bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tear biomarkers for Alzheimer’s disease screening and diagnosis (The TearAD study): design and rationale of an observational longitudinal multicenter study
Authors: van de Sande Nienke , Ramakers Inez H.G.B. , Visser Pieter Jelle , Verhey Frans R.J. , Verbraak Frank D. , Bouwman Femke H. , Berendschot Tos T.J.M. , Nuijts Rudy M.M.A. , Webers Carroll A.B. , Gijs Marlies 
Published: December 2023

AbstractBackgroundEarly diagnosis of Alzheimer’s disease (AD) is important to promote timely and optimal management. Currently, the diagnosis of AD involves the use of amyloid PET scan or biomarker‐based cerebrospinal fluid analyses. These tests are invasive and expensive therefore limiting their usage as a front‐line screener. Thus, there is a need for non‐invasive and cost‐effective tools to diagnose subjects in early stages of the disease. With the TearAD study, we propose using the eye as the window to the brain. The eye is closely connected to the brain through the optic nerve. Tears contain thousands of molecules and protein secretion in the lacrimal gland is regulated by (para‐)sympathetic innervation. A study performed by our group demonstrated that proteins associated with AD (Aβ38, Aβ40 and Aβ42, total‐tau and phosphor‐tau) are detectable in tear fluid (Gijs et al., 2021, Scientific reports). Tear total‐tau levels were significantly elevated in dementia patients compared to people with subjective cognitive decline (SCD). Besides changes in tear protein content, retinal abnormalities have been observed in AD patients, which include retinal nerve fiber thinning and optic nerve degeneration. This observational longitudinal multicenter study aims to evaluate diagnostic accuracy measures of tear and retinal biomarkers to discriminate individuals with and without neurodegeneration.MethodsA total of 200 subjects will be included, of which 100 with and 100 without neurodegeneration. The study includes three visits (baseline, 12 months, and 24 months). The tear fluid will be collected non‐invasively with a Schirmer strip. Retinal images will be obtained by a standard, ultra‐wide field (Optos) and hyperspectral (Optina) fundus camera. Additionally, cross‐sectional images of the retina will be obtained through optical coherence tomography. Protein levels in tear fluid will be determined using multiplex immunoassays.ResultsInclusion for baseline started in June 2022 and is expected to complete in June 2023. Currently (Jan, 2023) we included a total of 115 participants. Which consist of 50 cognitively healthy controls, 25 patients with SCD, 17 patients with mild cognitive impairment and 13 patients with dementia.ConclusionThe TearAD study will provide insight into the diagnostic accuracy of using tear and retinal biomarkers for screening and diagnosis of AD.
Episodic memory decline symptoms are strong predictors of Alzheimer’s disease defined by Positron Emission Tomography in participants with amnestic mild cognitive impairment and mild dementia
Authors: Booncharoen Kittithatch , Hiransuthikul Akarin , Thanapornsangsuth Poosanu , Thanprasertsuk Sekh , Sarutikriangkri Yuthachai , Tangnimitchoke Suchart , Rattanawong Wanakorn , Phanthumchinda Kammant , Likitjaroen Yuttachai 
Published: December 2023

AbstractBackgroundThe diagnosis of Alzheimer’s disease (AD) has been shifted from clinical to biomarker‐based approach. However, the disease‐specific biomarker investigations are either invasive, expensive, or unavailable. Episodic memory decline symptoms (EMDS) have been recognized as an early manifestation of AD. We aimed to determine the performance of integrating EMDS in predicting AD among participants with amnestic mild cognitive impairment (MCI) or mild dementia.MethodAmnestic MCI and mild dementia participants were recruited from memory clinic at King Chulalongkorn Memorial Hospital, Thailand. In‐house informant‐based questionnaire was used to interview participants’ caregivers, which comprise of (A) 7 questions on changes in EMDS during the past 10 years and (B) 6 questions on the average daily frequency of EMDS in the previous month. Amyloid (Florbetaben) and Tau (PI‐2620) Positron Emission Tomography (PET) were performed. The result with A+T+ was defined as AD, the result with A+T‐ or A‐T‐ were define as other cognitive impairments. Multivariable logistic regression models were employed to construct the predictive model. The likelihood ratio test and area under the curve of receiver operating characteristic curve (AUC‐ROC) were used to identify the best model.ResultAmong 50 participants enrolled (median [interquartile range] age 72 [65‐77] years), 24 (48%) had AD. A comparison of AD and other cognitive impairments is shown in Table 1. The combination of 3 symptoms, including (1) consistently worse in remembering events during the past 10 years; (2) at least once daily momentary confabulation; and (3) at least once daily repetitive questioning, had the best diagnostic performance in parsimonious model for predicting AD with AUC‐ROC of 0.77 (95% confidence interval [CI]: 0.64‐0.90). (Figure 1)
ConclusionEMDS are still a valuable clinical marker for predicting AD in participants with amnestic MCI and mild dementia. The combination of selected EMDS might be a useful screening tool for selecting patients for further AD specific biomarker investigations.
Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment
Authors: Noureldein Mohamed , Elzinga Sarah E , Kim Bhumsoo , Savelieff Masha G , Rigan Diana M , Feldman Eva L 
Published: December 2023

AbstractBackgroundOne in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.MethodTo accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).ResultWe observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.ConclusionCollectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.
Investigating two pore potassium channel THIK‐1 expression in Alzheimer’s disease
Authors: Tang Hao , Sun Yuhong , Fachim Helene A , Cheung To Ka Dorcas , Reynolds Gavin P , Harte Michael K 
Published: December 2023

AbstractBackgroundThe neuroinflammatory response, particularly the activation of the NLRP3 pathway, has been suggested as one of the key mechanisms of the pathological process in neurodegenerative diseases. Tandem pore domain halothane‐inhibited K+ channel 1 (THIK‐1) provides an upstream regulation of this neuroinflammatory response by modulating intracellular K+. While in vitro and in vivo model systems provide strong support for these mechanisms, unequivocal evidence from neurodegenerative disorders has been lacking.MethodThis research project investigated gene expression of markers in the THIK‐1/NLRP3 pathway by studying post‐mortem brain tissue of animal model representing Alzheimer’s disease (AD). In addition, THIK‐1 gene and protein expression in human post‐mortem brains of AD and Parkinson’s disease (PD) was investigated. Furthermore, DNA methylation of THIK‐1 gene in human post‐mortem brains of AD was analysed to explore a potential underlying mechanism of the changes of THIK‐1 gene expression.ResultA rat model of AD pathogenesis by intrahippocampal Aβ oligomer injection showed substantial up regulation of THIK‐1, glial activation markers, NLRP3 inflammasome components and IL‐1β. Changes in cortical gene expression for THIK‐1 support an inflammatory glial cell activation in both advanced AD and PD with dementia, not observed in the substantia nigra of the latter group. The increase in THIK‐1 expression was also supported by down‐regulation in DNA methylation of its corresponding gene in AD.ConclusionThe association between THIK‐1 expression and pathology changes observed in this study indicate a THIK‐1‐induced activation of this glial subtype in AD and PD. Therefore, specific blocks of the microglial THIK‐1 K+ channels at the early stage of AD and PD provides a potential therapeutic target.
Risk architecture for altered hippocampal connectivity in normal aging differ between men and women
Authors: Schweitzer Noah , Li Jinghang , Lopresti Brian J , Klunk William E , Snitz Beth E. , Tudorascu Dana , Cohen Ann D. , Kamboh M. Ilyas , Halligan Edye , Thurston Rebecca C , Villemagne Victor L , Iordanova Bistra , Aizenstein Howard J , Wu Minjie 
Published: December 2023

AbstractBackgroundFunctional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.MethodOur study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).ResultThree ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.ConclusionWe observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.
FERMT2 cleavage impacts APP metabolism in a Src‐dependent manner
Authors: NAJDEK Chloé , Demiautte Florie , Ayral Anne‐Marie , Flaig Amandine , Eysert Fanny , Lambert Jean‐Charles , Chapuis Julien 
Published: December 2023

AbstractBackground
FERMT2 has been identified as a genetic risk factor for AD. We have reported that the FERMT2 protein is a partner of APP and a loss of FERMT2 (kindlin‐2) function altered both axonal growth and long‐term potentiation in an APP‐dependent manner. In this study, we aimed to identify the molecular mechanisms leading to loss of FERMT2 function.MethodWe aimed to identify proteases and other factors that regulate the cleavage of FERMT2 protein, which appears to be a mechanism that modulates its functions. The impact on FERMT2 cleavage and molecular interactions were analyzed by Co‐IP and WB. Consequences of these molecular interactions between FERMT2 and its partners on APP metabolism were then investigated using HEK‐APP cell lines.ResultWe identified a caspase‐dependent cleavage of FERMT2 that could be a molecular mechanism involved in the regulation of cell adhesion processes by inhibiting the ability of FERMT2 to interact with its partners. Furthermore, these results suggest that c‐Src activity, already known to regulate FERMT2 pathway, may have an impact on APP metabolism through regulation of FERMT2 cleavage.ConclusionAltogether, our data provide new mechanisms for understanding the involvement of the genetic risk factor FERMT2 in the pathophysiological processes of AD.
The potential of immersive auditory‐cognitive training as a platform for studying hearing‐loss and cognitive decline
Authors: Frei Vanessa Laura , Giroud Nathalie 
Published: December 2023

AbstractBackgroundHearing loss (HL) is considered one of the top modifiable risk factors for cognitive decline and dementia. However, modifiability is still a challenge, with auditory‐cognitive training (ACT) representing a promising approach on top of hearing devices, although generalizability and transfer effects of such trainings remain a challenge.MethodThe objective of this study is to gain insights into the benefits of an ACT in audio‐visual immersion with the goal to improve speech comprehension in older adults at‐risk for dementia. Participants (with varying degrees of cognitive capacity and pure‐tone HL) answer questions about spoken content in a three‐dimensional immersive (virtual reality and stereoscopic stimulus presentation) conversation. Electroencephalography is used to measure neural responses simultaneously. Speech comprehension is measured on a behavioral level and concurrently cortical responses to speech as a function of baseline cognitive capacity, audiometric measures and varying cognitive demand is assessed. We address the challenge of generalizability and transferability by enriching our training with natural, relatable speech content, and increased immersion simulating day‐by‐day speech situations.ResultWe predict improved speech comprehension post immersive ACT and simultaneously gain a deeper understanding of the associated neural responses to speech with varying cognitive demands. We further intend to model these effects as a function of baseline cognitive capacity and degree of pure‐tone HL (data collection will start February 2022).ConclusionThe central objective is whether immersive ACT has the potential to improve speech comprehension and to what extent such benefits depend on individual cognitive capacity and pure‐tone HL in older adults at‐risk for dementia. The design allows for both a within‐ and a between‐person perspective, whereby individual prerequisites, environmental and motivational factors will be considered. Finally, it allows for valuable considerations for future trainings, particularly regarding transferability and generalizability, while enabling increased engagement of individuals.
Prevalence of risk factors for dementia and association with cognitive alterations in an elderly population from the South of Brazil
Authors: Nakakogue Lindsey Mitie , Fonseca Rafaela Lopes 
Published: December 2023

AbstractBackgroundThe number of elderly people is increasing globally, including those who live with their dementia. It is currently the seventh leading cause of death worldwide and a leading cause of disability and dependence among older people. “The Lancet Commission’s 2020 update on prevention and monitoring care” evidenced 12 modifiable risk factors for dementia, suggesting that up to 40% of cases could be prevented or delayed if exposure to such factors were eliminated. In view of the increase in the elderly population and dementia cases, it is understood that preventive actions focusing on modifiable risk factors and early detection of dementia cases are necessary.MethodCross‐sectional, quantitative, descriptive study. Cognitive screening was carried out in patients over 60 years of age in an area of the territory of a Basic Health Unit using the Mini Mental State Examination (MMSE) and a survey of 12 (twelve) risk factors were investigated with questions related to: schooling, hypertension, hearing loss, smoking, obesity, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head trauma, exposure to tobacco and pollution. The interviews were performed from August to October 2022. About 146 individuals were selected and 73 interviews were carried out. Exclusion criteria were: bedridden elderly, those with compromised mobility or inability to understand. Statistical analysis was performed using the SPSS program using the Pearson’s chi‐square tests at a significance level of 5%.ResultThe present study identified a significant association between altered MMSE and low education, with a p‐value of 0.016. Of the illiterate patients, 47.6% had changes in the MMSE. Among individuals with 1 to 4 years of schooling, 82.8% had altered MMSE.ConclusionIt can be concluded that low education is a risk factor for dementia, as evidenced in other studies. However, the need for further studies on cognitive assessment instruments should be considered, since low educational level can influence their results.
Hypoexcitation and connectome disintegration via whole‐brain semi‐empirical modeling in neurodegeneration
Authors: Coronel‐Oliveros Carlos , Gonzalez‐Gomez Raul , Sainz Agustín , Legaz Agustina , Fittipaldi Sol , Cruzat Josefina A , Herzog Ruben A , Moguilner Sebastian , Medel Vicente , Orio Patricio , Taglizucchi Enzo , Prado Pavel , Ibanez Agustin 
Published: December 2023

AbstractBackgroundNeuroimaging biomarkers are intensively investigated in Alzheimer disease (AD) and the behavioral variant frontotemporal dementia (bvFTD). However, advanced ND biomarkers (i.e., PET and plasma) are expensive or not widely available/validated in underrepresented regions. EEG emerges as a promising alternative, due to its low‐cost, non‐invasiveness, portability, and wide availability in clinical research, although they lack mechanistic explications and robust modeling approaches. The aim of our work was to characterize the functional alterations in AD and bvFTD by combining EEG source‐level metaconnectivity (that captures high‐order interactions), anatomical priors, whole‐brain modeling, and a perturbational approach.MethodDemographic‐matched data were collected via the Dementia Latin American Consortium (ReDLat; AD = 31, bvFTD = 18, Control = 46). From EEG source level recordings and using machine learning classifiers, we compared the pairwise functional connectivity with high‐order correlations captured by metaconnectivity. Then, neural mass modeling was used to propose biophysical mechanisms specifically ascribed to AD and bvFTD. Finally, a perturbational approach was employed to characterize the brain trajectories involved in the healthy and pathological states.ResultsUsing metaconnectivity, we found specific subnetworks of brain regions compromised in AD and bvFTD, yielding an excellent accuracy in classifying each group of patients. Brain dynamics turned more “viscous” (uncoordinated) in patients and were associated with multimodal disease progression (years of disease, cognitive impairment, atrophy). Then a whole‐brain Jansen & Rit model simulated the functional disturbances in AD and bvFTD. The DTI connectome disintegration (reduced structural integration) and hypoexcitability (altered excitation/inhibition balance) triggered the metaconnectivity dynamics observed in AD and bvFTD. Finally, in‐silico stimulation identified key regions involved in the transition from disease (AD and bvFTD models) to a healthy brain dynamics.ConclusionOur work suggests new possible EEG markers for characterizing AD and bvFTD, linking the functional disturbances in patients to alterations in the connectome and E/I balance, and evidencing possible anatomical targets to restore the normal brain function.
Establishing the DementiaBank Delaware Corpus: An Online Multimedia Database for the Study of Language and Cognition in Dementia
Authors: Lanzi Alyssa M , Saylor Anna K , Fromm Davida , MacWhinney Brian , Cohen Matthew L 
Published: December 2023

AbstractBackgroundTo better understand the progressive decline of language abilities in aging and dementia, we expanded the quality and quantity of resources in DementiaBank — an open‐access database of multimedia spoken language interactions for the study of speech and language abilities across the progression of dementia. This work builds from the success of the TalkBank Project with regard to data sharing, transcription, analysis, and web delivery. Specifically, this work collected connected speech and language data to develop the new “Delaware corpus” and to share resources for future analyses.MethodsCognitively unimpaired adults (n = 20) and adults with mild cognitive impairment (MCI) (n = 35) completed the DementiaBank discourse protocol and a cognitive‐linguistic battery in a 90‐minute session by Zoom with an administrator. The discourse protocol elicited four types of discourse: picture description, story narrative, procedural discourse, and personal narrative.ResultsThe new Delaware corpus is available on the DementiaBank website. Data include spoken language CHAT transcripts linked to audio, test results, and medical/demographic information for 55 participants. CHAT is a standardized format for transcription and coding that is compatible with the CLAN language analysis software. CLAN provides methods for linking transcripts to media and automatic computation of a wide range of morphosyntactic features and other complex linguistic analyses. Additional resources include an automatic speech recognition pipeline code with tutorials to help streamline the transcription process and a collaborative commentary system that allows consortium members to insert comments or codes directly into online transcripts linked to media files. The collaborative commentary system is beneficial for training research assistants in coding techniques and for collaborative analysis of discourse samples.ConclusionsDetailed digital measurement of speech and language abilities of older adults with and without mild cognitive impairment may help advance research and clinical practice by expanding the subtyping of MCI to include speech/language profiles. Open‐access databases, like DementiaBank, facilitate research collaborations, support advancements in computational analyses, and improve research dissemination to advance dementia science. The next steps for this project involve recruiting more researchers, clinicians, and students to use the new protocol and contribute their data to grow the database.