bluuebunny/crossref_metadata_2025_split huggingface dataset:
An AI‐based approach to detect cognitive impairment from digital voice recordings of neuropsychological assessments
Authors: Amini Samad , Hao Boran , Zhang Lifu , Song Mengting , Gupta Aman , Karjadi Cody , Kolachalama Vijaya B. , Au Rhoda , Paschalidis Ioannis 
Published: December 2022

AbstractBackgroundReliable cognitive impairment screening tools that are easy to administer and minimally time consuming are greatly needed. Given the high sensitivity of neuropsychological (NP) exams in detection of cognitive decline, we seek to develop an automated screening tool to detect dementia and mild cognitive impairment (MCI) based on digital voice recordings of NP assessments. This could enable wide‐spread screening for dementia and accelerate preventative efforts.MethodWe used natural language processing methods to create a screening tool that identifies different stages of dementia based on automated transcription of digital voice recordings. The transcribed sentences were classified into 8 main sub‐tests including memory assessment, naming and language skill, verbal fluency, general questions, etc. Using the idea of transfer learning, we encoded the participants' sentences into quantitative data. This data and the participants’ demographic variables such as age, sex, Apoe gene, and education were employed to train and test three binary classification tasks, (I) Normal cognition versus Dementia, (II) Normal/MCI versus Dementia, and (III) Normal versus MCI.ResultWe evaluated the performance of the classification tasks using the digital voice recordings of NP assessments, collected from the Framingham Heart Study, containing 410 cognitively intact subjects, 387 MCI, and 287 subjects with dementia. The average Area Under the Curve (AUC) on the held‐out test data reached 92.6%, 88.0%, and 74.4% for differentiating Normal from Dementia, Normal or MCI from Dementia, and Normal from MCI, respectively. Looking at the importance of the sub‐tests in differentiating MCI from Normal, we note that general questions can be more useful for assessment of MCI, whereas verbal fluency would not be as useful in this task.ConclusionThe proposed approach offers a fully automated identification of MCI and dementia based on a recorded NP test, providing an opportunity to develop a remote screening tool that could be easily adapted to any language.
LatAm Fingers Initiative: Bringing Diversity Upfront
Authors: Crivelli Lucia 
Published: December 2022

AbstractBackgroundLatAm FINGERS is the first Latin‐American non‐pharmacological trial to prevent cognitive decline. It coordinates 12 Spanish and Portuguese‐speaking countries and includes a multicultural heterogenic population. We aim to describe the challenges and barriers of adapting a successful high‐income‐born intervention for an ethno‐racially diverse population.MethodWe identified a tripartite challenge: 1) to guarantee a representative sample of a diverse population. This required the inclusion of low‐educated participants from rural and metropolitan areas with different ethnic backgrounds and standards on normal cognition, sedentarism, and dietary habits, 2) to harmonize our inclusion /exclusion criteria and outcomes with the original FINGER trial and the US POINTER trial, and 3) to provide a feasible intervention program for all included countries. For this purpose, multidisciplinary workgroups of experts from all the participating countries were assembled. Each workgroup was appointed to a specific aspect of the trial (e.g., cognitive outcomes, physical activity, nutrition).ResultThe LatAm fingers trial was launched in December 2021 and is in the recruitment stage. First, cognitive status for inclusion was defined using standardized cognitive measures adjusted for age and education from each region. The second challenge was tackled by including the international tools that are also valid for the 12 countries and replacing others with Latin American analogous tests validated in low‐educated populations. Finally, feasibility was accomplished by adapting the original intervention using a respectful perspective of diverse and cultural assets and exploring opportunities from local products and traditions. For example, the dietary intervention prioritized the use of autochthonous aliments but maintained the properties and composition of the original FINGER diet.ConclusionThe LatAm Fingers trial was able to bring dementia prevention strategies created in high‐income countries to low‐income and low‐educated populations. Our results support that intervention trials are feasible in diverse populations and in Latin America. Furthermore, including investigators from the populations to be included assures a respectful view of cultural characteristics and facilitates adaptation and feasibility.
Deciphering the genetic interaction between klotho and APOE with novel mouse models
Authors: Carter Gregory W , Preuss Christoph , Garceau Dylan , Kotredes Kevin P , Sasner Michael 
Published: December 2022

AbstractBackgroundApolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for LOAD, but APOE4 carriers do not always develop LOAD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klotho harbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models.MethodsWe introduced the human klotho variants into the mouse. Mouse klotho differs at the key amino acid position p.C370S rendering the native mouse haplotype as “KL‐F/S”, matching neither of the observed human haplotypes. We have replaced this native haplotype with the homozygous protective KL‐V/S and common KL‐F/C haplotypes using CRISPR/Cas9. To validate the effects of these klotho haplotypes on klotho secretion, soluble p‐KL serum levels of four month old mice were compared after cheek bleeding using ELISA. We also measured p‐KL in eight month old amyloidogenic App
SAA mutant mice, which have amyloid plaques in the brain.ResultsGenomic modifications in mouse klotho were confirmed by PCR and Sanger sequencing. Secreted p‐KL was decreased in KL‐F/C mice harboring the novel mouse risk haplotype when compared to age matched B6 controls and KL‐V/S mice. In contrast, KL‐V/S mice showed no significant differences in soluble p‐KL serum levels when compared to B6 controls. Secreted p‐KL levels in KL‐V/S mice were significantly elevated when compared to the App
SAA mice, whereas young KL‐F/C mice showed similar levels to the aged App
SAA model.ConclusionsTaken together, these data suggest the native mouse klotho allele may acts similarly to the protective KL‐V/S haplotype, while the KL‐F/C haplotype leads to lower secreted klotho and potentially greater disease risk. These models are therefore suitable for experiments to elucidate how klotho variants protect from LOAD pathologies, and will enable detailed studies of how this protection is specific to the APOE4 genotype.
Blood plasma biomarkers improve prediction accuracy over and above genetic predictors of Alzheimer’s disease
Authors: Stevenson‐Hoare Joshua O , Heslegrave Amanda , Leonenko Ganna , Fathalla Dina , Bellou Eftychia , Luckcuck Lauren , Marshall Rachel , Sims Rebecca , Morgan Paul , Hardy John A. , de Strooper Bart , Williams Julie , Zetterberg Henrik , Escott‐Price Valentina 
Published: December 2022

AbstractBackgroundPrediction models of Alzheimer’s disease using genetic information, such as polygenic risk scores, have been able to reach high levels of prediction accuracy. However, since confirmation of the disease is only possible post‐mortem, these levels of prediction accuracy are typically only achievable in pathologically confirmed cohorts. In living individuals who have been clinically assessed for AD, prediction accuracy by genetics is still good but much lower. Biomarkers can indirectly assess AD pathologies, and so may be able to bridge the prediction accuracy gap. Blood plasma biomarkers may have additional clinical utility as they are cheaper and more accessible compared to traditional CSF or PET methods.MethodWe measured five blood plasma biomarkers known to be linked to AD pathologies (Aβ40, Aβ42, GFAP, NfL, P‐tau181) in a cohort of AD cases (N=1439, mean age 68) and elderly screened controls (N=508, mean age 82). We also gathered information on APOE genotype, age at sample collection, sex, and age at onset and disease duration in cases.ResultLinear regression models showed that all biomarker measurements were associated with age at onset in cases and most were associated with disease duration. Biomarkers were also associated with age at sample collection in both cases and controls, demonstrating their effectiveness for tracking neurological change over time. Using logistic regression, we found prediction accuracies for AD status for each biomarker individually of AUC=0.56‐0.66 and by APOE and PRS AUC=0.73. A model combining all biomarkers had an AUC=0.75. The best prediction accuracy was achieved by combining all biomarkers with genetics and age at sample collection, which reached an AUC=0.81, and explained variance of R2=0.29.ConclusionWe found that blood plasma biomarkers predicted AD status and were associated with disease duration. Furthermore, biomarkers explain some variance not captured by genetic factors and therefore improve accuracy when combined in predictive models. Biomarkers also have the advantage of specificity over clinical assessments, which may confuse dementia subtypes due to phenotype similarity. Therefore, blood plasma biomarkers can be a useful tool for the assessment and prediction of AD on their own or in combination with genetic predictors.
Tau phosphorylation is more closely associated with amyloid‐β plaques than with tau neurofibrillary tangles
Authors: Vermeiren Marie , Therriault Joseph , Servaes Stijn , Lussier Firoza Z , Tissot Cécile , Pascoal Tharick A , Chamoun Mira , Bezgin Gleb , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Stevenson Jenna , Rahmouni Nesrine , Kunach Peter , Wang Yi‐Ting , Arias Jaime Fernandez , Vitali Paolo , Massarweh Gassan , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundWhile fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer’s Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles.MethodWe studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer’s clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI).ResultsWe observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman’s R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package “Cocor”, for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort.ConclusionPhosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework.
Knock‐in of P301L tau homolog in Drosophila leads to neuronal loss and widespread neurodegeneration
Authors: Bukhari Hassan , Feany Mel 
Published: December 2022

AbstractBackgroundMutations in tau protein, such as P301L, play an important role in the pathogenesis of Alzheimer’s disease and frontotemporal dementia. A knock‐in of P301L tau homolog in Drosophila led to extensive neuronal loss and widespread neurodegeneration.MethodThe human P301L tau homolog in Drosophila, P251L tau, was knocked in by using CRISPR/Cas9 gene editing. Markers of neurodegeneration were quantified by immunostaining. Mitochondrial bioenergetics was quantified by a seahorse analyzer. Single‐cell RNA sequencing analysis was done on the 10 days old P251L tau and control Drosophila brains.ResultThe results show that the P251L tau Drosophila brain shows an age‐dependent increase in DNA damage compared to the control. Other markers of neurodegeneration such as vacuolation, proliferating cell nuclear antigen (PCNA) and tau inclusion bodies were also found to be elevated in the tau P251L Drosophila brain. Furthermore, a decrease in mitochondrial bioenergetics, oxygen consumption rate, and extracellular acidification rate was also found in the P251L tau compared to the control Drosophila brain.ConclusionThe CRISPR/Cas9 mediated knock‐in of human P301L tau homolog in Drosophila leads to extensive neuronal loss and widespread neurodegeneration.
The Brain Health Platform: Combining Resilience, Vulnerability and Performance to assess brain health and risk of Alzheimer’s disease and related disorders
Authors: Galvin James E , Kleiman Michael J , Chang Lun‐Ching 
Published: December 2022

AbstractBackgroundOne of the great challenges in conducting ADRD research in community samples is the standardized measurement of medical, social, and environmental factors that may increase the risk of ADRD (vulnerability) or may provide some protective benefits from ADRD (resilience). While all physicians can diagnose mild cognitive impairment (MCI) and ADRD, it is much more difficult to assess the status of brain health and identify those at risk for future impairment. We developed and validated a novel clinical tool, the Brain Health Platform, to quantify brain health and identify risk factors for MCI and ADRD.MethodWe combined the Resilience Index (RI), a brief, quantifiable measure of 6 modifiable factors of brain health and risk of MCI and ADRD, the Vulnerability Index (VI), a weighted measure of cognitive impairment risk that assesses modifiable and non‐modifiable risk factors, and the Number Symbol Coding Task (NSCT), a brief, 90‐second executive task that incorporates attention, planning, and set‐shifting, to measure objective cognitive performance, into the Brain Health Platform to assess overall brain health and the presence of cognitive impairment. We tested this in a combined clinical and research sample (n = 400; 53 controls, 347 impaired) compared with a Gold Standard clinical‐cognitive‐behavioral evaluation.ResultThe Brain Health Platform was able to correctly segregate healthy controls from MCI and ADRD in time‐ and cost‐efficient fashion. We applied a linear discriminant analysis using the NSCT, RI and VI to predict control, MCI and ADRD groups performing 5‐fold cross validation with 1000 replications. The area under the curve for Controls vs MCI was 0.823±0.09, for Control vs ADRD was 0.974±0.03 and for MCI vs ADRD was 0.884±0.06. In an exploratory fashion, we also demonstrated the ability of the Brain Health Platform to assist in differential diagnosis.ConclusionThe Brain Health Platform can intake the inputs of three brief assessments (RI, VI, NSCT) and output a patient risk score to determine the cross‐sectional status of an individual’s brain health, from which effective, personalized, precision‐medicine‐like prevention interventions, including lifestyle changes, medications and clinical trial enrollment, can be implemented in at‐risk individuals to decrease the development or progression of cognitive decline.
Distinct patterns of neurodegeneration after TBI and in Alzheimer’s disease
Authors: Graham Neil SN , Cole James H , Schott Jonathan M , Sharp David J 
Published: December 2022

AbstractBackgroundTraumatic brain injury (TBI) is an established risk factor for dementia, with Alzheimer’s disease reportedly more prevalent post‐injury. Experimental injury models relate axonal injury to the generation of toxic proteinopathies including amyloid and hyperphosphorylated tau, but epidemiological data relating brain injury and Alzheimer’s disease specifically are inconsistent. Using longitudinal volumetric MRI, it is possible to assess commonalities and differences between chronic post‐traumatic neurodegeneration, Alzheimer’s disease and ageing in vivo, to better understand the long‐term consequences of TBI.MethodSerial volumetric T1‐weighted MRI was performed on two occasions a year apart in 55 patients after moderate‐severe TBI, a group of 23 age‐matched healthy volunteers, a group of 15 older healthy controls (healthy ageing group), as well as 45 patients with Alzheimer’s disease alongside 23 age‐matched controls comprising the MIRIAD dataset. Jacobian determinant (JD) brain atrophy rates in white, grey matter and CSF were quantified, spatial patterns defined and systematically compared between the groups. Diffusion imaging was acquired in TBI patients at baseline, facilitating the generation of the fractional anisotropy metric of axonal integrity via diffusion tensor imaging.ResultAtrophy rates were significantly increased in white matter only after TBI (P<0.01), in contrast to increases in both white matter and grey matter in Alzheimer’s disease (P<0.001). Common subcortical white matter regions showed atrophy in both Alzheimer’s disease and TBI, but deep white matter atrophy was TBI‐specific, and cortical atrophy Alzheimer’s disease‐specific. Post‐TBI atrophy patterns were distinct from ageing, which more closely resembled Alzheimer’s disease, and were predicted by the extent of axonal injury on diffusion tensor imaging at baseline (P<0.05).ConclusionNeurodegeneration after moderate‐severe TBI is distinct in location from both ageing and Alzheimer’s disease, with a characteristic central white matter predominance. This likely reflects the underlying spatial distribution of traumatic axonal injury, and may represent ongoing chronic Wallerian degeneration, and/or toxic proteinopathy‐driven neurodegeneration.
Determining best‐in‐practice dyadic discrete choice experiments to enable persons with dementia and informal caregivers to participate in health care decision‐making: a feasibility study
Authors: Wammes Joost D , Swait Joffre , Labrie Nanon , Monin Joan , Grob Esther de Bekker , Vroomen Janet MacNeil 
Published: December 2022

AbstractBackgroundDiscrete choice experiments (DCEs) are a powerful tool that potentially offer a method to quantify individual and joint care preferences of persons with dementia and their informal caregivers. DCE studies that have included persons with dementia revealed that choice task complexity is a serious challenge to this population, which can lead to heuristic decision making. This feasibility study aims to determine best‐in‐practice dyadic DCE design to enable both persons with dementia and informal caregivers to participate in health care decision‐making.MethodThis study included three DCE rounds: (1) persons with dementia alone, (2) informal caregiver only, and (3) persons with dementia and their informal caregivers in dyads. A flexible DCE design was employed, in which choice task complexity was increased systematically to explore individual cognitive limitations in DCE decision making. Choice tasks were presented by illustrations and simplified language to decrease cognitive burden on persons with dementia. A think aloud approach of survey administration was used to provide insights into individual and joint decision‐making processes. The Telephone Interview for Cognitive Status was used for cognitive screening.Results15 persons with dementia, 15 informal caregivers, and 14 dyadic discrete choice experiments were conducted. The majority of persons with dementia (53.3%) was able to complete choice tasks including two scenarios characterized by three attributes and completed on average 6.4 (SD 4.1) choice tasks before dropping out. The dyadic DCEs enabled persons with dementia to complete surveys that were somewhat more complex, and on average a higher number of choice tasks (7.9, SD 3.9). In the dyadic DCEs, informal caregivers assisted the person with dementia to understand the choice task, elicited choice motivation, and provided the means to discuss each other’s preferences.ConclusionPersons with dementia that have a mild to severe cognitive impairment can use discrete choice experiments with low choice task complexity. Dyadic DCEs can enable greater empowerment of the person with dementia while promoting joint decision making. Future work should further explore the mapping of severity of dementia and feasible choice task complexity, to enhance our understanding about designing choice elicitation tasks.