bluuebunny/crossref_metadata_2025_split huggingface dataset:
SGLT2 and DPP4 inhibitors improve Alzheimer’s disease‐like pathology and cognitive function through distinct mechanisms in T2D‐AD mouse model
Authors: Sim A Young , Kim Jong Youl , Lee Yong‐Ho , Lee Jong Eun 
Published: December 2023

AbstractBackgroundThere are common mechanisms between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D), such as insulin resistance. As insulin signaling has important roles in regulation of neuronal functions in the brain, the hypotheses and theories regarding the pathogenesis of AD implicate brain insulin resistance as a key factor. Also, recent studies demonstrated that sodium‐glucose cotransporter 2 inhibitor (SGLT2‐i) and dipeptidyl peptidase‐4 inhibitor (DPP4‐i) which are T2D drugs have been shown to exert beneficial effects on insulin sensitivity and neuroprotection beyond glucose‐lowering actions. However, in relation to the two drugs, the brain metabolic dysfunction and its mechanisms impaired by insulin resistance have never been investigated.MethodWe developed T2D‐AD mice model using 60% high‐fat diet for 12 weeks and a single dose of streptozotocin (100 mg/kg/i.p) at week 4 of the diet. Subsequently treated with SGLT2‐i (empagliflozin, 25 mg/kg/day/po) and DPP4‐i (sitagliptin, 100 mg/kg/day/po) for 7 weeks. After behavior tests, expression properties of brain insulin signaling, AD related proteins and drugs action‐associated proteins were examined by using western blotting and immunohistochemistry.ResultT2D‐AD mice not only increased blood glucose and body weight, but also had insulin resistance through insulin tolerance test and glucose tolerance test. SGLT2‐i and DPP4‐i were effective in ameliorating insulin sensitivity and reducing body weight gain. In addition, as a result of evaluating hippocampus‐dependent spatial learning and preference memory through behavioral tests, SGLT2‐i and DPP4‐i were found to improve learning, memory, and cognitive functions. Interestingly, SGLT2‐i and DPP4‐i reduced AD‐associated hyperphosphorylated tau (pTau) and amyloid β (Aβ) accumulation in different ways, respectively, along with enhancing brain insulin signaling. SGLT2‐i reduced pTau accumulation through ACE2/Ang(1‐7)/MasR, and DPP4‐i showed an effect of reducing Aβ accumulation by increasing IDE.ConclusionThese findings suggested that SGLT2‐i and DPP4‐i prevented AD‐like pathology and cognitive decline by affecting brain insulin signaling through different mechanisms.
The associations of socioeconomic status with structural brain damage and connectivity and cognition: The Maastricht Study
Authors: Geraets Anouk F.J. , Schram Miranda T. , Köhler Sebastian , Jansen Jacobus F.A. , van Boxtel Martin P.J. , Koster Annemarie , Stehouwer Coen D.A. , Bosma Hans , Leist Anja K. 
Published: December 2023

AbstractBackgroundSocioeconomic inequalities in the risk for cognitive impairment have been reported, which might partly act through structural brain damage or differential numbers of brain connections (structural connectivity). This study investigated the extent to which the association of early‐life socioeconomic status (SES) with later‐life cognitive performance is mediated by later‐life SES, and whether the association of SES with later‐life cognitive performance can be explained by structural brain damage and connectivity.MethodWe used cross‐sectional data from the population‐based Maastricht study (n = 4,839; mean age 59.2±8.7 years, 49.8% women). Early‐life SES was assessed retrospectively by self‐reported poverty and parental education. Later‐life SES included education, occupation, and household income. Participants underwent cognitive testing and 3 T magnetic resonance imaging to measure volumes of white matter hyperintensities, gray matter, white matter, cerebrospinal fluid, and structural connectivity. Multiple linear regression analyses tested the associations between SES, brain markers and cognition. Analyses were adjusted for age, sex, and type 2 diabetes (because of oversampling). Structural equation modeling tested mediation.ResultHigher SES was associated with higher grey matter volume, lower white matter volume, and higher structural connectivity. Structural brain damage and lower structural connectivity were associated with lower overall cognitive performance. Both higher early‐life and later‐life SES were associated with overall higher cognitive performance (B [95% CI] medium versus low early‐life SES = 0.17[0.12;0.23]; B high versus low early‐life SES = 0.26[0.20;0.32]; B medium versus low later‐life SES = 0.46[0.41;0.52]; B high versus low later‐life SES = 0.72[0.67;0.78]). The association of early‐life SES with later‐life cognitive performance was partly mediated by later‐life SES (73.8%). The extent to which the association of SES with cognitive performance could be explained by structural brain damage or connectivity was marginal (up to 5.9%).ConclusionThough there was an association between early‐life SES and later‐life cognitive performance independent of later‐life SES, a large part of this association could be explained by later‐life SES. Structural brain damage and connectivity marginally explained socioeconomic inequalities in cognitive performance. More research is needed to investigate alternative pathways that explain associations of life‐course SES with later‐life cognition.
Sensory‐Evoked 40Hz Gamma Oscillation: A Feasible and Promising Treatment Option for Alzheimer’s Disease
Authors: Hajos Mihaly , Boasso Alyssa , Cimenser Aylin , Shpokayte Monika , Hempel Evan , Da Xiao , Seshagiri Chandran , Megerian Jonathan Thomas , Vaughan Brent , Malchano Zach 
Published: December 2023

AbstractBackgroundDeveloping safe and disease modifying therapies for Alzheimer’s disease (AD) is still challenging, in spite of recent advancements in the understanding of AD pathophysiology. A fundamentally different therapeutic approach under development at Cognito Therapeutics targets abnormal neuronal activities using the company’s Gamma Sensory Stimulation System. This treatment is based on the recent breakthrough, demonstrating that 40Hz neuronal network oscillation evoked via optogenetic, or sensory stimulation profoundly reduces AD pathologies in AD‐related transgenic mice.MethodThis presentation will provide an overview of the main findings from a clinical trial (NCT03556280) which evaluated Cognito Therapeutics Gamma Sensory Stimulation System as a potential novel therapeutic intervention for AD, evaluating feasibility, safety, tolerability, and efficacy of this treatment. In the 6‐month long, double‐blinded, randomized, controlled, clinical trial, participants with clinical presentation on the AD spectrum, were randomized 2:1 (active:sham) to receive daily, one‐hour 40Hz audio‐visual stimulation treatment using Cognito’s Gamma Sensory Stimulation System or sham stimulation.ResultA total of 135 subjects were screened, of whom 74 were randomized and 53 completed (20 sham arm, 33 active arm). Daily use of the Gamma Sensory Stimulation System was confirmed to be safe with minimal side effects. MRI data confirmed the absence of ARIA in participants. High adherence to daily therapy was established based on device‐recorded usage. In assessing cognitive and functional abilities, changes in ADCS‐ADL and MMSE scores were statistically significant between the sham and treatment arms, demonstrating a significant slowing in functional and cognitive decline in the treatment group. Further, quantitative MRI analysis revealed a significantly reduced whole brain, white matter, and occipital lobe volume loss, along with a significantly attenuated reduction in occipital cortical thickness in the active arm relative to sham. These clinical benefits were achieved independent of a reduction in amyloid plaque loads.ConclusionOur results demonstrate that daily 40Hz sensory stimulation delivered by Cognito’s Gamma Sensory Stimulation System is safe and well tolerated; patients in the active arm maintained their functional and cognitive abilities, showed reduced brain atrophy. The upcoming pivotal clinical trial will further evaluate the clinical efficacy of this treatment, also evaluating its most relevant downstream mechanisms in AD patients.
Precuneus magnetic stimulation for Alzheimer’s disease: a novel TMS‐EEG based peronsalized therapeutic strategy
Authors: Koch Giacomo 
Published: December 2023

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS) may improve cognition in patients with Alzheimer’s disease (AD). rTMS therapy is currently limited by the relative short duration and the uncertainty on the most appropriate brain target area. AD patients primarily show alterations of the default mode network (DMN), a brain functional network for which the precuneus (PC) is a key node.MethodWe hypothesized that a long‐term 6 month course of rTMS applied over the precuneus could modify cognitive functions in patients with mild‐to‐moderate AD, by restoring cortical activity in the target network. To test this hypothesis we performed a randomized, double‐blind, sham‐controlled, phase II, 24‐weeks trial (NCT03778151). The primary outcome measure was change from baseline to week 24 of the Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SOB). Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS‐Cog)11, Mini Mental State Examination (MMSE) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS‐ADL).Personalization of treatment and monitoring of cortical activity changes were refined by combining TMS and electroencephalography (TMS‐EEG).ResultWe found that AD patients treated with PC‐rTMS showed almost no decline in the CDR‐SB score, showing a clear advantage in terms of cognitive functions and functional abilities as compared to the sham group. rTMS induced in parallel remarkable changes in cortical activity, as demonstrated by TMS‐EEG recordings.Conclusion24 weeks of PC‐ rTMS may slow down cognitive and functional decline in AD patients by enhancing brain plasticity. Non‐invasive brain stimulation of the DMN could represent a novel therapeutic approach in AD patients.
Towards an EEG/ERP Test Battery for the Neurophysiological Assessment in Alzheimer’s Disease Patients
Authors: Meixner Johannes M , Scheibner Hannah , Heinze Martin , Behr Joachim , Babiloni Claudio , Jost Kerstin , Dahling Volker 
Published: December 2023

AbstractBackgroundPrevious studies have shown that resting‐state electroencephalographic (rsEEG) and event‐related potential (ERP) biomarkers reflect the neurophysiological mechanisms underpinning vigilance dysfunctions and cognitive decline in persons with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (ADD). However, their best combination as inputs to artificial intelligence tools for clinical applications is unknown. This study aimed at identifying the most promising rsEEG and ERP biomarkers by their comparison among MCI, ADD, and cognitively normal (NOLD) persons towards their future use of those tools.MethodAt present, fifty (12 ADD, 16 MCI, and 22 NOLD) participants aged between 58 and 88 (mean age 76) were recruited at the memory clinics of the Brandenburg Medical School to take part in a multi‐session longitudinal study. Clinical, neuropsychological, neuroradiological, rsEEG, and ERP data probing attention (oddball task), working memory (n‐back task) and episodic memory (face name association task) were collected and analyzed with a cross‐sectional design.ResultsCompared to the NOLD group, the MCI and ADD groups showed the following abnormalities (more significant in the ADD than the MCI group): (1) slowing of the individual alpha frequency, reduction in the alpha power, and diffuse increase in the delta power from rsEEG activity; (2) delayed latency peak and reduced amplitude of the posterior ERP‐P3 peak from the oddball task; and (3) reduced amplitude of the ERP‐PN complex from the memory n‐back task.ConclusionThe results showed increased impairment in the cortical neurophysiological underpinnings of vigilance regulation (rsEEG “slowing"), attention (oddball P3), and working memory (n‐back task PN complex) in the MCI and ADD patients, respectively. These components will be used as inputs to artificial intelligence tools to test the accuracy of their combination for classification and identifying persons at‐risk for developing MCI or ADD.
Effectiveness of a digitally supported care management program for family and other informal dementia caregivers: baseline data and first results from the GAIN randomized controlled trial
Authors: Kilimann Ingo , Boekholt Melanie , Klein Olga A. , Thyrian Jochen René , Teipel Stefan , Hoffmann Wolfgang 
Published: December 2023

AbstractBackgroundAlmost two‐thirds of people with dementia (PwD) living at home receive care from informal caregivers. The caregiver’s work load can be comparable or above a full‐time employment. Evidence shows that family caregivers have a higher risk for psychiatric and non‐psychiatric diseases compared to non‐caregivers. A dyadic approach on disease management can help to reduce the burden of care and increase the quality of life (QoL) of caregivers and PwD.MethodsThe cluster randomized controlled trial “Gesund Angehörige Pflegen” (GAIN; ClinicalTrials.gov Identifier NCT04037501) conducted in general practitioner (GP) practices and memory clinics in Northern Germany aimed to evaluate the effectiveness of a 6‐months digitally supported care management program delivered by specifically qualified study nurses to reduce unmet needs of informal caregivers of PwD. Primary outcomes were the number of self‐reported unmet needs, regarding the caregiver and the PwD, assessed with a modified version of the Camberwell Assessment of Need for the Elderly (CANE) and the health‐related quality of life with the EQ‐5D‐5L questionnaire. A generalized linear mixed effects model was used with intercept as random effect.ResultsThe recruitment for the GAIN trial (October 2020 to January 2022) yielded n = 192 participants (mean age: 65 years, women 75%). The number of identified unmet needs was on average 8.66 (range 1 – 30). Analyses of the primary endpoints revealed a statistically significantly higher reduction of unmet needs of caregivers in the intervention group compared to the control group. Evaluation of the EQ‐5D‐5L showed no significant difference between groups.ConclusionThe GAIN care management program was able to lower the number of unmet needs for informal dementia caregivers. Health related quality of life showed a major ceiling effect (high scoring at baseline), which might explain the lack of an effect. The study shows the benefit of a computerized self‐assessment system in primary care and should be further developed as an entry point to the existing health care system.
Isomerization and phosphorylation significantly influence the effect of beta amyloid on blood‐brain barrier endothelial cells
Authors: Petrovskaya Aleksandra , Tverskoi Artem , Barykin Evgeny , Varshavskaya Kseniya , Dalina Alexandra , Mitkevich Vladimir , Makarov Alexander , Petrushanko Irina 
Published: December 2023

AbstractBackgroundThe blood‐brain barrier (BBB) is typically compromised in Alzheimer’s disease (AD): its permeability and intracellular parameters of the endothelial cells are affected. AD‐related amyloid isoforms –Aβ42, isoD7‐Aβ42 and pS8‐Aβ42, inducing amyloidogenesis in a different mode – may have peripheral origin and affect the BBB cells. This study aimed to assess this effect.MethodMouse brain endothelial cells bEnd.3 underwent incubation with 10 µM of Aβ42, isoD7‐Aβ42 and pS8‐Aβ42 for 4, 24 and 48 hours to assess nitric oxide (NO), glutathione (GSH), reactive oxygen species (ROS), mitochondrial potential, Ca2+, cell viability by flow cytometry and mitochondrial functioning by Seahorse technology. To analyze the integrity of the cellular monolayer, the expression level of tight junction proteins and permeability of bEnd.3 monolayer to fluorescent tracers were assessed by Western Blotting and transwell‐modeling, correspondingly .ResultpS8‐Aβ42 and isoD7‐Aβ42 effects on the redox status of the cells and mitochondria functioning differ from the effects of Aβ42. Even at 4 hours, Aβ42 and isoD7‐Aβ42 induce immense changes in mitochondrial potential and NO level but pS8‐Aβ42 does not. Prolonged incubation with three isoforms leads to an increase in ROS, and greater increase is observed after incubation with isoD7‐Aβ42. pS8‐Aβ42 induces ROS increase later than other isoforms. Above all, incubation with pS8‐Aβ42 results in a less pronounced NO и GSH growth compared with Aβ42 и isoD7‐Aβ42 which induce activation of mitochondrial respiration and increase in mitochondrial potential, compared with pS8‐Aβ42. IsoD7‐Aβ42 is mostly toxic to bEnd.3 cells. Although Aβ42 and isoD7‐Aβ42 significantly affect redox parameters of bEnd.3 cells, their effects on BBB permeability and tight junction protein expression are less pronounced. Our data demonstrate that inhibition of NO synthases and NMDA receptors induces changes in BBB cells’ response to Aβ peptides.ConclusionAmyloid isoforms differently affect redox parameters of BBB cells significantly modulating mitochondria functioning. Iso‐Aβ42 induces higher cytotoxicity, thus, being a more pathogenic form. Post‐translational modifications of Aβ42 alter the amyloid effect on the BBB cells. It may result in different changes in BBB functioning and its permeability under amyloid isoforms.This research was funded by Russian Science Foundation (Grant No. #19‐74‐30007).
Investigating the impact of treatment timing on urinary tract infections in dementia at the population level
Authors: Lai Helen , Kolanko Magdalena A , Li Lucia , Tzoulaki Ioanna , Sharp David J , Soreq Eyal 
Published: December 2023

AbstractBackgroundUrinary tract infections (UTIs) are common causes of avoidable emergency hospitalisation in people living with dementia (PLWD). PLWD are at higher risk of UTIs, which can often cause death. Previous research in older adults has suggested that survival following infection is reduced by delays in antibiotic treatment (Gharbi et al., 2019). Here we investigate the incidence of UTIs in people with and without dementia and test whether delays in antibiotic treatment particularly increase mortality in PLWD.MethodData were extracted for 2.47 million people aged 50 and living in Wales from 2000‐2021 using the SAIL Databank (Figure 1). UTI incidence was calculated as the number of cases identified in GP and hospital records using diagnostic codes. Temporal clustering was applied to remove redundant coding occurring within 90 days. Eligible PLWD and paired non‐dementia (ND) groups were selected monthly using propensity sampling, matching for age, sex, and socioeconomic deprivation. Cox regression was used to study the effects of immediate and deferred treatment (1‐7 days after diagnosis) on survival, focusing on the last recorded UTI in a subset of patients diagnosed and treated at the primary care level.ResultUTI incidence was higher in PLWD compared to ND (11.21.85 vs 4.30.75, 1:1000) over 22 years (Figure 2). We also observed an increase in UTIs leading to death within 60 days of the infection (1.560.4 vs 0.60.2, 1:1000). We performed Cox regression survival analysis on 76,283 last UTIs with 2,973 observed events (deaths). Age, sex, dementia, and treatment timing were used as predictors. Mortality risk was significantly increased in PLWD relative to ND (***HR = 2.06,[1.91,2.23],z = 18.2) (Figure 3). Mortality was also increased in older adults (***HR = 1.07,[1.07,1.08],z = 36.4) and in males (***HR = 1.50,[1.40,1.61],z = 11.3). Furthermore, deferred treatment was associated with increased mortality (***HR = 1.58,[1.43,1.74],z = 8.93), replicating previous findings. The interaction between dementia and treatment timing was not significant.ConclusionOur study found increased UTI incidence and mortality rates in PLWD. Deferred treatment was associated with higher mortality, regardless of dementia diagnosis. Early intervention and frequent screening may reduce adverse health outcomes. Further research is needed to determine the best strategies to prevent and manage UTIs in PLWD.
What influence does self‐reported history of single or repeated mild TBI have on cognitive performance and brain volume at mid‐life?
Authors: Thayanandan Tony , Filippini Nicola , Griffanti Ludovica , Dounavi Maria‐Eleni , Mak Elijah , Low Audrey , O'Brien John T , Mackay Clare , Ritchie Craig W. , Raymont Vanessa 
Published: December 2023

AbstractBackgroundThe long‐term consequences of mild traumatic brain injury (mTBI) are poorly understood. Prior studies have shown that a history of mTBI is associated with a 2 fold increase of dementia diagnosis. However, the precise mechanisms for increased dementia risk which could start in mid‐life remain unclear. TBI can cause varying degrees of damage to different regions of the brain, and as a result, may affect distinct subdomains of cognitive function in distinct ways. This study investigated cognitive performance and brain volume among individuals at risk of Alzheimer’s Disease (AD) in mid‐life with a history of self‐reported mTBI.Method578 participants (118 no head injury, 116 single mTBI & 344 repeated mTBI) aged 40‐60 years participating in the PREVENT study, a large cohort study examining the risk of AD in mid‐life, underwent structural 3T MRI and neuropsychometric evaluation (ACE‐III and COGNITO) at baseline. Self‐reported, cross‐sectional data on head injury were collected through the Brain Injury Screening Questionnaire (BISQ). FSL (version 6.0.1) was used to calculate brain volume (correcting for head size). Comparisons between participants with no history of head injury and single or repeated mTBI were done using a one‐way ANOVA.ResultThere was no statistically significant difference in total brain volume between participants with or without a history of mTBI (F(2,576) = 1.24, p = 0.29). There was also no significant difference between self‐reported mTBI and ACE‐III total scores F(2,579) = 0.0112, p = 0.99) or performance on memory (p = 0.87), language (p = 0.24), visuospatial abilities (p = 0.61) and attention (p = 0.14) in the COGNITO battery.ConclusionWe found no evidence that a history of mTBI (single or repeated) is associated with cognitive impairment in this cohort. Future longitudinal studies are necessary to further evaluate self‐reported mTBI and how the aging process might interact with cognitive outcome post‐injury. Future analysis of covariates such as lower socioeconomic status, gender, physical health and history of alcohol/drug use, that are known to impact cognitive performance and are related to greater rates of TBI, will be studied to determine the influence of a history of mTBI on dementia risk.