bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling neuropathology of Alzheimer’s disease in aged patient‐derived neurons through 3D direct neuronal reprogramming
Authors: Sun Zhao , Chen Shawei , Cates Kitra , Kwon Ji‐Sun , Sviben Sanja , Ren Yudong , Lv Xinguo , Karahan Hande , Sato Chihiro , Houlden Henry , Karch Celeste M. , Bateman Randall J. , Mennerick Steven , Kim Jungsu , Diamond Marc , Tanzi Rudolph E. , Holtzman David M. , Yoo Andrew S 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of adult‐onset neurodegenerative diseases characterized by three hallmarks of neuropathology including the extracellular deposition of amyloid β (Aβ), intracellular tau tangles, and neurodegeneration. The mechanisms that underlying the late‐onset AD (LOAD), the most common form of AD, remain largely unresolved due to the complexity of risk factors underlying the disease. Currently, endogenously recapitulating these events in patients‐derived neurons remains a major challenge, limiting our ability to understand the biology of the disease.MethodBy optimizing the potency of microRNA‐mediated direct neuronal conversion of patient fibroblasts, we developed a matrigel‐based three‐dimensional (3D) culture system for generating cortical neurons, a subtype known to be susceptible to develop AD pathologies. For characterizing AD‐associated phenotypes such as amyloid β(Aβ) plaques, tau pathology, and neurodegeneration in the reprogrammed cortical neurons, we carried out immunofluorescence staining, RNA‐sequencing and other biochemistry‐based assays.ResultsThe 3D reprogrammed neurons derived from familial AD and LOAD patients endogenously displayed all three AD hallmark pathologies, including increased extracellular Aβ deposition, phosphorylated tau, dystrophic (beaded) neurites characterized by the colocalization between Ubquitin‐K63 and pTAU, as well as spontaneous neuronal cell death in culture without additional cellular insult. By using this 3D reprograming model, we found that treating AD neurons with β or γ secretase inhibitors at pre‐Aβ aggregation phase, significantly ameliorated Aβ formation and subsequent tauopathy and neuronal cell death, whereas treating during the post‐Aβ aggregation phase only had a mild effect. Additionally, comparative transcriptomic analysis between AD neurons and age‐matched healthy control neurons showed enrichment of genes involved in inflammatory pathways.ConclusionWe established a novel patient derived neuronal 3D direct reprogramming model which robustly recapitulates key AD hallmarks including the extracellular deposition of Aβ plaques, formation of intracellular Tau tangles, and neurodegeneration. By using this 3D platform, we further demonstrated that inhibition of Amyloid β formation reduces tauopathy and neuronal cell death. Our unique patient specific 3D model system provides opportunities to investigate the interplay between AD pathological events and could serve as a platform for screening compounds and developing personalized therapeutics for AD.
Association between the use of antihypertensive medication and amyloid‐beta deposition in older adults with hypertension
Authors: Keum Musung , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Jung Gijung , Jung Joon Hyung , Kong Nayeong , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2023

AbstractBackgroundRecent evidences suggest that the use of antihypertensive medications (HTNmed) may decrease the incidence of Alzheimer’s disease (AD) dementia. We investigated whether the use of HTNmed is associated with in vivo AD pathologies, particularly cerebral beta‐amyloid (Aβ) deposition, and whether the relationship between HTNmed and cerebral Aβ deposition differs according to the characteristics of HTNmed in older adults.MethodParticipants were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. Both cognitively normal and cognitively impaired older adults (age range: 55‐90 years) who met the following criteria of hypertension (HTN) were included for this study: i) clinical diagnosis of hypertension or ii) systolic blood pressure higher than 130mmHg or diastolic blood pressure higher than 80mmHg measured at baseline. All participants underwent comprehensive clinical assessment and [11C] Pittsburgh Compound B positron emission tomography PET for measuring Aβ deposition.ResultAmong total 413 older adults with hypertension, 227(54.8%) were taking HTNmed. Overall, individuals taking HTNmed showed significantly lower Aβ deposition compared to those without HTNmed (B = ‐0.104, p = 0.007), even after controlling age, sex, apolipoprotein E e4 positivity, and mean arterial blood pressure(MAP). Drug‐class specific analyses showed that the use of renin angiotensin system (RAS) inhibitor (i.e., angiotensin converting enzyme inhibitor and angiotensin receptor blocker) was associated with less cerebral Aβ deposition among older adults with HTNmed (B = ‐0.142, p = 0.006), but the use of other HTNmeds was not. In addition, the blood‐brain barrier permeability of HTNmed also did not have any relationship with Aβ deposition.ConclusionThe present finding suggests that the use of HTNmed, particularly RAS inhibitor, is associated with less Aβ deposition in older adults with hypertension. Further studies to explore the mechanism underlying the effect of RAS inhibitor on Aβ accumulation may provide clues for new therapeutic targets of AD.
Interpreting trial results in an era of disease‐modifying therapies: Efficacy of approved anti‐amyloid drugs in the context of the long‐term Alzheimer’s trajectory
Authors: Raket Lars Lau , Cummings Jeffrey L. , Moscoso Alexis , Schöll Michael , Villain Nicolas 
Published: December 2023

AbstractBackgroundEarly‐stage Alzheimer’s disease (AD) typically presents with slow progression of clinical symptoms. Approved high‐potency anti‐amyloid‐β (Aβ) therapies have demonstrated changes in the disease trajectory in these early stages and offer potential benefits beyond the period for which they have been studied in trials.MethodsBased on published results, the time‐slowing of disease progression based on change in CDR sum of boxes (CDR‐SB) was approximated. Disease progression modeling using long‐term cohort data was used to estimate the natural history trajectory of CDR‐SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria was used to estimate the interval of the natural history trajectory of AD that were included in trials and different scenarios for long‐term treatment effects were explored.ResultsIn positive phase 3 studies, the high‐potency anti‐Aβ therapies appeared to slow disease progression 20‐30% resulting in a 4‐6‐month delay of progression during the 18‐month study period. Included patient populations were found to differ substantially, with the EMERGE and ENGAGE studies including an earlier group of patients than CLARITY‐AD. Consistent with trial subgroup analyses, natural‐history modeling suggested that more progressed patients would see an apparent greater absolute benefit during 18 months, but less absolute benefit over longer durations. Under an assumption of continued slowing beyond the study period, a treatment slowing disease progression by 30% (5.4 months delay in disease progression after 18 months) would lead to treatment differences on CDR‐SB of ‐0.42 and ‐0.72 points for typical MCI and mild dementia patients. With continued slowing beyond the length of the trial, typical MCI patients would have a treatment effect of ‐0.96 points once reaching the same disease stage as the mild dementia patients. Five‐year treatment differences would be approximately ‐2.5 and ‐3.2 points, well beyond all estimates of clinically meaningful differences. Even in the most conservative disease‐modifying scenario assuming no increased time delay after 18 months, observed treatment differences would still increase beyond 18 months due to the nonlinear trajectory of CDR‐SB.ConclusionDisease‐modifying effects of the magnitude observed in recent trials can potentially translate into clearly meaningful differences over a longer duration.
Early locus coeruleus degeneration impairs the longevity of fear memory in APPswe/PS1dE9 mice
Authors: Kushwaha Srishti , Choudhury Rupsa Roy , Karunakaran Smitha 
Published: December 2023

AbstractBackgroundThe locus coeruleus (LC), a brainstem noradrenergic nucleus is known to modulate cognitive functions and behaviour. LC is one the first sites of appearance of misfolded tau protein which later develops into neurofibrillary tangles. Hyperphosphorylated tau and amyloid β are best protein correlates of cognitive decline in Alzheimer’s disease (AD). In early onset AD, subtle cognitive deficits develop <25 years before the patients develop dementia. Loss of LC neurons and its innervation has been found to be significantly associated with behavioural deficits observed during prodromal stage of AD. However, the extent and consequences of LC‐noradrenergic system degeneration during early stages of AD pathogenesis are still under investigation.MethodTo address this question, we have performed contextual fear conditioning (cFC) behavioural task to test fear memory in 2‐month‐old APPswe/PS1dE9 (APP/PS1) mice, a transgenic amyloidogenic model of AD. We further investigated the status of LC terminals and the distribution of β‐adrenoceptors (β‐AR) in the hippocampus using dopamine‐β‐hydroxylase (DBH), tyrosine hydroxylase (TH), and β‐AR immunohistochemistry respectively. Finally, we checked if stereotaxic delivery of β‐AR agonist to the hippocampus could rescue the impairments in long‐term fear memory.ResultOur study demonstrates that 2‐month‐old male but not female APP/PS1 mice exhibit impaired long‐term fear memory in cFC task. Immunohistochemical analysis of DBH and TH positive nerve terminals revealed loss of noradrenergic and dopaminergic terminals in male but not female APP/PS1 mice hippocampus. Further, male APP/PS1 mice were found to have low levels of β‐AR in the hippocampus and intra‐hippocampal administration of isoproterenol hydrochloride, a β‐AR agonist, immediately before cFC could restore long‐term contextual fear memory.ConclusionLC‐noradrenergic system degeneration displayed an inherent sex‐specific difference on longevity of fear memory with deficits occurring only in male APP/PS1 mice during early stages of AD.
Olfactory impairment and domain‐specific cognitive decline: A 12‐year population‐based study
Authors: Laukka Erika J , Palmquist Eva , Ekström Ingrid , Olofsson Jonas , Dintica Christina S. , Bäckman Lars , Larsson Maria 
Published: December 2023

AbstractBackgroundOlfactory impairment has been associated with both cognitive impairment and dementia and Alzheimer’s disease (AD). This study aimed to investigate the association between olfactory dysfunction (OD) and change trajectories in different cognitive domains in aging.MethodParticipants (n = 2473, mean age = 72 years, 61% female) from the population‐based Swedish National study on Aging and Care‐Kungsholmen (SNAC‐K) were repeatedly assessed with tasks measuring episodic memory, semantic memory, verbal fluency, and perceptual speed across 12 years. OD was measured at baseline and participants were categorized as normosmic, hyposmic, or anosmic based on the Sniffin’ Sticks odor identification task. Linear mixed‐effects models were used to assess the associations between baseline OD and rates of cognitive decline.ResultOD was related to poorer baseline performance and faster rates of decline during follow‐up in all examined domains, as well as in global cognition. Associations were generally more pronounced for anosmia compared to hyposmia.ConclusionOlfactory impairment is associated with accelerated decline in aging across a wide range of cognitive domains.
Imaging diagnosis and emotion recognition relationship in mild cognitive impairment
Authors: Cháfer‐Pericás Consuelo , Álvarez Lourdes , Gandia‐Ferrero M Teresa , Adrián‐Ventura Jesús , Torres‐Espallardo Irene , Martínez‐Sánchez Begoña , Ferrer Inés , Baquero Miguel 
Published: December 2023

AbstractBackgroundRecent research has focused attention on social cognition impairment in Alzheimer Disease (AD). Specifically, emotion recognition can be evaluated with Reading the Mind in the Eyes Test (RMET). Some neuroanatomical changes could be related with social and cognitive deficits in patients. Therefore, future research combining cognitive indicators (RMET) with brain structure and function parameters (volumes, glucose metabolism, blood flow, amyloid deposits…) is required.MethodParticipants are patients from the Neurology Unit (Hospital Universitari i Politècnic La Fe). They were neuropsychologically evaluated, and CSF samples were obtained to determine some biomarkers (β‐amyloid‐42, β‐amyloid‐40, p‐Tau…). Also, brain imaging techniques (magnetic resonance (MR) and Positron Emission Tomography with [18F]Fluorodeoxyglucose (FDG‐PET/CT)) were applied to obtain brain structural and functional information, and to evaluate the relationship between them and emotion recognition evaluation (RMET). Imaging data were processed following SPM and CAT12 pipelines, a brain parcellation based on the Hammers atlas was used. Finally, 166 patients (with MR and/or FDG‐PET/CT) diagnosed with mild cognitive impairment (MCI) were included in the study.ResultThe correlation analysis between FDG‐PET/CT and RMET results showed significant correlations. Specifically, with prefrontal medial L and R (r = 0.36), posterior cingulate L and R (r = 0.34), parietal inferior L and R (r = 0.31), anterior cingulate L and R (r = 0.32), prefrontal lateral L and R (r = 0.32), insula R (r = 0.31) and basal ganglia R (r = 0.3). So, they are considered potential brain function biomarkers in MCI. Regarding the correlation analysis between MR (GM volumes (TIV‐corrected)) and RMET results, some significant correlations were observed. Specifically, with the straight gyrus L (r = 0.40), superior frontal gyrus L (r = 0.37), insula anterior inferior cortex R (r = 0.36), fusiform gyrus R (r = 0.36), anterior cingulate gyrus R (r = 0.36), insula anterior short gyrus L (r = 0.36), posterior and anterior cingulate gyrus L (r = 0.36, 0.35), and anterior orbital gyrus L (r = 0.35). So, they are considered potential brain structure biomarkers in MCI.ConclusionThe relationship between brain imaging parameters and emotion recognition impairment variables could provide important information for further biomarkers identification, as well as to identify potential physiopathological mechanisms involved in neurodegenerative development since early steps.
CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Huguet Jordi , Garcia Marina , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

AbstractBackgroundSoluble Aβ dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aβ drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aβ and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum.MethodThe first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aβ42, Aβ40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aβ42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aβ status (CSF Aβ42/40 < 0.071) on brain structure was determined.ResultTable 1 shows sample’s characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aβ42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aβ status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aβ42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2).ConclusionIndependently of p‐tau, early Aβ dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aβ+ individuals. Pathophysiological alterations other than Aβ, but correlated with CSF Aβ levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages.
Evaluating the sensitivity of Centiloid quantification to pipeline design and image harmonization
Authors: Shekari Mahnaz , García David Vállez , Collij Lyduine E. , Heeman Fiona , Roé‐Vellvé Núria , Bullich Santiago , Buckley Christopher , Barkhof Frederik , Farrar Gill , Pemberton Hugh , Gispert Juan Domingo ,   the AMYPAD consortium
Published: December 2023

AbstractBackgroundThe Centiloid scale is a well‐established standardized metric for estimating amyloid load in clinical and research settings. In this study, we evaluated the stability of Centiloid to pipeline design options, tracer, and image harmonization.MethodA total of 670 participants of the AMYPAD DPMS and PNHS multicenter studies with either [18F]flutemetamol or [18F]florbetaben PET scans and T1‐weighted MRI were included (Table1). PET images were harmonized to achieve an 8 mm Full‐Width‐at‐Half‐Maximum(FWHM) effective image resolution. Using SPM12, 32 Centiloid pipelines were created, calibrated and validated, based on combinations of four reference regions (Whole Cerebellum[WCB], Cerebellar Gray[CG], Whole Cerebellum+Brainstem[WCB+BSTM], Pons), two target VOI types (standard GAAIN vs subject‐based), two reference region types (standard GAAIN vs subject‐based) and two analysis spaces (native vs MNI). Generalized Estimating Equations (GEE) were used to evaluate the impact of the different factors on Centiloid. First, a base model including only the pipeline design factors was defined. Then, harmonization status (original vs harmonized PET images), tracer, and grey matter volume, as a measure of cerebral atrophy, were added to the base GEE model. Analyses were performed in the two cohorts separately and changes >5 Centiloid were considered relevant.ResultQuantification space, target VOI, and reference region type had a small impact on Centiloid. Selection of reference region had the largest impact on Centiloid as using the Pons resulted in ∆Centiloid∼‐12.00 compared with using the standard reference region, WCB (Table2). Harmonization status affected Centiloid only for some reference regions: CG and Pons were sensitive to harmonization status (∆Centiloid∼ 5.45 and ‐5.70 respectively). In contrast, Centiloid was minimally affected by harmonization when using WCB and WCB+BSTM (Table3). Tracer and atrophy had a minimal effect on Centiloid for both DPMS and PNHS cohorts.ConclusionCentiloid quantification is robust against differences in analysis space, reference region type, target VOI, tracer and the presence of atrophy. However, choice of reference region can significantly influence Centiloid, with the Pons having the largest impact on Centiloid relative to other reference regions. Centiloid is stable against harmonization status and image resolution heterogeneities while using WCB as reference region.
A Centiloid cut‐off to help predict true amyloid accumulation
Authors: Bollack Ariane , Collij Lyduine E. , García David Vállez , Shekari Mahnaz , Altomare Daniele , Payoux Pierre , Dubois Bruno , Grau‐Rivera Oriol , Rovira Mercè Boada , Nordberg Agneta K , Walker Zuzana , Scheltens Philip , Schöll Michael , Wolz Robin , Schmidt Mark E , Gismondi Rossella , Stephens Andrew W. , Buckley Christopher , Frisoni Giovanni B , Hanseeuw Bernard J , Visser Pieter Jelle , Vandenberghe Rik , Drzezga Alexander , Yaqub Maqsood , Boellaard Ronald , Markiewicz Pawel J , Cash David M , Farrar Gill , Gispert Juan Domingo , Barkhof Frederik ,   the AMYPAD consortium
Published: December 2023

AbstractBackgroundLongitudinal amyloid‐PET‐based imaging endpoints are often included in clinical trials, where they provide critical evidence of treatment efficacy. We assessed the longitudinal variability of the Centiloid (CL) scale and its ability to predict early amyloid accumulation.MethodLongitudinal amyloid‐PET with 18F‐flutemetamol and 18F‐florbetaben (N = 711 at follow‐up 1, time interval: 3.0±1.3years; N = 98 at follow‐up 2, 5.1±0.7years) was conducted in predominantly cognitively unimpaired participants of the AMYPAD Prognostic and Natural History Study (PNHS). Quantification of scans was performed using the MR‐based CL pipeline and visually read (VR) by local certified assessors. Longitudinal change in CL was modelled using linear mixed effects models corrected for age, sex, and education. Subjects were classified based on VR status over time (i.e., Stable VR‐, VR‐Converters or Stable VR+) and based on amyloid accumulation over time (i.e., Accumulator or Non‐accumulator; Accumulator if annualised rate of change [ARC]>95th percentile of a subset of 110 subjects for whom no amyloid accumulation was expected, selection criteria in Table‐1). Finally, a baseline CL cut‐off to identify future Accumulators was derived from a receiver operating characteristic (ROC) curve analysis.ResultParticipants had a median age of 65 years, 57% were females, 41% were APOE‐ε4 carriers, and 18% had baseline VR+ scan (Table‐1). The 95th percentile of ARC in the stable 110 subjects was 2.7 CL/year. Baseline CL was higher in Accumulators compared to Non‐accumulators (24.8 versus 8.7 CL, p<.001). Based on the ROC analysis, the optimal baseline CL threshold to predict Accumulators was 12.1 CL (sensitivity = 67% and specificity = 74%, Figure B‐C‐D), in line with the baseline CL threshold that best predicts VR conversion (11.6 CL). Baseline CL values and ARC were also higher in Stable VR+ and VR‐Converters compared to Stable VR‐ (p<.001), but no significant difference in ARC was found between VR‐Converters and Stable VR+ (Table‐1, Figure A). Results were robust across tracers.ConclusionIncreases over 2.7 CL/year can be indicative of reliable amyloid accumulation. A CL cut‐off of ∼12CL can help identify subjects more likely to accumulate amyloid in the short future. Annualised rates of change in amyloid deposition where highly comparable across tracers.