bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial
Authors: Lanctôt Krista L. , Perin Jamie , Vieira Danielle , Rosenberg Paul B. , Herrmann Nathan , Shade David , Lerner Alan J. , Padala Prasad R , Brawman‐Mintzer Olga , van Dyck Christopher H , Porsteinsson Anton P. , Craft Suzanne , Levey Allan I. , Mintzer Jacobo E 
Published: December 2022

AbstractBackgroundApathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment.MethodIn this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect.ResultOf the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale.ConclusionIndividuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.
Cell‐type specific alterations in intrinsic excitability and neurotransmission in short‐term virally induced model of Alzheimer’s Disease
Authors: Goettemoeller Annie M , Rowan Matthew JM 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative cascade resulting in neuronal dysfunction and memory loss, classically characterized by the deposition of amyloid plaques throughout the brain. Although deposition of these proteins correlates with cognitive loss in AD, these aggregates may not be causally related to initial neuronal and circuit pathology in AD. Interestingly, evidence in AD patients and mouse models has reported cortical circuit hyperexcitability prior to plaque pathology. The cell and molecular mechanisms underlying hyperexcitability in early‐stage AD remain unclear. In healthy brains, normal circuit operations are maintained through a fine‐tuned balance between excitatory (pyramidal) and inhibitory neuron activity. In several APP‐expressing mouse models, pyramidal and inhibitory neuron physiology are differentially affected and also evolve with disease severity. However, these parameters have not been explored in an adult‐onset APP model.MethodWe examined rapidly emerging physiological changes in cortical PV interneurons and neighboring pyramidal neurons in an adult‐onset AD model. We analyzed contributions of overexpressed wild‐type human amyloid precursor protein (WT hAPP) using an AAV viral approach. We fluorescently targeted cell types for whole‐cell patch‐clamp electrophysiology using a PV‐specific enhancer labeling technique or an excitatory neuron‐specific AAV. Lastly, we optogenetically stimulated PV interneurons to assess neurotransmission onto neighboring pyramidal cells.ResultWe report alterations in cortical PV interneuron and pyramidal neuron intrinsic excitability, as well as PV‐to‐pyramidal neurotransmission, after short‐term induction of hAPP virally. Interestingly, each of these two neuronal subtypes displayed unique changes suggesting different cell‐type‐specific molecular alterations.ConclusionThis breakdown of APP processing and its effects on PV interneuron and pyramidal neurons provides potential insights into early cell‐type‐specific mechanisms of the pathogenesis of Alzheimer’s Disease, thus providing specific interventions to ameliorate early symptoms and potentially slow the progression towards severe disease.
Cerebrovascular Dysfunction at the Intersection of Ischemia and Alzheimer’s Disease
Authors: Ismail Ozama , Pike Martin , Zhang Wenri , Mishra Anusha 
Published: December 2022

AbstractBackgroundCerebrovascular dysregulation is one of the earliest detectable changes in Alzheimer’s disease (AD) etiology that precedes the descent into dementia1. Ischemic events such as stroke and silent infarcts trigger cerebrovascular dysfunction2,3, accelerate cognitive decline4 and increase dementia risk5. Further, the resulting decrease in cerebral blood flow (CBF) can induce the formation of amyloid β6. Thus, we examined cerebrovascular function at the intersection of ischemia and AD by measuring CO2‐evoked hyperemia and neurovascular coupling (NVC) after small strokes in wild type and Tg2576 model of AD‐related amyloidosis.MethodWe established a model of small ischemic strokes by performing a short 30‐minute middle cerebral artery occlusion, yielding a mild subcortical infarct (MSCI). We performed MSCI in 6‐month old Tg2576 and littermate wild‐type mice (WT) and compared them to naïve mice. We used arterial spin‐labeling (ASL) MRI to quantify CBF and CO2‐evoked hyperemia at 10 and 14 months of age and Laser Doppler flowmetry (LDF) to measure NVC at 14 months of age. We also quantified hippocampal volumes.ResultThere was no apparent change in hippocampal volume after MSCI in either genotype. There was a reduction in NVC in WT+MSCI mice in both hemispheres, with a trend towards greater reduction in Tg2576+MSCI mice. The CO2‐evoked hyperemia was also reduced in WT+MSCI and Tg2576+MSCI mice compared to WT naïves. Curiously, naïve Tg2576 mice showed the most severe impairment in CO2‐evoked hyperemia, which appeared improved in Tg2576+MSCI. We are re‐examining this finding.ConclusionUsing an innovative mixed model of mild ischemia and amyloidosis, here we report that the two pathologies can synergize to accelerate cerebrovascular impairments. Strikingly, we found that even a small one‐sided stroke can impair cerebrovascular function bilaterally. Future studies will determine the extent to which amyloid pathology and cognitive deficits are exacerbated by such impairments. Our findings suggest that targeting early cerebrovascular dysfunction after ischemia may prove useful in deterring the onset of dementia later in life.References:Iturria‐Medina, Y. et al. (2016) Nat. Commun. 7, 11934.Salinet, A.S.M., Robinson, T.G. & Panerai, R.B. (2015) J. Appl. Physiol. 118, 170–177.Li, Z., McConnell, H.L. & Mishra, A. (2021). Front Cell Nuerosci. 15: 762843.Levine, D.A. et al. (2015) JAMA. 314, 41–51.Vermeer, S.E., Longstreth, W.T. & Koudstaal, P.J. (2007) Lancet Neurol. 7, 611–9.Wen, Y., Onyewuchi, O., Yang, S., Liu, R. & Simpkins, J.W. (2004) Brain Res. 1009, 1–8.
Multi‐parametric Neuroimaging in a Non‐Human Primate Model of Sporadic Cerebral Amyloid Angiopathy (Saimiri boliviensis boliviensis)
Authors: Murray Sean , Veraart Jelle , Karimi Sohail , Genovese Thomas S , Leung Jonathan , Goldman Hannah , Patel Akash G , Gray Stanton B , Zhang Jiangyang , Hopkins William D , Williams Lawrence E , Wisniewski Thomas , Zaim‐Wadghiri Youssef , Scholtzova Henrieta 
Published: December 2022

AbstractBackgroundSquirrel monkeys (SQMs) are a unique non‐human primate model (NHP), which unlike other NHPs, develops extensive age‐associated cerebral amyloid angiopathy (CAA). The growing recognition of CAA contribution to clinical decline and CAA‐related complications in current clinical trials underscore the utility of the SQM model for studying CAA pathology development. Neuroimaging can play a key role in noninvasively detecting and monitoring disease progression in conjunction with histological methods. We have previously shown the utility of quantitative R2
* to map age‐related differences in SQM neuropathology cross‐sectionally and longitudinally. Here we aim to complement our protocol with advanced MRI approaches sensitive to brain microstructure to enable early and specific detection of alteration in tissue integrity. Our overarching goals aim to establish the in vivo and ex vivo MRI metrics profile of young and geriatric SQM cohorts.Method2D T2‐w (a) Turbo‐spin‐echo (TSE) and (b) FLAIR MRIs were acquired in vivo and ex vivo, while (c) multi‐shell diffusion‐weighted MRI (DWI) was limited to ex vivo imaging. Diffusion tensor imaging (DTI) and Diffusion kurtosis imaging (DKI) metrics were derived from comprehensive DWI datasets. Immunohistochemistry was subsequently performed to characterize the microstructural underpinnings of MRI abnormalities.ResultBothin vivo and ex vivo T2‐w TSE and FLAIR helped identify spontaneous asymmetric hyperintensities (ARIA‐E) in geriatric SQMs (21‐23yrs), predominantly in the parieto‐occipital WM, not seen in the young cohort (5‐yrs). Importantly, DKI‐derived mean kurtosis proved to be the most sensitive of DWI metrics for detecting lesions in the parieto‐occipital region. Widely adopted DTI metrics were far less sensitive in identifying microstructural changes. Histological assessment of region‐matched sections revealed Iba1 microgliosis, as well as immunoreactivity for both extravascular fibrinogen and decreased MBP when compared to the contralateral side. Aß immunohistochemistry (6E10/4G8) confirmed presence of CAA in the affected regions.ConclusionAdvanced DWI models are sensitive and specific neuroimaging tools for identifying abnormalities associated with tissue integrity that are potentially linked to age‐associated cerebrovascular dysfunction. Ex vivo conventional MRI detected similar abnormalities observed in vivo and proved to be a useful step to validate the performance of advanced imaging strategies, which can help bridge the gap between in vivo MRI and histology.
Higher physical activity is associated with greater myelin content in older adults with cerebral small vessel disease and mild cognitive impairment
Authors: Silva Nárlon Cássio Boa Sorte , Dao Elizabeth , Hsu Chun Liang , Tam Roger , Lam Kevin , Alkeridy Walid Ahmed , Stein Ryan G , Laule Cornelia , Vavasour Irene M , Liu‐Ambrose Teresa 
Published: December 2022

AbstractBackgroundMyelin loss is considered a marked feature of cerebral small vessel disease (cSVD). Although physical activity levels may exert protective effects over cSVD pathological changes, its specific relationship with myelin content in this population is unknown. Therefore, we investigated whether physical activity levels are associated with myelin content in community‐dwelling older adults with cSVD and mild cognitive impairment.MethodWe analyzed cross‐sectional data from older adults with cSVD and mild cognitive impairment in our laboratory. Myelin content was assessed using MRI with a multi‐echo gradient and spin echo T2 relaxation sequence, indexed as myelin water fraction (MWF). Physical activity levels were estimated using the Physical Activity Scale for the Elderly (PASE). Hierarchical regression models adjusting for total intracranial volume, age, sex, body mass index, and education were conducted to determine the associations between MWF and PASE. Significant models were further adjusted for white matter hyperintensity volume.ResultIndividuals (n = 102) with cSVD and mild cognitive impairment (mean [SD], age = 74.7y [5.5], Montreal Cognitive Assessment = 21.76 [3.2]), 63.7% female) were included. In adjusted models of tract‐specific cerebral white matter, physical activity was linked to higher MWF in the sagittal stratum (Unstandardized B [95% CI]: 0.014 [0.004 to 0.023], R2
change = 0.08, p = 0.004), anterior corona radiata (0.008 [0.000 to 0.015], R2
change = 0.04, p = 0.049), and genu of the corpus callosum (0.011 [0.002 to 0.020], R2
change = 0.05, pchange = 0.018). Similarly, physical activity also associated with MWF in whole‐brain white matter (0.007 [0.000 to 0.014], R2
change = 0.04, pchange = 0.046). White matter hyperintensity volume did not modify any of these associations.ConclusionPhysical activity may be one important component of maintaining myelin in older adults with cSVD. Future research should address whether myelin content is a sensitive neuroplasticity marker sensitive to physical activity changes or exercise interventions.
Plasma Signatures of Lipid and Cellular Energy Metabolism in the 5xFAD Mouse
Authors: Gross Thomas J , Vu Michael M , Malhas Rond , Green Kim N , MacGregor Grant R , Tenner Andrea J , LaFerla Frank , Mapstone Mark 
Published: December 2022

AbstractBackgroundIdentifying early biomarkers of Alzheimer’s disease (AD) could help us understand mechanisms of AD and provide opportunities to develop novel therapeutics. The plasma metabolome is a rich source of potential biomarkers. Our goal is to analyze metabolomics in new models of AD being developed by MODEL‐AD. Here, we examine lipid and cellular energy metabolism via plasma metabolomics in the 5xFAD mouse.MethodWe examined age‐dependent changes in the abundance of plasma metabolites obtained from 10 (5M,5F) 5xFAD and 10 (5M,5F) wild type (WT) mice at 4‐, 12‐, and 18‐months. Blood was collected at time of death and the plasma fraction was analyzed using liquid chromatography mass spectrometry (LC‐MS). We measured 762 lipids and 204 polar metabolites. We used Metaboanalyst 5.0 for all analyses.ResultWe found increased abundance of acylcarnitines in 5xFAD mice relative to WT mice at 4‐months of age (q < 0.05) which reversed by 18 months of age where there was a relative depletion of acylcarnitines in the 5xFAD mice (q < 0.05). The best 10 discriminant features from Component 1 of a sPLS‐DA were acylcarnitines (4/10) and lipids (4/10) at 4‐months, lipids (8/10) at 12‐months, and acylcarnitines (6/10) at 18‐months. Using these 10 features, ROC area under the curve (AUC’s) was 0.95 (95%CI 0.78‐1.0) at 4‐months, 0.91 (95%CI 0.61‐1.0) at 12‐months, and 1.0 (95%CI 1.0‐1.0) at 18‐months.We examined changes in multivariate lipid and metabolite patterns between the two groups over time. We found 30 metabolites with significant interactions between Time and Group. Pathway analysis using these 30 metabolites showed enrichment for Glycerophospholipid Metabolism (q < 0.05) indicating the 5xFAD mice show more rapid depletion of these particular lipids over time.ConclusionWe see changes in cellular energy and lipid metabolism in aging 5xFAD mice. These changes in energy metabolism may reflect an early compensatory shift as amyloid plaques appear which then fails as the plaques establish and the animal ages. We also find significant time‐dependent changes in lipid and metabolite abundances especially metabolites associated with glycerophospholipid metabolism. These age‐dependent changes in lipid and metabolomic profiles of the 5xFAD relative to WT suggest a dynamic and complex metabolic milieu.
Machine learning‐based prediction of cognitive outcomes in de novo Parkinson's disease
Authors: Harvey Joshua , Reijnders Rick A , Cavill Rachel , Duits Annelien , Köhler Sebastian , Eijssen Lars M.T. , Rutten Bart P.F. , Shireby Gemma , Torkamani Ali , Creese Byron , Leentjens Albert F.G. , Lunnon Katie , Pishva Ehsan 
Published: December 2022

AbstractBackgroundCognitive impairment is a debilitating symptom in Parkinson’s disease (PD), with high variability in onset and course of progression. This present study aimed to establish an accurate multivariate machine learning model to predict cognitive outcome in newly diagnosed PD.MethodUsing baseline measures from the Parkinson’s Progression Markers Initiative (PPMI) cohort we subset clinical, biofluid and genetic/epigenetic variables. Annual cognitive assessments over an eight‐year time span were used to define two outcomes of i) dementia conversion, and ii) cognitive impairment. Outcomes and variable subsets were tested using multiple machine learning (ML) algorithms (random forest, elasticnet, SVM‐linear and cforest) to predict prognosis of individual cognitive decline in PD. Prediction was assessed using multiple measures including Area under the Curve (AUC) and Mathews Correlation Coefficient (MCC).ResultFor both cognitive outcomes, irrespective of the of ML algorithm, models consisting of clinical variables alone performed best, with high specificity and the largest AUC's (0.88 ‐ 0.92) and MCC's (0.57‐0.80). Notably, cognitive impairment outcome showed better sensitivity than dementia conversion outcome (0.72 – 0.81 vs 0.29 – 0.64, respectively). Addition of biological and genetic variables did not largely improve the model performance. However, a number of cerebrospinal fluid (CSF) proteins and epigenetic markers showed high predictive weighting in multiple models, when included alongside clinical variables.ConclusionMachine learning algorithms can accurately predict cognitive impairment development in PD. Within the generated models, clinical predictors appear to play a more prominent role than biological predictors. We further present additional future study data, expanding epigenetic research into PD dementia.
High tau PET binding reveals a constellation of beta‐amyloid positivity and fast cognitive decline
Authors: Ioannou Konstantinos , Bucci Marco , Nordberg Agneta K , Chiotis Konstantinos 
Published: December 2022

AbstractBackgroundBeta‐amyloid Positron Emission Tomography (PET) efficiently detects beta‐amyloid plaques supporting the presence of a pathophysiological landmark of Alzheimer’s disease (AD) continuum, but lacks specificity regarding the prediction of future cognitive status. The increasing validation of tau PET tracers raises questions about whether a tau PET biomarker could predict clinically relevant cognitive decline and its potentially beneficial role in the assessment of individuals who belong to the AD continuum.MethodWe identified 335 subjects [cognitive normal (CN; n=217), mild cognitive impairment (MCI; n=99), dementia (n=19)] with baseline beta‐amyloid and tau PET scans that have completed a follow‐up of at least two years, from the Alzheimer’s Disease Neuroimaging Initiative dataset. First, we assessed the accuracy of tau PET to discriminate the MCI patients that will convert to AD. Based on Alzheimer’s Disease Assessment Scale–Cognitive Subscale, we used linear mixed‐effects models to define the annual rate of cognitive change of all individuals and Gaussian mixture modelling to cluster them as either fast or slow decliners. Next, group comparisons and the accuracy of tau PET to discriminate between them were tested. Finally, the association between baseline tau PET SUVR and cognitive rate of change was assessed with linear modelsResultThe individuals with beta‐amyloid positivity and fast cognitive decline showed the highest tau PET binding values independently of baseline cognitive status, compared to the other groups (beta‐amyloid negative with fast or slow decline and beta‐amyloid positive with slow decline). Baseline tau PET binding could determine fast decliners with a beta‐amyloid positive scan with an accuracy of 85% (composite temporal region of interest). Similarly, tau PET binding accuracy was high in determining MCI patients that would be both beta‐amyloid positive and show progress in their diagnosis. Linear models showed that baseline tau PET binding is related to the annual rate of cognitive decline in beta‐amyloid positive individuals.ConclusionHigh baseline tau load is coupled with both beta‐amyloid pathology and an accelerated profile of cognitive decline. Tau PET imaging could offer substantial advantages over beta‐amyloid PET imaging since it provides important information about both the underlying pathophysiology and the prognosis of the disease.
Temporal Characterization of the Amyloidogenic APP/PS1dE9;hAPOE4 Mouse Model of Alzheimer’s Disease
Authors: Grenon Martine , Bathini Praveen , Papavergi Maria‐Giusy , Schroeder Maren K , Lemere Cynthia A. 
Published: December 2022

AbstractBackgroundThe development of immunotherapies against Aβ is burdened by clinical adverse events (AEs) observed as amyloid‐related imaging abnormalities (ARIA) on magnetic resonance imaging scans. The vascular inflammatory AEs have been reported in AD clinical trials administrating certain anti‐Aβ plaque‐binding antibodies and are thought to represent cerebral microhemorrhages and vasogenic edema. ARIA incidence appears apolipoprotein (APOE) genotype‐dependent, wherein APOE E4 allele carriers are at higher risk when compared to non‐carriers. With hopes to robustly model patients most at risk for the vascular complications of anti‐Aβ immunotherapy, we selected a relatively new transgenic mouse model bearing the human APOE E4 gene. The model has not yet been extensively characterized at multiple age points. To assess the face validity of the mouse model, we are conducting a battery of histological and biochemical tests.MethodsTo evaluate age‐ and sex‐related pathological changes, we collected brain and blood plasma from euthanized male and female APP/PS1dE9;hAPOE4 (APP/E4) mice across 3 ages: 8‐, 12‐ and 16‐months. General‐ and pGlu3‐Aβ levels were quantified using enzyme‐linked immunoassays (ELISA). Prussian Blue hemosiderin staining was used to examine microhemorrhages.ResultsImmunoassays of brain homogenates exhibited significantly higher insoluble Aβx‐40, Aβx‐42 and pGlu3Aβ levels in 16‐month‐old mice compared to 8‐ and 12‐month‐old mice. Moreover, the 16‐month‐old females demonstrated significantly higher levels of Aβx‐40 and pGlu3Aβ than age‐matched males. Hemosiderin staining was observed in all 12‐ and 16‐month mice, however no significant differences in abundance was found between the 2 age points. Immunostainings for plaque deposition of various Aβ species, vascular amyloid, dystrophic neurites and gliosis are ongoing.ConclusionsAge‐ and sex‐dependent increases in Aβ deposition were revealed in the APP/E4 mouse model. Preliminary evidence for microhemorrhage was observed. Subsequent analyses will better characterize the translational credibility of APP/E4 as a model for future nonclinical immunotherapies targeting Aβ. (1RF1AG058657‐CAL)