bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying the essential roles of light and sonication in dual‐stimuli regulated bulk atom transfer radical polymerization by multiscale simulation
Authors: Li Shen , Bian Chao , Liu Zhong‐Xin , Zhou Yin‐Ning , Luo Zheng‐Hong 
Published: June 2023

AbstractMore and more attention has been paid to the important roles of external fields in controlled radical polymerization (CRP). However, their essential roles have not been studied thoroughly yet, which hinders the in‐depth understanding of the mechanism and kinetics. Herein, a strategy combining quantum chemical calculations (QCC) and kinetic modeling was adopted to identify the essential roles of light and ultrasonication in the dual‐stimuli regulated bulk atom transfer radical polymerization (ATRP). At the molecular level, the impact of light on Cu‐catalyzed ATRP was investigated. The CuIIBr/Me6TREN has high absorbance at an experimental wavelength of 365 nm (main excitation S0 → D7 accounts for 84.93%). Electron transfer reactions involving Me6TREN are more favorable paths for photochemical reactions, and the mechanism of the copper activation/deactivation pathway is inner sphere electron transfer. At the micro‐scale, a kinetic model based on the method of moment was established with a “series” encounter pair model to consider the influence of ultrasound on diffusional limitation. Simulation results show that the changes of the reaction rate coefficients ka, kda, and kt at high conversion reflect the degree of diffusional limitation by ultrasound. The multiscale modeling strategy applied in this study identifies the essential roles of photo and ultrasonication in dual‐stimuli regulated model systems, which can be extended to other external‐field regulated CRP to improve the mechanistic understanding.
The association between allostatic load, Alzheimer biomarkers and cognition among patients at the memory clinic: A longitudinal study
Authors: Adedeji Dickson O. , Holleman Jasper , Juster Robert‐Paul , Udeh‐Momoh Chi T. , Kåreholt Ingemar , Hagman Göran , Aspö Malin , Håkansson Krister , Solomon Alina , Kivipelto Miia , Sindi Shireen ,   Cortisol and Stress in Alzheimer’s Disease (Co‐STAR)
Published: June 2023

AbstractBackgroundVarious lifestyle and physiological dementia risk factors have been identified. However, little is still known about the role of stress‐related risk factors. Chronic psychological stress affects several systems, such as the immune and cardiovascular systems, and increases the risk for physical, behavioral and mental disorders and reduced cognitive function. The goal of this study is to assess whether allostatic load (AL), a composite biomarker measure of chronic stress, is associated with AD biomarkers and cognitive function among memory clinic patients.MethodsData were derived from the Co‐STAR study at Karolinska University Hospital Memory Clinic, Sweden. Participants underwent baseline assessments including blood tests for AL measures, and cerebrospinal fluid sampling for AD biomarkers (Ab1‐42, total Tau (T‐tau), phosphorylated Tau (P‐tau)), a neuropsychological test battery was performed with measures for the following cognitive domains: general cognition, memory, working memory, processing speed and perceptual reasoning. Multiple linear regressions were conducted, adjusting for age, sex and education. P‐value <0.05 was used to identify significant associations.ResultsHigher AL was associated with lower CSF Ab1‐42 level (β = ‐0.175, p = 0.025) reflecting higher brain levels of Ab1‐42. Analyses stratified by sex showed that these associations were only present for women, but not for men. AL was not significantly associated with T‐tau level and P‐tau level. Multiple regression analyses showed that there were no significant association between AL and general cognitive functioning, processing speed, working memory, memory, and perceptual reasoning. AL modified the association between Ab1‐42 and perceptual reasoning; the non‐significant association was significant when additionally adjusted for AL (β = 0.157, p< 0.05).ConclusionThis study identified a significant negative association between AL and Ab1‐42 among women, and AL modified the association between Ab1‐42 and perceptual reasoning. This suggests that AL may play a role in dementia pathophysiology. Further evidence is needed on whether specific subgroups in memory clinic samples are particularly vulnerable to the effects of high AL burden.
Identifying Protein Quantitative Trait Loci in the Cerebrospinal Fluid Proteome
Authors: Reus Lianne M. , Teunissen Charlotte E. , Gobom Johan , Vos Stephanie J. B. , Blennow Kaj , Zetterberg Henrik , Bertram Lars , Visser Pieter Jelle , Tijms Betty M. ,   the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF‐AD MBD) study group
Published: June 2023

AbstractBackgroundGenome‐wide association studies (GWAS) on dementia have successfully identified variants conferring risk to disease. Still, how such variants impact exact biological mechanisms underlying disease remains largely unclear. Protein quantitative trait loci (pQTLs) measured in cerebrospinal fluid (CSF) may provide insight into these neurobiological mechanisms, since CSF protein levels can reflect ongoing processes in the brain and have been related to genetic variants. We used a CSF pQTL approach in individuals along the Alzheimer’s disease (AD) spectrum to reveal intermediate molecular pathways by which genetic variance influences neurobiological processes. Improving the functional interpretation of genetic variants in a matrix relevant to neurological disease helps deciphering biological mechanisms underlying neurological traits.MethodWe selected 243 subjects (106 controls/67 mild cognitive impairment/70 AD‐dementia, age 66.8±8.1 years, 53.9%female) from the EMIF‐AD MBD study, who had genetic data and CSF data (n = 1,351 proteins, tandem mass tag (TMT) mass spectrometry) available. Association signals between genetic variants and CSF proteins were tested using linear regression, adjusted for principal components (PC1‐3), age and sex using the genome‐wide significance threshold (P<5.0e−8). CSF pQTLs were identified as novel if the association has not been previously reported in Yang et al., (2021), Sasayama et al., (2017) or Kauwe et al., (2014).ResultsTwenty‐four out of 1,351 CSF proteins (1.78%) showed genome‐wide significant associations with in total 147 SNPs (Table 1; Figure 1). We identified 25 CSF pQTLs, representing three cis‐acting (IGH, LTF and ADAMTS8) and 22 trans‐acting pQTLs. Results included mostly novel CSF pQTL associations, exception for the cis association of LTF with LTF protein levels. Two novel cis‐acting pQTLs were previously reported in a study on human lymphocytes (IGH on IGHV2‐70D) (Theusch et al., 2020) and prefrontal cortex brain data (ADAMTS8 on ADAMTS8) (Ng et al., 2017).ConclusionsThese results contribute to the functional interpretation of genetic variance on neurobiological processes, by pinpointing inflammation and tissue remodeling as potential contributing mechanisms in AD.
12‐weeks of caloric restriction diet improves cortical cerebral blood flow in healthy middle‐age adults
Authors: Rahmani Farzaneh , Piccio Laura , Wang Yong , Benzinger Tammie L.S. , Tosti Valeria , Ghezzi Laura , Raji Cyrus A. 
Published: June 2023

AbstractBackgroundCaloric restriction (CR) improves neuronal stress resistance in animals and improves cognitive performance in older adults (1‐3). Neuroinflammation is an increasingly recognized mechanism relevant to Alzheimer disease (AD). We investigated the effect of a 12‐week CR diet on imaging markers of dementia and neuroinflammation in midlife individuals with multiple sclerosis (MS), a prototype neuroinflammatory disease.MethodsIn a single‐blind randomized controlled trial, 10 participants with MS (8 women and 2 men, age: 45.5±10.67 and education: 16.4±2.5 years) were recruited from the Washington University John L. Trotter MS Center and randomly assigned to participate in either a 12‐week CR or control group on their regular diet. Participants fasted 2 days a week and during those days eating no more than 500 calories. Participants underwent MRI scanning at the time of recruitment and at the end of the 12‐week program. Volumetric analyses were conducted through FreeSurfer 7.1.1 (4), relative regional cerebral blood flow (rCBF) was obtained through ASL‐MRICloud (5), and hindered and restricted diffusion fractions (HF and RF) were calculated through the diffusion basis spectrum imaging (DBSI), representing tissue edema and inflammatory cell infiltration respectivelyResultsSix participants were obese, two were overweight and two had normal weight with an average BMI of 30.3±5.48 kg/m2 across participants. Following 12‐weeks of CR, participants showed an increase in normalized hippocampal volume (p:0.02) compared to those on regular diet. CR also resulted in improved cortical thickness in the bilateral medial orbitofrontal cortices compared to the control group (p:0.014). An average increase in relative perfusion (rCBF) in the bilateral inferior temporal gyri (p:0.02, & p:0.004) and bilateral fusiform gyri (p:0.008 & p:0.002) was observed in participants undergoing CR compared to those on a regular diet at the end of 12‐weeks (Figure 1 and 2). Being on a CR diet was associated with reduced HF and RF in the bilateral inferior longitudinal fasciculi (p:0.04 & p:0.002) indicating reduced edema and cellularity (6).ConclusionCR is associated with alterations in brain’s structure and function in terms of improved volumetric measurements, regional perfusion and reduced tissue inflammation, and hence implicated as a neuroprotective intervention in midlife persons.
The cross‐sectional association between peripheral TNF‐∝, white matter hyperintensities, and cognitive outcomes in the HABS‐HD study
Authors: Vintimilla Raul , Hall James , Johnson Leigh , O'Bryant Sid E. ,   HABS‐HD Study Team
Published: June 2023

AbstractBackgroundLow‐grade inflammation appears with advance age, with the end result of an increase ratio of pro to anti‐inflammatory cytokines. Inflammatory cytokines are considered cerebrovascular disease markers, but the association of cytokine levels with poorer cognition is not conclusive. TNFα, a pro‐inflammatory cytokine, may have a role on neurodegenerative diseases, such as Alzheimer’s disease. The effect of peripheral TNFα on brain structure and cognitive outcomes in cognitively normal older adults is not well understood. A few studies have described this relationship in White cohorts, but there is a lack of research in minorities like Mexican Americans.MethodWe studied 510 cognitively normal Mexican Americans from the Health and Aging Brain Study (HABS‐HD) with signed consent, fasting blood samples, 3T MRI, clinical evaluation, and cognitive testing. TNFα was assayed via a multiple‐plex biomarker assay platform using electrochemiluminescence. White matter hyperintensities (WMH) volume was measured from FLAIR using the Statistical Parametric Mapping Lesion Segmentation Tool. Pearson correlations were used to assess the association between TNFα with WMH, global cognition (MMSE), memory (SEVLT), executive function and attention (Trails B and digit symbol substitution) measures. Linear regression was used to predict the effect of TNF‐α on WMH volume and cognitive measures. APOE4 status was assessed, and age, sex, systolic blood pressure and education were entered as covariates in the models.ResultSeventy percent of the sample were female. Sample means were 62.84 years of age, 9.94 years of education, and 137.33 for systolic blood pressure (SBP). There was not significant difference in TNFα and WMH values between APOE4 carriers and non‐carriers. TNFα had a positive significant correlation with age, education, SBP, WMH volume, and digit symbol substitution scores. Linear regression showed no association between TNFα value and WMH volume nor cognitive measures, with the exception of digit symbol substitution (B = ‐2.62; t = ‐2.03; p = 0.04).ConclusionThese results suggest TNFα peripheral values are not related to WMH volume, but were related to executive‐attention measures. Prospective studies are necessary to evaluate the use of TNFα as a potential biomarker of brain health in Mexican Americans.
Variations in rest‐activity cycle length and peak timing during Alzheimer’s progression
Authors: Gao Chenlu , Gao Lei , Gaykova Nicole , Yu Lei , Yang Jingyun , Bennett David A , Buchman Aron S , Hu Kun , Li Peng 
Published: June 2023

AbstractBackgroundRest‐activity rhythm is commonly used to assess the circadian regulation and its changes with aging and Alzheimer’s disease (AD). Traditional rhythmicity analyses such as Cosinor analysis assume a rhythm of a constant waveform while ignoring the variations in the length and peak timing between different cycles/days. We introduced a novel rhythmicity analysis based on the uniform phase empirical mode decomposition (UPMEMD) that can provide detailed information of each individual cycle in rest‐activity rhythm. We tested whether variations in rest‐activity cycles change during aging and at different stages of AD.MethodParticipants were 1,065 older adults (baseline age = 80.9±7.3[SD], 807 females) from the Rush Memory and Aging Project. Actigraphy (∼10‐day) was performed annually for up to 13 years. For each recording, the UPMEMD was used to extract the rhythm of ∼24‐h; the length and peak timing were obtained from each cycle; and standard deviations (SD) of cycle lengths and peak timings were computed for each participant. Linear mixed effects models were performed to quantify the within‐subject changes over time in SD of cycle lengths, and separately, SD of peak timings, with adjustments of age, sex, and education years. Change points at diagnoses of mild cognitive impairment (MCI) and Alzheimer’s dementia were considered in the mixed models to examine whether the rates of changes were altered after the diagnoses.ResultSD of cycle length increased by 0.04 hours/year when participants were cognitively intact (95%CI: 0.02‐0.05, p<0.001); the rate increased by an additional 0.04 hours/year after the onset of MCI (95%CI: 0.02‐0.06, p<0.001) and increased further by 0.18 hours/year (95%CI: 0.12‐0.24, p<0.001) after the onset of AD. Moreover, SD of peak timing increased by 0.04 hours/year when the participants were cognitively intact (95%CI: 0.02‐0.05, p<0.001); the rate was accelerated by 0.06 hours/year after the onset of MCI (95%CI: 0.03‐0.08, p<0.001) and further accelerated by 0.26 hours/year (95%CI: 0.20‐0.32, p<0.001) after the onset of AD.ConclusionInterdaily variability in rest‐activity rhythm increased with aging, and the ageing‐related circadian disturbance was accelerated as AD progressed. The markers of rest‐activity rhythm based on proposed rhythmicity analysis may facilitate identification of AD and monitoring of its progression.
Apathy and dysfunction early in the course of behavioral variant frontotemporal dementia
Authors: Zhu Carolyn W , Grossman Hillel , Sano Mary 
Published: June 2023

AbstractBackgroundApathy is highly prevalent in frontotemporal dementia (FTLD) but its impact on function is less understood. This study (1) examined the natural history of apathy in a large, national sample of well‐characterized patients clinically diagnosed with FTLD who had regular assessments over time, and (2) estimated the impact of apathy on function longitudinally across spectrum of disease severity.MethodSample includes individuals enrolled in the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS, 9/2005‐12/2019) who had a primary clinical diagnosis of FTLD at baseline with suspected underlying etiology of behavioral variant of FTLD (bvFTLD) with at least one follow‐up visit (N = 888). Apathy was identified using clinician judgment. Prevalence, incidence, and persistence of apathy at each visit and cumulatively over time were assessed. Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). Dementia severity as measured by baseline CDR. Linear mixed model (LMM) was used to estimate relationships between apathy, baseline CDR, and function over time.ResultAverage age of the sample = 63.4±9.1, 61% male, 92% non‐Hispanic white, average education = 15.4±3.1. Average MMSE = 23.0±6.7, GDS = 3.2±3.1 NPIQ = 8.4±5.9, CDR Sum of Boxes = 5.6±4.2, FAQ = 14.5±9.4. Presence of apathy fluctuated between 52‐65% for those with baseline CDR = 0.5, 73‐83% for CDR = 1, and 82‐87% for CDR = 2. Cumulative prevalence of apathy, i.e., proportion of participants with an endorsement of apathy in at least one visit over participant’s entire follow‐up, was 81.4% in CDR = 0.5, 93% in CDR = 1, and 94% in CDR≥2. LMM estimation results showed that independent of dementia severity and other participant characteristics, FAQ was 3.3±0.8 points higher at baseline in participants with persistent apathy and 2.1±0.8 points higher in those who always had apathy compared to (those without apathy or with intermittent apathy. Interaction terms between apathy and time were not statistically significant.ConclusionResults confirm apathy is highly prevalent across the range of dementia severity in bvFTLD. Independent of dementia severity, more persistent apathy was strongly associated with worse function. However, apathy was not associated with the rate of decline in function over time, likely because function was already highly impaired by CDR = 1. Interventions to support function may be needed early in the course of bvFTLD.
Integrated actigraphy‐based biomarker for Alzheimer’s dementia progression
Authors: Yang Hui‐Wen , Li Peng , Sun Haoqi , Lim Andrew , Bennett David A , Yu Lei , Buchman Aron S , Hu Kun 
Published: June 2023

AbstractBackgroundActigraphy derived measures including amplitude, regularity, and variability of daily rhythm, have been shown to predict incident Alzheimer’s dementia. Here we developed an integrated actigraphy biomarker (IAB) for Alzheimer’ risk and investigated whether the IAB predicted the conversion from mild cognitive impairment (MCI) to Alzheimer’ dementia.MethodWe studied 1195 participants (age 80.8±7.2yrs [SD]) from the Rush Memory and Aging Project who had finished baseline actigraphy assessment (∼10 days), were free from Alzheimer’s dementia at actigraphy baseline and had been followed for up to 15 years with annual cognitive assessment and clinical diagnoses. Ten sleep/circadian related features were derived from baseline actigraphy recordings and were fed into a random forest survival model for prediction of time and incident Alzheimer’s dementia. IAB was derived from the model as the relative risk. Cox proportional hazards and logistic regression models were used to evaluate the performance of IAB in predicting incident Alzheimer’s dementia (all 1195 participants) or MCI (858 without MCI at baseline) and predicting the conversion from MCI to Alzheimer’s dementia. Demographic variables including age, sex, and education were controlled in all Cox and logistic regression models.ResultTotal 287 participants developed Alzheimer’s dementia during the follow‐up. The derived IAB was 0.6 SD larger in the participants developed Alzheimer’s dementia as compared with the controls. Larger IAB was associated with increased risk of AD with a hazard ratio (HR) = 1.63 (95% CI = 1.46‐1.81, P<0.0001) for 1‐SD increase in IAB. IAB did not predict incident MCI (P = 0.8). Within participants with MCI (337 at baseline and 308 developed), larger IAB was associated with a higher risk for AD, i.e., HR = 1.34 for 1 SD increase (95% CI = 1.18‐1.51, P<0.0001). The logistic model using the cutoff of 3 years for the MCI‐Alzheimer’s dementia conversion gives the odd ratio = 1.56 for 1 SD increase of IAB, and results in AUC = 0.68, with a sensitivity = 0.68 and specificity = 0.61.ConclusionDerived actigraphy biomarker was predictive of Alzheimer’s risk at preclinical stages, and the conversion from MCI. Actigraphy provides useful information for early prediction and detection of AD thought its performance needs to be improved.
Pandemic caregiving: Results from a survey of Alzheimer’s disease research center study partners
Authors: Sewell Margaret , Neugroschl Judith A. , McSpedon Sinead , Weinrib Gila , Woodhead Jessica , Loizos Maria , Zhu Carolyn W , Sano Mary 
Published: June 2023

AbstractBackgroundCaregivers are at increased risk for psychological distress and social isolation. The COVID‐19 pandemic presents extra challenges for caregivers of research participants.MethodUsing NACC’s caregiver COVID survey as a model, we developed a 25‐item questionnaire with Likert‐type questions concerning the pandemic’s impact on caregiving, the emotional/cognitive health of the research participant, and willingness to participate in research. Data was collected in summer 2021, with responses focused on 3/2020‐3/2021. ADRC participants with CDR ≥ 1 and their caregivers were identified. Data was previously collected on 267 participants with CDR 0‐0.5.Result32 caregivers of research participants (50% adult children, 41% spouses, 9% other) completed the survey (15‐75 minutes). Participants were 59% female (mean age 80 and education 15y). 66% non‐Hispanic White, 13% non‐Hispanic Black, 19% Hispanic. Mean CDR SOB was 12±5. Demographics on the 267 normal/MCI participants not shown.Caregivers (55%) felt “some‐extremely” isolated compared to 39% of CDR 0‐0.5 participants; mean caregiver isolation scores were 3.4/5 and 2.5/5 for those who cared for participants with CDR = 3 and 1‐2, respectively. Caregivers (91%) and participants (56%) found the pandemic “some‐extremely” disruptive; mean caregiver disruption scores were 4/5, 3.6/5 and 3.8/5 for those who cared for participants with CDR = 3, 2 and 1, respectively. Caregivers (63%) said that vaccination “very‐extremely” reduced caregiving stress. 41% endorsed “a lot” as to how challenging it was to ensure participants complied with COVID safety precautions. 47% felt that COVID “moderately‐severely” impacted the participant’s cognition. Caregivers’ biggest barriers were lack of access to day programs (31%), decreased support from family/friends (31%), and lack of in‐person medical care (25%). 42% of caregivers were “somewhat‐extremely” uncomfortable with in‐person research. Caregivers (63%) said that going forward, flexibility of in‐person vs. remote evaluations was “very‐extremely” important.ConclusionThis diverse group of caregivers reported more isolation and disruption than CN/MCI participants, particularly with participants with CDR’s of 2‐3. Caregivers also expressed continued desire to participate in research. Research centers should be mindful of the impact of isolation, loss and stress (e.g. helping loved ones with cognitive impairment manage safety protocols). Increased social work services and prioritizing flexibility (e.g. telehealth) is key.