bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal resting‐state EEG along the Alzheimer’s disease continuum: Sample size considerations for clinical trials.
Authors: Scheijbeler Elliz P. , de Haan Willem , Stam Cornelis J , Gouw Alida A 
Published: December 2023

AbstractBackgroundTo enable successful inclusion of resting‐state electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we (retrospectively) mapped the progression of EEG markers over time in amyloid‐positive subjects.MethodsResting‐state 21‐channel EEG was recorded in 173 subjects positive for amyloid deposition (subjective cognitive decline, n = 16; mild cognitive impairment, n = 94; dementia due to AD, n = 63). Two or more EEG recordings were available for all subjects. We computed whole‐brain and regional relative power (i.e., theta (4‐8Hz), alpha1 (8‐10Hz), alpha2 (10‐13Hz), beta (13‐30Hz)), peak frequency, signal variability (i.e., theta Permutation Entropy) and functional connectivity values (i.e., alpha and beta corrected Amplitude Envelope Correlation, theta Phase Lag Index, weighted Symbolic Mutual Information, inverted Joint Permutation Entropy). Whole‐group linear mixed effects models were used to model the development of EEG markers over time. Group‐wise analysis was performed to investigate potential differences in change trajectories between diagnostic groups. The longitudinal relation between EEG and cognition was evaluated. Finally, we estimated the minimum sample size required to detect a stabilizing treatment effect using EEG markers, in hypothetical clinical trials of 1‐ or 2‐year duration.ResultsWhole‐group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased alpha2 and beta power), with strongest effects for temporal and parieto‐occipital regions. Signal variability showed stronger decline on a global scale. We report no significant longitudinal changes in functional connectivity strength. Disease severity at baseline influenced EEG markers’ rates of change, with fastest deterioration in MCI subjects. A decrease of the parieto‐occipital peak frequency, temporal relative alpha2 and beta power, as well as an increase in temporal relative theta power, were significantly associated with a decline in Mini Mental State Examination score. We estimate that 1‐year trials, focusing on amyloid‐positive MCI subjects, require 148 or 438 subjects per arm to detect a stabilizing treatment effect on temporal relative theta‐ or beta power, respectively.ConclusionResting‐state EEG markers can facilitate early detection of target engagement in an objective, non‐invasive, low‐cost manner. Spectral measures, particularly recorded from temporal regions, present robust secondary endpoints for AD interventions.
Ageing, dementia, and the mortality experience of older Lebanese people: findings from a prospective cohort study
Authors: Chaaya Monique , Idokoko Abraham Braimah , Assaad Sarah , Asmar Khalil El 
Published: December 2023

AbstractBackgroundAgeing is a foremost predictor of mortality and neurodegenerative disorders such as dementia, a global priority ageing‐related sequelae that significantly influence quality of life. There is limited published knowledge of the survival experience of the rapidly ageing Lebanese population. This study examined the mortality experience of older Lebanese adults and assessed the influence of ageing, dementia, and other covariates on all‐cause mortality hazard.MethodsCOLDS (Cohort of Older Lebanese Adults) is a prospective population‐based study of Lebanese participants aged ≥65 years at baseline, along with their designated informants. In this study, 476 participants consented to follow‐up out of 502 surveyed at baseline for dementia, and 344 had their mortality status assessed after 3 years. Proportionate, age‐specific and crude mortality rates were estimated while, Cox proportional regression model of mortality hazard was built, adjusted for covariates.ResultsAfter 3.34±0.69 person‐years, 114 deaths were observed among participants yielding an age‐adjusted death rate of 32.2% (95% CI. 31.2, 33.2). Cardiovascular diseases were the commonest (50%) reported cause of death. Dementia and age were not statistically significantly associated with mortality. Literacy, place of residence, religion, physical activity, and diabetes were significantly associated with mortality at 95% confidence level.ConclusionsBeing physically active was the most powerful protective factor against mortality among the older adults, while living in Beirut, the capital city, heightened death‐risk. These findings have extensive implications for more research, which is crucial to improving health system policies and action in support of healthy ageing.
Alzheimer’s pathology in older people with HIV in South Africa: protocol of a case‐control study examining mechanisms of inflammation and infection
Authors: Nightingale Sam 
Published: December 2023

AbstractBackgroundDue to the success of modern antiretroviral therapy, people with HIV in South Africa are now living into older age. This provides an opportunity to study Alzheimer’s pathology in the context of chronic inflammation and infection. Here we present the protocol of a large case‐control study examining Alzheimer’s pathogenesis.Method250 South African people over 70 years of age will be recruited from a low‐income area of Cape Town with high HIV prevalence. Half will be living with HIV and half will be HIV‐negative and sociodemographically similar. Our primary outcome is CSF biomarkers of amyloidopathy. We have power to detect a 1.5‐fold increase in CSF amyloid positivity from 40% to 60%. Secondary analyses will compare clinical diagnoses of Alzheimer’s disease, and correlate indicators of HIV‐related neuroinflammation with degree of amyloidopathy.ResultProtocol presentation only. Funding is from the Race Against Dementia.ConclusionThis unique cohort will provide a valuable resource for mechanistic studies of Alzheimer’s pathogenesis.
Phase‐locked auditory stimulation in three consecutive nights to prevent cognitive decline
Authors: Zeller Céline J. , Wunderlin Marina , Nissen Christoph , Klöppel Stefan , Züst Marc Alain 
Published: December 2023

AbstractBackgroundOver the past 10 years, disturbed sleep has been indicated as potential early, modifiable risk factor for severe cognitive decline and dementia. When we get older, sleep becomes more fragmented, we have more awakenings during the night and less deep sleep. During deep slow‐wave sleep (SWS) memory is strengthened and metabolic waste‐products like amyloid beta are cleared from the brain. Losing SWS therefore entails losing opportunities for these important functions. Leading to impairments of sleep and cognitive decline being caught in a vicious cycle. These effects are more pronounced in individuals with mild cognitive impairment (MCI) and dementia. An improvement of SWS might break this vicious cycle by recuperating the brain and ameliorating the progression of cognitive decline.MethodWe use phase‐locked auditory stimulation (PLAS) to boost slow‐wave activity in older adults with subjective cognitive decline (SCD) or MCI to prevent dementia across multiple nights of stimulation.ResultPreliminary results show that physiological responsiveness to PLAS is associated with memory gains (F(1,10) = 6.58, p = .028, R2 = .34), replicating our previous results in healthy older individuals.ConclusionWe show first evidence that PLAS can improve memory performance in older individuals with MCI or SCD if applied across several nights of intervention. PLAS has emerged as a promising non‐invasive tool to enhance slow‐wave sleep, potentially ameliorating cognitive decline.Keywords:Sleep, dementia, prevention, phase‐locked auditory stimulation, blood‐based biomarkers
Long‐read sequencing of the whole‐blood compartment reveals similar telomere lengths between Alzheimer’s disease patients and cognitively‐healthy centenarians
Authors: Salazar Alex N , Tesi Niccoló , Hulsman Marc , Holstege Henne , Knoop Lydian , Wijesekera Sanduni 
Published: December 2023

AbstractBackgroundTelomere stability may be a potential biomarker for Alzheimer’s disease progression. Indeed, previous studies have observed significant associations with telomere length and risk for Alzheimer’s disease (AD) in both carriers and non‐carriers of APOE4. In contrast, (cognitively healthy) centenarians—an extreme control group in the spectrum of brain health—have been observed to harbour longer telomere lengths relative to younger age groups. In this study, we investigated telomere stability in the whole‐blood compartment of AD patients, centenarians, and centenarian children through single‐molecule long‐read sequencing.MethodLong‐read HiFi sequencing of the whole‐blood compartment was performed in AD patients (n = 59, mean age = 68.5), centenarians (n = 84, mean age = 101.6), and centenarian children (n = 10, mean age = 71.0), using the Pacific Bioscience Sequel II instrument. For each sample, we identified reads with telomeric content based on alignments to the CHM13 reference genome. Per‐read telomere lengths were calculated via a high‐density clustering approach of the TTAGGG repeat sequence, keeping only reads that have a higher likelihood of harbouring complete telomeric content. The sub‐telomeric portion of each read was then used to assign chromosomal origin based on sequence similarity all chromosomes in CHM13. Whole‐blood and chromosome‐specific telomere lengths were then compared across the three sample‐groups.ResultCentenarian children were observed to harbour the longest telomeres with a median length of 6.88 kbp, and 95% C.I. of 6.78‐7.00 kbp. This was followed by AD patients with median length of 5.82 kbp, 95% CI 5.78‐5.85 kb; and centenarians with a median length of 5.52 kbp, and 95% C.I. of 5.50‐5.55 kbp. Telomere lengths across all groups were significantly different (p < 0.001). A similar pattern was observed across each individual chromosome, with the exception of chromosome X which harboured smaller telomere lengths in AD patients and centenarians.Centenarians harboured significantly smaller telomere lengths than their children (p < 0.001), with the exception of two centenarians that did not have significant differences.ConclusionDespite being aged‐match, AD patients harbour shorter telomere lengths than centenarian children, and only slightly longer telomere lengths than centenarians.
Caring through Graphic Medicine
Authors: Sethurathinam Pushpanathan S 
Published: December 2023

AbstractBackgroundHumanity is developed with language and memory. Memory gives us personality, emotional intelligence, family relations, and community. Alzheimer’s is a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks. There is a notion that caregiving for patients is the primary responsibility of female family members.Certainly, caregiving has been associated with women, at least since it was incorporated into the emerging feminine sphere of domesticity in nineteenth‐century notions of gendered separate spheres.Physical nature of female and emotional strength are also centered on caring. All over the world women are the predominant providers of informal care for family members with chronic medical conditions or disabilities, including the elderly and adults with mental illnesses. It has been suggested that there are several societal and cultural demands on women to adopt the role of a family‐caregiver. Many theories propose that women are more likely to be exposed to caregiving stressors.This study explores how challenges of care giving Alzheimer/Dementia patients affect the caregiver especially female care givers in multiple perspectives. The activity of care giving involves economic, social and psychological impact not only on the care recipient but also the care giver, who devotes the entire period of care giving sacrificing the personal needs and ambitions.MethodPrimary data were collected from caregivers located in different parts of India.Secondary data from Govt agencies were also used for analysis. Wherever possible case studies were conducted and also personal interviews with family members. Analysis was effected through SPSS with relelevant inputs.ResultPost Covid caregiving has become a challenging task for caregivers especially female caregivers throughout the world.As there was slowdown in economic activity, challenges commuted in terms of finance,emotions and moral support.ConclusionThere is a need for understanding the issues involved in caregiving and appropriate steps are to be initiated for provision of adequate support from the Govt and also the social responsibility has to be properly propogated among all sections of the society.
Anesthetic Drugs as a Pharmacologic Stress Test for the Aging Brain: Towards a Real Time EEG Read‐Out
Authors: Berger Miles 
Published: December 2023

AbstractBackgroundRoughly 65 million older adults (ie age >65 years) undergo anesthesia/surgery each year and are at risk for postoperative delirium. Further, postoperative delirium is itself associated with increased long term risk for Alzheimer’s Disease and Related Dementias (ADRD). Recent work has also shown that some patients have deeply suppressed neurophysiologic (ie EEG) patterns in response to relatively low anesthetic drug doses, and that these patients are more likely to have preoperative cognitive impairment and to develop postoperative delirium. However, to date few if any studies have examined the role of specific ADRD pathologic processes and neuroimaging abnormalities in these altered anesthetic dose‐dependent EEG response patterns in older adults.MethodWe examined relationships between intraoperative 32 channel EEG data (in cognitively normal older non‐cardiac surgery patients who received inhaled anesthetics such as isoflurane) and both 1) preoperative CSF ADRD biomarker levels and 2) preoperative structural and functional MRI imaging characteristics. CSF abeta, tau and p‐tau‐181p were measured using the Roche elecsys platform. Frontal‐parietal alpha band phase lag index and alpha power were calculated from frontal and parietal electrode regions of interest (ROIs), and normalized to inhaled anesthetic dosage.ResultLower anesthetic dose‐adjusted frontal‐parietal alpha band phase lag index values were associated with higher preoperative CSF p‐tau/Ab ratios (p = 0.013, N = 9‐18 per group, Fig 1A), lower cortical thickness in the left and right parahippocampal regions (Fig 1B, N = 16, p<0.001), and altered resting state fMRI connectivity between the left anterior entorhinal cortex and both the left medial prefrontal cortex and the left angular gyrus (two key default mode network regions; Fig 1C, N = 16, peak voxel p<0.01).ConclusionThese data suggest that both molecular markers and neuroimaging features of preclinical AD neuropathology in cognitively normal older adults are associated with altered anesthetic dose‐dependent changes in neurophysiologic/EEG functional connectivity. More generally, these data demonstrate the need for additional studies to understand the extent to which intraoperative EEG data can be used to make inferences about ADRD‐related neuropathologic processes in older adults, which could provide a real‐time EEG “readout” for the stress test of anesthesia and surgery on the aging brain
Role of microglial extracellular vesicles in the propagation of early synaptic dysfunction in Alzheimer’s disease
Authors: Gabrielli Martina , Tozzi Francesca , Falcicchia Chiara , D'Arrigo Giulia , Amoretti Stefano , Joshi Pooja , Tonoli Elisa , Rutigliano Grazia , Masini Greta , Nardi Gabriele , Battocchio Elisabetta , Zenatelli Rossella , Radeghieri Annalisa , Verderio‐Edwards Elisabetta , Ratto Gianmichele , Arancio Ottavio , Prada Ilaria , Origlia Nicola , Verderio Claudia 
Published: December 2023

AbstractBackgroundSynaptic dysfunction is an early mechanism in Alzheimer’s disease (AD) which involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. We hypothesised that large extracellular vesicles (EVs) released by microglia may be responsible for these early events in AD.MethodLarge EVs carrying Aβ peptides (Aβ‐EVs) were obtained from primary microglia exposed to Aβ42. Optical manipulation was combined with time lapse imaging to study EV‐neuron interaction. Then, EVs were stereotaxically injected into naïve mice entorhinal cortex (EC), a vulnerable region in AD, to evaluate: i) long‐term potentiation (LTP) in EC and its main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in slices; ii) possible alterations in cortico‐hippocampal network activity by chronic EEG recordings; iii) progressive memory impairment in behavioural tasks. Finally, taking advantage of high‐resolution accurate‐mass spectrometry SWATH™‐MS, we investigated the molecular differences between Aβ‐ and ctrl‐EVs (from cells not exposed to Aβ). The influence of mesenchymal stem cell (MSC) indirect co‐colture with microglia primed with Aβ on cell phenotype, EVs and functions is also being explored.ResultAβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction, altering dendritic spine morphology in vitro. LTP was impaired in the EC 1h after Aβ‐EV (but not ctrl‐EV) local injection, while 24h later LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between connected regions. This translated into network alterations and progressive memory deficits. Interestingly, Aβ42 alone was unable to spread alterations. Aβ‐EVs limited in their motion could neither propagate impairment nor cause network abnormalities, thus implicating Aβ‐EV extracellular motion in these processes. Proteomic analysis provided insights into the molecular mechanisms underneath Aβ‐EV motion at the neuronal surface.ConclusionOur data provide evidence of the involvement of microglial EVs in early synaptic dysfunction in AD, through a new mechanism ‐ extracellular motion at the neuronal surface ‐ not implying EV internalization, paving the way for novel therapeutic strategies. Reference: Gabrielli et al., Brain, 2022 https://doi.org/10.1093/brain/awac083 Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM
New Anti‐Hyperglycaemic Medications and the Risk of Dementia: A Nationwide Population‐Based Study
Authors: Cohen Avi , Levine Stephen Z , Vainstein Gabriel , Weinstein Galit 
Published: December 2023

AbstractBackgroundDrug repurposing has been encouraged to accelerate the drug discovery process. The new generation of type 2 diabetes (T2D) medications have neuroprotective properties that may extend beyond their glycaemic control effects. We examined the association between exposure to newer anti‐hyperglycaemic medications and the risk of dementia in a nationwide sample of Israeli older adults with T2D.MethodIn this retrospective cohort study, we utilized electronic medical record data from “Maccabi Healthcare Services”, a large health maintenance organization in Israel. The source population was adults aged ≥55 years with a T2D diagnosis from 2000 to 2022. The exposure was defined as the use of the following new T2D medications: Dipeptidyl peptidase 4 inhibitors (DPP‐4i), Sodium‐glucose cotransporter inhibitors (SGLT2i), and Glucagon‐like peptide‐1 (GLP‐1) analogues. We compared individuals exposed to the new T2D medications (alone or in combination) to those unexposed (using other antidiabetic drugs and non‐users; i.e., lifestyle only). Exposure accounted for the use period was based on the Prescription drug purchase to Drug Use Periods method. Dementia diagnosis was based on ICD‐9 codes for any dementia or anti‐dementia drug use. Competing risk Cox model regression models with age as the underlying time scale were implemented to quantify the associations between medication exposure and dementia risk with inverse probability weights, with and without adjustment for time‐varying covariates.ResultOf the total sample (N = 87,323), the mean age at T2D diagnosis was 64.3±6.8 years, 49.6% were women and 13,584 (15.56%) developed dementia during a mean follow‐up of 14.8±5.6 years. Of the total sample, 26,867 (30.77%) individuals purchased more than one new anti‐hyperglycaemic medication (13,081 DPP‐4i, 9,698 SGLT2i, and 12,547 GLP‐1). The group exposed to new T2D medications did not differ compared to the unexposed group (HR = 1.01, CI = 0.95‐1.06). However, analysis by specific medications showed that the group exposed to SGLT2i had a 29% reduced dementia risk compared to the unexposed group (HR = 0.71, CI = 0.58‐0.87). The associations of DPP‐4i and GLP‐1 exposure with dementia risk were null (HR = 1.00, CI = 0.90‐1.10, HR = 0.99, CI = 0.83‐1.17, respectively).ConclusionEvidence from our large‐scale observational study suggests that SGLT2i exposure may be associated with a reduced risk of dementia in individuals with T2D.
Correlation between heartrate and alpha Event‐Related Desynchronization during a Stroop task helps reveal cognitively healthy individuals with pathological CSF amyloid/tau
Authors: Molloy Cathleen , Choy Elizabeth Hok Yee , Al‐Ezzi Abdulhakim Abdullah A , Buennagel David P , Aguda Shelly , Nolty Anne , Spezzaferri Mitchell , Sin Caleb , Rising Shant , Fonteh Alfred N. , Minazad Yafa , Kleinman Michael T. , Kloner Robert A , Arakaki Xianghong 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) impacts brain regions associated with memory and executive function in early stages. The Stroop task is used to evaluate inhibition, a common factor for executive functioning. Alpha Event‐Related Desynchronization (ERD) from electroencephalogram (EEG) analysis evaluates brain activation during a task. Also of interest is cardiovascular function such as heart rate (HR) and blood pressure (BP) as it relates to cognitive functioning in AD progression. However, the combined analysis of functional EEG with HR and BP have not been thoroughly reported in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task.MethodWe previously reported Stroop alpha ERD of CH participants when their cerebrospinal fluid amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (<2.71, CH‐PATs). Their heart rate (HRmax, HRmin, and HRmax‐HRmin) were analyzed from 5‐minute electrocardiogram (ECG) during resting or Stroop testing. Using a second cohort, including 22 CH‐NATs and 15 CH‐PATs, we analyzed alpha ERD while participants completed a Stroop task on a computer wearing a dry electroencephalogram (EEG) headset with 19 head sensors, which were correlated with HR and BP collected pre‐ and post‐task using an automatic blood pressure monitor.ResultHRmax and HRmax‐HRmin from rest to task were significantly increased in CH‐PATs but not CH‐NATs, while HRmin significantly increased in CH‐NATs (Fig. 1). Frontal alpha ERD during incongruent trials were positively correlated with pre‐(R2 = 0.43, p = 0.008) and post‐(R2 = 0.42, p = 0.009) task HR in CH‐PATs but not CH‐NATs. Pre‐test diastolic BP correlated positively with central alpha ERD during congruent trials in CH‐NATs (R2 = 0.20, p = 0.039) but not CH‐PATs (Fig. 2).ConclusionThese pilot results suggest 1) from resting to task, CH‐NATs presented greater HRmin, while CH‐PATs presented greater HRmax and HRmax‐HRmin; 2) HR is positively correlated with alpha ERD in CH‐PATs such that higher HR related to less brain activation (less negative alpha ERD). Higher pre‐task diastolic BP related to less brain activation in CH‐NATs. Although a larger sample is needed, these results support a potential application of non‐invasive EEG and ECG to identify those at higher risk of cognitive decline.