bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating neuronal senescence marker, p19INK4d, in mouse and human brains
Authors: Hudson Hannah R. , Orr Timothy C. , Orr Miranda E. 
Published: December 2023

AbstractBackgroundThe cellular senescence stress response allows damaged, toxic cells to survive. Clearing senescent cells is a promising therapeutic approach and has moved to clinical trials for Alzheimer’s disease and related dementias (ADRD). We previously identified a link between the cell cycle inhibitor CDKN2D/p19INK4d and neuronal senescence in human postmortem brains with various levels of AD neuropathology. We hypothesized that senescence could be induced by overexpressing this gene in mouse neurons in vivo.MethodAdeno‐associated virus 9 (AAV9) with the neuron specific human Synapsin I (hSyn1) promoter was used to deliver experimental Cdkn2d‐GFP, or control GFP gene expression. Precise delivery of 0.5µl of 1013 IU virus into four neuronal populations per mouse, bilateral hippocampal CA1 and cortical layer 5 neurons was accomplished with the assistance of a stereotaxic robot. Male and female wild type, human tau transgenic and mouse tau knockout mice were used (12‐13 months‐old, n = 47). Mice were euthanized at either two weeks or eight weeks post‐surgery to determine the short‐ and long‐term effects of Cdkn2d expression. GeoMx digital spatial profiler was utilized to quantify protein expression between Cdkn2d infected and uninfected neighboring neurons. ROI selection is displayed in Figure 1.ResultHistological analyses confirmed p19INK4d protein expression in AAV9‐infected cells. GeoMx DSP analyses performed on hippocampus, cortex, and thalamus revealed a protein expression pattern consistent with senescence (i.e., resistance to apoptosis), in Cdkn2d‐expressing neurons of the hippocampus and cortex compared to the un‐infected thalamus (Figure 2). Moreover, proteins associated with apoptosis were higher in the thalamus compared to the cortex and hippocampus.ConclusionsThe data indicates that AAV9‐hSyn1‐Cdkn2d‐GFP is an appropriate method to increase p19INK4d expression in mouse neurons in vivo. Over‐expressing p19INK4d caused neurons to acquire a protein expression signature consistent with senescence. The concomitant expression of apoptosis proteins in the thalamus leads me to hypothesize that the senescent cells in the cortex may cause cell death in the thalamus through the corticothalamic tract. Further studies with increased sample size are needed to confirm the results and continue exploring the effects of Cdkn2d on neuronal senescence, and how tau protein may influence this stress response.
Sexual dimorphisms in longitudinal associations of the blood lipidome with cognitive decline in Alzheimer’s disease
Authors: Marella Bharadwaj , Weinisch Patrick , Huynh Kevin , Risacher Shannon L , Wilhelm Mathias , Kaddurah‐Daouk Rima F. , Meikle Peter J , Kastenmuller Gabi , Arnold Matthias 
Published: December 2023

AbstractBackgroundLate‐onset Alzheimer’s disease (AD) is the leading cause of dementia with neither cure nor a clearly understood disease trajectory. Previous studies have shown cross‐sectional and longitudinal associations of the blood lipidome and AD. We previously reported on significant sex differences in the associations of lipids with AD biomarkers and it has been suggested that such sex differences may result in distinct trajectories of AD progression. We performed an association study of sex‐stratified longitudinal lipidomics data with cognitive function to further characterize sexual dimorphisms in lipidomic manifestations of AD.MethodWe used a subset of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset: 1349 individuals (745 males and 604 females) with blood samples and clinical data collected at 10 time points with intervals of 6 to12 months (4145 samples total). We analyzed 749 lipid species measured by quantitative LC‐MS lipidomics profiling (Baker Heart and Diabetes Institute, Melbourne, Australia). We calculated linear mixed models (LMMs) and generalized additive mixed models (GAMMs) to analyze time‐resolved associations between lipids and two composite cognitive scores (ADNI memory and executive function) while adjusting for age, sex (pooled analysis only), BMI, HDL‐C, total cholesterol, copies of APOE ε4, years of education as well as significant medication effects.ResultWe observed a significant difference in lipid concentrations between males and females in line with previous studies, however, these differences were not fully consistent across diagnostic groups. In longitudinal association analyses, we found a substantial fraction of lipid species to have significant sex‐specific associations with cognitive function, which were not observed in the pooled analysis. These lipids were distributed across several lipid classes with enrichment in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and triglycerides (TG). Comparisons between LMMs and GAMMs further indicated that some lipids might have a nonlinear relationship with cognitive trajectories.ConclusionOur results suggest that there are substantial sex differences in longitudinal associations of the blood lipidome with cognitive decline resulting in complex and partially nonlinear relationships. The highlighted lipid pathways can serve as a starting point to better characterize sex‐specific molecular changes linked to cognitive decline in AD.
Locus coeruleus microstructural integrity is linked to plasma GFAP concentration and Aβ42/40 ratio in cognitively unimpaired individuals: a 7T MRI study
Authors: Patsyuk Yuliya , Van Egroo Maxime , van Hooren Roy W.E. , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Poser Benedikt A , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundRecent autopsy and in vivo MRI studies supported structural integrity of the brainstem locus coeruleus (LC) as a potential indicator of initial AD‐related pathological processes. Importantly, in the earliest stages of the disease, these changes to the neuronal density of the LC are associated with changes to the somatic morphology and dendritic atrophy. Here, we aimed to examine whether LC microstructural integrity, assessed in vivo with advanced diffusion‐weighted magnetic resonance imaging (dMRI), is related to plasma AD biomarkers in a sample of cognitively unimpaired individuals.MethodFifty‐seven cognitively unimpaired participants (mean age = 59.3±14.7y; 28 females) (Table 1) underwent a dMRI scanning session using a multi‐shell, high angular resolution acquisition protocol in a 7T scanner. LC microstructure was evaluated by applying the Neurite Orientation Dispersion and Density Imaging (NODDI) biophysical model on the dMRI data, yielding two metrics of microstructural integrity: Neurite Density Index (NDI) and Orientation Dispersion Index (ODI). Additionally, blood samples were analyzed to assess AD plasma biomarkers, including Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau phosphorylated at threonine 181 (pTau181) or threonine 231 (pTau231).ResultHigher age was associated with lower LC ODI (t = ‐2.77, p = 0.008) but not LC NDI values (t = 0.44, p = 0.658). Multiple linear regressions adjusted for age, sex, and estimated Total Intracranial Volume (eTIV) showed that lower NDI in the LC was associated with higher plasma GFAP levels (t = ‐2.08, p = .04, Figure 1). In addition, we found a negative association between ODI within the LC and Aβ42/40 (t = ‐2.79, p = .007, Figure 2). No significant relationships were found between LC NDI/ODI values and plasma NfL or pTau biomarkers.ConclusionConsistent with animal studies, these findings suggest that microstructural changes in the LC are associated with astroglial activation in the earliest stages of the disease. Associations with Aβ42/40 were unexpected but might reflect loss of white matter compartments or changes in lipid density. In future analyses, we will further examine the biological interpretation of the NODDI metrics in subcortical regions, in particular in the context of AD‐related processes.
The extent of Lead‐induced Pathogenesis of Alzheimer’s disease, Synaptic Dysfunction and Cognitive Impairment in Rats
Authors: Iliyasu Musa Omoyine , Ajayi Abayomi 
Published: December 2023

AbstractBackgroundThe hallmarks of Alzheimer’s disease (AD), like amyloid plaques and neurofibrillary tangles, are constituted of amyloid beta (Aβ) peptide and phosphorylated tau, respectively. Many studies reported the relationship between lead exposure and the progression of AD. However, the extent of lead‐induced pathogenesis and changes in proteins regulating synaptic plasticity in AD is lacking. The proposed study is designed to evaluate the pathogenesis of AD, synaptic dysfunction and cognitive impairment following lead exposure in rats.MethodThirty (30) Wistar rats (3 weeks old) will be obtained, acclimatized for one week, and randomly divided into five groups (n = 6). The rats will receive distilled deionized water containing 0% lead acetate [Pb2+] (ddH2O) or 0.5% [Pb2+] (ddH2O + 0.5% Pb2+) solution with a standard rat diet. Group I (baseline) will receive ddH2O for three (3) weeks. Group II (control) will receive ddH2O for nine (9) weeks. Groups III, IV, and V will receive (ddH2O + 0.5% Pb2+) solution for 3, 6, and 9 weeks respectively. Cognitive function will be conducted using 8‐ARWM as well as object recognition tests. The hippocampus will be extracted for immunohistochemical and biochemical studies. The levels of β‐secretase, Aβ42, tau protein (p‐tau), NMDAR subunit NR2B, postsynaptic density protein 95 (PSD‐95), Synaptophysin (SYP), and brain‐derived neurotrophic factor (BDNF) will be determined using Enzyme‐linked immunosorbent assay (ELISA) method. The expression levels of Aβ42, neurofibrillary tangle (NFT), NR2B, PSD‐95, and SYN will be determined using the immunohistochemical method. The expression of β‐secretase and BDNF will be determined using quantitative real‐time PCR.ResultLead could affect the levels of β‐secretase, Aβ42, p‐tau, NR2B, PSD‐95, SYP BDNF; the expression of Aβ42, NFT, NR2B, PSD‐95, SYN, and BDNF; and cognitive function.ConclusionThe results could reveal the extent to which lead‐induced pathogenesis, synaptic dysfunction and cognitive impairment in AD
Blood biomarkers and lifestyle factors in dementia prevention
Authors: Shan Liu , Nishimura Yoshinori , Uchida Kazuhiko 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder with preclinical period that may begin more than 15‐20 years before onset without any clinical symptoms. Risk factors for intervention include obesity in middle age, lack of exercise, hypertension in middle age, diabetes mellitus, smoking, and hearing loss in middle age. Our research indicated that plasma proteins, such as apoA1, transthyretin, and complement C3, may serve as potential biomarkers for mild cognitive impairment (MCI) and Alzheimer’s disease. In this study, we analyzed the associations between risk and protective factors and these plasma protein levels to establish a risk assessment method for dementia.MethodIn present study, we measured blood biomarkers, including apoA1, transthyretin, and complement C3, in 1,736 subjects. We collected medical data from annual health examinations and clinical records of the participants. Additionally, lifestyle questionnaires were incorporated into the research.ResultOur analyses revealed that the risk values in the composite score indicated by the three blood biomarkers were higher in those with a history of dementia and diabetes than in those without a history of dementia and diabetes. The odds ratios (OR) for MCI were 5.27 (CI: 2.14‐13.2) and 1.59 (CI: 1.04‐2.45), respectively. Smoking exhibited a high‐risk value (OR: 1.87, CI: 1.15‐3.01), while smoking cessation led to higher apoA1 levels than in those who continued to smoke. Utilizing the composite score as an index, we analyzed factors that increase or decrease the composite score based on the receipt diagnosis history, health checkup data, and lifestyle questionnaires. We found that the high‐risk group in the composite score was associated with low HDL cholesterol (OR 0.94), high HbA1c (OR 1.6), and right high frequency hearing loss (OR 2.97). Furthermore, we identified several protective factors against MCI, including regular walking and strong physical exercise, drinking 100% fruit and vegetable juices, and avoiding sweetened beverages, and eating sashimi and miso soup.ConclusionOur findings suggest that a firm commitment to lifestyle‐related disease treatment and high‐impact exercise from middle age can help prevent dementia. Additionally, the blood test we used may be useful in presenting specific methods of dementia prevention and evaluating their effectiveness.
Exploring the Potential of Radiomics Features of the Hippocampus in Alzheimer’s Disease Considering Standard versus Parallel Imaging
Authors: Pereira Helena Rico , Ferreira Hugo Alexandre 
Published: December 2023

AbstractBackgroundRadiomics features obtained from anatomical magnetic resonance imaging (MRI) have been showing potential as biomarkers for the diagnosis of Alzheimer’s disease (AD). Nevertheless, little is known about how accelerated parallel MRI acquisitions impact such features and their potential in diagnosing AD. Therefore, this study aimed to compare the radiomics features extracted from the hippocampus considering standard and parallel imaging.MethodA total of 235 age and gender‐matched subjects (128 cognitively normal (CN) and 107 AD) with both T1‐weighted MPRAGE (standard) and accelerated MPRAGE GRAPPA or SENSE images were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Freesurfer was used to process the images and to obtain the volumes of these regions: hippocampus, entorhinal cortex, amygdala, and inferior lateral ventricle (summed bilaterally); and caudal and rostral midfrontal, pars opercularis, pars triangularis, inferior parietal, superior parietal, supramarginal, and superior temporal gyri (all summed into one feature). Using Pyradiomics, the following radiomics features from the bilateral hippocampus were extracted: kurtosis, mean, range, contrast, elongation, flatness, and maximum 3D diameter. To compare the two acquisitions (standard vs parallel), support vector machine models were created to classify AD vs CN. To mitigate AD heterogeneity in ADNI, 5‐fold cross‐validation was used to create 5 train and test sets based on the hippocampus volumes: (each train fold has 80% of 1st quartile AD and 80% 1st quartile CN, and the test fold has 20% of 1st quartile AD and 20% 1st quartile CN volumes, and so on – randomly selected).ResultAdding radiomics features improved the classification of AD vs CN in both acquisitions (Table 1): the positive predictive value increased from 77.2% to 90.3% in the standard, while the negative predictive value increased to 84.7% to 91.6% in the parallel acquisition. In both cases, models using all volumes surpassed those using only the hippocampus volume by 7.4% (86.0% balanced accuracy, standard) and 4.2% (85.5%, balanced accuracy, parallel) (Table 1).ConclusionRadiomics features of the hippocampus improve the performance of the models in both acquisitions, but with different predictive values, confirming their potential. Also, the relevance of other brain regions in AD besides the hippocampus was observed.
GRADUATE I AND II: Revisiting the key findings from two Phase III studies evaluating the efficacy and safety of subcutaneous gantenerumab in early Alzheimer’s disease (AD)
Authors: Lane Christopher , Smith Janice , Perry Richard J , Grimmer Timo , Lansdall Claire J , Voyle Nicola , Delmar Paul , Bittner Tobias , Klein Gregory , Schwab Dietmar , Schneider Andres , Salloway Stephen , Cummings Jeffrey L. , Baudler Monika , Fontoura Paulo , Doody Rachelle S. ,   for the GRADUATE I and GRADUATE II Investigators and the gantenerumab study group
Published: December 2023

AbstractBackgroundGantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).MethodEligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed.ResultGRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL).ConclusionThe GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined.
Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation directed to hippocampus in 3xTg‐AD/PVcre mice
Authors: Cushing Sarah Danielle , Moseley Shawn C , Stimmell Alina C , Wilber Aaron A 
Published: December 2023

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired (Allison et al., 2016). We reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial‐reorientation‐task (VM) that requires memory for using landmarks to navigate (Cushing et al., 2020). Memory replay during sleep is critical for learning related plasticity (Ego‐Stengel & Wilson, 2009; Jadhav et al, 2012; Maingret et al, 2016), and hippocampal‐cortical dysfunction is a potential mechanism for memory impairments in AD (Gennaro et al, 2017; Khan et al, 2014). Consistent with this hypothesis, we previously found deficits in hippocampal‐parietal cortex (HPC‐PC) coordination during sleep coinciding with impairments on the VM (Cushing et al, 2020). 40Hz stimulation has been shown to clear AD pathology in mice (Iaccarino et al, 2016; Martorell et al, 2019), and improve functional connectivity in preclinical AD patients (He et al, 2021), but see (Soula et al, 2023).MethodThus, we assessed HPC‐PC coordination in 3xTg‐AD/PVcre mice learning the VM. We implanted a 16‐tetrode recording array targeting PC and HPC and an optical fiber targeting HPC. Daily recording sessions of rest‐task‐rest commenced as mice learned the VM, followed by HPC optogenetic stimulation, with either 40Hz or SHAM stimulation. We assessed sleep quality metrics, delta waves (DW) in PC, and HPC markers of memory replay (SWRs) during slow wave sleep (SWS).ResultIn SHAM stimulated mice SWR‐DW cross‐correlations were reduced, similar to 3xTg‐AD mice (Cushing et al, 2020); while in the 40Hz stimulated mice, this phase‐locking was rescued. Furthermore, the 40Hz stimulated mice have restored performance on the VM compared to SHAM mice. However, this rescued HPC‐PC coupling no longer predicted performance as in NonTg animals (Cushing et al, 2020). Instead, DWTs independently predicted performance in 40Hz animals, but not SHAM animals. We also found paradoxical reduction of amyloid beta in contralateral PC and ventral CA1, but no reduction in contralateral dorsal CA1, synaptically closer to where stimulation occurred.ConclusionThus, 40Hz stimulation of HPC rescued learning and memory related functional interactions in the HPC‐PC network during sleep and as a consequence rescued impairments in spatial navigation, despite a decoupling between HPC‐PC coupling and learning and memory.
Creating National Dementia Caregiver Profiles: A Pilot Study
Authors: Sivananthan Saskia , Whate Alexandra , Apostolides Haridos , Armstrong Joshua J. 
Published: December 2023

AbstractBackgroundThere will be an estimated 1 million people living with dementia (PLWD) in Canada in 2031, with a further 613,500 Canadians thrust into the role of caregiver to support them. These unpaid caregivers, who tend to be spouses or adult children, shoulder significant physical, mental, emotional, and financial burdens while caring for their loved ones. Yet there is almost no information available nationally on caregivers of people living with dementia and their needsMethodThe First Link® program by the Alzheimer Society offers tailored support and connection to caregivers reaching ∼200,000 clients nationally. Consistent quantitative data will be collected from 30,000 individuals across 5 pilot provinces. The pilot recruitment ensures representation and inclusivity of all communities served by the Society. A framework and data set were agreed to through a collaborative community of practice approach engaging provincial Societies, subject matter experts and PLWD. Data sharing agreements were established for automated, secure, de‐identified data transfers into a centralized data repository.ResultThe framework includes a common dataset with demographic (race, ethnicity, gender identity, sexual identity), health status, level of stress/caregiver burden, confidence/preparedness to deliver care, quality of life and connections to local supports. Through an individualized tailored approach, each pilot site receives training in consistent data collection processes as well as equity, diversity, inclusion and belonging sensitivity training. This approach allowed staggered onboarding while ensuring all front‐line staff are trained for longitudinal data collection with 100% uptake. The next step will be engagement to develop caregiver profiles that highlight demographic characteristics, insights into current supports, and priorities for future programming for this population, and allow for subgroup analysis that provides further information on the different sizes of each provincial site, as well as styles of First Link® delivery, healthcare connectedness, and geography.ConclusionOver time, this comprehensive dataset will provide insight into the effectiveness of caregiver resources that are currently being provided (e.g., public education, community support groups, crisis support), including ease of access for caregivers, and establish a Canada‐wide surveillance system for caregivers of PLWD