bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual level prediction of cognitive impairment status from neuronal networks using machine learning in the Alzheimer’s Disease Connectome Project
Authors: Kulkarni Arman P. , Adluru Nagesh , Nair Veena A. , Li Shi‐Jiang , Meyerand Elizabeth M. , Alexander Andrew L. , Bendlin Barbara B. , Prabhakaran Vivek 
Published: February 2022

AbstractBackgroundAlzheimer’s disease dementia (AD) and mild cognitive impairment (MCI) are characterized by degeneration of myelinated axonal fiber bundles which subserve network connectivity, and degeneration of which ultimately leads to the dementia syndrome. Most of the prior disease related findings derived from diffusion weighted magnetic resonance imaging (dMRI) are based on group comparisons, although individual‐level measures of abnormality would have greater clinical utility as well as serve clinical trial enrichment and provide novel outcome measures. In this study, fiber bundle capacity (FBC) was employed to derive a proxy for “communication bandwidth” between brain regions based on dMRI. The purpose of this study was to perform a preliminary investigation of individual level predictive value of FBC based neuronal networks in the Alzheimer’s disease connectome project using machine learning.MethodMulti‐shell dMRI data (Table‐1) were processed using a state‐of‐the‐art ‘connectography’ pipeline using FSL, ANTS and MRtrix3. The IIT‐Desikan atlas with 84 nodes was used to derive 3486 neuronal connections (FBC‐edges). FBC‐edges, after feature preprocessing, were input into a stratified three‐fold nested leave‐one‐out cross‐validation framework with a random forest classifier for binary classification (cognitively unimpaired (CU) vs. MCI/AD). Recursive feature elimination was employed in the outer loop to aid with the interpretation of predictive features. Receiver‐operating‐characteristic curves were derived per outer fold, and the area under the curves (AUC) were reported.ResultThe average AUC was 0.73 as shown in Fig‐1, with additional cross‐validation accuracies and test‐set accuracies shown in Table‐2. The top (20) features per outer fold are reported in Fig‐2.ConclusionFBC based neuronal networks offer significant predictive value in differentiating the MCI/AD brain from that of the CU brain at an individual level, indicating alterations in information pathways across the brain. Depending on the fold, there were alterations in FBC connections 1) involving the right parietal lobe, and in particular, the precuneus to the left parietal lobe, 2) parietal‐parietal, parietal‐temporal, and parietal‐frontal interactions, and 3) left parietal interactions and intratemporal interactions. Connections of the precuneus with other nodes were predominant across all folds. Future work will determine the extent to which these metrics are predictive of amyloid burden among individuals with asymptomatic preclinical AD.
Unfolding the medial temporal lobe to characterize neurodegeneration due to Alzheimer's disease pathology
Authors: Ravikumar Sadhana , Wisse Laura , Lim Sydney A. , Ittyerah Ranjit , Xie Long , Bedard Madigan L. , Das Sandhitsu R. , Irwin David J. , Lee Eddie B. , Tisdall Dylan M. , Prabhakaran Karthik , Detre John A. , Trojanowski John Q. , Robinson John , Schuck Theresa , Grossman Murray , Mizsei Gabor , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , del Mar Arroyo Jimenez Maria , Munoz Monica , Romero Francisco Javier Molina , del Pilar Marcos Rabal Maria , Sanchez Sandra Cebada , Gonzalez Jose Carlos Delgado , de la Rosa Prieto Carlos , Parada Marta Corcoles , Wolk David A. , Insausti Ricardo , Yushkevich Paul A. 
Published: February 2022

AbstractBackgroundMeasurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we directly link changes in MTL structure to underlying NFT pathology by combining ex vivo MRI with ratings of NFT severity derived from serial histology using a dataset of 18 human MTL specimens. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.MethodEx vivo specimens from 18 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. Following MRI scanning, the specimens underwent histological processing with staining for cytoarchitecture and in 15 specimens, immunohistochemistry (IHC) with the anti‐tau AT8 antibody. Using a topological unfolding method (DeKraker et al. 2018), we created 2D representations of the extra‐hippocampal cortex which implicitly align cortical folding patterns across specimens (Fig. 1). An average MTL subregion segmentation was generated in unfolded space using manual segmentations completed in 11 specimens on the basis of cytoarchitecture. Additionally, heat maps quantifying NFT burden in each of the specimens with anti‐tau IHC sections were generated using a deep learning algorithm (Yushkevich et al. 2021). Using the heatmaps and the average subregion segmentation, we investigated the relationship between NFT severity and cortical thickness.ResultCorrelation analysis between NFT measures and thickness (correcting for age) reveals strong associations in the entorhinal cortex and the border of Brodmann Area 35, consistent with the early Braak regions, and parts of Brodmann Area 36 (Fig. 2).ConclusionWe present an unfolding framework applied to the MTL cortex, which allows us to visualize, for the first time, the distribution of MTL subregions and NFT pathology in an unfolded space. This framework provides a promising tool for detailed investigation of structural changes due to NFT pathology while explicitly accounting for the complex topology of the MTL, thereby enhancing our understanding of early AD.
Characterization of vascular dementia with TMS: A systematic review and meta‐analysis
Authors: Salcido‐Montenegro Alejandro , Quintanilla‐Sanchez Carolina , Nañez‐Terreros Homero 
Published: February 2022

AbstractBackgroundVascular dementia (VaD) is the second most common cause of dementia. However, the variety of lesions in different vessels make VaD heterogeneous. VaD has been studied using transcranial magnetic stimulation (TMS) in patients with multi‐infarct dementia, subcortical ischemic vascular dementia (SIVD), and with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is, however, some controversy about the reported impairment in cortical excitability and cortical circuits in VaD(1–5). Therefore, we reviewed systematically TMS characterization in patients with VaD.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to VaD and TMS and was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies, comparing any type of VaD to healthy controls (HC) using TMS. Case reports and series were excluded. Risk of bias was assessed using QUADAS. Meta‐analyses comparing various TMS parameters between VaD and HC were conducted. Demographic data (age, sex, comorbidities, years of education, onset age, diagnosis information), subtype of vascular dementia, reference standard, and TMS parameters were extracted.ResultAfter duplicates were removed our search yielded 216 results. After applying the eligibility criteria, 26 articles were fully screened and finally 8 articles were reviewed and included in the meta‐analysis(4–11). A total of 145 patients with VaD were analyzed, and most of them had SIVD (69.65%) and CADASIL (11.72%); 140 HC were also analyzed. When compared VaD patients to HC, the mean differences of resting motor threshold (RMT) and short‐latency afferent inhibition (SAI) values were statistically significant (Fig 1‐2).ConclusionThis is the first systematic review to describe the differences of TMS parameters between patients with VaD and HC. RMT and SAI values were significantly altered in patients with VaD suggesting that both cortical excitability and cholinergic transmission are affected. These parameters could be further used to understand the impact of vascular events in neurotransmission. Furthermore, because of the difficulty of detecting vascular lesions in structural imaging studies, TMS characterization may allow a clearer diagnosis of VaD.
Association between basal forebrain tau and memory in older adults without dementia
Authors: MacAlpine Maiya F. , Bañuelos Cristina , Resnick Susan M. , Bilgel Murat , Shafer Andrea T 
Published: February 2022

AbstractBackgroundTau pathology is a hallmark of Alzheimer’s disease and can be assessed in vivo using 18F‐Flortaucipir positron emission tomography (PET). Recent literature suggests a role of the basal forebrain (BF) early in tau accumulation pathways, but knowledge on BF tau and cognition is limited. We assessed the utility of BF flortaucipir PET signal and its relationship with cognition in a sample of individuals without dementia.Method114 older adults in the Baltimore Longitudinal Study of Aging underwent flortaucipir PET imaging. Standardized uptake value ratio (SUVR) was computed in regions of interest (ROI’‐s) (BF, entorhinal cortex (EC), hippocampus (HC)) and in a control region with no tau pathology (4th ventricle, including choroid plexus). 110 participants had concurrent and prospective cognitive testing (memory). The relationship between BF SUVR and cognition was assessed with correlation and linear mixed effects models.Result4th ventricle SUVR was positively associated with SUVR of the EC (Pearson’s r=.33, p<.001) and HC (r=.55, p<.001), but not the BF (r=.16, p=.10). In unadjusted analyses, higher BF SUVR was associated with amyloid positivity (difference in means=.12, p=.01) and lower memory (r=‐.21, p=.03) at baseline. There was no association between baseline BF SUVR and concurrent or prospective change in cognition once adjusted for age, sex, and education.ConclusionThe lack of a relationship between BF and 4th ventricle SUVR may indicate lower susceptibility of BF to non‐specific binding signal spillover compared to the EC and HC. BF SUVR was associated with amyloid positivity and memory in the expected directions, but the association with memory was not statistically significant after controlling for factors relevant to cognition. Further analysis is necessary to assess whether the lack of an association with cognition is due to limited statistical power.
Towards fingerprinting and identifiability within the Alzheimer’s continuum using resting‐state functional connectivity
Authors: Stampacchia Sara , Asadi Saina , Ribaldi Federica , Tomczyk Szymon , Altomare Daniele , Pievani Michela , Frisoni Giovanni , Amico Enrico , Garibotto Valentina 
Published: February 2022

AbstractBackgroundResting‐state functional connectivity (FC) has been extensively investigated in AD and yet its susceptibility to noise prevents its use as biomarker. Moreover, previous studies focused on group averages, overlooking heterogeneity among individuals and often lacked characterisation of amyloid and tau pathology. Recently, it has been showed that FC‐patterns are reliable across test‐retest in the healthy, and that they can be used to identify a given individual from a population (Finn et al., 2015), hence constituting a “fingerprint”. Yet, it is unclear whether FC‐fingerprints could be used for mapping disease from human brain data. To this aim, here we investigate the associations between brain connectivity fingerprints and measures of AD pathology.MethodWe analysed memory‐clinic individuals having rs‐fMRI (N=85) and explored associations with ATN biomarkers and clinical measures – acquired within a maximum gap of 20 months – using structural MRI, amyloid‐PET, tau‐PET and neuropsychology. For each participant, a functional connectome (FC) was computed as matrix of pairwise Pearson correlations between 278 grey‐matter regions. FC‐fingerprint was computed as (i) test‐retest reliability across the first 100 and second 100 volumes within the same scan (I‐self) and (ii) similarity scores of each patient’s FC profile against controls (N=16 cognitively unimpaired amyloid negative; I‐clinical). FC and FC‐fingerprint measures were extracted within‐and‐between 7+1 cortical and subcortical resting state networks.ResultFC‐patterns resembled those previously found in the literature, i.e., reduction in FC for cognitively impaired (CI, N=61) vs. unimpaired (CU, N=24) in the Default Mode network (DMN) yet comparisons did not survive FDR 𝛼=.05. All cases showed higher similarity with themselves (I‐self) as opposed to others, with no differences across groups, confirming the reliability of fingerprinting in AD. I‐clinical (i.e., similarity to controls) was significantly higher in CU+ (N=8; CU amyloid or tau positive) vs. CI (N=61) in Salience, DorsalAttention‐Frontoparietal and Salience‐Frontoparietal networks (FDR 𝛼=.05), showing deviation from normality. Finally, while FC measures were not significantly associated with AD biomarkers, we found associations between I‐clinical and I‐self with ATN measures (Amyloid & TauSUVRs and hippocampal volume; FDR 𝛼=.05).ConclusionThese results suggest that FC‐fingerprinting could constitute a new promising biomarkers of brain dysfunction in AD.
Baseline neuroimaging characteristics in the randomized pivotal study of renew NCP‐5 for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease or mild dementia of the Alzheimer's type
Authors: Salat David H. , Almaktoum Randa , Helfgott Jonathan S. , Helmer Karl G. , Jacoby John , Jang Ikbeom , Juttukonda Meher R. , Loveley Allison , Moreno Tom , Peled Noam , Stufflebeam Steven , Greve Douglas N. 
Published: February 2022

AbstractBackgroundRenew NCP‐5 is an FDA‐cleared, external counterpulsation (ECP) device used clinically to improve coronary and peripheral vascular hemodynamics by sequential compression and decompression of vascular beds in synchrony with the cardiac cycle. NCP‐5 treatment may have a beneficial effect on disorders of blood flow including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We describe here the baseline neuroimaging characteristics of the participants from a randomized pivotal study of Renew NCP‐5 for the treatment of MCI due to AD or mild dementia of the Alzheimer's type.MethodNeuroimaging was conducted across ten sites in the United States for safety screening, baseline imaging assessment including disease severity, and for acquisition of exploratory neuroimaging markers of treatment modification. Imaging protocols were based on the cross‐platform protocols developed for the Alzheimer's Disease Neuroimaging Initiative (ADNI3). Participant characterization and exploratory outcome neuroimaging measures included T1‐weighted hippocampal volume and arterial spin labeling‐based measures of cerebral blood flow (CBF).ResultBaseline structural data were acquired in 97 participants in the NCP‐5 group, and 89 participants in the active sham group. ASL data were available on a subset of scanners and acquired in 60 participants in the NCP‐5 group and 48 participants in the active sham group. Baseline neuroimaging assessment revealed expected variation with age and disease severity in the total cohort. A difference in baseline hippocampal volume and CBF was detected between the randomized groups with the NCP‐5 group having reduced measures (reduced hippocampal volume and reduced CBF) compared to the active sham group. These effects were apparent when splitting the treatment groups by disease severity and cardiovascular risk.ConclusionWe present here the baseline characteristics for the participant cohort for the randomized pivotal study of Renew NCP‐5 for the treatment of MCI due to AD or mild dementia of the Alzheimer's type. Imaging measures were in accord with expected directional effects for age and for disease. There was an unexpected difference between the NCP‐5 treatment and active sham group at baseline with the NCP‐5 group having greater neurodegeneration. Longitudinal imaging data are being examined in ongoing work.
Loneliness, social connectedness, and resilience during COVID pandemic among those with and without cognitive impairment
Authors: Padala Kalpana P , Wilson Kerrie B , Jendro Ashlyn M , Crawford Christina G , Gauss C Heath , Das Aparna , Padala Prasad R 
Published: February 2022

AbstractBackgroundLoneliness in older adults is multifactorial. Social connectedness and resilience are protective against loneliness and have been adversely affected by the COVID pandemic. The objective was to measure loneliness in older adults with and without cognitive impairment and to compare the interaction of loneliness with resilience and social connectedness in these subgroups.MethodsA cross‐sectional study was conducted in community dwelling older adults (N=254) (November 2020‐ongoing). Demographic data were collected along with variables related to social determinants of health. Loneliness was assessed with the 3‐item loneliness questionnaire, resilience with the Brief Resilience Coping Scale (BRCS) and social connectedness using the 6‐item Lubben social network scale.ResultsMean age was 74.6 (±8.0) years, 93.7% male, 50.8% rural, 79.5% Caucasian, and 17.3% African American. Mean education was 14 years (±2.4). The majority of the participants reported loneliness (57.5%). Mean Lubben social network score was 14.7 (±7.1) and mean resilience score was 15.0 (±4.1). Loneliness was higher in those living alone compared to those living with someone (5.6 vs. 4.6, p<0.001, 95% CI: ‐1.6, ‐0.48). There were strong negative correlations between social connectedness and loneliness (p<0.001, r=‐0.43) and resilience and loneliness (p=0.001, r=‐0.19). Compared to those without cognitive impairment (N=151), participants with cognitive impairment (N=101) had a significantly lower mean social network score (p=0.007, 95% CI: 0.69, 4.23). Compared to those without cognitive impairment, participants with cognitive impairment had lower mean resilience score, however the difference was not statistically significant (p=0.080, 95% CI: ‐0.11, 1.97). T‐MoCA and FAQ mean scores for the cognitively impaired older adults were 15.2 (±4.6) and 8.0 (±9.3), respectively. The strong negative correlation between resilience and loneliness scores persisted in the subgroup with cognitive impairment (p=0.028, r=‐0.22).ConclusionsLoneliness was commonly reported among older adults during the COVID pandemic. Loneliness was negatively correlated with social connectedness and resilience. Compared to cognitively intact counterparts, those with cognitive impairment reported significantly lower social connectedness. This finding indicates that those with cognitive impairment may need more attention during natural disasters that foster physical separation.
Determination of diagnostic cutoffs for tau‐PET: A preliminary study based on tau and beta‐amyloid PET measurements
Authors: Pereira Helena Rico , Ferreira Hugo Alexandre 
Published: February 2022

AbstractBackgroundAlzheimer’s Disease (AD) is characterized by abnormal concentration of beta‐amyloid (AB) and tau proteins which can be assessed using positron emission tomography (PET). Currently, no relative standardized uptake value (rSUV) cutoff defines an AD diagnostic tau‐PET, and the literature is mainly focused on defining a cutoff per Braak stage which correlates with disease progression.MethodIn this study, we used tau‐rSUV values of cortical and subcortical regions to define three diagnostic cutoffs for tau‐PET using age‐ and gender‐matched data (average age = 72.9 ± 7.36 y.o.; gender = 56.1% male) of AD and mild cognitive impairment (MCI) patients, and cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative. The diagnostic groups were: 1) CN (n = 54) vs MCI and AD (nMCI = 46, nAD = 14); 2) AB negative CN (n = 35) vs AB positive MCI and AD (nMCI = 26, nAD = 12); and 3) AB negative (n = 87: 65 CN, 20 MCI, 2 AD) vs AB positive (n=73: 36 CN, 26 MCI, 12 AD).Tau‐rSUV values were normalized for each region volume using the inferior cerebellum as a reference. Regions that provided significant differences in rSUV values between the diagnostic groups were considered to compute a composite tau‐rSUV value. Then, for each case, a cutoff value was defined using the composite tau‐rSUV value that maximizes the chi‐square statistic value with the highest significance.ResultFor the case CN vs (MCI+AD) the diagnostic cutoff tau‐rSUV value was 1.10 (Qui‐square = 19.9; p‐value < 0.001); for AB negative CN vs AB positive MCI and AD the cutoff tau‐rSUV was 1.16 (Qui‐square = 30.3; p‐value < 0.001); while in AB negative vs AB positive the cutoff tau‐rSUV was 1.21 (Qui‐square = 31.0; p‐value < 0.001).ConclusionOur diagnostic cutoff tau‐rSUV values are within the interval of values [1.19 to 1.34] previously reported [1]–[3]. The results highlight that the cutoff values are related to AB status: if the latter is unknown, the cutoff may be more restricted; while the third cutoff indicates that AB negative MCI and AD subjects already show the presence of tau protein.
Reduced brain atrophy by gamma sensory stimulation in Alzheimer’s disease patients
Authors: Hajos Mihaly , Megerian Jonathan Thomas , Hempel Evan , Vaughan Brent , Malchano Zach 
Published: February 2022

AbstractBackgroundAccelerated brain atrophy, correlating with cognitive decline and loss of function in Alzheimer’s disease (AD) patients compared to age‐matched healthy subjects is well established. Since recent experimental findings demonstrated that sensory‐evoked brain gamma oscillation reduces brain atrophy and neurodegeneration in AD‐related transgenic mice, effects of gamma sensory stimulation were explored on brain volumetric changes in AD patients.MethodPatients with clinical presentation ranging from prodromal to MCI and mild‐moderate AD (MMSE 14‐26, inclusive; n=74) were randomized 2:1 to receive daily, one‐hour, EEG‐calibrated, 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Brain volumetric changes, including whole brain (excluding CSF/ventricles), lateral ventricle and hippocampal volumes were assessed by MRI, taken at baseline and after 6‐months of treatment. Assessments of occipital and temporal lobe volumes and temporal lobe composite cortical thickness are currently in progress.ResultQuantitative MR imaging analysis revealed that whole brain volume loss in the sham group (n=19) was 1.5%, comparable to the historic value of 1.12% in this patient population, whereas in active treatment group (n=30) whole brain volume loss was 0.6%, demonstrating a significant, 65% reduction in brain atrophy (p<0.01) by gamma sensory stimulation over a 6‐month period. No significant differences in volumes of lateral ventricles or hippocampi were detected between groups.ConclusionBrain atrophy in patients on the AD spectrum was significantly reduced by gamma sensory stimulation indicate potential disease‐modifying effects of this therapy. These findings are in accord with a recent report of reduced brain atrophy in mild AD patients by applying the same therapy (medRxiv 2021.03.01.21252717).