bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiological biomarkers of silent brain damage leading to cognitive impairment and Dementia – direct and accessible clinical evidence
Authors: Tanne David 
Published: June 2023

AbstractBackgroundCognitive assessment is the best clinical tool to detect cognitive impairments, yet it is evident only at late stages of disease progression. In contrast, silent brain network changes occur at early stages of the disease and it is estimated that a large proportion of dementias may be prevented or at‐least delayed if detected during early pathophysiology stages. Neuroimaging studies have shown that silent brain network findings, including white matter hyperintensities, lacunar infarctions and temporal atrophy are evident before objective cognitive impairment is detected and even more in ‘at risk’ population with risk factors for dementia. We aimed to evaluate direct physiological biomarkers that provide accessible clinical evidence of silent brain network damage that precede clinical cognitive findings and provide early clinical biomarkers that can facilitate early interventions.MethodBrain network performance was evaluated in 168 subjects ‘at risk’ for developing dementia (Table 1). Direct electrophysiological imaging (“Delphi”) was used to measure magnetically induced brain network electrophysiological response. MRI scans included T1, T2, FLAIR, Diffusion Weighted Imaging (DWI) and (SWI). They were analysed according to Fazekas scale for white matter Hyperintensities (WMH), lacunar Infarctions and medial temporal lobe atrophy (MTA). Objective cognitive evaluations were performed by a neuropsychologist interview and a computerized cognitive battery (NeurotraxTM).ResultDirect electrophysiological imaging (“Delphi”) was able to distinguish between severities of different MRI detected silent brain network damage findings. Magnetically induced direct electrophysiological response wave form adherence (WFA) significantly decreased with increase in WMH (Fig.1A; p<0.0001) and increase in MTA levels (Fig.1B; p<0.0001). Furthermore, WFA significantly decreased in subjects with lacunar infarctions (Fig.1C; p<0.0001).ConclusionSilent brain network deficits preceding dementia and cognitive decline are widely under detected due to lack of accessible tools. Data presented in this study demonstrates “Delphi” technology’s ability to detect silent brain network damage findings and severity levels that are identified in MRI scans. “Delphi” is a clinically accessible, direct, and objective technology that can facilitate early detection, prevention, delayed progression and management of mild cognitive impairment and dementia.
The effect of the lockdown during the COVID‐19 pandemic on the risk of developing dementia; A cohort study
Authors: Baron Daniel Hendrik , Sinclair Lindsey I , Carslake David J , Coulthard Elizabeth 
Published: June 2023

AbstractBackgroundIncreased social activity, relationships and being cognitively active have been associated with decreased risk of dementia. The COVID‐19 pandemic has significantly influenced these and increased the feeling of loneliness throughout society. Protective measures against the virus, such as social distancing and isolation, were enforced to reduce contact between people. We hypothesised that this would lead to an increased risk of transition to dementia.MethodWe obtained data from the Brains for Dementia (BDR) cohort, which has been collecting roughly annual data on 3,726 older adults with and without dementia since 2008. Data continued to be collected during the lockdowns, although by telephone and /or video call instead of in person. Individuals diagnosed with dementia at study entry were excluded from this study as were individuals with only one visit. Cognitive status was classified using the CDR global score.Poisson regression with cubic splines to account for differences in age was used to compare the rate ratio of developing dementia before/after March 1st 2020.ResultOut of 2,242 individuals, 205 individuals developed dementia before and 40 developed dementia after 1/3/20. The rate ratio of developing dementia after 1/3/20 was 0.770 (95% CI 0.438 – 1.356, p = 0.366) but there was evidence that this differed with age.ConclusionThe chance of individuals developing dementia did not change significantly after the first lockdown, although power was low. We will now perform sensitivity analyses to assess whether the type of assessment or using the CDR sum of boxes/MMSE to define cognitive status alters this relationship.
Copper ions and the R peptides of tau: structural and functional study
Authors: Seneviratne Dev , Martic Sanela 
Published: June 2023

AbstractBackgroundOne of the common neurodegenerative disorders is the aggregation of Tau protein plays a major role in Alzheimer’s disease. Transmission metals ions such as Cu, Zn, and Fe are vital ingredients that must maintain homeostasis in the biological system. Tau Protein has four repeat peptide units (R1 R2 R3 R4) which may coordinate divalent copper ions to form neurofibrillary tangles (NFTs) and generate reactive oxygen species (ROS).The abnormal amount of Cu2+ accumulation in the intracellular environment, regulating the biological systems is not clearly understood.MethodThe main objective of this study was to evaluate the coordination of four R peptides to Cu2+ by MALDI‐MS‐TOF and determine the interaction of Cu2+ ions with peptides (R1 R2 R3 R4) of Tau protein in vitro. Also, their role in the formation of ROS with a natural reducing agent‐ ascorbate was probed.ResultAs the principal findings of this experiment, metal ion coordinated all 4 R peptides, via His and Cys residue including N terminal and amide groups. All the metallo‐peptide complexes were singly charged peaks, and observed even in the presence of ascorbate. R2 and R3 peptides formed the homodimers by disulfide bond formation. The metallo‐peptides were antioxidants and prooxidants depending on the conditions, indicating that a complex behavior may exist in the biological setting.ConclusionThis work indicates that metal ions interact with R peptides, which may mitigate ROS levels. The finding of this study is greatly beneficial for understanding the Tau protein behavior to develop a potential medication.
Alzheimer’s Disease (AD): High cholesterol is associated with lower Mini‐Mental State Exam (MMSE) scores
Authors: Komatsu Caroline , Komatsu Ricardo S. 
Published: June 2023

AbstractBackgroundAlzheimer’s Disease (AD) is the leading cause of dementia in the elderly. The epsilon 4 allele of the apolipoprotein E gene that encodes the major brain lipid carrier and metabolic disorders, such as obesity and type 2 diabetes, were identified as AD risk factors, suggesting that abnormal lipid metabolism could influence the progression of the disease. Additionally, lowering cholesterol is associated with reduced central nervous system (CNS) amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies.Method154 outpatients with the diagnosis of AD conforming to criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their cholesterol levels assessed and MMSE scores evaluated.Results90 patients (58,44%) presented high cholesterol (total cholesterol level ≥ 190 mg/dL and/or LDL level ≥ 130 mg/dL) and 64 patients (41,56%) presented cholesterol normal range (total cholesterol level < 190 mg/d L and/or LDL level < 130 mg/dL). From the high cholesterol group, 10 patients (11,11%) presented severe cognitive impairment (MMSE < 10), 50 patients (55,55%) presented moderate cognitive impairment (MMSE = 10 – 20) and 30 patients (33,34%) presented mild cognitive impairment (MMSE > 20). From the cholesterol normal range group, 5 patients (7,81%) presented severe cognitive impairment, 19 patients (29,69%) presented moderate cognitive impairment and 40 patients (62,5%) presented mild cognitive impairment. Both groups, high cholesterol and cholesterol normal range, had on average the same educational level: 2,91 and 3,42 years, respectively.ConclusionIn this sample of patients with AD, high cholesterol is associated with lower MMSE scores when compared to cholesterol normal range.
Does aerobic exercise affect physical function and quality of life in those diagnosed with dementia? A systematic review
Authors: Marocco Samantha L , O'Connor James J , York Ashley , Haab Ricki , Drake Austin 
Published: June 2023

AbstractBackgroundIt has been proposed that aerobic exercise can have positive effects on people who have cognitive impairments. While systematic reviews have been completed on the effects of aerobic exercise on the cognitive function in those with Alzheimer’s Disease, there has yet to be a systematic review that focuses on the effects of aerobic exercise on physical function and quality of life in patients diagnosed with dementia. The purpose of this systematic review is to analyze the existing literature concerning how aerobic exercise should be prescribed to those with dementia.MethodMultiple databases were searched for randomized controlled trials published from: Medline Complete, CINAHL Complete, Cochrane Central Register, SportsDiscus, PEDro, Health Source, PubMed, Ageline, Health Reference Center Academic, OT Seeker, and Science Direct. Our search included articles published from January 2011 through February 2021. A screening of relevant articles was then performed to identify literature to be included in the systematic review. Data was extracted for the following information: specific details about the study populations, interventions, and outcomes of significance related to the review analysis.ResultTen studies, all of which were found to be fair to excellent quality according to the PEDro scale, met the inclusion criteria for this systematic review. Overall results indicated positive effects of aerobic exercise on the physical functioning of patients diagnosed with dementia. Many of the studies indicated a change with small effect sizes for the outcome of physical function. Other outcomes such as cognition, activities of daily living, and quality of life had inconsistent effect sizes between studies.ConclusionThe results of this systematic review indicate that there is currently mild to moderate evidence in support of implementing an aerobic exercise program for patients diagnosed with dementia. Additional higher quality studies are needed to establish specific exercise parameters that promote physical function in people with dementia.
Hippocampal place cells exhibit impairments in spatial information coding in an APP‐knock in model of Alzheimer’s Disease
Authors: Wood Ruth A , Burton Stephen , Katsouri Loukia , Greenaway Borgel , Chan Dennis , O'Keefe John 
Published: June 2023

AbstractBackgroundThe hippocampus is one of the first cortical regions to exhibit Alzheimer’s Disease (AD) pathology. The spatially‐related firing of hippocampal place cells provides the cellular basis for spatial memory and this is impaired relatively early in AD, yet few studies examine place cell activity in AD mouse models. We undertook an in‐depth characterisation of hippocampal pyramidal cell activity in an APP knock‐in model of AD.MethodMicrodrives carrying 8 tetrodes were implanted into the left CA1 hippocampal subfield of 14‐month female mice (four APPNL‐G‐F, four wild‐type littermates). Mice undertook daily foraging sessions in an open field and ran on a linear track as CA1 activity was recorded. On completion of experiments, 40µm coronal sections of fixed brain tissue were stained using Cresyl Violet to verify tetrode placement and Thioflavin‐S to quantify amyloid β plaque burden.Result270 cells were recorded (119 wild‐type, 151 APPNL‐G‐F). CA1 pyramidal cells were classified as “place cells” or “non‐place cells” based on their spatial information content (bits/spike). Pyramidal cells recorded in wild‐type mice had significantly greater spatial information content than APPNL‐G‐F pyramidal cells (Figure 1), and a higher proportion were classified as place cells. Wild‐type place cells had significantly greater spatial information content than APPNL‐G‐F place cells. Corresponding differences were identified in place field size (Figures 2, 3). A positive correlation was identified between Aβ plaque burden and pyramidal cell spatial information content in the four APPNL‐G‐F mice (Figure 4).Coordination of place cell firing by the hippocampal theta rhythm was disrupted in APPNL‐G‐F mice; phase‐locking of pyramidal cells and place cells was significantly reduced (Figure 5), there was less coherence in the preferred theta phase across the pyramidal cell population, and a reduction in theta phase precession was observed.ConclusionAPPNL‐G‐F CA1 place cells exhibited deficits in both rate coding and temporal coding of spatial information indicating that amyloid β pathology, in the absence tau tangles, was associated with a disruption of hippocampal place cell function. These results provide preliminary support for the hypothesis that disruption of hippocampal function by AD pathology manifests as altered place cell activity and spatial behaviour.
Challenges and approaches when addressing dementia in the context of chronic comorbid conditions in primary care settings
Authors: Sideman Alissa Bernstein , Alagappan Cecilia , de Jesus Alma Hernandez , Ma Melissa , Dohan Daniel , Rosen Howard J. , Chodos Anna H , Possin Katherine L , Borson Soo , Rankin Katherine P 
Published: June 2023

AbstractBackgroundA diagnosis of dementia impacts all other comorbid conditions and areas of patient care. Yet, in primary care settings, dementia is often underdiagnosed and misdiagnosed due to competing clinical concerns. Delayed diagnosis and care of dementia can lead to more rapid cognitive decline, and increased hospitalizations, health care costs, and mortality. The objective of this work was to understand the challenges and successful approaches among primary care providers working in safety net settings when caring for patients with dementia and co‐existing chronic conditions.MethodsQualitative interviews focused on practices and challenges diagnosing and caring for patients with dementia, challenges related to comorbidities, needs for practice improvement, and successful approaches. Data was analyzed using thematic analysis.ResultsWe interviewed primary care physicians (n = 29) and primary care nurse practitioners (n = 6) based in California safety net settings in the SF Bay Area, Central Valley, and Southern California. PCPs identified the following comorbidities as most challenging to co‐manage with dementia: mental illness (depression/anxiety), hypertension, diabetes, heart disease, stroke, pain, substance use, and trauma. Most PCPs made a distinction between poorly controlled and well‐controlled chronic conditions. Challenges identified included: difficulty differentiating symptoms of dementia from other conditions, medication management and adherence; time constraints when making decisions about prioritizing acute comorbidities or dementia; need for family/caregiver involvement; and challenges controlling comorbid conditions when dementia is present. Successful approaches included: using team‐based care and targeted referrals (e.g. social work, community health workers, geriatrics); the importance of familiarity and long‐term relationships with patients; finding ways to involve family members; and simplifying visits, care plans, and communication.ConclusionPCPs face difficulties when providing care to patients with dementia and comorbid conditions, but they also identified opportunities for improvement by sharing successful approaches used in challenging healthcare settings. Findings can help shape intervention development to better support PCPs.
Application of neurovascular uncoupling and whole brain network connectomics to assess the role of genetic and dietary risk factors in the LOAD2 mouse model
Authors: Silvola Rebecca , Persohn Scott C , Oblak Adrian L , Lamb Bruce T , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Howell Gareth R , Sasner Michael , Territo Paul R ,   MODEL‐AD Center
Published: June 2023

AbstractBackgroundAs research efforts to discover and develop promising future therapeutics continues, the necessity to develop clinically significant Alzheimer’s disease (AD) mouse models and analysis is more important than ever.MethodThe study utilizes a novel MODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) mouse model that incorporates APOE4, Trem2*R47H, and humanized amyloid‐beta (Aβ) allele into C57BL/6J (B6) mice to produce LOAD2. Two cohorts of male and female LOAD2 mice received either control or high fat diet (HFD) followed by brain metabolism imaging using 18F‐FDG PET/CT. Brain regions were segmented using the Paxinos‐Franklin atlas and analyzed using a whole brain neurovascular uncoupling and connectivity approach. To do this, we computed z‐score statistics for all mice relative their control diet group, and conducted hierarchical modularization of all 28 brain regions and statically compared results across sex and high‐risk diet in 12‐month‐old mice.ResultAn initial network analysis detected metabolic hypo‐perfusion and metabolism for female mice, while males showed neurovascular uncoupling. Hierarchical analysis revealed primary modules within the whole brain network. These primary modules were then further modularized to yield a final breakdown of six secondary sub‐modules consisting of 3‐7 brain regions. Predominate functional associations of the sub‐modules’ brain regions were sensory (S) and learning (L), while sub‐module 2.1 had the strongest visual (V) representation. Statistical analysis of the six sub‐modules exhibited significant, module‐, sex‐, and dietary‐dependent effect for LOAD2 mice on high fat diet (HFD) by 12mo.ConclusionThe incorporation of APOE4, Trem2*R47H, and humanized Ab sequence in combination with HFD induced age‐dependent LOAD‐relevant changes in neurovascular coupling and whole brain network connectivity consistent with known brain circuit variations observed clinically. These findings support application of this newer LOAD2 mouse model to improve knowledge regarding disease mechanism. Additionally, our connectivity analysis approach shows promise for implementation in future therapeutic development and testing.
Measurement invariance of the Cognitive Function Index across race in the A4 study
Authors: Ruthirakuhan Myuri , Cogo‐Moreira Hugo , Amariglio Rebecca E. , Buckley Rachel F. , Sperling Reisa A. , Swardfager Walter , Black Sandra E. , Rabin Jennifer S. 
Published: June 2023

AbstractBackgroundAccumulating evidence suggests that subjective concerns expressed by cognitively normal older individuals may be a sensitive indicator of early Alzheimer’s disease (AD). The Cognitive Function Index (CFI) is a 14‐item questionnaire developed to assess subjective decline in cognitively unimpaired individuals. Previous studies have reported that greater CFI scores are associated with greater amyloid burden and faster cognitive decline in cognitively unimpaired individuals. These findings, however, have been found in predominantly White samples, and the equivalence of the CFI across different races has not been investigated. The goal of this study was to evaluate measurement invariance (i.e., equivalence) of the CFI across race using data from the Anti‐Amyloid in Asymptomatic AD (A4) Study.MethodThis study analyzed screening data from the A4 Study. Participants (N = 5735) were classified as Black, Asian, or White using self‐reported race. Latino/Hispanic individuals were excluded due to low numbers (N = 232). A multi‐group confirmatory factor analysis using a single‐factor model was conducted in Mplus to evaluate invariance of the CFI across race. Acceptable model fit was confirmed using the following: χ2/df <3, comparative fit index>.95, and the root‐mean‐square error of approximation (RMSEA)<.1. Measurement invariance was established with a ∆comparative fit index≤.01, and ∆RMSEA≤ .015 between invariance tests.ResultOf the individuals included N = 267 were Black, N = 277 were Asian, and N = 5241 were White (mean±SD age: 71.7±4.9, education (years): 16.4±3.0, and male: 2466 (43%)). Configural, metric, scalar, and strict measurement invariance was supported by race (Table 1).ConclusionThe results demonstrate equivalent performance of the CFI across cognitively unimpaired participants who self‐identify as Black, Asian, or White. Differences between these groups measured by the CFI can be considered to reflect true inter‐group differences in subjective cognitive concerns rather than differences in the measurement properties of the scale. Future work should examine measurement invariance of the CFI in additional racial/ethnic groups.
Genetic association of apolipoprotein E genotype with EEG alpha rhythm and resting‐state functional MRI connectivity in non‐demented adults during aging
Authors: Ponomareva Natalya V , Andreeva Tatiana , Protasova Maria , Kolesnikova Ekaterina P , Malina Daria , Kanavets Elena V. , Konovalov Rodion , Krotenkova Marina V. , Fokin Vitaly , Illarioshkin Sergey , Rogaev Evgeny I 
Published: June 2023

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) genotype is a major genetic risk factor for Alzheimer’s disease (AD), but the mechanisms underlying its influence are not completely understood. The study was aimed at determining the possible effect of APOE genotype on spontaneous EEG alpha rhythm characteristics and on the resting‐state functional MRI (fMRI) connectivity (rsFC) in large brain networks in non‐demented adults during aging.MethodWe examined individual alpha peak frequency (IAPF), the EEG alpha sub‐bands power and the fMRI rsFC in 137 non‐demented volunteers, age range 26‐79 years, stratified by APOE genotype. APOE ε3/ε3 subgroup (APOE4‐) included 91 subjects, APOE ε4/ε3+ (APOE4+) subgroup – 46 subjects. The individuals underwent resting‐state fMRI of the brain, the CONN Matlab/SPM‐based toolbox was used to study connectivity in brain networks (Whitfield‐Gabrieli and Nieto‐Castanon, 2012). Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening.ResultThe presence of the APOE4+ genotype was associated with lower IAPF and lower relative power of the 11‐13Hz alpha sub‐bands. The age‐related alpha rhythm slowing was more pronounced in the APOE4+ than in the APOE4+ non‐carriers. The negative rsFC between the left hippocampus and the right posterior parietal cortex was reduced for the APOE4+ carriers compared to the APOE4‐ carriers. EEG IAFT showed a significant inverse correlation between rsFC of the left hippocampus and the right posterior parietal cortex.ConclusionAPOE4+ genotype is associated with marked age‐related alpha rhythm slowing and the dysfunction of the inhibitory large‐scale hippocampal networks. Inhibitory deficit of these networks function, interconnected with alpha rhythm slowing, may be related to learning and memory impairments and contribute to the subsequent AD development.This study was supported by Russian Science Foundation (Project No. 19‐75‐30039, genotyping)