bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive reserve: the association between lifestyle enrichment and incident dementia
Authors: Wu Zimu , Pandigama Danushika , Wrigglesworth Jo , Owen Alice , Woods Robyn , Chong Trevor T.‐J. , Orchard Suzanne , Shah Raj C , Sheets Kerry M. , McNeil John J , Murray Anne , Ryan Joanne 
Published: December 2023

AbstractBackgroundWhether socially and mentally stimulating activities in older age can contribute to cognitive reserve and influence dementia risk remains unclear. This study investigated the association between lifestyle enrichment and dementia risk in older individuals, after adjusting for education, socioeconomic status and a range of health‐related factors.MethodData came from a cohort of community‐dwelling adults aged 70+ recruited in Australia, who were generally healthy and without major cognitive impairment at baseline. Exploratory factor analysis was performed using 19 individual measures of leisure activities and social networks. The adjusted association between seven composite factors of lifestyle enrichment and incident dementia was examined using Cox proportional hazards regression.ResultAmong 10,318 participants, more frequent engagement in adult literacy (writing, computer usage and education classes) and active mental activities (games/cards/chess, crosswords/puzzles) was associated with an 11% (95% CI: 0.85‐0.93) and a 9% (95% CI: 0.87‐0.95) lower risk of dementia respectively. To a lesser extent, participation in creative artistic (craftwork/woodwork/metalwork, painting/drawing) (HR: 0.93, 95% CI: 0.88‐0.99) and passive mental activities (reading, watching television, music/radio listening) (HR: 0.93, 95% CI: 0.86‐0.99) were also associated with reduced dementia risk. In contrast, interpersonal networks, social activities and external outings were not associated with dementia risk in this sample.ConclusionThese findings may guide policies for geriatric care and interventions targeting dementia prevention for older adults. Engagement in adult literacy, creative art, as well as active and passive mental activities, may help reduce dementia risk in late life.
Validity, Feasibility and Effectiveness of a Voice‐recognition Based Digital Cognitive Screener for Dementia and Mild Cognitive Impairment in Community‐dwelling Older Chinese Adults: A Large‐scale Implementation Study
Authors: Zhao Xuhao , Wen Haoxuan , Xu Guohai , Pang Ting , Zhang Yaping , He Xindi , Hu Ruofei , Yan Ming , Chen Christopher , Wu Xifeng , Xu Xin 
Published: December 2023

AbstractBackgroundTo investigate the psychometric properties, administration efficiency and implementational feasibility of a previously piloted voice recognition‐based digital cognitive screener for dementia detection in a large‐scale community of elderly participants.MethodEligible participants completed the demographic, lifestyle investigations and the DCS. Domain‐specific and global cognition was assessed by a comprehensive neuropsychological test battery. Diagnosis of mild cognitive impairment(MCI) and dementia was made based on the clinical dementia rating. Completion rate and administration time for the DCS were recorded. Correlation between the DCS and domain‐specific and global cognitive performance were assessed. Receiver operating characteristic (ROC) analyses examined the discriminate validity of the DCS in detecting MCI and dementia. A cost‐consequences analysis was conducted to compare the screening efficacy of DCS with two traditionally administered cognitive assessment tools, the Mini‐Mental State Examination(MMSE) and the Montreal Cognitive Assessment (MoCA), was conducted.ResultAmong a total of 11,186 participants, the completion rate of the DCS was 97·5% with a conduction time of 5·6–6·1 minutes, regardless of gender, age and education stratifications. DCS total score was significantly associated with domain‐specific and global cognitive z‐scores. Area under the curves (AUCs) of the DCS were 0·95 (0·92, 0·99) and 0·83 (0·79, 0·88) for dementia and MCI detection, respectively. There was no significant difference on the AUCs among different age‐ and education‐stratified subgroups. Comparing with the MoCA and MMSE, DCS resulted in time savings of 35·4%–36·0% and 30·7%–31·2% for identifying dementia cases, as well as 22·6%–22·8% and 16·2%–16·4% for identifying MCI cases.ConclusionOur findings demonstrated that the DCS was an effective and efficient tool for case‐finding of dementia and MCI in a Chinese community. The large‐scale implementation of the DCS among older Chinese adults could be an practical cognitive screening strategy to improve the management of healthcare resources.
Does FOXO3 longevity genotype explain the conflicting data on late‐life hypertension and risk of Alzheimer’s disease?
Authors: Chen Randi , Morris Brian J , Donlon Timothy A , Ross G. Webster , Kallianpur Kalpana J , Willcox Bradley J , Allsopp Richard C , Nakagawa Kazuma , Masaki Kamal H 
Published: December 2023

AbstractBackgroundThe association of late‐life hypertension (LHTN) with Alzheimer’s disease (AD) remains controversial. We hypothesize that FOXO3 longevity‐associated genotype modulates the association between LHTN and incident AD.MethodSubjects were 2,688 American men of Japanese ancestry (baseline age: 77.0 ± 4.1 years, range 71‐93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, LHTN at baseline, and diagnosis of incident dementia over 21 years follow‐up. Association of FOXO3 genotype with LHTN and incident all‐cause dementia, vascular dementia (VD) and Alzheimer’s disease was assessed using Cox regression.ResultDuring the follow‐up, 725 men were diagnosed with all‐cause dementia, 513 with AD and 104 with VD. A multivariable Cox model, adjusting for age, education, APOE‐ε4 and cardiovascular risk factors, showed LHTN increased VD risk (HR = 1.71, 95%CI = 1.08–2.71, p = 0.022), but not AD risk. We found no significant protective effect of FOXO3 longevity genotype, nor of LHTN, on all‐cause dementia and AD at the population level. However, in a full Cox model adjusting for age, education, APOE‐ε4 and other cardiovascular risk factors, there was a significant interaction effect of LHTN and FOXO3 longevity genotype on incident AD (ß = –0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), LHTN showed protection against AD (HR = 0.72; 95% CI = 0.55–0.95, p = 0.021). In men with FOXO3 rs2802292 non‐longevity genotype (TT), LHTN had no protective effect (HR = 1.16; 95% CI = 0.90‐1.51, p = 0.25).DiscussionSince the effect of LHTN on AD incidence differed according to FOXO3 genotype, the overall effect, namely, a weighted average effect of LHTN on AD across different FOXO3 genotypes, would be moving towards the null (i.e., HR = 1). This would explain why most studies have found no significant association between LHTN and AD. One exception is the Ibadan study, in which all participants were African American. African Americans have the highest proportion (94%) of FOXO3 rs2802292 longevity genotype (TG/GG) in all races, and the strongest effect of LHTN in protecting against AD (RR = 0.33).ConclusionThis longitudinal study found that FOXO3 genotype modulates the effect of late‐life hypertension on incident AD, thus explaining the conflicting data on late‐life hypertension and Alzheimer’s disease.
Combined DTI and NODDI Scalars Improves Understanding of At‐Risk Tissue in and Around White Matter Hyperintensities
Authors: Sudhakar Tejaswi D , Anderson Cole E , Peskind Elaine R , Li Ge , Iliff Jeffrey J , Levendovszky Swati Rane 
Published: December 2023

AbstractBackgroundThe novel diffusion‐based Neurite Orientation and Dispersion Imaging (NODDI) model may provide complementary information to Diffusion Tensor Imaging (DTI) to increase sensitivity in characterizing tissue microarchitecture. We examined if one or a combination of both approaches can improve our understanding of at‐risk tissue in and around white matter hyperintensities (WMH).MethodFrom ADNI3, we identified individuals [n = 54, age = 78 ± 7, 46% F) with concurrent measures of multi‐shell DTI, 3D FLAIR, and 3D MPRAGE. We segmented WMH from structural data using Lesion Segmentation Toolbox. We derived DTI (FA, MD) and NODDI parameters (NDI, ODI, Fiso) using QSIprep. We dilated up to 5 mm outside the WMH, applied an FA threshold of ≥ 0.2 to exclude gray matter, calculated DTI and NODDI parameters at 1 mm intervals within this region. We performed Pearson correlations between all parameters. Assuming normal white matter at 5 mm, we normalized these parameters with their respective values at 5 mm and plotted the spatial variation of each parameter in and outside the WMH.ResultNormalized DTI and NODDI parameters representing spatial variations within the 5 mm region are shown in Fig 1A. Table 1 shows p‐values comparing DTI and NODDI parameters between WMH the subsequent regions outside it. Compared to WMH, Fiso was significantly different at all distances. FA showed similar spatial characteristics with NDI and was negatively correlated with ODI. Fiso correlated very strongly with MD.ConclusionIn the WMHs and its immediate vicinity, low FA, NDI, ODI suggest lower cell density, while low Fiso and MD suggest low extracellular fluid volume. Together these observations may reflect cytotoxic edema, cell loss, and injury. Normal appearing white matter (3‐5 mm) showed high FA, NDI, ODI, and low MD consistent with high cell density and normal extracellular water. In the transition between WMH vicinity and normal white matter, low FA, NDI, ODI, high MD and Fiso suggest cell loss only. This transition region could be at risk of converting to WMH. Future work will include longitudinal evaluation of WMH growth in the at‐risk tissue. However, final validation of WMH pathology will need histological confirmation.
Spontaneous‐ and Perturbation‐Based Cortical Excitability Markers of Plasma pTau181 Concentrations in Healthy Middle‐aged Adults
Authors: Perellón‐Alfonso Ruben , Abellaneda‐Pérez Kilian , Cabello‐Toscano María , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Cattaneo Gabriele , Redondo‐Camós María , España‐Irla Goretti , Delgado‐Gallén Selma , Pileckyte Indre , Sánchez Javier Solana , Zetterberg Henrik , Franzmeier Nicolai , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is characterized by cortical hyperexcitability in the early stages, which may be attributed to the intricate interplay between tau and amyloid β pathologies. To combat the propagation of tau pathology and cognitive decline, it may be beneficial to maintain a high degree of functional brain network segregation. Additionally, the use of non‐invasive brain stimulation techniques to alter cortical excitability could help alleviate cognitive deficits. However, it is unclear how these interventions are related to tau or amyloid biomarkers.MethodIn this study, 530 participants aged 40 to 65 from the Barcelona Brain Health Initiative cohort were analyzed to investigate the connection between plasma concentration of tau phosphorylated at amino acid 181 (pTau181), cortical excitability, and segregation of functional brain networks. Participants had functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and pTau181 available. A subset of 47 participants also underwent transcranial magnetic stimulation with concurrent EEG (TMS‐EEG). Cortical excitability was assessed using the one‐over‐f slope of the EEG power spectrum (1/f‐slope) and evoked response to a TMS perturbation (TEP) of the left prefrontal cortex (L‐PFC) between 160‐240ms post single‐pulse TMS. The degree of segregation between major functional networks was measured from fMRI data using the system segregation statistic.ResultA generalized linear model with a gamma distribution (Table 1) revealed that steeper 1/f‐slope correlated with higher pTau181 concentration, particularly in participants older than 53 years of age (Figure 1.A), or system segregation below 0.28 (Figure 1.B). A multiple linear regression within the TMS‐EEG subsample (Table 2) revealed that the TEP response correlated positively with pTau181 as age increased, and that this model, despite including a smaller sample size, better explained pTau181 concentrations.ConclusionThe study shows that cortical excitability is related to pTau181 based on age and system segregation. The TEP response is a more sensitive marker than unperturbed EEG metrics in explaining the relation between excitability and pTau181 concentrations. Combined TMS with EEG could potentially be an inexpensive and scalable approach for early identification and longitudinal tracking of middle‐aged adults at risk for cognitive decline and dementia.
Preliminary results investigating synaptic density across the Alzheimer’s Disease continuum
Authors: Giorgio Joseph , Soleimani‐Meigooni David N. , Chen Xi , Toueg Tyler N , Weimer Robby , Zinnhardt Bastian , Baker Suzanne L. , Janabi Mustafa , Rabinovici Gil D. , Jagust William J. 
Published: December 2023

AbstractBackgroundProgressive loss of synapses occurs throughout the Alzheimer’s Disease (AD) continuum and is closely associated with cognitive impairment. Here, we present pilot data investigating variation in synaptic density across aging and AD using 18F‐SynVesT‐1 molecular imaging, a ligand for the SV2A site.Method26 participants underwent 18F‐SynVesT‐1 imaging to estimate synaptic density in‐vivo. Participants were young adults (Y) (n = 7; Age = 26.1+‐3.8; Sex(F) = 4), cognitively unimpaired older adults (O) (n = 13; Age = 79.7+‐4.27; Sex(F) = 7) or patients (P) (n = 6; Age = 66.3 +‐8.2; Sex (F) = 1; Diagnoses EOAD = 3, MCI = 1, PCA(AD) = 1; lvPPA(AD)). We collected a 90 min dynamic sequence after injection of 5 mCi of tracer. Participant whole brain Distribution Volume Ratio (DVR) images were generated using a cerebellar grey matter reference region. O and P groups also underwent tau and β‐amyloid (Aβ) PET imaging (O: 18F‐flortaucipir,11C‐PiB; P: 18F‐PI‐2620, 18F‐Florbetaben) and a visual assessment of tau and Aβ positivity for AD was determined by an expert reviewer (DSM).ResultWe contrasted 18F‐SynVesT‐1 uptake in four cortical regions for Y, O and P. In each region, we observed a significant effect of group (Hippocampus F(1,23) = 4.35, p = 0.025 (uncorrected); Meta‐Temporal ROI F(1,23) = 4.36, p = 0.025 (uncorrected); Temporal F(1,23) = 9, p<0.01(FWE corrected); F(1,23) = 14.4, p<0.001 (FWE corrected)) Figure 1. Further, we observe non‐significant numerical differences suggesting lower synaptic density in participants with biomarker evidence of Aβ and tau Figure 1. Finally, we observe a positive partial correlation between temporal cortical thickness and temporal 18F‐SynVesT‐1 uptake controlling for age (r(23) = 0.54,p = 0.006) Figure 2. We observe no relationship between age and tracer uptake in the cerebral white matter (r(24) = ‐0.01,p = 0.95), suggesting the reference region selected does not introduce systematic biases in the DVR image.ConclusionThis demonstrates 18F‐SynVesT‐1 PET can capture age and AD related decreases in synaptic density across the cortex. Further, we show an association between cortical thickness and synaptic density in the temporal cortex controlling for biases due to age. Future work will incorporate additional participants and investigate participant level associations between regional 18F‐SynVesT‐1 uptake, cognition, and in‐vivo AD pathologies.
Cholinergic white matter hyperintensity volume, cognitive decline, and incident dementia in older adults
Authors: Lu Heyang , Wang Yingzhe , Jiang Yanfeng , Chen Xingdong , Cui Mei 
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMHs) are frequently observed in the elderly and their severity tends to increase with age. Previous studies have revealed that WMHs are closely related to cognitive dysfunction. However, as inter‐individual variations and a clinicoradiological discrepancy exist, not all individuals with severe WMH burden experience worse cognitive performance. Furthermore, the location of WMHs appears to be a critical factor in the relationship between WMHs and cognitive function. Few studies take both volume and location of white matter hyperintensities (WMHs) into account to explore the association between WMH burden and cognitive impairment. We therefore investigated associations of cholinergic WMH volume (WMHV) with global cognitive function, cognitive decline, and incident dementia in older adults.MethodA total of 752 older adults (mean age 60 years, 50% female) from the Taizhou Imaging Study were involved. Brain magnetic resonance imaging data at baseline and repeated measures of cognition over 5 years were collected and analyzed. WMHV in whole brain, the cholinergic pathways, and different tract classes in the Montreal Neurologic Institute standard space was obtained using the Lesion Segmentation Toolbox and tools from FMRIB Software Library. Multivariable linear regression, Cox regression, and partial correlation tests were performed.ResultOver a median 5.67 (IQR: 2.88‐6.84) years of follow‐up, cholinergic WMHV was associated with annual decline of Mini‐Mental State Examination (MMSE) (β = ‐0.206; P = 0.006), and incident dementia (HR = 3.45; 95%CI: 2.08‐5.74). Within the cholinergic pathways, WMHs in commissural fibers were related to incident dementia. However, greater global WMHV only slightly increased the risk of incident dementia (HR = 1.03; 95%CI: 1.01‐1.06). Neither global nor cholinergic WMHV was associated with MMSE in cross‐sectional analysis.ConclusionCholinergic WMHV is associated with longitudinal cognitive decline and incident dementia in older adults. Within the cholinergic pathways, commissural fiber tracts were strategic locations correlated to incident dementia. Our findings suggest cholinergic WMHV might be a potential indicator of cognitive deterioration.
Neuropathological changes of a patient with AD treated with verubecestat
Authors: Lleo Alberto 
Published: December 2023

AbstractBackgroundClinical trials with BACE‐1 inhibitors in patients with Alzheimer’s disease (AD) have been discontinued due to safety concerns. The adverse effects included reversible early cognitive worsening and brain atrophy. Some data suggest that these effects could be due to an off‐target effect of the inhibitor on other BACE‐1 substrates that could impact synaptic function and structure. However, the precise underlying mechanisms of these effects in humans remain controversial.MethodWe describe the neuropathological examination of a patient with AD treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat.ResultBrain examination showed small plaque size, reduced dystrophic neurites around plaques, and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated sporadic AD (SAD) cases. We also describe a detailed analysis of synaptic morphology in this case.ConclusionOur findings suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD. Neuropathological data could help to understand the effect of BACE inhibition in humans.
Impact of Empathy on Oxytocin and Cortisol Responsivity in Caregivers to Older Adults with Chronic Conditions
Authors: Beadle Janelle , Warren David E 
Published: December 2023

AbstractBackgroundIndividuals who provide care for older adults with chronic conditions, such as dementia, experience poorer mental health when care recipients have low empathy. Empathy is thought to have two components: cognitive empathy (i.e., understanding others’ mental perspectives) and emotional empathy (i.e., feeling empathic concern/sympathy). Due to chronic stress, many caregivers experience burnout and compassion fatigue (i.e., emotional exhaustion and secondary traumatic stress). However, the impact of the caregiving role on empathy has not been well‐characterized in caregivers to older adults. Evidence from other populations show that stress hormones (e.g., cortisol) decrease when individuals engage in social bonding which in turn can increase levels of oxytocin. The present research study is highly novel because no previous studies have specifically investigated how empathy affects cortisol and oxytocin hormone levels in caregivers to older adults with chronic conditions.MethodsParticipants included 21 women caregivers to older adults with chronic conditions (Mage = 54.1; Medu = 16.1). Participants watched one video to induce empathy (empathy condition) and a separate video to induce an unemotional state (control condition) and completed self‐report ratings of empathy and distress before and after the videos. Saliva was collected using the passive drool method at baseline and after each video. Salivary hormone assays were conducted for cortisol and oxytocin. Participants completed standard measures of empathy (Interpersonal Reactivity Index) as well as compassion fatigue and burnout (Professional Quality of Life Scale).ResultsCaregivers with higher compassion fatigue reported higher levels of burnout (p<.05) and burden (p<.05). In addition, caregivers with higher compassion fatigue reported a reduced tendency to help others in daily life (p<.05). In response to an empathy‐evoking video, momentary feelings of distress were positively associated with greater oxytocin (p<.01), and there was a non‐significant trend towards lower cortisol (p = .1). Caregivers who reported higher levels of momentary empathic concern in response to the empathic video had lower oxytocin (p<.05), whereas participants reporting higher cognitive empathy had greater oxytocin (p<.05).ConclusionsThese results help to lay the groundwork for the possibility of developing hormonal interventions that may help to increase empathy and reduce stress in caregivers to older adults with chronic conditions.