bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between Verbal Memory Performance and Regional Brain Volumes Differ by APOE4 Carrier Status in Midlife Women
Authors: Wugalter Katrina A , Thurston Rebecca C , Wu Minjie , Schroeder Rachel A , Aizenstein Howard J , Derby Carol A. , Maki Pauline M 
Published: December 2023

AbstractBackgroundAPOE4 genotype is a stronger risk factor for Alzheimer’s disease (AD) in women than men, and its influence on memory and AD biomarkers differs by disease stage. Among cognitively normal older APOE4 carriers, APOE4 status influences memory similarly in males and females but adversely influences hippocampal volume in males. The effect of APOE4 status on regional brain volumes earlier in life, and in relation to memory, are less well understood. We examined whether associations between verbal memory performance and regional brain volumes differed by APOE4 status in cognitively normal midlife women. We hypothesized that APOE4 carriers would show weaker associations between memory performance and brain volumes than non‐carriers, particularly in the temporal lobe.MethodParticipants were enrolled in MsBrain, a cohort study of midlife women. Verbal memory was assessed with the California Verbal Learning Test (CVLT‐II). Cortical thickness was measured and segmented by FreeSurfer using individual T1w MPRAGE images. Multiple regressions were conducted to determine associations between memory (learning, free recall) and regional brain volumes by APOE4 status (carriers versus non‐carriers), controlling for age, education, and race.ResultIn 148 cognitively normal postmenopausal women (mean age = 59.17 years, 84.4% white, n = 37 APOE4 carriers), APOE4 status had no main effect on CVLT‐II measures or brain volumes, except the volume of the left supramarginal gyrus. However, APOE4 status modified the magnitude of association between verbal memory and brain volumes, specifically the association between: a) verbal learning and volume in the left caudal middle frontal gyrus (CMFG), left isthmus cingulate gyrus, left parahippocampal gyrus, left insula, right precuneus, right lateral orbitofrontal gyrus (LOG), and right temporal pole (TP); and b) free recall and volume in the left CMFG, right LOG, right posterior cingulate gyrus, and right TP. The direction of the associations between verbal memory and brain volumes was positive in non‐carriers and negative in carriers.ConclusionIn cognitively normal midlife women, APOE4 carrier status may influence the extent to which the hippocampal, temporal, and frontal lobe structures support verbal memory performance. This subtle effect may emerge before the main effect of this genetic risk factor on brain volume and memory.
The evaluation of translated neuropsychological assessments tools for the early detection of mild cognitive impairment (MCI) in low‐ and middle‐income countries (LMICs)
Authors: Ghosheh Mohammad , Ghosheh Ghadeer , Ghosheh Jamal 
Published: December 2023

AbstractBackgroundThe incidence of mild cognitive impairment (MCI), particularly in low and middle‐income countries (LMICs) has been noticeably on the rise. With the high cost of dementia care, the need for tools that aid with the early detection of MCI is becoming of high importance, especially in LMICs. As a part of screening for MCI, many tests have been proposed evaluating for impairments in cognitive, behavioral, and functional domains, which are important for ruling out and evaluating for any reversible causes. While useful, most of these tests were developed in the west, limited works exist reporting the appropriateness and experience of using such tests for patients from LMICs.MethodIn this work, we aim to evaluate the use of translated digital assessment for detecting MCI in an Arabic‐speaking population in Palestine. For this purpose, we developed a digital test covering three cognitive, behavioral, and functional domains, where MMSE and the Neuropsychiatric Inventory ‐ Questionnaire (NPI‐Q) together with two functional assessment questionnaires were translated to Modern Standard Arabic (MSA) and presented in a digital interface. Upon the development and translation of the digital tests, field testing was conducted to check for use experience and appropriate patient comprehension of the questions to match their intended use.ResultFollowing the implementation of the digital assessment tools, quantitative and qualitative data was collected summarizing the user experience, where numerous limitations were noted. Despite being asked in their native language, several patients expressed the need for more clarifying questions. While all patients were Arabic speakers, some patients required the use of simpler terminology that matches their local dialects. Other patients reported the lack of relevance of certain questions, regarding the activities of daily living in the functional assessments. Overall, the patient’s experience and comprehension of questions varied with their age and literacy level.ConclusionDespite the high prevalence of dementia in LMICs, there are limited available neuropsychological assessment tools that are fit for the local cultural and linguistic. The findings suggest the need for the development of culturally and linguistically appropriate assessments to ensure appropriate patient comprehension, and avoid misdiagnosis of patients.
Working memory binding failures and abnormal alpha power in Alzheimer’s disease
Authors: Mallas Emma‐Jane , David Michael CB , Karakoc Hanim , Tsoi Chris ML , Malhotra Paresh A , Scott Gregory , Sharp David J 
Published: December 2023

AbstractBackgroundAssociative binding is key to normal memory function and is selectively impaired in Alzheimer’s disease (AD).1 Electrophysiological abnormalities are frequently reported in AD including during tasks requiring associative binding.2 We use a precision spatial working memory test to investigate the binding of distinct visual features (object and location) in working memory in AD patients and test the hypothesis that misbinding is related to electrophysiological abnormalities.Methods36 AD patients and 29 healthy age‐matched controls (HC) were tested with a precision working memory paradigm that required the association of object and location information (Fig 1A). Participants were excluded if they were unable to perform the identification element of the task significantly above chance level (p>0.05). High‐density eyes‐closed resting‐state EEG was used to assess changes in electrophysiological power across frequency bands.Results25 AD and all HC performed above chance level (Fig 1C). AD patients showed abnormalities in working memory function and made significantly more misbinding errors (p<0.001) than HC (Fig1E) indicating that working memory recall was abnormally biased by the spatial locations of distractor items (Fig 1F). AD patients demonstrated significant reductions in global alpha and increases in global theta (Fig 2A). Channel‐wise analysis revealed significant clusters of decreased power in AD across occipital‐parietal channels in alpha and beta bands (p<0.05; Fig 2C). Misbinding errors significantly correlated with alpha power in AD but not HC (p<0.05; Fig 2D).ConclusionsThese results offer further support for a deficit in working memory binding being a sensitive cognitive biomarker of AD. Pathologically reduced alpha power may offer mechanistic insight into the profound working memory binding impairments seen in AD.
References:1. Della Sala S, Parra MA, Fabi K, Luzzi S, Abrahams S. Short‐term memory binding is impaired in AD but not in non‐AD dementias. Neuropsychologia. 2012;50(5):833‐840. https://doi.org/10.1016/j.neuropsychologia.2012.01.0182. Han Y, Wang K, Jia J, Wu W. Changes of EEG Spectra and Functional Connectivity during an Object‐Location Memory Task in Alzheimer’s Disease. Front Behav Neurosci. 2017;11:107. https://doi.org/10.3389/fnbeh.2017.00107
Late‐onset behavioural change is enriched with C9orf72 repeat expansion regardless of family history or diagnosis
Authors: Boer Sterre C.M. , Krudop Welmoed A. , Gossink Flora T , Oudega Mardien L , Kerssens Cora J. , Dols Annemiek , van Ruissen Red , Lee Sven J , Pijnenburg Yolande A.L. 
Published: December 2023

AbstractBackgroundThe C9orf72‐repeat expansion (C9RE) is the most prevalent genetic cause of frontotemporal dementia (FTD). Since its discovery, studies have shown that both family history (FH) and medical history of FTD patients carrying a C9RE are often not only positive for dementia, but also for psychiatric disorders and late‐onset behavioural change. Conversely, finding a C9RE carrier in a primary psychiatric disorder (PPD) cohort is rare. These findings justify clinicians to test for the C9RE, regardless of FH, when diagnosing a patient with FTD but not to screen for C9REs in PPD cohorts. It is unknown what the frequency is of C9RE in cases presenting with late‐onset behavioural change. Therefore, we investigated the diagnostic value of screening for C9RE in cases with late‐onset behavioural change.MethodPatients with late‐onset (>45years) behavioural change referred to the Alzheimer Center Amsterdam between 2011 and 2023, that received a baseline diagnosis of FTD or non‐FTD were included. Genetic screening was performed and mutation carriers other than C9RE were excluded. The cohort was devided in C9RE‐carriers and non‐carriers. FH data was retrieved. Positive FH (FH+) was defined as having a first‐degree relative with dementia or psychiatry, negative FH (FH‐) without a first‐degree relative with dementia or psychiatry. Distribution of FH(+/‐) between C9RE‐carriers and non‐carriers was studied. Within the C9RE‐carriers, distribution of FH between FTD and non‐FTD diagnosis was measured. Distributions were compared using chi‐squared tests.ResultA total of n = 344, of which 16,2% C9RE‐carriers, were included. Of the C9RE‐carriers, 66.7% had a FH+ versus 35.7% of the non‐carriers (p = 4.36e‐05). Within the C9RE‐carriers group, n = 34 cases received a FTD diagnosis of which n = 20 had a FH‐ (58.5%) versus n = 20 cases receiving a non‐FTD diagnosis of which n = 14 (70%) having a FH‐ (p‐value = 0.596, table 1).ConclusionWithin a cohort of late‐onset behavioural change, 14 cases (4.2% of total cohort) received a non‐FTD diagnosis, had a negative FH for dementia and psychiatry but turned out to have a C9RE. This shows late‐onset behavioural change is enriched with C9RE, regardless of FH or baseline diagnosis, and suggests that screening for C9RE is of both diagnostic and prognostic value in late‐onset behavioural disorders.
Investigating the Role of APOE Genotype in Human Microglia
Authors: Ulm Brittany , Amin Najaf , Bahnassawy Lamiaa , Reinhardt Peter , Curado Marco Rocha , Peitz Michael , Fliessbach Klaus , Ramirez Alfredo , Ruiz Agustin , Ried Janina S , Bakker Margot H.M. , Van Duijn Cornelia M ,   IMI ADAPTED Consortium
Published: December 2023

AbstractBackgroundAlthough the pivotal role of apolipoprotein E () in AD has been recognized for three decades, its function in different brain cells is far from understood. Knockout studies of the APOE gene may shed light of the function of ApoE. The aim of the present study was to unravel its function in induced pluripotent stem cell (iPSC) derived microglia.MethodWe studied two human iPSC‐derived microglia cell cultures, one derived from a healthy control (Bioni010‐C – endogenous genotype apolipoprotein E34 (APOE34)) and one from an AD patient (UKBi011‐A – endogenous genotype APOE44) and their edited isogenic cell‐lines (for UKBi011‐A, APOE22 and APOE33 and for Bioni010‐C, hemizygous due to gene editing, APOE2‐ and APOE3‐ (32971461, 29753274)). Additionally, APOE KO lines were generated from both backgrounds. We performed whole genome transcriptomic (IlluminaTruSequencing) and proteomic (TMT‐labelled Nano‐LC peptidomic MS) analysis (n = six per genotype). For transcriptomic data, log2‐normalized intensities were analysed with (in R); there were 13115 unique transcripts. For proteomics analysis, after global normalization, the data were locally normalized (by protein), the limma package was used to calculate FDR‐corrected p‐values (1% cut off); there were 3975 (Bioni010 samples) and 4349 (UKBi011 samples) proteins. In the quality control analysis for the proteomics, we excluded one outlier of the six per line based on principle component/Euclidean distance analysis. We extracted pairwise comparisons to APOE KO in transcriptomic (|logFC|>0.5, FDR <0.05) and proteomic (|logFC|>0 and FDR <0.05) data.ResultTwenty transcripts (including APOE) were concordantly differentially expressed across all comparisons between APOE‐expressing and KO. These are broadly involved in processes related to mitochondrial function/organization, apoptosis, transcriptional regulation, immune functions, extracellular matrix, and energy metabolism among others. Seven proteins were concordantly differentially expressed across all pairwise comparisons with APOE KO, involved in extracellular matrix, immune signalling, energy metabolism, and cytoskeletal structure.ConclusionOur study finds APOE knockout leads to a number of changes related to immune, mitochondrial, and extracellular matrix genes, suggesting that APOE in human iPSC‐derived microglia cells influences immune and mitochondrial functions.
Fine semantic segmentation of hands for human functional pattern recognition in IADLs using deep learning
Authors: Babatope Eyitomilayo Yemisi , Acosta‐Franco Jesus Alejandro , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is an irreversible degenerative brain disease and the most common cause of dementia, in the elderly population (age 65 and above) although people younger may develop the disease (Clemmensen, 2020). AD is characterized by impairment in behavior and cognition which eventually obstruct the Instrumental Activities of Daily Living (IADL) (Kumar, 2022). Researchers have predicted functional capacity by assessing IADL as they are strongly associated with cognitive impairment. With the availability of big data and public repositories of multimedia data such as images and videos, artificial intelligence algorithms have been used in classifying and making informed decisions that could help in disease prediction and monitoring. In the context of early diagnosis of Alzheimer, researchers have worked with machine learning techniques applied to neuroimaging for AD classification (Lama, 2021). Researchers and practitioners often use Activity of Daily Living to monitor independent‐living senior citizens’ self‐care ability, wellness status, and disease progression (Zhu, 2021). Automating the assessments of IADL will ease the evaluation of functional and cognitive function and strengthen the prediction of AD.MethodOur work approaches the timely detection and diagnosis of AD by exploring the deficiency in hand dexterity and visuospatial skills while performing IADL using egocentric videos. Therefore, in this work, we propose a fine semantic segmentation of hands, optimizing the predictions at the level of the relationship between pixels in a deep learning method. We trained the optimized RefineNet‐Pix convolutional neural network, obtaining a higher accuracy in the segmentation of semantic maps of hands.ResultsWith the optimization of RefineNet‐Pix we obtained an accuracy higher than 87.9% (Urooj, 2018) in the semantic segmentation of hands. By integrating the RefineNet‐Pix results to the base model for human functional pattern recognition, we obtain an accuracy higher than 74% with respect to the base model (Yemisi, 2022).ConclusionThe optimized RefineNet‐Pix model segments pixel‐wise the hand regions in egocentric videos, providing hand motion information that can be used to classify impairment based on human functional patterns. Optimization of these models is a way forward in building a technological device for the support of Alzheimer’s diagnosis.
Area Deprivation Index is associated with biomarkers of inflammation cross‐sectionally and longitudinally over a 9‐year follow‐up period
Authors: Gogniat Marissa A. , Khan Omair A. , Bolton Corey J , Ratangee Brina A. , Liu Dandan , Pechman Kimberly R. , Yates Alexis , Eaton James , Houston Michelle L , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundLiving in a socioeconomically disadvantaged neighborhood has a negative impact on health outcomes, including increased risk for Alzheimer’s disease (AD). The biological mechanisms underlying this risk are poorly understood. We examined how neighborhood disadvantage relates to core AD pathology, neurodegeneration, and inflammatory biomarkers in community‐dwelling older adultsMethodVanderbilt Memory and Aging Project participants (n = 327, 73±8 years, 41% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.8 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind & Buckingham, 2018)]. Ordinary least squares regressions cross‐sectionally related ADI to plasma and CSF biomarkers adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, apolipoprotein E‐e4 status, and cognitive status. Linear mixed‐effects regression models related baseline ADI to longitudinal biomarkers with identical baseline covariates plus follow‐up time. Outcomes included CSF chitinase‐3‐like protein 1 (YKL‐40), CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2), CSF amyloid‐b40 (Ab40), CSF amyloid‐b42 (Ab42), CSF Ab40/Ab42 ratio, CSF tau, CSF phosphorylated tau (ptau), plasma high sensitivity C‐reactive protein (CRP), and plasma and CSF neurofilament light chain (NfL).ResultOn average, the sample was from relatively less disadvantaged neighborhoods (ADI national decile = 35.4±25.0, range = 1‐98). Greater neighborhood disadvantage at study entry was cross‐sectionally associated with elevated CSF YKL‐40 (β = ‐0.733, p = 0.003), sTREM2 (β = 19.74, p = 0.04), Aβ40 (β = 35.96, p = 0.01), tau (β = 2.31, p = 0.02), and ptau (β = 0.33, p = 0.03). Greater neighborhood disadvantage at study entry related to longitudinal increases in CRP (β = 0.012, p<0.001) and decreases in plasma NfL (β = ‐0.025, p = 0.04) over the follow‐up period.ConclusionAmong community‐dwelling older adults, greater neighborhood disadvantage was associated with elevated inflammatory and AD CSF biomarkers cross‐sectionally, and longitudinal increases in a non‐specific inflammatory blood biomarker. Collectively, findings suggest that neighborhood disadvantage confers immediate risk for systemic neuroinflammation and AD and future risk for non‐specific inflammation, providing valuable evidence of a sociobiological mechanism underlying health disparities in aging adults based on geographic location.
Funding. R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082
Association between plasma inflammatory biomarkers and [18F]FDG‐PET signal in a transgenic amyloid rat model
Authors: Lazzarotto Gabriela , Machado Luiza Santos , da Rocha Andreia Silva , Siebert Marina , Limberger Christian , Soares Carolina , Schlickmann Thomas , Ferreira Pamela C.L. , Pascoal Tharick A. , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundNeuroinflammation is thought to play an important role in the pathogenesis of Alzheimer’s disease (AD). It has recently been demonstrated that [18F]FDG positron emission tomography (PET) signal is sensitive to central inflammatory changes in AD. However, it is unknown whether blood cytokines, which are important signaling molecules that regulate the peripheral inflammatory process, are associated with the cerebral [18F]FDG‐PET signal. In this work, we aimed to investigate whether plasma cytokines are associated with brain glucose metabolism in a transgenic amyloid rat model.MethodBrain metabolism of 4‐ and 10‐month‐old wild‐type (WT) and APP/PS1 rats (TgF344‐AD) were assessed with [18F]FDG‐PET imaging. Plasma inflammatory markers (IFN‐γ, IL‐1α, IL‐1β, IL‐6, IL‐10 and TNF‐α) were measured by multiplex immunoassay. [18F]FDG‐SUVr was calculated with pons as the reference region. Correlation between inflammatory markers and [18F]FDG‐PET signal was conducted at the voxel level (RMINC; p<0.05 and t>2).ResultAt 4 months, IL‐10 levels significantly associate with [18F]FDG‐PET signal in the frontal and temporoparietal cortices (FCx and TPCx) and hippocampus (Fig1A), whereas other biomarkers present only small clusters associated with [18F]FDG‐PET signal (Fig1A). At 10 months, a positive association with [18F]FDG‐PET was found between IL‐1α and IL‐1β at FCx and TPCx, while IL‐10 showed a positive correlation at the TPCx (Fig1B). Additionality, IFN‐γ and TNF‐α presented small correlation clusters at the TPCx, and IL‐6 at the TPCx and CxF (Fig1B).ConclusionAt the pre‐amyloid plaque stage, only an anti‐inflammatory cytokine, IL‐10, presented positive associations with brain glucose metabolism. However, multiple pro‐inflammatory cytokines correlated with brain glucose metabolism at the amyloid plaque stage. These findings suggest a dual peripheral inflammatory response impacting brain metabolism, which can be associated with amyloid species and deposition.