bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher glucose parameters at baseline are related to hippocampal volume decline after a 2‐year multidomain lifestyle intervention to prevent cognitive decline in people at risk of developing Alzheimer’s disease: Exploratory results from the FINGER study
Authors: Lorenzo Thais , Solomon Alina , Ngandu Tiia , Lehtisalo Jenni , Gispert Juan Domingo , Torre Rafael , Kivipelto Miia 
Published: December 2023

AbstractBackgroundLifestyle interventions for preventing cognitive decline have provided promising results in older at‐risk individuals. Two modifiable risk factors are insulin resistance and diabetes mellitus, since they’ve been associated with higher risk of cognitive decline. However, it remains unclear if healthy individuals with higher normal glucose levels are free from suffering the negative effect of pathological glucose values on brain and cognition. The Oral Glucose Tolerance Test (OGTT) is a sensitive measurement for non‐detected glucose metabolism disorders and might be related with changes in brain structure and cognition. In this study we hypothesised that changes in glucose parameters will be associated with brain structural changes.Method1.259 participants of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) were included [Table 1]. A sample of 132 participants had brain MRI scans, and 47 also underwent PiB‐PET and FDG‐PET scans. Global GMv, hippocampal volumes, WMHv and cortical thickness measurements were analysed to assess the association between brain structural changes and glucose homeostasis. AD‐signature composites were also calculated from FDG‐PET and PiB‐PET scans data for the analysis. SPSS was used for linear regression models.ResultsBaseline AUC‐OGTT, 120min‐OGTT and fasting glucose were negatively associated (p<0.05) with 2‐year change in hippocampal volume [Table 2]. A negative association was also found between baseline AUC and change in FDG‐PET‐AD‐composite (p = 0.028). Three negative associations were additionally found at baseline between AUC‐OGTT and cortical thickness (p = 0.015), fasting glucose and total GMv (p = 0.015), and HbA1c and FDG‐PET‐AD‐composite (p = 0.033) [Table 3]. Interestingly, a positive association was found in a smaller sample (n = 38) between the TyG index and change in PiB‐PET‐AD‐composite (0.014). No associations were found between glucose parameters and the remaining imaging data.ConclusionIn a sample of participants at risk for dementia, baseline higher measures of peripheral glucose metabolism such as AUC‐OGTT and 120min‐OGTT glucose were related to greater decline in hippocampal volume, irrespective of the randomisation group and after considering abnormal glucose metabolism. These results suggest that glucose homeostasis might have an impact on brain structure in participants with higher normal glucose parameters measurements.
Early Results of a Pilot Program Providing Virtual Support to Family Caregivers of People with Alzheimer’s Disease to Reduce Their Stress and the Risk of Complications for Their Loved Ones
Authors: Laird Rosemary D. 
Published: December 2023

AbstractBackgroundThe Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) have formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease living at home. The program targets patients with high‐level daily care needs and with increased risk for future decline and need for costly Medicaid‐supported care.ObjectivesTo reduce stress for family caregivers and reduce risk of complications for their loved ones with Alzheimer’s disease.MethodsFamily caregivers who qualify for state assistance were offered a 12‐month support program. Support included regular meetings (Zoom or phone) with a personal licensed social worker. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention” or “may need attention,” along with resources to address identified needs. For the following three months, the social worker met with the family caregiver regularly to help resolve areas identified as high risk and discuss other relevant issues as they arose. After three months of guidance and support, the social worker conducted a re‐assessment with the family caregiver.ResultsData are available for the first hundred family caregivers participating in the pilot for three months. Initial results demonstrate a positive impact on AD patients’ medical, emotional, legal/financial outcomes including hospitalizations, falls, depression, anxiety, advanced directives, and financial planning. Early results also show reduced Zarit Burden Scale scores for family caregivers.ConclusionProviding virtual support to family caregivers of people with Alzheimer’s disease shows early signs of reducing the caregivers’ stress and the risk of complications for their loved ones. The Florida Department of Elder Affairs and NAN continue to evaluate the program’s impact on family caregivers, people with AD, and the cost of supporting this complex population.
Tau accumulation within the default mode network as a predictor of longitudinal clinical decline in atypical Alzheimer’s disease
Authors: Howe Inola , Eckbo Ryan , Wong Bonnie , Quimby Megan , Hochberg Daisy , McGinnis Scott M. , Touroutoglou Alexandra , Putcha Deepti , Dickerson Brad C. , Katsumi Yuta 
Published: December 2023

AbstractBackgroundIdentifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes.MethodFifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline.ResultCompared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline.ConclusionGreater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.
Association of Traumatic Brain Injury, Mild Cognitive Impairment and Dementia in the Framingham Heart Study
Authors: Durape Shruti , Joshi Prajakta S. , Burton Rebecca , Chien‐Young Kurtis , Price Eden , Yhang Eukyung , Liu Yulin , Ang Ting Fang Alvin , Devine Sherral A. , Gurnani Ashita S , Katz Douglas I , Tripodis Yorghos , Alosco Michael L , Dams‐O'Connor Kristen , Au Rhoda , Mez Jesse B. 
Published: December 2023

AbstractBackgroundResearch on the relationship between traumatic brain injury (TBI), Alzheimer’s disease (AD) and related dementias is inconsistent. Population based studies have been limited by their characterization of TBI, dementia or both.Design/MethodsThe Framingham Heart Study (FHS) is a population‐based cohort study which recruited its original cohort between 1948‐1950, and its offspring cohort between 1971‐1975. Information on TBIs was collected across the lifespan by comprehensive review of medical records, FHS health history updates and exams and self‐report. TBI occurrence and severity were operationalized using modified American Congress of Rehabilitation Medicine and Veterans Affairs/Department of Defense criteria respectively. Mild cognitive impairment (MCI), dementia, and AD dementia consensus diagnoses were operationalized using modified Petersen criteria, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, and National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association criteria respectively. Participants with history of TBI were matched to those without TBI for age and sex, with a 1:3 ratio. Participants with prevalent MCI or dementia were excluded.Results1,676 participants with TBI (cognitively normal at time of TBI) and 5,260 age‐ and sex‐matched participants without TBI were followed for 357,483 person‐years. 336 (20.05%), 267 (15.93%) and 177 (10.56%) of those with TBI developed MCI, all‐cause dementia and AD dementia respectively compared with 728 (13.84%), 536 (10.19%) and 440 (8.37%) participants without TBI. For mild TBI, hazard ratios (HRs) for MCI, all‐cause dementia and AD dementia were 1.56 (95%CI 1.16–2.11), 1.30 (95%CI 0.91–1.87), and 0.99 (95%CI 0.64–1.54) respectively. For moderate‐to‐severe TBI, HRs for MCI, all‐cause dementia and AD dementia were 3.95 (95%CI 1.25–12.45), 5.13 (95%CI 1.09‐24.19), and 7.42 (95%CI 0.87–63.55) respectively.ConclusionIn these cohorts comprehensively assessed for TBI and dementia‐related outcomes and followed for more than a decade after TBI, there were small to moderate sized associations of mild TBI and large associations of moderate‐severe TBI with MCI and all‐cause dementia. Association between mild TBI and dementia may be driven by non‐AD etiologies.
Relationship of Atrophy and Tau Imaging Subtypes in Prodromal and Clinical AD
Authors: Risacher Shannon L , Deardorff Rachael , Saykin Andrew J. 
Published: December 2023

AbstractBackgroundAmyloid‐positive MCI and AD participants show heterogeneity in patterns of atrophy and tau‐deposition. We sought to directly compare the previously‐defined subtypes (hippocampal sparing (HpSp), limbic predominate (LP), typical AD (tAD), and minimal atrophy) derived from [18F]flortaucipir PET (T) and structural MRI (N) in the context of positive amyloid (A). In addition, we examined assessed associations between demographic factors and subtype group for atrophy or tau.Methods243 amyloid‐positive participants from ADNI with MRI and tau PET scans at the same visit were included (160 MCI, 83 AD). Brain volumes were extracted using Freesurfer version 6 and tau PET SUVR values were extracted using standard techniques. Hippocampal to cortical ratios for grey matter volume and tau SUVR were calculated as previously described (Risacher et al. 2017 Neurology). Minimal pathology subjects showed similar levels of atrophy relative to cognitive normal participants. Relationships between atrophy‐ and tau‐based subtypes, as well as their relationship to sex and race/ethnicity were assessed using a Chi‐square test. An ANOVA model was used to compare age and education between atrophy‐ and tau‐based subtypes.ResultsA significant association between tau‐based and atrophy‐based subtypes was observed, driven by consistency in minimal atrophy, HpSp, and tAD groupsp = 0.024). In addition, differences by sex and race/ethnicity were also observed for atrophy but not tau subtypes with non‐Hispanic Whites most likely to be either minimal atrophy or tAD, while African Americans were more likely to be HpSp. Finally, significant differences in age and education were observed across the atrophy subtypes, with the HpSp group being younger and less educated, while the LP were older and more educated.ConclusionsOverall, we observed consistency between atrophy‐based and tau‐based subtypes, especially minimal pathology, tAD, and HpSp forms. Interesting associations between demographics and atrophy but not tau subtypes were also observed. Future studies in larger and more diverse samples are needed. These results underscore the importance of examining heterogeneity in amyloid‐positive MCI and AD across multiple modalities to better understand patterns of A/T/N pathophysiology that may have implications for risk of progression and personalized therapeutic strategies.
Synapse dysfunction and astrocyte reactivity are associated independently of amyloid‐β and tau pathologies
Authors: Rohden Francieli , Bellaver Bruna , Ferreira Pamela C.L. , Aguzzoli Cristiano Schaffer , Lussier Firoza Z , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Zalzale Hussein , Leffa Douglas Teixeira , Abbas Sarah , Cabrera Arlec , Lemaire Peter Charles , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundBiomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.MethodCerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aβ and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aβ/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.ResultDemographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, β = 0.1076; SYT1: p<0.0001, β = 0.0024; SNAP‐25 long: p<0.0001, β = 0.0008) as well as postsynaptic markers (Ng: p<0.05, β = 0.0066) independently of Aβ and tau burden (Figure 1).ConclusionOur biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aβ and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.
Baseline Amyloid and Tau Deposition Predict Distinct Patterns of Longitudinal White Matter Degeneration: A Diffusion MRI Investigation
Authors: Blujus Jenna K , Oh Hwamee 
Published: December 2023

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles are hallmark features of Alzheimer’s disease (AD) pathology. While concomitant differences in white matter (WM) integrity were found in association with Aβ deposition or tau pathology, a unique effect of each pathology on WM integrity remains unknown. In this study, we examined the unique effects of AD pathologies on WM integrity both cross‐sectionally and longitudinally.MethodA total of 334 participants (188 cognitively normal (CN), 114 mild cognitive impairment, and 32 AD) was selected from the ADNI database, based on the availability of two timepoints of diffusion MRI (dMRI) data, and baseline amyloid and tau PET data. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA) and annualized FA change maps were created to measure voxel‐wise WM change over time. Baseline global amyloid SUVR values were converted to a centiloid scale. Baseline tau SUVRs were evaluated by Braak staging (I‐entorhinal, II‐hippocampal, III/IV‐limbic, V/VI‐neocortex). The associations between AD pathologies and cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age and sex.ResultCross‐sectionally, baseline tau burden in Braak stages I, III/IV, and V/VI related to lower WM integrity, independent of Aβ, while there was no association between baseline Aβ and WM integrity, independent of tau. Longitudinally, limbic and neocortical tau at baseline uniquely predicted WM integrity loss across widespread regions, including left superior longitudinal fasciculus and the body and splenium of corpus callosum. Moreover, baseline Aβ burden significantly related to WM integrity loss across widespread regions, only when entorhinal and hippocampal tau was controlled for. Similar, but weaker, patterns of the associations between baseline AD pathology and longitudinal WM integrity loss were also found only within CN group.ConclusionThese findings suggest distinctive associations between AD pathology and WM degeneration such that Aß exerts widespread deleterious effects on WM integrity primarily early in AD pathophysiology, whereas, once spreading to the neocortex, tau burden drives WM neurodegeneration. The distinctive downstream pathways associated with each AD pathology may underlie differential cognitive profiles across the disease stages.
Developing a brief, accurate and adaptive version of the Boston Naming Test based on high‐fidelity estimates of item properties
Authors: Giauque Thomas A. , Shaughnessy Lynn , Lin George , Smith Maurice , Press Daniel Z. 
Published: December 2023

AbstractBackgroundCurrent naming tests such as the Boston Naming Test (BNT) and the Multilingual Naming Test have demonstrated significant clinical utility in detecting naming deficits in mild cognitive impairment (MCI), assisting with differential diagnosis among neurodegenerative disorders, and measuring disease progression in AD. However, the tests are time‐consuming due to their large number of items, and pen‐and‐paper administration. A computerized, adaptive naming test could increase the accuracy and speed of assessment, enhance usability, and minimize cross‐cultural testing disparities.MethodCurrent naming tests that produce accurate results over a range of naming abilities are lengthy, because they must both include items that densely cover the large range of potential abilities. In contrast, an adaptive test can be more efficient, by quickly zeroing in on a narrow range and then concentrating test questions only in the vicinity of the participant’s underlying ability. This maximizes efficiency in terms of information obtained per item, by tailoring the test to avoid items that would, based on previous responses, be either too easy or too difficult for the current participant.ResultWe show via a series of probabilistic simulations that the precision of item property estimates would limit effectiveness of adaptive strategies previously attempted (Fergadiotis et al., 2015). In fact, we find that the mismatch between the true properties of items and existing estimates, due to the broad confidence regions of these estimates (Embretson & Reise, 2000) considerably reduces achievable accuracy. We are therefore in the process of delineating item properties with considerably higher fidelity than those currently available in order to achieve the efficiency improvement that adaptive testing can in principle deliver, analyzing the results of individual item responses from over a 1000 BNT administrations from participants distributed across a range of ability levels. We will test the ability of adaptively‐chosen 12‐item subsets of the BNT to estimate the full scores from our clinics via simulation and implement a new ipad‐based adaptive tool, prospectively testing its accuracy in predicting the BNT score and its ability to identify MCI and AD.ConclusionThe development of a computerized, adaptive, naming test may allow considerable time savings while maintaining accuracy.
Hi‐C analysis in frontal cortex using local ancestry identifies ancestry‐specific chromatin 3D interactions
Authors: Wang Liyong , Xu Wanying , Liu Xiaoxiao , Rajabli Farid , Celis Katrina , Lu Leina , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Schuck Theresa , Scott William K. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan I. , Jin Fulai , Vance Jeffery M. 
Published: December 2023

AbstractBackgroundGenetic risk for Alzheimer Disease (AD) varies across populations with different ancestry. Three‐dimensional (3D) genome architecture regulates gene transcription. Genome‐wide Hi‐C analyses have revealed dynamic 3D genome changes during development and disease progression. The variation of 3D genome architecture on different ancestral background, however, has not been extensively studied, especially at high‐resolution level. Recently, we developed the DeepLoop pipeline enabling robust high‐resolution analysis. We applied DeepLoop to characterize 3D genome architecture in frontal cortex from African American (AA) and European (EU) donors while considering local ancestry (LA) in admixed samples.MethodsHi‐C libraries were constructed and ∼500 million of paired‐end reads were obtained in 8 samples (4 AA and 4EU) that were sex‐matched and homozygous for APOEε4. We partitioned Hi‐C data into compartment A (open and transcriptionally active chromatin) and compartment B (compacted and transcriptionally silenced chromatin). In total, 6206 compartment bins across the genome were compared at a 500kb resolution. DeepLoop was used to call chromatin loop (often represents promoter‐enhancer interaction) at a 5kb‐resolution. LA was calculated using RFMix with SNP‐array data and a reference panel from 1000 Genomes for EU, African (AF) and Amerindian (AI) ancestry.ResultsMost of the A and B compartments were consistent among individuals with only <5% of them switched between AA and EU individuals. The EU samples have slightly (107 bins) more transcriptionally active bins than the AA samples. While many of homozygous LA blocks displayed same chromatin loop pattern between and within ancestries, we did observe ancestry‐specific loop as well as differences between individuals of the same ancestry. Importantly, the presence of heterozygous LA (African/EU) at some loci displayed a composite loop pattern that was present in the same region of homozygous LA of African or EU ancestry.ConclusionThe 3D genome architecture can be variable between different ancestral backgrounds as well as between individuals of the same LA. We hypothesize that admixture of LA can create novel or demolish chromatin interactions observed in the homozygous LA. These data emphasize the importance of LA in identifying the causal loci contributing to AD in admixed population such as AF and Hispanic/Latino.