bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fine‐grained ordering of white matter degeneration in the Alzheimer’s disease pathophysiological cascade
Authors: Parker Christopher S 
Published: June 2023

AbstractBackgroundThe role of white matter (WM) neurodegeneration in Alzheimer’s disease (AD) is poorly understood. Fine‐grained sequencing of WM neurodegeneration could provide new avenues for early diagnosis and novel disease‐modifying therapies to slow or halt AD progression. Previous approaches are limited by their coarse granularity and incomplete disease coverage. In this study, we apply event‐based disease progression modelling (DPM) (Fonteijn et al, Neuroimage, 2012), which can provide fine‐grained ordering, to estimate progression of regional WM abnormality in AD.MethodDiffusion tensor imaging (DTI) markers of WM abnormality and Freesurfer volumetric markers of grey matter (GM) atrophy were obtained from ADNI. DTI markers were hemisphere‐averaged and GM volumes were normalised by head size. Eleven WM ROIs with reported AD abnormality and 4 reference GM ROIs were selected for sequencing (abbreviations in Table 1), yielding complete data for 83 cognitively normal subjects, 40 AD patients and 102 MCI subjects. Event‐based DPM (github.com/ucl‐pond/kde_ebm) was used to estimate a data‐driven sequence of neurodegeneration and its uncertainty (positional variance), and individuals were assigned to their most likely stage (Young et al., Brain, 2014). Resampling analysis assessed the robustness of the estimated sequence.ResultFig. 1 shows the first data‐driven sequence of WM abnormalities in AD, including positional variance, with GM abnormality events for reference. The earliest WM events are increases in mean diffusivity (MD) in CGH and axial diffusivity (AxD) in FX and BCC. Subsequently, a cascade of AxD events in corpus callosum regions precedes abnormality in other medial temporal lobe WM structures.Fig. 2 shows the sequence is relatively robust under resampling, with low positional variance and similar median positions for most ROIs. Subject staging (Fig. 3, 4) shows that the fine‐grained approach splits MCI subjects with hippocampal atrophy into those with hippocampal atrophy and those with additional increased MD in CGH.ConclusionThis study finds WM microstructural abnormality among the earliest events in AD. Early hippocampal WM abnormality and corpus callosum ordering are consistent with early memory deficits in AD and inferences from cruder group‐based comparisons. The order suggests Wallerian degeneration rather than retrogenesis is the primary driver of WM neurodegeneration in AD.
MRI‐based measure of dementia risk derived using machine learning is strongly associated with measures of longevity and biological age
Authors: Casanova Ramon , Anderson Andrea , Barnard Ryan , Justice Jamie , Kucharska‐Newton Anna , Windham B Gwen , Palta Priya , Gottesman Rebecca F. , Mosley Thomas H. , Hughes Tim M. , Wagenknecht Lynne E , Kritchevsky Stephen B 
Published: June 2023

AbstractBackgroundMachine learning and artificial intelligence methods have been applied to brain images to estimate measures of brain aging. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI‐based measure of dementia risk the Alzheimer’s disease pattern similarity (AD‐PS) scores with measures of longevity and biological age.MethodParticipants were those from visit 5 of the Atherosclerosis Risk in Community Study with cognitive status adjudication and MRI available. The AD‐PS score was estimated based on previously reported machine learning methods. We evaluated associations of the AD‐PS score with all‐cause mortality. Participants were stratified by AD‐PS tertiles and the analyses were adjusted for age, race, sex, hypertension and smoking. AD‐PS score was examined in association with 32 proteins reported to be associated with age. In these analyses, we used Bonferroni correction (α = 0.05,p<0.0016). Finally, associations with a deficit accumulation index(DAI) based on 38 health items was investigated. In both cases, linear regression models were adjusted for age, race and sex. Sensitivity analyses using only cognitively normal (CN) individuals were performed.ResultMortality – A total of 356 participants died within 8 years of follow‐up. The AD‐PS score was significantly associated(p<0.001) with time to all‐cause mortality. Participants in the lowest tertile had lower all‐cause mortality rate compared to those in the highest tertile (HR: 0.43;95% CI:0.31,0.60). The association remained significant when restricting the sample to only CN subjects (HR for lowest tertile:0.53; 95% CI:0.35,0.81, p = 0.0028).Age related proteins ‐ The AD‐PS scores were significantly associated (p<0.05, uncorrected) with 10 of the 32 proteins. Growth/differentiation factor 15(GDF‐15) and pleiotrophin remained significant after correction for multiple‐testing. Analysis of CN participants showed a subset of the same proteins to be significant (p<0.05,uncorrected) but only the GDF‐15 remained significant after correction for multiple‐testing.DAI ‐ A linear regression model showed a significant association between DAI and AD‐PS scores overall (coeff = 0.52; 95% CI:0.37‐0.67) and in the CN subset (coeff = 0.3,95% CI:0.13‐0.48).ConclusionWhile the AD‐PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.
Continuation rates of newly prescribed donepezil among patients with Alzheimer’s disease in Japan: Life study
Authors: Fukuda Haruhisa , Maeda Megumi , Murata Fumiko 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a major public health problem. Although donepezil is used as a first‐line pharmaceutical treatment for AD, studies from various countries have reported low continuation rates. However, the only available data from Japan are from post‐marketing observational study reports. This study investigated the continuation rates of newly prescribed donepezil among AD patients in Japan.MethodThe study was conducted using health care claims data and long‐term care claims data from 17 Japanese municipalities participating in the Longevity Improvement & Fair Evidence (LIFE) Study. The study period was from April 2014 to October 2021, and the study population comprised patients who had been newly prescribed donepezil after receiving a diagnosis of AD. The treatment discontinuation was defined as a gap of ≥61 days between the last donepezil prescription and subsequent donepezil, cholinesterase inhibitors, or memantine prescription. Kaplan‐Meier curves were plotted to estimate the duration (days) from the start of a new prescription of donepezil until discontinuation, and patients were censored at the end of the observation period or death. The treatment continuation rates were also analyzed according to the patients’ certified long‐term care needs levels (ranging from levels 1‐5) at the time of the initial prescription.ResultWe analyzed 20,474 patients (mean age: 82.2 years, women: 65.7%) with a mean follow‐up duration of 483 days. The treatment continuation rates at 30 days, 90 days, 360 days, and 540 days after initial prescription were 89.1%, 79.4%, 64.5%, and 58.3%, respectively. By excluding patients with long‐term care needs levels 3‐5, we analyzed 18,924 patients with lower care needs levels (mean age: 82.0 years, women: 65.4%); their treatment continuation rates were almost identical to those of all patients (<1% difference). Within 60 days of donepezil discontinuation, only 2.9% and 3.1% of patients had been switched to galantamine and rivastigmine, respectively.ConclusionThe AD patients showed a rapid discontinuation of donepezil and subsequent AD treatments by 90 days, and approximately 40% had ceased this therapy after 1.5 years. In view of the limited pharmaceutical options available for AD in Japan, this finding emphasizes the need for AD preventive measures in the pre‐clinical stage.
Self‐report sleep duration associates with plasma Aβ42/40 rate of change in late middle‐aged, African American Adults
Authors: Cook Jesse D , Malik Ammara , Plante David T , Koscik Rebecca Langhough , Du Lianlian , Bendlin Barbara B , Kirmess Kris , Holubasch Mary S. , Meyer Matthew R. , Venkatesh Venky , West Tim , Verghese Philip B. , Yarasheski Kevin E. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Zuelsdorff Megan , Gleason Carey E. 
Published: June 2023

AbstractBackgroundSleep abnormalities may play a prominent role in the pathogenesis or exacerbation of Alzheimer’s disease (AD). Sleep is considered a modifiable target for prevention and treatment. Racial sleep health disparities exist, and may contribute to the disproportionately increased risk for developing AD associated with being African American. Yet, the relationships between sleep health and AD pathophysiology in African American individuals are under‐studied. This investigation was designed to address research gaps by evaluating the associations of self‐report sleep duration, sleep disturbances, and daytime sleepiness with change in plasma‐derived amyloid β 42/40 ratio (Aβ42/40) in an African American sample.MethodArchival data from African American participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study and the Wisconsin Alzheimer’s Disease Research Center were utilized. Data included the Medical Outcomes Study Sleep Scale (MOS‐Sleep), Epworth Sleepiness Scale (ESS), and demographic information. Sleep duration was determined by MOS‐Sleep #2, sleep disturbances were captured by a related MOS‐Sleep subscale (SLPD4), and ESS assessed daytime sleepiness. Participants provided plasma samples across multiple timepoints. PrecivityADTM assays quantified Aβ42/40. Aβ42/40 rate of change (Aβ42/40_ROC) was computed for follow‐up collections to serve as the primary outcome measure. Aβ42/40_ROC was computed as the difference in Aβ42/40 between follow‐up and first collection divided by years between collections. Linear mixed‐effects models determined associations with Aβ42/40_ROC. Observations were nested within participant. Fully adjusted models included age at collection, gender, BMI, education, parental history of dementia, and APOEe4 carrier status.ResultData included 339 follow‐up collections from 143 participants. Women provided 70.8% of collections, with average age at collection = 66.6 ± 8.84 years, Aβ42/40_ROC = ‐0.0005 ± 0.003, and sleep duration = 6.35 ± 1.00 hours. Sleep duration significantly associated with Aβ42/40_ROC in the fully adjusted model (β = ‐0.0005; SE = 0.0002; p = 0.02) (Figure 1). Associations between SLPD4 and ESS with Aβ42/40_ROC were nonsignificant.ConclusionLonger self‐report sleep duration associated with a steeper reduction rate for plasma Aβ42/40, a biomarker for amyloid pathology. Further research is necessary to clarify the relationships between sleep health components and changes in AD‐related biomarkers within African American adults to identify focal risk factors and interventional strategies.
Methodology dependent sex differences in Aβ‐PET measured with SUVR
Authors: Coath William , Modat Marc , Cardoso M Jorge , Markiewicz Pawel J , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Keuss Sarah E , Harris Matthew J , Bollack Ariane , Burgos Ninon , Dickson John , Barnes Anna , Thomas David L , Beasley Daniel , Malone Ian B , Murray‐Smith Heidi , Wong Andrew , Erlandsson Kjell , Thomas Benjamin A , Schöll Michael , Ourselin Sebastien , Richards Marcus , Fox Nick C , Schott Jonathan M , Cash David M 
Published: June 2023

AbstractBackgroundDetermining Aβ‐PET status is crucial for Alzheimer’s disease trials. Standard uptake value ratio (SUVR) using a reference region is a common semi‐quantitative technique. Sex differences in regional blood flow and white matter (WM) could impact SUVR differentially depending on the reference region. It is important to understand how methodological factors can influence SUVR derived Aβ status.MethodIndividuals from Insight 46 (1946 British birth cohort) underwent PET/MR scanning with [18F]florbetapir (N = 425; mean age (SD) 70.6 (0.7); 49% female). Regions derived from T1‐weighted MRI with geodesic information flows (GIF) were resampled to PET space. SUVR was calculated (50‐60 mins post‐injection) using a cortical composite target normalised to whole cerebellum (WC) or eroded WM, with/without partial volume correction (PVC). Additionally, SUV was calculated normalising to injected dose and weight. Distribution volume ratio (DVR) from Logan graphical analysis (cerebellar grey matter reference) was calculated for N = 391 (51% female). Linear regression was used to investigate differences in Aβ‐PET measures by sex adjusting for region volumes. Aβ status was defined with Gaussian‐mixture modelling. Sex differences in SUVR and DVR were investigated in individuals rated concordantly Aβ‐ with all four SUVR methods. SUVR Aβ status discordance was examined in relation to sex and APOE e4 genotype.ResultFemales had significantly higher SUVR with a WC reference; and there were no sex differences with a WM reference or with dynamic DVR (Figure 1). Males had higher SUV in all regions and the difference was greater in the WC compared to WM (Figure 2). PVC decreased the influence of volume on SUV in the WC but not WM. 87% of individuals were classified concordantly Aβ+/‐ on SUVR measures with equal proportion of males/females. More females were Aβ+ only with WC reference with PVC, whereas more males were Aβ‐ only on WC without PVC (Figure 3).
Similarities in Pathobiology of Alzheimer’s Disease and Type 2 Diabetes Mellitus: A Proof of Concept by a Case Study
Authors: Noreen Zarish , Mondal Tanmoy , Loffredo Christopher A. , Nunlee‐Blnad Gail , Simhadri Jyothirmai J. , Johnson Jheannelle , Cotin Sharleine T. , Korbe Brent E. , Quartey Ruth , Howell Charles D. , Arif Maria , Bhatti Attya , Chandra Vijay , Jana Siddhartha S. , Shahzad Sharoon , Ghosh Somiranjan Ghosh 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia worldwide. Developing countries will have >3 times the prevalence of the developed countries by the year 2050. Our previous studies with a Pakistani population have suggested that type 2 diabetes mellitus (T2DM) is strongly associated with impaired cognitive functioning, and genetic pathways showed strong resemblance to known AD patterns. The present case studies investigated two important pathways, i.e., Amyloid Precursor Protein (APP) processing and Lipid Metabolism, using gene expression profiling arrays to compare and contrast AD and T2DM patients from Pakistan.MethodWe performed high‐throughput qRT‐PCR with preconfigured a TaqMan Low Density Profiling Array specific to Human Alzheimer’s Disease (ABI, CAT # 441887) to measure the altered gene expressions and their corresponding pathways (Ingenuity Pathway Analysis, IPA®). Both the T2DM (n = 2; M/F each) and AD (n = 2, M/F each) patients (cases) were recruited from outpatient departments of a regional hospital, and were compared with their respective matched, healthy controls.ResultOverall, we observed a differential gene expression profile in AD and T2DM participants compared to controls. CYP46A1, MAPT, CAPNS1, GAL, AGER, CAPN1, PSENEN, ST6GAL1, GRIN2B, GRIN2C, GRIN2A, and GAP43 was downregulated in both T2DM and AD patients. ACHE, CHRM3, GRIN2C and GAP43 significantly (p value <0.05) downregulated in all T2DM patients. CDC2, UCHL1, CTSG, CASP3, IDE, NAE1, CDK5R1, IL6, APBB2, GLS are the top 10 common genes that were upregulated in both AD and T2DM groups. The IPA analysis revealed important Canonical Pathways, that included, viz., Amyloid Processing, Neuroinflammation Signaling, ErB4 Signaling, nNOs Signaling. Molecular Mechanisms of Cancer. The top disease and biofunctions included Metabolic Disease, Neurological disease, Organismal Injury and Abnormalities, Psychological Disorders, Cardiovascular Disease, with the top upstream regulators PHLPP2, IL33, APP, CRP, TAC1.ConclusionThe differential gene expression patterns and associated disease pathways from this pilot study suggest that specific genes and pathways were common to both diseases and may suggest common underlying processes and causes. Information from such biochemical and genetic studies will be crucial to the development of therapeutic targets to treat AD.
Differential associations between plasma neurofilament light and brain functional connectivity in patients with Alzheimer’s disease and fronto‐temporal dementia
Authors: Chong Joanna Su Xian , Tan Yi Jayne , Koh Amelia Jialing , Zhou Juan Helen , Ng Adeline Su Lyn 
Published: June 2023

AbstractBackgroundNeurofilament light chain (NfL), a marker of axonal loss, is elevated in both Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD)[1‐6]. AD and bvFTD have been shown to spread along specific networks reflective of their symptom profiles[7,8], with AD associated with declines in default mode network (DMN) functional connectivity (FC), and bvFTD linked to disruptions in salience network (SN) FC[9]. However, the association between plasma NfL and FC in these two groups remains unknown. Given evidence linking plasma NfL to hypometabolism in circumscribed regions within the DMN in mild cognitive impairment (MCI) patients[10], we hypothesize that NfL would similarly be associated with FC in a network‐specific manner in AD and bvFTD.MethodPlasma NfL and neuroimaging data from young‐onset patients with bvFTD (n = 16) and AD (n = 38; including AD and MCI of AD type (AD+MCI)) were analyzed. Plasma NfL was measured by single molecule array (SIMOA). Seed‐based FC maps using regions‐of‐interest from DMN (left posterior cingulate cortex) and SN (right anterior insula) were derived for each patient. Voxelwise analyses examining associations between plasma NfL and seed‐based FC were first performed in each group separately. Clusters showing significant FC‐NfL associations were then examined for group differences between AD+MCI and bvFTD, and correlated with neuropsychological performance. All analyses accounted for age, sex, education, handedness and total intracranial volumes.ResultsWe demonstrated differential associations between plasma NfL and FC in AD+MCI and bvFTD patients: AD+MCI patients showed significantly lower DMN FC with higher plasma NfL compared to bvFTD patients (Figure 1A), while bvFTD patients showed lower SN FC (Figure 1B) with higher plasma NfL relative to AD+MCI patients. Further, lower NfL‐related DMN FC in AD+MCI patients was significantly associated with lower MoCA scores (Figure 2).ConclusionPlasma NfL is associated with FC changes in a network‐specific manner in bvFTD and AD+MCI patients, which may be in turn be predictive of cognitive decline. Our study suggest that axonal protein loss has differential effects on functional brain networks in different dementia subtypes. Future studies are warranted to confirm these findings in a larger cohort.
A unique transgenic model that expressing Aβ oligomers: PS1V97L mutation discovered from Chinese Alzheimer’s disease families
Authors: Quan Meina , Li Xinyue , Wei Yiping , Wang Wei , Xu LingZhi , Li Fangyu , Nie Shuya , Jia Jianping 
Published: June 2023

AbstractBackgroundTransgenic mouse models are important tools for studying the pathogenesis of Alzheimer’s Disease (AD) and drug development. Commonly used models are constructed from early‐onset AD mutations in the Caucasian population, and are usually overexpression or knock‐in of multiple pathogenic gene mutations. However, they are not consistent with the genetic characteristics in real world where single gene mutation occurs most of the time. Furthermore, AD transgenic mouse models have been mostly depending on a few institutions/companies and limited by intellectual property protection.MethodWe systematically summarized the research progress of a transgenic mouse model based on a single gene mutation (PS1V97L) found uniquely in Chinese familial AD, as well as the underling mechanisms such as Aβ oligomers (AβO) self‐replication (figure 1). We further compared them with other single‐transgene models, and summarized the preliminary findings of several drugs targeting AβO.ResultPS1V97L transgenic mice showed age‐related AD phenotypes such as Aβ accumulation, tau phosphorylation, neurofibrillary tangles, gliosis, synaptic degeneration and cognitive impairment (figure 2). The unique characteristics of this model is the aggregation of interneuronal AβO in cortex and hippocampus, but no plaques formed up to 24 months. Other mechanisms of PS1V97L model include oxidative stress, inflammation, abnormal energy metabolism, and alterations in AD‐related signaling pathways, such as PI3K/Akt and Nrf2/ARE pathways. Several drugs including sulforaphane, honokiol, tenuifolin, isoliquiritigenin, ginsenoside, butylphthalide and oxiracetam were found effective in PS1V97L mouse model as well as rat and cell models based on AβO mechanism.ConclusionAlthough carrying only one mutation, PS1V97L transgenic mouse model can mimic almost all AD pathological phenotypes, and supports AβO pathogenic hypothesis. It provides important basic and translational tool for exploring the upstream mechanisms, risk factors, and multi‐target drug development in AD.
Simultaneous mediation effect estimation of APOE through multiple neuropathological pathways on cognitive outcomes
Authors: Xia Fan , Culhane Jessica E. , Chan Kwun Chuen Gary , Keene C. Dirk , Kukull Walter A. 
Published: June 2023

AbstractBackgroundIndividual associations of APOE genotype with Alzheimer’s disease neuropathologic changes (ADNC) have been studied extensively, but the effects through comorbid neuropathological pathways are rarely evaluated simultaneously. In addition, conventional statistical methods for mediation analysis rely heavily on assumptions on causal directions among different pathologies.MethodUsing the National Alzheimer’s Coordinating Center database, we use state‐of‐the‐art mediation analysis methods for multiple mediators effect decomposition to simultaneously estimate the indirect effects of the APOE ε4 allele through different pathologies, including ADNC, TDP‐43, and Lewy body disease, on cognitive outcomes. Unlike the conventional Baron and Kenny approach, we do not assume a causal structure between different pathologies, making causal interpretations under fewer assumptions. We control for cerebrovascular diseases, cardiovascular diseases, and age at death that are potentially affected by the APOE ε4 allele and could confound the pathologies.ResultOur results show that the APOE ε4 allele has a negative effect on cognitive outcomes (MoCA: ‐4.97 (‐6.92, ‐3.03); CDR Sum of Boxes: 1.34 (0.70, 1.98)). Most of the effect goes through ADNC (MoCA: ‐3.37 (‐4.68, ‐2.05); CDR Sum of Boxes: 1.20 (0.92, 1.49)), and there is evidence that the indirect effect through ADNC is significant for both outcomes. There is a small indirect effect through TDP‐43 pathology of the same direction as the total causal effects. It is significant for the standard CDR sum of boxes (0.26 (0.13, 0.39)) but not for the MoCA score (‐0.37 (‐0.81, 0.07)). There is little evidence of an indirect effect through Lewy body pathology for both outcomes. In addition, the effect that goes through the dependence or interaction between the pathologies is small.ConclusionWe utilize novel causal mediation analysis methods on neuropathology data to quantify the effects of APOE genotype on dementia risk through different ADRD pathologies without requiring knowledge of their causal relationship. Most of the effect of the APOE ε4 allele goes through ADNC, as expected, but there is also evidence of a smaller indirect effect through TDP‐43. This work provides insights into the understanding of the dementia disease process and introduces a new statistical tool for future AD and related dementias research.