios (HRs) ranging from 0.70 to 1.10. Among subgroups based on age, sex, and race, PD HRs ranged from 0.59 to 1.00. For MCI, heterogeneity was not detected (p = 0.23), and HRs ranged from 0.70 to 1.00. No evidence of harm (i.e., HR > 1) was detected.ConclusionsHeterogeneity based on frailty in the effect of BP control may impact subsequent cognitive outcomes. Future studies with cognitive outcomes should consider stratifying by frailty status.
The Types and Consistency of Participant‐Specified Proxies During SPRINT
Authors: Gaussoin Sarah A. , Jaeger Byron C , Lerner Alan J. , Perdue Letitia H. , Rapp Stephen R. , Reboussin David M. , Williamson Jeff D. 
Published: January 2025

AbstractBackgroundFor clinical trials or patient care, reports from a person familiar with the trajectory of a participant’s cognitive and functional performance (i.e., proxies) may improve adjudication of events, such as mild cognitive impairment and dementia. Proxies offer a unique perspective on cognitive status that is different from what is captured through standard cognitive examinations. Clinical trials in which cognitive status is adjudicated, such as the Systolic Blood Pressure Intervention (SPRINT) trial, provide information about the contributions and consistency of proxies throughout extended follow‐up.MethodSPRINT participants named proxies and relationship to them at study onset. Proxies provided information for the Functional Activities Questionnaire and Dementia Questionnaire. We collapsed proxy relationships into seven categories and evaluated the proportion of proxies in each category at baseline and how frequently the same proxy was retained to the last visit. We explored associations between proxy relationship and various baseline demographics and examined the association between not having a proxy, as well as proxy relationship, and adjudicated outcome.ResultOf the 9,361 randomized SPRINT participants (35.6% female, mean age 67.9 years), 7,586 (81%) participants listed a proxy relationship from which we identified 7 categories: spouse/partner (51.7%), child (23.6%), sibling (8.7%), other family member (6.2%), and unrelated (8.8%). Male participants were more likely to name a spouse as their proxy (64%) while female participants more likely to name a child (42%). The overall consistency of proxy continuation between the baseline and final SPRINT visit (mean 6.9 years) was 90.7%. Proxy consistency from first visit to last visit for a child was 94.8%, spouse/partner (91.9%) brother/sister (87.5%), other family member (82.4%), non‐related (81.2%), and parent (78.2%). Adjudications that resulted in ‘Cannot Classify’ were greatest for proxies who were parents (15%) followed by none (12%), sibling and grandchild (9%), child and unrelated (7%), spouse and other family (6%).ConclusionThe majority of proxies in SPRINT were immediate family members (spouse, child, or sibling). Over 90% of identified proxies at baseline continued to be available over a mean of almost 7 years of follow‐up. Not having a proxy available led to a higher rate of ‘cannot classify’ adjudications.
Empowering Communities: Examining Korean Dementia‐friendly Community Policies through a Lens of Dementia Inclusive Societies Framework
Authors: Chung Soondool 
Published: January 2025

AbstractBackgroundAs the global prevalence of dementia continues to rise, South Korea faces the imperative of developing comprehensive policies to address the multifaceted challenges posed by this condition. Creating dementia‐friendly communities is important for the inclusion of patients with dementia (PWD) and their families. Therefore, the purpose of this study is to analyze dementia‐friendly community policies in Korea using the WHO’s dementia inclusive societies framework and to suggest ways to improve such policies.MethodsThe WHO’s framework consists of key principles and actors such as key partners and target groups, etc.. The social environment, specifically Leading Institutions for Overcoming Dementia (LIOD) and Dementia Relief Members, was chosen as dementia‐friendly community policies in Korea.ResultsThe Dementia‐friendly Communities Initiative was started in 2017, aiming to support social activities of PWD. Firstly, the key principle of LIOD was to make communities safe for PWD and their families, with key partners being both for‐profit and non‐profit entities such as businesses, schools, universities, and libraries. They engage in activities, campaigns, educational programs, etc., related to dementia. The target groups were employees of business, students, and user of libraries. Secondly, the key principles of Dementia Relief Members were to promptly protect and report when encountering older individuals wandering the streets, and to encourage early dementia screening and increase awareness of dementia. Key partners were small business owners such as restaurant and convenience stores after their staff received Dementia Partners education. The target groups were owners and staffs of those shops.ConclusionsDementia‐friendly community policy in Korea represents a critical step towards addressing the growing prevalence of dementia and promoting the rights and dignity of individuals living with the condition. However, there are some drawbacks to this policy. The system for sustaining the continuous activities of dementia LIOD is limited. Furthermore, the monitoring system for continuous activities of Dementia Relief Members is also inadequate. Dementia‐friendly establishments are only monitored for closure and changes in location, thus there is no effective management of continuous participation in activities. Further measures for improvement should be taken.
Diagnostic journey and barriers to diagnosis for patients with mild cognitive impairment or dementia due to Alzheimer’s disease in Canada: results from a real‐world survey
Authors: Glass Jennifer , Boulay Luc , Vasileva‐Metiodiev Simona , Walker Chloe , Cotton Sarah , Tarride Jean‐Eric , Laforce Robert , Gauthier Serge 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) dementia progresses from preclinical brain changes, through mild cognitive impairment (MCI), to AD with dementia. Early diagnosis and confirmation of underlying AD pathology is crucial; however, there is still much to learn about patients’ diagnostic journey. We aimed to describe the diagnostic journey and barriers to diagnosis for patients with MCI or dementia due to AD in Canada.MethodData were collected from the Adelphi Real World AD Disease Specific Programme (DSP)™, a cross‐sectional survey of general practitioners (GPs) and specialists in Canada, from March to October 2023. GP surveys covered patient management and referral patterns. Specialists completed a survey capturing attitudes towards diagnosis, advanced testing, and future treatment landscape. Physicians saw ≥5 (GPs) or ≥10 (specialists) patients per week with MCI or dementia/AD. Analyses are descriptive.ResultThe survey was completed by 20 GPs and 30 specialists (19 neurologists, 6 psychiatrists, and 5 geriatricians). GPs reported patient difficulty remembering people’s names (65%) was the patient complaint that most often prompted further testing (Table 1). Other important patient complaints were problems concentrating on everyday tasks (45%) and worry about forgetting things, such as appointments so they have to rely on notes and calendars (45%). GPs reported referring an average of 25±22% of patients with MCI to a specialist after seeing them an average of 3.9±1.3 times. On average, 49±28% of patients with MCI or dementia/AD managed by GPs were not referred to a specialist. Specialists reported the top three barriers to early identification of patients with MCI and patients with mild dementia due to AD were delay due to lack of awareness of the condition (67% and 53%), lack of understanding what constitutes “normal” ageing (63% and 40%), and slow referral (37% and 40%) (Figure 1).ConclusionMany patients with MCI or dementia/AD in Canada are not referred by GPs, especially in early‐stage AD. Referrals from GPs were also often delayed, with specialists citing delay due to lack of patient awareness of MCI as the main barrier to early diagnosis. Improving awareness of early AD symptoms and AD pathology, and accelerating access to specialists, are warranted.
Sex‐specific associations between plasma biomarkers and risk factors for dementia: a 10‐year follow‐up of community‐dwelling older individuals
Authors: Ryan Joanne , Murray Anne , Wu Zimu , Mielke Michelle M. 
Published: January 2025

AbstractBackgroundEvidence is growing supporting sex‐ and gender‐ specific differences in risk factors for dementia, and varying pathways to diagnosis. Recognized sex differences in brain structure and function could contribute to differences in plasma biomarker concentrations and in susceptibility to brain pathologies. Furthermore, differences in comorbidities between males and females (e.g. kidney function) could influence sex differences in the clearance and measurement of these biomarkers. The aim of this study was to investigate the association between risk factors and plasma biomarkers, with incident dementia, separately in men and women.MethodIn the U.S and Australia, we recruited 19,114 community‐dwelling individuals aged ≥70 years (U.S African‐Americans and Hispanics ≥65 years), without cognitive impairment and cardiovascular disease. Plasma amyloid‐beta (Aβ40 and Aβ42), phosphorylated tau (p‐tau 181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured [Simoa N4PE and Ptau181 v2 assays] at baseline. Dementia was adjudicated by an expert panel according to DSM‐IV criteria. The association between a range of factors (Table 1), and the risk of dementia was assessed using multivariable logistic regression, separately in men and women.ResultParticipants had a mean age of 74 years at baseline and plasma biomarker data was available for 7,218 women and 5,942 men. Of these participants, 824 developed dementia, with a similar proportion of men (6.4%) and women (6.2%). Age, a family history of dementia, BMI and slow gait speed were significantly associated with dementia risk, in both men and women (Table 2). All of the plasma biomarkers were associated with dementia risk, but NfL was not significant after adjustment for GFAP (particularly in women). In men only, depression and diabetes were significant risk factors, while in women poor grip strength was associated with increased risk, and U.S whites compared to Australian whites, had decreased risk.ConclusionPlasma biomarkers of Alzheimer’s Disease were found to be associated with dementia risk in both men and women, however associations between other risk factors and dementia varied. These findings suggest the importance of considering sex and gender differences, as this could open up possibilities for personalized prevention.
Reevaluating Melatonin’s Efficacy in Alzheimer’s Disease: A 20th‐Anniversary Updated Literature Review of Sleep Disturbances and Treatment Trials
Authors: Malhotra Alisha , Daga Vrushabh , Singer Cliff 
Published: January 2025

AbstractSleep disturbances in Alzheimer’s disease (AD) are stressful for patients and families. This review provides an update on the efficacy of melatonin and other interventions for nighttime sleep disturbances in AD patients, building on the original Alzheimer’s disease Cooperative Study trial, the first large trial for sleep disturbance in AD. The initial multicenter, randomized, placebo‐controlled study investigated the effects of two melatonin formulations – 2.5 mg sustained‐release (ML2.5SR) and 10 mg immediate‐release (ML10) –compared to placebo (PLA) in 157 participants. The primary outcomes, measured via wrist‐actigraphy, indicated no significant changes; however, secondary outcomes suggested improvement in sleep quality with ML2.5SR. This suggests the efficacy of melatonin in AD may be related to time and exposure rather than dosage, as sustained‐release formulations showed a greater trend for efficacy than immediate.Melatonin’s antioxidant properties have been shown to be neuroprotective, balancing Aβ production and clearance, but have been equivocal in reducing sleep disturbances. Recent research has demonstrated actigraphy to be an imperfect method for measuring sleep and wakefulness, misclassifying asleep time as awake in people with AD, and overestimating sleep in others. Combined with the subjective nature and poor compliance with sleep diaries in the ADCS study, methodological questions as to how to do large studies of sleep in people with AD arose. Updated studies have looked at melatonin in comparison to interventions like bright‐light therapy and other drugs. Circadian rhythm disturbances are common in AD, and different therapies have been trialed to improve sleep onset, duration, and quality. There has also been updated information regarding the efficacy of different measure to accurately record sleep including EEG and polysomnography.We analyzed studies in the 20 years since the ADCS trial was published. Our findings, while mixed, suggest that melatonin may be more effective improving sleep outcomes in AD, than reported in the ADCS paper‐ particularly when used in conjunction with other interventions. Suggestions for further study include finding a new way to objectively gather sleep data in a large trial so that another multicenter trial looking several sustained release formulations and other interventions may be attempted.