bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurofibrillary Tangles Prediction Based On MRI
Authors: Saifullah Khalid , Tazwar Mahir , Evia Arnold M , Tamhane Ashish A , Bennett David A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2022

AbstractBackgroundNeurofibrillary tangles, one of the hallmark pathologies of Alzheimer’s disease, are closely related to brain atrophy and cognitive decline. The purpose of this work was to develop an MRI‐based classifier of neurofibrillary tangles by combining ex‐vivo MRI and neuropathology in brain autopsies from a large number of community‐based older adults.MethodCerebral hemispheres from 878 older adults participating in three longitudinal, clinical pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), and the Minority Aging Research Study (MARS) (Fig. 1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners, once within 24 hours postmortem and a second time approximately 30 days postmortem followed by detailed neuropathologic examination.An SVM classifier with l2 regularization was trained to distinguish participants at a Braak stage of V‐VI from those at a Braak stage of 0‐IV, based on features extracted from ex‐vivo MRI as well as demographic information (age, sex). The MRI features included volumetric, cortical thickness, subcortical shape, diffusion, and R2 measurements. When a feature contained multiple measurements per person, they were used to train a separate model that generated a separate risk score which was used as a feature in the final model. Because different groupings of features were available on different subgroups of the participants, the performance of the classifier was tested in a total of 74 participants (Fig. 2) that had measurements on all features.ResultThe average AUC of the classifier based on all MRI and demographic features was 0.87 with 82% mean sensitivity and 77% mean specificity (Fig. 3). In comparison, recently published work combining in‐vivo MRI and pathology data trained an MRI‐based classifier of people at Braak stage V‐VI vs. 0‐II and achieved an AUC=0.69 [1].ConclusionSuccessful completion of ex‐vivo to in‐vivo translation of our work may result in a non‐invasive classifier of neurofibrillary tangles aiding in refined participant selection and targeted therapies. Reference: [1] Dallaire‐Théroux, Caroline et al., Braak neurofibrillary tangle staging prediction from in vivo MRI metrics, Alzheimer's & dementia, vol. 11, 2019.
Measuring subtle Blood‐Brain Barrier permeability changes with reduced scan time in DCE‐MRI
Authors: Bae Jonghyun , Ge Yulin , Kim Sungheon Gene 
Published: December 2022

AbstractBackgroundIncreasing evidence suggests the subtle changes of Blood‐Brain Barrier (BBB) permeability in normal aging and in Alzheimer’s disease using Dynamic Contrast‐Enhanced MRI (DCE‐MRI). However, measuring this subtle change poses great challenge for accurate measurement, resulting in inconsistent results among previous studies. Two major challenges are long scan times, as suggested by previous studies and selection of the arterial input function (AIF). In this study, we aim to estimate the capillary level input function (CIF) using a deep learning network to overcome these two challenges.MethodsHealthy volunteers (n= 8, ages: 21‐76) were recruited for DCE‐MRI scan for 28min. Golden‐angle RAdial Sampling Parallel (GRASP) sequence was used to obtain the dynamic images at ∼5s/frame. Individual AIF was sampled from the superior sagittal sinus of the brain (Fig.1a). FSL was used to segment the gray and white matters (Fig.1b). Each voxel was fitted using the graphical Patlak model (Fig.2a) to assess the vascular permeability‐surface area product (PS) for both 28‐min data and 10‐min truncated data. We used a 3x3 kernel sliding through the images (Fig.3) and feed each voxel’s dynamic as the input to our vision‐transformer. Training data were generated using individual AIFs with a mathematical model, consisting of two Gaussian and one exponential function, and used to simulate dynamic patches using the Extended Patlak model (Fig.2b).ResultWhen the 10‐min data are used, the conventional approach with AIF results in overestimation of PS when the scan‐time is reduced, while the network‐predicted CIF allows more accurate estimation, with refence to the results using the 28‐min data, as illustrated by an example in Figure 4. Figure 5 shows the regional permeability differences between young and old subjects, where the conventional approach with AIF does not show the difference, while the approach with CIF shows subtle increases in PS with aging.ConclusionOur proposed CIF‐based approach provides an appropriate input‐function for DCE analysis, allowing assessment of subtle permeability changes in the BBB.
Longitudinal changes in plasma p‐tau181 as a surrogate variable to populational interventions
Authors: Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Benedet Andréa Lessa , Ashton Nicholas J. , Tissot Cécile , Bellaver Bruna , Leffa Douglas Teixeira , Brum Wagner S. , Therriault Joseph , Chamoun Mira , Lussier Firoza Z , Kang Min Su , Stevenson Jenna , Soucy Jean‐Paul , Gauthier Serge , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackgroundIt has already been shown that longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) correlate with longitudinal Alzheimer’s disease (AD) progression. However, it is unclear whether longitudinal plasma p‐tau181 is a suitable measure to be used as a surrogate variable in clinical trials. This study aims to evaluate the utility of using longitudinal changes in plasma p‐tau181 to monitor drug effects in AD clinical trials.MethodWe evaluated 715 individuals (227 cognitively unimpaired (CU) amyloid‐beta (Aβ ) negative, 103 CU Aβ positive, 265 mild cognitive impairment (MCI) Aβ positive, and 120 Alzheimer’s disease (AD) dementia Aβ positive) from the Alzheimer’s Disease Neuroimaging Initiative. Individuals diagnosed with AD or MCI were classified as cognitive impaired (CI). The subjects had [18F]florbetapir Aβ PET at baseline and longitudinal plasma p‐tau181 (up to 4‐year follow‐up duration). We determined the longitudinal rates of change in plasma p‐tau181 concentrations and its effect sizes, calculated as mean change divided by the standard deviation. Logistic regression tested whether the longitudinal change in p‐tau181 status was associated with individuals’ clinical deterioration.ResultPlasma p‐tau181 slope of change was positively associated with baseline plasma p‐tau concentrations (Fig 1). Longitudinal increase in plasma p‐tau181 was correlated with longitudinal worsening in cognition. Long‐term increase in plasma p‐tau181 values was more consistent in CU Aβ negative (48‐month effects size=0.4) and CU Aβ positive (48‐month effects size=0.6) than in CI Aβ positive (48‐month effects size=0.2) individuals (Fig 2).ConclusionMonitoring change in plasma p‐tau181 status from negative to positive can be helpful to identify individuals on the verge of cognitive deterioration in clinical practice. Longitudinal changes in plasma p‐tau181 values can open a new frontier in AD research offering a cost‐effective and scalable alternative to be used as a surrogate variable in large‐scale trials designed to test the effects of population interventions on the natural history of tau pathology in elderly populations.
Extracellular Tau Oligomers Rapidly Induce Nuclear Invagination in Neurons
Authors: Sun Xuehan , Shi Yu , Saibaba Subhi , Mandell James W , Bloom George S 
Published: December 2022

AbstractBackgroundNeuronal nuclei are normally spheroidal with a smoothly contoured surface. In Alzheimer’s disease (AD) and other tauopathies, however, neuronal nuclei often develop deep invaginations that include the nuclear lamina, a meshwork of intermediate filaments on the inner face of the inner nuclear membrane. The lamina is involved in numerous nuclear activities that might be adversely affected by invagination, including chromatin organization, nucleocytoplasmic trafficking of macromolecules, cell cycle regulation and apoptosis. Previous work showed that in vivo expression of pathogenically mutated human tau in Drosophila melanogaster neurons causes nuclear lamina invagination and that invaginated neuronal nuclei are found in human AD brain (Frost, et al. 2016. Current Biology 26; 129‐136). In light of this background we sought to shed further light on the mechanism of pathological nuclear invagination in mammalian neurons.MethodLamina invagination was assessed by immunofluorescence microscopy in human and mouse brain tissue, and in cultured mouse neurons using an antibody against lamin B1, a major subunit protein of the nuclear lamina. To ensure thorough neuroanatomical coverage in mouse brain, we stained lateral, medial, and middle sections from each brain, and imaged across the cortical region. To seek stimuli that would cause neuronal nuclear invagination, cultured mouse neurons were exposed to extracellular tau oligomers (xcTauOs).ResultWe detected nuclear invagination in neurons in brains of AD patients and CVN (APPSwDI;NOS2−/−) mice, in the latter of which nuclear invagination in cortical neurons was more frequent than in age‐matched wild type control neurons. In cultured mouse neurons, lamina invagination was induced by xcTauOs within one hour of exposure. This effect of xcTauOs was found to depend on intracellular tau, because nuclear invagination was not detected in neurons derived from tau knockout mice unless they expressed human tau by lentiviral transduction.ConclusionOur data confirm that nuclear invagination is common in both naturally occurring human AD and a transgenic mouse model of AD, and implicate xcTauOs as likely triggers of this phenomenon by a mechanism that also requires intracellular tau.
Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns
Authors: Silva‐Rodríguez Jesús , Labrador‐Espinosa Miguel , Moscoso Alexis , Schöll Michael , Mir Pablo , Grothe Michel J. 
Published: December 2022

AbstractBackgroundIn differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.MethodThe study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr across cases with LB pathology (pure‐LB+AD‐LB).ResultCompared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p<0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.ConclusionIn autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.
Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease
Authors: Guimaraes Fernanda Burle dos Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno 
Published: December 2022

AbstractBackgroundThere is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.MethodWe analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p<0.05 FWE corrected, with subsequent cluster‐level FDR correction p<0.05. In addition, only anatomical regions with more than 10 voxels were described.ResultSignificant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.ConclusionHyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.
Identifying Subtypes of Alzheimer’s Disease: An analysis of possible cognitive subgroups through the life span
Authors: Lima Bruna Seixas , Freedman Morris , Binns Malcolm , Tang‐Wai David F. , Black Sandra E. , Leach Larry , Tartaglia Carmela , Stokes Kathryn A. , Goldberg Yael , Chertkow Howard 
Published: December 2022

AbstractBackgroundTypical Alzheimer’s disease (AD) is linked to memory impairment and medial temporal lobe atrophy. However, different patterns of cognitive decline in individuals with AD have been described in the literature (e.g., Murray et al., 2011; Lam et al., 2013; Scheltens et al., 2015). The variability of AD is also observed throughout the life span, as aging processes develop (Ferreira et al., 2017), which highlights the importance of investigating changes over time and establishing possible stages and therapeutic windows.MethodThe Toronto Cognitive Assessment (TorCA) was used to provide a characterization of cognitive profiles including orientation, immediate recall, delayed recall, delayed recognition, visuospatial function, executive control and language in 609 individuals with possible AD. Normative data for the TorCA (Freedman et al., 2018) suggest different levels of impairment can be identified depending on age groups. The present study investigated 27 neuropsychological subtests within the TorCA. Scores were summed based on cognitive domains and transformed into z‐scores. Further, the dataset was split into 4 age groups (Group 1 = less than 59; Group 2 = 60 to 69; Group 3 = 70 to 79; and Group 4 = over 80 years of age). The scores were analyzed with latent profile analyses (LPA) to identify cluster memberships among subjects.ResultDifferent AD subtypes were identified in each age group characterized by patterns of cognitive impairment as follows:a) Group 1:1. Cluster 1: mild;2. Cluster 2: amnestic;3. Cluster 3: executive;4. Cluster 4: moderate diffuse.b) Group 2:1. Cluster 1: mild diffuse;2. Cluster 2: executive / visuospatial;3. Cluster 3: moderate with preserved orientation and visuospatialc) Group 3:1. Cluster 1: moderate executive;2. Cluster 2: mild diffuse;3. Cluster 3: amnestic;4. Cluster 4: moderate diffuse.d) Group 4:1. Cluster 1: severe diffuse;2. Cluster 2: mild diffuse.ConclusionThese findings suggest that different subtypes of AD can be identified throughout the life span. Further investigation of these differences will aid in the development of clinical tools to diagnose and treat subgroups, in the development of protocols that stratify this population for better research recruitment, and establishing relevant neuropsychological and clinical tools.
Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease
Authors: Burle Fernanda , Guimaraes Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno 
Published: December 2022

AbstractBackgroundThere is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.MethodWe analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p<0.05 FWE corrected, with subsequent cluster‐level FDR correction p<0.05. In addition, only anatomical regions with more than 10 voxels were described.ResultSignificant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.ConclusionHyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.
Intact olfactory and cognitive abilities predict lack of transition to dementia in a biracial sample of older adults
Authors: Motter Jeffrey N , Choi Jongwoo , Lee Seonjoo , Goldberg Terry E. , Devanand Davangere P. 
Published: December 2022

AbstractBackgroundOdor identification deficits predict transition to dementia, whereas intact odor identification and global cognition may identify lack of transition. The purpose of this study is to examine intact odor identification and global cognitive functioning as prognostic indicators of lack of transition to dementia in a well‐characterized biracial (Black and White) cohort.MethodIn a community‐dwelling sample of 2,270 older adults without dementia participating in the Health, Aging, and Body Composition (Health ABC) study, odor identification was measured using the Cross‐Cultural Smell Identification Test (BSIT) and global cognition was measured using the Teng Modified Mini‐Mental Status Examination (3MS), both in Year 3. Incident dementia was defined by diagnosis in medical/hospital records or prescription of anti‐Alzheimer’s disease medications. Survival analyses for dementia transition over 4 years and 8 years were conducted using Cox proportional‐hazards models.ResultSurvival analyses adjusted for demographic and medical covariates indicated that impaired odor identification (hazard ratio [HR] = 2.17, 95% confidence interval [CI] = 1.5‐3.1) and global cognition (HR = 2.75, 95% CI = 1.8‐4.3) each independently predicted transition to dementia (n = 287). Odor identification interacted with ApoE genotype, such that the effect of impaired odor identification on dementia transition risk was significantly greater in ApoE e4 carriers (HR = 4.0) than noncarriers (HR = 1.6). This interaction was significant for White participants, though not for Black participants. Among participants with intact odor identification (BSIT ≥ 11/12 correct) and global cognition (3MS ≥ 77/100 correct), 6.4% (49/765) transitioned to dementia over 8 years of follow‐up. Only 0.9% (4/451) of participants aged 70–75 with intact performance on both measures transitioned to dementia over 4 years of follow‐up.ConclusionOdor identification testing paired with global cognitive screening identified individuals at low risk for transition to dementia in a biracial community cohort with this decrease in risk being pronounced in the seventh to eighth decade of life. Identification of such individuals can obviate the need for extensive investigation to establish a diagnosis and has potential for screening participants for clinical trials.