bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline blood amylin levels predict longitudinal cognitive decline in participants at risk for or with mild cognitive impairment and dementia
Authors: Jicha Gregory A , Goldstein Larry B , Wilcock Donna M , Despa Florin 
Published: December 2022

AbstractBackgroundAmylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells that co‐aggregates with parenchymal and vascular b‐amyloid in the CNS. Cross‐sectional data shows that higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment and dementia. The present study sought to determine whether baseline blood amylin levels are associated with longitudinal cognitive decline.MethodWhole blood amylin levels were ascertained from 83 participants in a longitudinal cohort spanning the cognitive continuum from normal to MCI and dementia who were evaluated initially in 2017 and followed to present. Cognitive change data including MMSE, MoCA, CDR global and sum‐of‐box scores at baseline and longitudinal follow‐up were analyzed in relation to baseline amylin levels.ResultParticipants were followed for a mean 2.0 ± 1.1 years. Baseline whole blood amylin levels varied widely (mean of 8.8 ± 12.2 pg/ml). Seventy‐one participants had complete baseline and follow‐up data were included in this analysis. Of these, 20 had objective evidence for longitudinal decline. Participants with above vs below modal baseline amylin levels scored lower on baseline and follow‐up assessment scores including MMSE, MoCA, CDR global and CDR sum‐of box scores (p‐values all < 0.05). Annualized cognitive change scores (loss) for the MMSE (1.4 ± 2.4 vs. 0.3 ± 1.3; p < 0.05) and MoCA (1.5 ± 2.5 vs. 0.4 ± 1.8; p < 0.05) were greater in the above median baseline amylin level vs below median groups.ConclusionBaseline amylin whole blood levels are predictive of objective decline in MMSE and MoCA scores over periods as short as 2 years. These data suggest that the higher pancreatic hormone amylin may accelerate disease pathogenesis and cognitive decline as a result of altered pancreatic β‐cell function, potentially explaining, at least in part, the strong epidemiologic link between diabetes and dementia found across global observational cohorts. These data further suggest that the use of amylin biomarkers may serve as a useful tool for identifying subjects at high risk for short term cognitive decline. Additional work elucidating the role of amylin in degenerative disease cascades is warranted.
Bulk and single‐cell gene expression network analysis in mouse models of AD using PyWGCNA
Authors: Rezaie Narges , AD MODEL , Mortazavi Ali 
Published: December 2022

AbstractBackgroundMouse models of human diseases such as Alzheimer disease (AD) are one of the most important tools for studying pathogenic mechanisms and testing interventions and therapeutics. While much of the characterization of gene expression changes to date has been done with “bulk” RNA‐seq in tissues such as hippocampus and cortex, the advent of single‐cell and single nucleus functional genomics assays allow us to analyze those changes at the level of individual cell subtypes. However, we would like to compare the relatively sparse and noisy single‐cell assays to bulk RNA‐seq to deconvolve which cells are driving the changes observed in the previously collected bulk datasets.MethodHere we develop a python package called PyWGCNA that is designed to identify and compare gene expression modules in bulk RNA‐seq data as well as compare them to scRNA‐seq data and snRNA‐seq clusters.ResultAs a proof of concept, we apply this to bulk RNA‐seq of the cortex and hippocampus from 5xFAD as well as matching control mice from MODEL‐AD to identify gene modules associated with the genotype and phenotypes. Comparisons of these modules to single‐nuclei reveal the specific cell‐types driving specific modules in a region‐specific manner.ConclusionThis deconvolution approach allows us to interrogate existing bulk datasets using single‐cell data to look for the signature of cell‐type specific changes in gene expression.
An examination of white matter integrity and functional network organization in Subjective Cognitive Decline using Diffusional Kurtosis Imaging‐based tractography resting state fMRI
Authors: Nowling Duncan , Bustos Nicholas , Barlis Katie L , Crull Jory , Lawson Andrew , Mintzer Jacobo E , Benitez Andreana , Jensen Jens H. , Joseph Jane E 
Published: December 2022

AbstractBackgroundSubjective Cognitive Decline (SCD) may increase the risk of Alzheimer’s Disease and related dementias (ADRD). Brain network changes may occur at both the functional and structural levels in SCD. To better understand these network changes, diffusional kurtosis imaging (DKI) and functional connectome (FC) measures were examined in SCD and healthy controls (HC). We hypothesized that DKI and FC measures in the medial temporal lobe would be sensitive to differences between SCD and healthy controls (HC).MethodSCD classification was determined by clinician evaluation or Everyday Cognition average item score > 1.6, with objectively healthy cognitive performance (Montreal Cognitive Assessment score > 22). DKI and fMRI images were acquired on a Siemens PRISMA scanner in 33 SCD subjects and 33 age/sex matched HCs (mean age=69.1 yr). DSI Studio’s Automatic fiber tracking extracted the DKI measure mean kurtosis (MK) in 3 bilateral white matter bundles associated with ADRD: inferior longitudinal fasciculus (ILF), cingulum‐parahippocampus (CP), and uncinate fasciculus (UF). FC measure eigenvector centrality (Evc) was calculated in 19 medial temporal nodes using the Brain Connectivity Toolbox. Generalized Linear Models were conducted for each bundle to determine whether EVC in the left ventrolateral amygdala (LAMG) was predicted by MK, Diagnosis or the MK*Diagnosis interaction.ResultIn the left ILF, the effect of MK approached significance (p = .054) as did the MK*Diagnosis interaction (p = .059). Lower MK was associated with higher LAMG EVC in HC (r = ‐.40) but there was no association between MK and EVC for SCD. In the left UF, effect of MK was significant (p = .003), but no effect of Diagnosis and no interaction. Lower MK was associated with higher LAMG EVC (r = ‐.359) in both SCD and HC.ConclusionThis preliminary study showed that in HC, white matter integrity of the ILF was associated with LAMG functional connectivity, but this association was absent in SCD. While present results should be interpreted with caution due to small sample sizes, these findings indicate that healthy aging structural‐functional associations are disrupted in SCD, but future studies should determine whether this is a reliable marker of brain organization changes.
Postmortem neocortical 3H‐PiB binding and levels of unmodified and pyroglutamate Aβ in Down syndrome and sporadic Alzheimer’s disease
Authors: Pivtoraiko Violetta , Racic Tamara , Abrahamson Eric E , Villemagne Victor L , Handen Benjamin L , Lott Ira T , Head Elizabeth , Ikonomovic Milos D 
Published: December 2022

AbstractBackgroundIndividuals with Down syndrome (DS) have a genetic predisposition for amyloid‐β (Aβ) overproduction and earlier onset of Aβ deposits compared to sporadic late‐onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound‐B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood.MethodWe performed quantitative in‐vitro 3H‐PiB binding assays and enzyme‐linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N‐terminus truncated and pyroglutamate‐modified AβNpE3‐40 and AβNpE3‐42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43‐63 years and 17 late‐onset AD cases aged 62‐99 years.ResultCompared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3‐40, while the two groups did not differ by Aβ42 and AβNpE3‐42 levels, in both the frontal cortex and precuneus. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3‐42/AβNpE3‐40 in the DS group compared to the AD group, in both cortical regions. Correlations of Aβ42/Aβ40 and AβNpE3‐42/AβNpE3‐40 ratios with CAA severity were strong in DS cases, and weak in AD cases. The two diagnostic groups did not differ significantly by 3H‐PiB binding levels in the frontal cortex or in the precuneus.ConclusionThese results demonstrate that compared to late‐onset AD cases, adult DS individuals with similar burden of cortical Aβ plaques have a preponderance of both pyroglutamate‐modified AβNpE3‐40 and unmodified Aβ40 forms which are associated with greater CAA pathology. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H‐PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. These results underscore the need for development of CAA‐selective PET radiopharmaceuticals in order to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques at the earliest pathology stages in individuals with DS.
Integrity of callosal white matter moderates the relationship between white matter hyperintensities and executive function in older adults
Authors: Marshall Anisa J , Nation Daniel A 
Published: December 2022

AbstractBackgroundWhite matter integrity (WMI) may contribute to brain and cognitive reserve in the face of cerebrovascular disease. We investigated WMI in the genu of the corpus callosum (GCC), an area associated with age‐related WMI and cerebrovascular health, and whether it moderates the relationship between WMH and executive functioning in older adults.MethodParticipants were dementia‐free older adults (N = 175; age range 55‐89 years, M = 72.78; SD = 0.52; 52% male) from the Alzheimer’s Disease Neuroimaging Initiative. Diffusion weighted imaging, T1, and FLAIR scans were used to calculate diffusion tensor imaging (DTI) measures (fractional anisotropy; FA and mean diffusivity; MD) and WMH. Participants were divided into high and low GCC integrity using a median split, stratified by hemisphere and measure (i.e., Right/Left; FA/MD) Neuropsychological tests included Trail Making Test B (TMT B) and Animals. Multiple linear regression determined moderating effects of GCC WMI on WMH and executive function. Education, age, and sex were included as covariates.ResultIn individuals with low GCC WMI, WMH correlated with TMT B (Right FA: p = 0.004, R2= .215; Left FA: p = .014, R2= .222; Right MD: p = .009, R2 = .122 ; Left MD: p = .018, R2= .216) and Animals (Right FA: p = .005; Left FA: p = .022; R2= .131; Right MD: p = .054 (trended); R2= .049). In contrast, WMH did not correlate with TMT B (Right FA: p = .219; Right MD: p = .064; Left MD: p = .095) or Animals (Right FA: p = .411; Left FA: p = .280; Right MD: p = .124; Left MD: p = .274) in older adults with high GCC WMI.ConclusionWe observed a differential effect of GCC WMI on the relationship between WMH and executive function, such that greater WMH predicted lower executive functioning only in individuals with low GCC WMI. No relationship between WMH and executive function was found in individuals with high GCC WMI. GCC WMI may thus be a source of cerebrovascular‐related brain reserve and contribute to cognitive resilience by mitigating the clinical consequences of WMH in individuals with cerebrovascular disease.
Choroid Plexus Calcification Associations with Brain Morphology and Family History of Alzheimer's Disease
Authors: Gari Iyad Ba , Zhu Alyssa H , Haddad Elizabeth , Dixon Daniel , Islam Tasfiya , Gadewar Shruti , Low Kevin , Nir Talia M , Jahanshad Neda 
Published: December 2022

AbstractBackgroundThe choroid plexus (CP) is the primary source of cerebrospinal fluid (CSF) production and forms the blood‐CSF barrier which regulates nutrients and hormones to the brain. Changes in CSF production are associated with aging and Alzheimer’s disease (Saade 2019, Hubert 2019). CP calcification (CPcal) has been associated with metabolic disorders, cerebrovascular diseases, and tumors (Wu, 2009). Here, we used MRI‐derived quantitative susceptibility mapping (QSM) from the UK Biobank(Miller, 2016) to investigate whether CPcal is associated with morphological brain alterations and family history of Alzheimer's disease or related dementias (ADRD).MethodWe analyzed susceptibility weighted images (SWI) from 32,426 participants (aged 45‐83 years, F = 54%) from the UK Biobank, and 1716 follow‐up scans (aged 50‐83 years, F = 53%) Table 1. CPcal volumes were extracted from processed QSM maps (Figure 1) within FreeSurfer‐defined brain ventricles: total, lateral (LV), third (3rdV), and fourth ventricle (4thV). 34 regional cortical thickness and surface area measures, and 11 subcortical volumes were extracted using FreeSurfer. Linear regressions were used to assess the relationship between log‐transformed CPcal volumes and cross‐sectional and longitudinal change in FreeSurfer brain metrics (tp2‐tp1/tp1) adjusting for age, sex, LV and intracranial volumes. The false discovery rate (FDR, q=0.05) was applied to adjust for multiple comparisons across brain regions. Linear regression was used to investigate whether CPcal volumes were associated with family history of AD or dementia.ResultGreater CPcal volumes were associated with regional brain morphometry, cross sectionally, and longitudinally (Figure 2). Total CPcal were associated with family history of AD; specifically maternal history of AD showed a stronger association with total CPcal while paternal history showed no association (Table 2).ConclusionUsing QSM, we show that CP calcification impacts structural brain measures and is associated with family history of ADRD. This suggests that CPcal may be an important biomarker for tracking age related changes and AD, and may be an important biomarker for imaging genetic studies.
Psychosocial Considerations in Management of Corticobasal Degeneration in Indian American Population
Authors: Singh Neeraj 
Published: December 2022

AbstractBackgroundCorticobasal degeneration (CBD) is a neurodegenerative tauopathy primarily affecting the cerebral cortex and basal ganglia, often featuring cognitive decline and parkinsonism. With no proven treatments for this rare condition, the goals of management are to improve patients' quality of life. We evaluate here the unique psychosocial factors that were considered for two women of Asian Indian descent with CBD.MethodPatient 1 was a 77‐year‐old woman who exhibited short‐term memory loss, and then suffered an acute left anterior cerebral artery territory ischemic stroke with right‐sided hemiparesis and neurogenic pain. MRI Brain confirmed the stroke’s location, but did not account for cognitive decline. Patient 2 was a 75‐year‐old woman who initially experienced dysphagia, and then developed right‐sided hemiparesis, right neck spasms, unstable gait, and short‐term memory loss. MRI Brain and Cervical Spine revealed only showed mild chronic microvascular changes and multilevel cervical spondylosis.ResultsPET‐FDG Brain studies were performed for both patients. Patient 1’s study revealed severe hypometabolism affecting bilateral basal ganglia, bilateral thalami, and left supplementary motor cortex, out of proportion to the known stroke and consistent with CBD. Patient 2’s study revealed mild hypometabolism at the left frontal and parietal lobes, sparing the precuneus and posterior cingulate, also consistent with CBD and helping to explain the right‐sided hemiparesis.ConclusionVarious psychosocial factors were considered during the evaluation and management for both patients. Both had limited English proficiency, so cognitive testing was performed with the aid of a medical interpreter to ensure accurate results. Symptomatic treatment was tailored for each patient: Patient 1 received carbidopa/levodopa for parkinsonian tremors, and Patient 2 received cyclobenzaprine for intermittent muscle spasms. Both patients had multigenerational households, and results and prognoses were discussed with multiple relatives so they could coordinate responsibilities. Both families initially resisted recommendations to have home health aides, expressing their cultural belief that families should take care of their relatives on their own. As we discussed this belief over time, and explained the expected progression of symptoms over time, both families came to be more accepting of introducing home health aides, seeing them as a supplement, and not a replacement, for the family’s role.
Deep spatial phenotyping of microglial populations and pathological features in Alzheimer’s disease brains using CODEX Multiplexed Imaging
Authors: Sanchez‐Molina Paula , Pratapa Aditya , Singh Jasmine , Chiot Aude , Bogachuk Alina , Nikulina Nadezhda , Woltjer Randy , Braubach Oliver , Ajami Bahareh 
Published: December 2022

AbstractBackgroundRecent high‐throughput transcriptomics and proteomics analysis have shown a remarkable heterogeneity of microglia phenotypes across various disease conditions. Differently from neurons, microglia appearance can be characterized as a continuum between ramified and amoeboid morphologies. The transcriptional and proteomic profiles associated to each degree of morphology are potentially multiple and dependent on the healthy/pathological conditions in consideration with sex, anatomical area of the brain and disease stage. While single‐cell RNA sequencing (scRNA‐seq) has been instrumental in revealing microglia sub‐populations, it is lacking in spatial information and phenotypic characterization. The scarcity of fresh human brain tissue imposes a bottleneck for RNA‐seq studies, while paraffin‐embedded tissues are widely available in most brain banks. CODEX multiplexed imaging technology permits a deep characterization of microglial cells preserving their morphology and avoiding cell activation by aggressive sample preparation methods as occurs in tissue homogenates. Moreover, we can discriminate the immune cells in brain blood vessel from those in the parenchyma.MethodUsing this technology, we characterize microglia sub‐population localization in relationship to the distance from neurodegenerative disease pathogenic features in post‐mortem AD brain samples and matching controls. Bioinformatics analysis were performed to achieve microglial segmentation to a single‐cell level and cell clustering by protein expression.ResultOur results show the existence of different microglial cells populations, which vary between AD and control brains. Expression of blood‐derived macrophages markers was observed in parenchymal ramified cells close to blood vessels and/or Aβ plaques. We were able to deeply characterize this population and measure their distance to the nearest blood vessel and Aβ plaque. Microglial/macrophages activation markers were increased correlating with the distance to the plaques.ConclusionThis study allowed us to characterize the changes of microglia phenotype in the immediate neighborhood of pathogenic features. Such observation will be instrumental to understanding the role of several Late Onset Alzheimer’s Diseases associated genes and potentially identify novel drug targets.
Centiloid harmonisation across PET cameras without using paired scan
Authors: Li Shenpeng , Bourgeat Pierrick , Lebrat Leo , O'Keefe Graeme , Fripp Jurgen , Villemagne Victor L , Rowe Christopher , Dore Vincent 
Published: December 2022

AbstractBackgroundThe Centiloid (CL) scale allows quantification of amyloid‐b accumulation across multiple PET tracers for the diagnosis of Alzheimer’s disease. The CL quantification on different PET cameras may result in significant quantification bias when merging cohorts acquired from multiple cameras or in the longitudinal studies when change of camera occurs. In this study, we propose a harmonisation method, based on the non‐negative matrix factorisation (NMF), to reduce the quantification bias between different cameras without using paired scans.MethodThree hundred and forty‐eight 18F‐NAV4694 scans from Australian Imaging Biomarkers and Lifestyle study acquired on three PET cameras (N=116 each), Siemens Biograph mCT, Philips Allegro and Philips Gemini TF64 were used to train the model. Participants who switched camera between two consecutive timepoints were selected as the validation data. Seventeen participants imaged on the Biograph mCT and Gemini (2.63±0.51 years scan interval), and fifty‐two participants imaged on the Gemini and Allegro (2.73±0.73 years). One hundred participants who have two scans (2.26±0.82 years) on Gemini were used to define a reference rate of change (CL/year). Figure 1 illustrates the harmonisation workflow.ResultFigure 2 compares the curves of CL change rate against baseline CL for mCT to Gemini compared to the reference. The harmonised fitting is closer to the reference than the one without harmonisation in the low to middle CL range. The fitting in high CL range (CL>80) deviates from the reference probably because of the lack of subjects in this range. Figure 3 compares the results between Phillips Allegro and Gemini TF 64. The harmonised fitting in Figure 3 is nearly parallel to the reference for the entire CL range. In contrast, the fitting on the unharmonized data shows negative rate of change for the very negative subjects and much higher CL change rate for the very positive subjects, which are strongly different compared to the reference.ConclusionWe propose a practical and economical CL harmonisation for different PET cameras without using paired data. The NMF based method shows promising results for scanner harmonisation, though more validation are needed in future for different PET models.
Artificial Intelligence/Machine Learning Approaches for Gene Discovery and Target Identification in ADSP Data
Authors: Vardarajan Badri N. , Fornage Myriam 
Published: December 2022

AbstractBackgroundBy 2023, the ADSP will generate and harmonize 68000 whole genome sequences (WGS) from cohorts around the world. Joint analysis of WGS and complex phenotypic data such as imaging, and integration with omics layers at this scale requires non‐traditional statistical and bioinformatics approaches.MethodsCognitive systems encompassing Artificial intelligence, machine learning, and deep learning can be leveraged to identify patterns and associations from complex heterogenous datasets for gene and target discovery in Alzheimer’s Disease.ResultsRecently, NIA formed the AI/ML AD consortium to apply cognitive systems approaches to AD genetic and multi‐omics data. The goal of the consortium is to apply machine learning algorithms to existing GWAS, and sequencing data with AD endophenotypes in ethnically diverse cohorts for gene discovery. Insights from these approaches could identify risk and protective factors and pathways perturbed in AD and novel therapeutic approaches to the disease.ConclusionWe will discuss these technological advances especially in the context of brain imaging and their application to the identification of novel genetic loci for AD.