bluuebunny/crossref_metadata_2025_split huggingface dataset:
A longitudinal structural brain MRI template for non‐demented older adults
Authors: Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Wu Yingjuan , Qi Xiaoxiao , Bennett David A , Arfanakis Konstantinos 
Published: December 2020

AbstractBackgroundOne of the major challenges in constructing a longitudinal structural template of the older adult brain is to ensure spatio‐temporal consistency. Here, a new method was introduced to construct a spatio‐temporally consistent longitudinal template of the older adult brain using high‐quality cross‐sectional older adult data from a large cohort. The new template was compared to templates generated with previously published methods in terms of spatio‐temporal consistency and image quality and showed superior performance.MethodT1‐weighted MPRAGE brain data collected on a 3T MRI scanner from 222 non‐demented older adults (65‐95 age‐range, male: female=1:1) participating in the Memory and Aging Project were used for longitudinal template construction. In Method 1, 10 years wide kernel with constant weight was moved to cover eight age‐ranges (65‐75,68‐78,71‐81,74‐84,77‐87,80‐90,86‐95), each including 58 participants with male:female=1:1. Each age‐ranged data were normalized (SyGN) and averaged, resulting into a longitudinal template with eight time‐points:Rage‐range(Fig.1 steps 1,2,3). Method 2 was a variant of Method 1 and included an initial affine‐registration of individual datasets to the same initial template to limit group biases. This method resulted into a second longitudinal template:Aage‐range
. The proposed method first builds a common population template using data from all participants(65‐95 age‐range) using SyGN registration(Fig.1 steps 1,2,3). Next, the inverse of the non‐linear deformations and the inverse of the shape‐update deformation for participants in each age‐range were concatenated and averaged separately. Each resulting deformation was applied to data from corresponding sub‐group and were averaged, resulting into the proposed longitudinal template:Lage‐range. The three longitudinal templates were compared in terms of spatio‐temporal consistency and image quality.ResultThe longitudinal template constructed using the proposed method resulted in the highest spatio‐temporal consistency as illustrated both visually (Figs.2,3) and quantitatively for gray matter, white matter and the lateral ventricles (Fig. 4). Image sharpness was similar across methods (Fig.3). No image artifacts were detected.ConclusionWe introduced a new method for the development of a longitudinal structural template of the older adult brain that exhibited higher spatio‐temporal consistency compared to two previously published methods and was characterized by high image sharpness and no image artifacts. The new longitudinal template is part of the MIITRA atlas (www.nitrc.org/projects/miitra).
Visual impairment and dementia risk in two population‐based prospective cohorts
Authors: Littlejohns Thomas J , Hayat Shabina , Luben Robert , Conroy Megan , Foster Paul J , Kuzma Elzbieta , Khawaja Anthony P 
Published: December 2020

AbstractBackgroundVisual impairment (VI) has been associated with an increased risk of cognitive decline and dementia, however studies using objective measures of visual function are lacking. Therefore, we investigated the association between objectively‐measured VI and risk of incident all‐cause dementia in two large population‐based prospective cohorts.MethodCox‐proportional hazards models were used to assess the association between VI and incident all‐cause dementia in 62,311 UK Biobank (UKB) and 7,506 EPIC‐Norfolk participants aged ≥60 years and dementia free at baseline. In both cohorts, visual acuity was measured with habitual correction (glasses or contact lenses) using a logarithm of the minimum angle of resolution (LogMAR) chart with the participant sitting 4 metres away. VI was defined as a score of ≥0.24 LogMAR, which is the threshold used to meet UK driving standards. In both cohorts, incident dementia was ascertained through cohort‐wide linkage to longitudinal hospital inpatient and death registry records, and, additionally, mental health data in EPIC‐Norfolk.ResultIn UKB and EPIC‐Norfolk, respectively, 3,918 (6.3%) and 470 (6.2%) participants were visually impaired at baseline, and over 8 years (mean=6.5) and 14.5 years (mean=9.6) of follow‐up, 373 and 535 participants developed all‐cause dementia. In UKB, VI was associated with double the risk of developing all‐cause dementia when adjusting for age, sex, ethnicity, socioeconomic status, education, alcohol consumption, smoking, body mass index, self‐reported diabetes and cardiovascular disease (Hazard Ratio (HR)=2.06, 95% Confidence Interval (CI) 1.54‐2.75). In EPIC‐Norfolk, VI was associated with almost a 50% increased risk of developing all‐cause dementia when adjusting for the same covariates (HR=1.49, 95% CI 1.16‐1.92). After excluding participants who were diagnosed with all‐cause dementia within the first three years of follow‐up to account for reverse causation, the HRs were 1.86 (95% CI 1.32‐2.61) and 1.44 (95% CI 1.10‐1.88) in UKB and EPIC‐Norfolk, respectively.ConclusionIn two large, independent, cohorts of healthy, late middle‐ to older‐aged adults, VI was associated with an increased risk of developing all‐cause dementia. These findings suggest that VI could potentially be a modifiable risk factor for dementia or target for identifying those at high risk of the condition.
Tau pathology, relative cerebral flow and cognition in dementia with Lewy bodies
Authors: Wolters Emma E. , van de Beek Marleen , Ossenkoppele Rik , Verfaillie Sander C.J. , Coomans Emma M. , Timmers Tessa , Visser Denise , Tuncel Hayel , Golla Sandeep S.V. , Windhorst Albert D. , Scheltens Philip , van Der Flier Wiesje , Lemstra Afina W. , Van Berckel Bart N.M. 
Published: December 2020

AbstractBackgroundDementia with Lewy Bodies (DLB) is characterized by the presence of neuronal inclusions containing alpha‐synuclein proteins, and often co‐occurs with Alzheimer’s disease (AD) pathology. We aimed to determine the pattern of tau pathology and relative cerebral blood flow (rCBF) in DLB, compared to AD and controls, and their association with cognitive impairment using a single dynamic [18F]flortaucipir PET scan.MethodEighteen patients with DLB (66 ± 8 years, MMSE 25 ± 4, 44% amyloid positive (abnormal CSF (Aβ42 <813 pg/mL)/visual read amyloid‐PET), 100% FP‐CIT SPECT abnormal, Table 1), 65 amyloid positive cognitively impaired patients (MCI‐AD (n = 13), AD (n = 52)) and 50 controls underwent a dynamic 130‐minute [18F]flortaucipir PET scan. Receptor parametric mapping (cerebellar gray matter reference region) was used to extract (regional, Hammers based) binding potential (BPND) and R1, which reflect tau pathology and rCBF, respectively. We performed voxel‐wise comparisons (Puncorrected < 0.001) of [18F]flortaucipir BPND and R1 between diagnostic groups using SPM, adjusted for age and sex. DLB patients underwent extensive neuropsychological assessment covering memory, executive functioning, language, attention and visuospatial domains. For DLB only, we performed linear regression analyses between [18F]flortaucipir BPND, R1 and cognition in the following regions‐of‐interest (ROIs); medial and lateral temporal/ parietal, occipital and frontal cortex, adjusted for age, sex and education.ResultAveraged [18F]flortaucipir BPND images across groups showed visually minimal tau uptake in the inferior temporal lobe in DLB (Figure 1). Voxel‐wise comparisons showed lower [18F]flortaucipir R1 in the occipital lobe in DLB compared to AD and controls (Figure 2). Regional [18F]flortaucipir BPND was lower in DLB compared to AD and comparable with tau binding in controls (Figure 3). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p<0.01, Figure 3). R1 but not BPND was related to cognition (language only); lower medial temporal (stß = 0.76, p = 0.001), medial parietal (stß = 0.64, p = 0.02) and frontal (stß = 0.64, p = 0.02) R1 was related to lower language score (Figure 4).ConclusionIn our sample, tau load in patients with DLB did not differ from controls, but there were DLB‐specific occipital and lateral parietal flow reductions compared to both controls and AD patients. Our results indicate that rCBF may be of more clinical relevance than tau pathology in DLB.
Selective association of neurogranin gene expression with amyloid and tau pathology in the parahippocampal gyrus in Alzheimer’s disease
Authors: Sun Xiaoyan , Wang Qian , Blennow Kaj , Zetterberg Henrik , McCathy Micheline , Loewenstein David A. , Yue Zhenyu , Zhang Bin 
Published: December 2020

AbstractBackgroundBrain region‐specific neuronal and synaptic damage is associated with clinical symptomatology and pathogenesis of Alzheimer’s disease (AD). The mechanism underlying such regional vulnerability in AD remains elusive.MethodPublic access datasets from the Mount Sinai NIH NeuroBioBank (MSBB), The Religious order Study and the Memory and Aging Project(ROSMAP) and the Harvard Brain Tissue Resource Center (HBTRC) were used in this study. Using a large‐scale transcriptomic dataset from the prefrontal cortex (BA 10, 261 samples), the superior temporal gyrus (BA 22, 240 samples), the parahippocampal gyrus (BA 36, 215 samples) and the pars opercularis (BA 44, 222 samples) of MBSS post‐mortem brains of AD and normal control subjects, we studied the association of the post‐synaptic protein neurogranin (NRGN) gene expression with amyloid and tau pathology (plaque and tangle counts), clinical dementia scale (CDR), and pathological diagnosis of AD. Integrative gene network analysis was conducted by using a combination of the datasets from three brain banks.ResultWe show that NRGN gene expression in post‐mortem brain is associated with the certainty of pathological diagnosis of AD, and negatively associated with amyloid and tau pathology only in parahippocampal gyrus among the four brain regions examined. NRGN gene expression in parahippocampal gyrus is also negatively associated with CDR scores. Integrative gene network analysis reveals that the positively correlated genes with NRGN in AD are associated with synaptic transmission and cation channel pathways.ConclusionOur results suggest that synaptic damage in selective brain regions contributes to the clinical phenotype in AD. Understanding of synaptic functional pathways associated with synaptic damage may provide another avenue to prioritize targets for AD.
A new functional biomarker of cognitive impairment in Alzheimer's disease
Authors: Stothart George , Smith Laura 
Published: December 2020

AbstractBackgroundFast Periodic Visual Stimulation (FPVS) provides a new objective electroencephalographic method for assessing an individual’s ability to discriminate between different categories of stimuli. Participants do not need to understand the task, or provide any response, making it ideal for the assessment of cognition in patient populations. We have adapted FPVS to examine a range of cognitive processes that deteriorate in Alzheimer’s disease, see Figure 1, with the ultimate aim of developing a functional biomarker to aid early diagnosis.MethodHealthy younger (n=42, ACE‐III=92 +‐ 6) and older adult controls (n=39, ACE‐III=95 +‐5), and Alzheimer’s disease patients (n=20, ACE‐III=62+‐15) completed a battery of FPVS and behavioural tasks designed to measure their recognition memory, semantic categorisation and visual object processing, see Figure 2.ResultFPVS provided an objective measure of recognition memory, semantic categorisation and visual object processing in just 1min of EEG recording time with no behavioural response or comprehension of the task required. There were no significant differences between younger and older adults in any FPVS measures of cognitive function. Alzheimer’s disease patients showed significant FPVS decreases in all three cognitive domains compared to healthy controls, with the greatest deficits in recognition memory (Old vs Alzheimer’s, t(58)=3.68, p=0.001, Hedge’s g = 1.38). FPVS measures of recognition memory separated AD from healthy ageing in binary classification approaches, outperforming behavioural measures, see Figure 3.ConclusionWe have demonstrated that FPVS can be adapted to measure a range of cognitive functions pertinent to dementia. It provides a fast, objective and implicit measure of cognitive function that remains stable in healthy ageing. Alzheimer’s disease has a significant impact on FPVS measures of cognition, and the approach holds promise for the development of new early diagnosis tools.
A novel MRI contrast agent for identifying hyperphosphorylative neurons as a marker of future tau pathology
Authors: Badachhape Andrew , Parekh Parag A. , Mu Qingshan , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Tanifum Eric , Ghaghada Ketan , Annapragada Ananth 
Published: December 2020

AbstractBackgroundHyperphosphorylated tau (pTau) is a precursor to tau tangle formation in Alzheimer's disease (AD). We have identified aptamers that bind to specific cell membrane receptors of human neuronal cells that are hyperphosphorylating tau. In this work, we built a novel targeted nanoparticle magnetic resonance imaging (MRI) contrast agent, TauX, that binds such neurons, and tested its efficacy in vivo in the P301S mouse model of tau pathology.MethodDNA aptamers preferentially binding on the cell membrane of hyperphosphorylative SH‐SY5Y cells were selected using a modified SELEX protocol. Mass spectrometric proteomic analysis of the bound aptamers was used to identify the binding targets on the cell‐surface, and target presence was validated on both mouse and Alzheimer’s disease patient brain tissues. P301S transgenic mice (n=8) and age‐matched wild type mice (n=6) were intravenously injected TauX contrast agent and imaged by MRI using a T1‐weighted spin‐echo (T1w‐SE) sequence at 2 months of age. An additional control group of transgenic mice (n=8) received untargeted gadolinium nanoparticle contrast agent. T1‐weighted images were acquired on 1T MRI scanner at pre‐ and 4 days post‐contrast injection. Receiver operator characteristic (ROC) curves were generated with a six‐point ordinal scale to assess sensitivity and specificity for TauX. Mice were aged to 8 months and their brains were histologically assessed with AT100 antibody to confirm pTau pathology.ResultTauX‐enhanced post‐contrast images showed MR signal enhancement in most of the transgenic mice that went on to develop tau pathology 4‐6 months later, but not in wild type animals lacking tau pathology (Figure 1). Transgenic mice given untargeted nanoparticle contrast also did not show MR signal enhancement (Figure 1). AT100 staining of P301S cortical brain sections demonstrated elevated pTau levels related to wild type counterparts (Figure 2). ROC curve constructed over the entire tested group, including controls, showed overall AUC and accuracy ∼0.8 (Figure 3).ConclusionA novel MRI contrast agent that can identify mice that develop tau pathology several months in the future has been demonstrated. If successful in humans, this agent could advance the identification of patients at risk of tau pathology to a very early pre‐symptomatic stage of the disease.
Continuous and risk‐score‐based predictors of ATN Alzheimer's disease status among cognitively healthy individuals: Findings from the EPAD‐LCS study
Authors: Calvin Catherine M , de Boer Casper , Raymont Vanessa , Gallacher John , Koychev Ivan G ,   EPAD consortium
Published: December 2020

AbstractBackgroundThe Amyloid/Tau/Neurodegeneration (ATN) framework has been proposed as means of evidencing the biological state of Alzheimer’s disease (AD). Predicting ATN status in pre‐dementia individuals therefore provides an important opportunity for targeted recruitment into AD interventional studies. We investigated the extent to which ATN phenotype can be predicted by known AD risk factors as well as validated risk scores.MethodWe used baseline data from the European Prevention of Alzheimer’s Disease Longitudinal Cohort Study (v1500.0). 1181 participants with complete data (mean age 65±7 years, 57% female) were categorised into four ATN subgroups: no pathology, AD pathologic change, AD pathology, and, non‐AD pathology. Multinomial logistic regression tested composite risk scores (CAIDE, Framingham Vascular and Stroke scores) and the following individual risk exposures for association with ATN subgroups: age, sex, education, APOE e4, family history of dementia, systolic blood pressure, body mass index (BMI), high cholesterol, physical inactivity, smoking, hypertensive medication, prior cardiovascular disease, atrial fibrillation, and white matter lesion volume. ROC curve models were used to estimate the added value of predicting each pathology group according to significant risk factors and composite scores.Result53.4% of the sample showed no brain pathology, 24.0% showed AD pathologic change, 14.1% showed non‐AD pathology, and, 8.5% had biological AD. In age and sex‐adjusted multinomial logistic regression there were significant group effects for age, APOE e4, family history of dementia, BMI, and white matter lesion volume. In ROC models, discriminative accuracy (AUC) in predicting AD pathologic change and AD pathology (vs no pathology), was improved by 4% and 3% respectively after adding family history, BMI and white matter lesion volume to the most basic model (age, sex and APOE e4). Risk composite scores did not add to the models.ConclusionLow BMI and high white matter lesion volume but not established risk scores associated with AD pathology; white matter lesions were also greater in the AD pathologic change group. Specific vascular risk factors, particularly white matter lesion volume, may be of additional value to ATN profiling (i.e. ATN(V) for biological AD in a pre‐dementia stage.
Uncovering the multicausality of Alzheimer’s disease: A systems modeling approach
Authors: Uleman Jeroen , Melis René JF , Hoekstra Alfons , Quax Rick , Rikkert Marcel GM Olde 
Published: December 2020

AbstractBackgroundIn the onset and progression of Alzheimer’s disease (AD), many factors and processes are involved. Our understanding of the multicausal and complex nature of AD may benefit from computational modeling approaches that can be used for knowledge synthesis at the level of the whole system. We have developed a systems dynamics (SD) model of AD.MethodWe have applied the group model building methodology to develop from expert input and literature review a causal loop diagram (CLD) that graphically describes the relationships between important risk factors and proposed causal mechanisms in non‐familial AD from midlife onwards. This CLD was implemented computationally as a SD simulation model.ResultFor the resulting CLD, experts identified 38 variables and 144 connections between them. The experts modeled hypotheses about their relations with a multitude of important processes ranging from amyloid‐β accumulation and cerebral endothelial dysfunction, via physical activity and sleep to social functioning. The SD model was parametrized using empirical information taken from the Global Alzheimer’s Association Interactive Network (GAAIN) and is able to simulate preventive interventions on potentially modifiable risk factors.ConclusionThe CLD and SD model described and quantified hypotheses about relationships and feedback loops implicated in AD onset in a comprehensive way. Our approach showed the potential of systems‐oriented simulation models for studying the complex etiology of AD.
A comparison of methods of defining objective cognitive impairment in preclinical Alzheimer’s disease based on Cogstate One Card Learning accuracy performance
Authors: Pudumjee Shehroo , Lundt Emily S. , Albertson Sabrina M. , Alden Eva , Machulda Mary M. , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Mielke Michelle M. , Stricker Nikki H. 
Published: December 2020

AbstractBackgroundThe numeric clinical staging scheme described by the NIA‐AA workgroup proposes evidence of subtle decline on longitudinal cognitive testing as one option to define transitional cognitive decline for individuals in the Alzheimer’s continuum. Few studies have compared longitudinal and cross‐sectional definitions of subtle objective cognitive impairment (sOBJ). The study aim was to compare the diagnostic accuracy of cross‐sectional sOBJ and longitudinal objective cognitive decline (ΔOBJ) for preclinical Alzheimer’s disease (AD) based on Cogstate One Card Learning (OCL) performance.MethodWe included Mayo Clinic Study of Aging cognitively unimpaired (CU) participants who were A+T+ by amyloid and tau PET assessment (n=32) and A‐T‐ (n=211); all had at least two follow‐up visits. sOBJ was defined as performance ≤ ‐1SD on OCL accuracy using age‐corrected normative data. ΔOBJ was measured using two different methods: (1) within subjects’ standard deviation (WSD) using a ≤ ‐1 z‐score for change to define decline based on Cogstate’s normative change data, and (2) extracted subject‐specific slopes from a linear mixed effects model (LME) which can be interpreted as approximate annual change; decline was defined as slope < 10%ile among a reference sample of CU participants aged 50‐65 at baseline (N=732).ResultssOBJ and ΔOBJ‐WSD both showed low sensitivity in detection of A+T+ (9.4% and 12.5%, respectively). Total AUC values did not differ significantly (p=.31) across sOBJ (AUC = .64, CI = .53‐.75) and ΔOBJ‐WSD (AUC = .53, CI = .42‐.65) methods. Sensitivity of the ΔOBJ‐LME method to predict A+T+ was improved (37.5%) when using a conventional cutoff of <10%ile slope and was further improved (56%) when using an optimal derived cutoff equivalent to <17%ile slope within the reference group. Like the sOBJ method, the ΔOBJ‐LME method differentiated groups better than chance (AUC = .69, CI = .58‐.80). Despite increased sensitivity, total AUC values were not significantly different across sOBJ and ΔOBJ‐LME methods (p=.34). However, total AUC of ΔOBJ‐LME was significantly better than ΔOBJ‐WSD (p=.03).ConclusionsΔOBJ may be more sensitive to preclinical AD than sOBJ and may serve as a helpful method for identifying at risk CU individuals if advanced statistical methods are used for defining change.
Molecular alterations of protein tau in the cingulate cortex of human brain with Alzheimer’s disease
Authors: Apatiga‐Perez Ricardo , De la Cruz Fidel , Garcés‐Ramírez Linda , Hernandes‐Alejandro Mario , Ontiveros‐Torres Miguel Ángel , Luna‐Muñoz José 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) brain tissue at different stages were examined to compare the events of protein tau hiperphosphorilation and its assemble into Neurofibrillary tangles (NFT) in the hippocampus and the cingulate cortex and how this may be involved in the appearance of the Behavioral and Psychological Symptoms of Dementia (BPSD).MethodBrain tissue previously fixed with 4% paraformaldehyde from 7 patients with different stages of AD were examined in this study. Sections were blocked with 0.2% IgG free albumin and the primary antibody (Table 1) was incubated overnight. Secondary antibody HRP was incubated considering the specie and isotype. Finally, the reaction was revealed with 0.0006% 3´3´diaminobenzidine and 0.006% H2O2
ResultThe cases with early stages of AD are morphologically characterized by diffuse and granular deposits of tau aggregate in a non‐fibrillar state in the transentorhinal region of the hippocampus and to a lesser extent in the cingulate cortex. Following this pattern, in cases with mild stage was found in less proportion extracellular NFT (E‐NFT) in CA1 region of the hippocampus, in contrast, there was a major labelling for this antibody in the cingulate cortex but for intracellular NFT. Finally, in moderate AD cases was found E‐NFT both in the cingulate cortex and hippocampus, being the latter where it was observed to a greater extent.ConclusionThere is a direct relationship in the processes of NFT formation and subsequent disease progression between the cingulate cortex and the hippocampus, having its origin in the latter.