bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition
Authors: Mastenbroek Sophie E , Sala Arianna , Gispert Juan Domingo , García David Vállez , Schmidt Mark E , Stephens Andrew W. , Gismondi Rossella , Farrar Gill , Frisoni Giovanni B , Boada Mercè , Ritchie Craig W , Visser Pieter Jelle , Bucci Marco , Hansson Oskar , Barkhof Frederik , Ossenkoppele Rik , Nordberg Agneta K , Rodriguez‐Vieitez Elena , Collij Lyduine E. ,   the AMYPAD consortium
Published: December 2023

AbstractBackgroundDiscordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐β (Aβ) occurs in up to 20% of individuals. Generally, Aβ discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aβ CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.MethodWe included 383 non‐demented subjects (N
unimpaired = 326, N
mildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aβ42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance<0 reflecting greater Aβ abnormality in CSF relative to PET and Zimbalance>0 greater Aβ abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.ResultSample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aβ abnormality in PET relative to CSF) (β = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aβ abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, β = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (β = ‐0.03±0.02, p = .038) (Figure‐2).ConclusionWe found that methodological factors did not contribute to a continuous model of Aβ CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aβ relative to soluble Aβ being related to increased CSF p‐tau levels and excess pathological levels of soluble Aβ relative to aggregated Aβ to increased white matter hyperintensities and steeper cognitive decline.
Apoe ε4 exacerbates age‐dependent decline of cortical microstructural changes in cognitively normal midlife individuals: the PREVENT‐Dementia and ALFA studies
Authors: Mak Elijah , Dounavi Maria‐Eleni , Operto Grégory , Ziukelis Elina T , Jones P Simon , Low Audrey , Swann Peter , Newton Coco , Muniz‐Terrera Graciela , Malhotra Paresh A , Koychev Ivan , Falcon Carles , Mackay Clare , Lawlor Brian , Naci Lorina , Wells Katie , Ritchie Craig W , Ritchie Karen , Su Li , Gispert Juan Domingo , O'Brien John T 
Published: December 2023

AbstractBackgroundThe APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals.MethodData from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models.ResultAPOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness.ConclusionWe found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD.
Longitudinal change in CSF β‐amyloid1−42 predicts PTSD symptomatology after the COVID‐19 lockdown in cognitively unimpaired older adults
Authors: Palpatzis Eleni , Akinci Muge , Argiris Georgette , Contador Israel , Brugulat‐Serrat Anna , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Carboni Margherita , Minguillón Carolina , Navarro Arcadi , Gispert Juan Domingo , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M 
Published: December 2023

AbstractBackgroundCognitively unimpaired (CU) adults with Alzheimer’s disease (AD) pathologic change may be more vulnerable to developing neuropsychiatric symptoms. We reported an association of higher β‐amyloid (Aβ) and increased anxiety/depression during the COVID‐19 lockdown in CU adults (Akinci et al., 2022). Here, we investigated whether changes in Aβ1−42 predict post‐traumatic stress disorder (PTSD) symptomatology following COVID‐19 lockdown in CU adults at risk for AD.MethodWe included 128 CU participants who underwent lumbar puncture 2.3±0.6 years before and 1.1±0.4 years after the lockdown. The outcome of interest was self‐reported PTSD symptomatology (Impact of Event Scale Revised) measured 1.7±0.1 years after the lockdown. The main predictor was annual rate of change in cerebrospinal fluid (CSF) Aβ1−42 measured with the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Other predictors included sex, age, years of education, stressors during COVID‐19, and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) and perceived stress (Perceived Stress Scale, PSS) measured during lockdown. We performed regression analyses to explore the association between annual rate of change in Aβ1‐42 with PTSD scores adjusting for demographic and stressor variables, and further adjusting for HADS and PSS scores. We then explored the mediating effect of HADS and PSS on the association between change in Aβ1‐42 and PTSD scores.ResultParticipant age ranged from 53−72 and 59% were women (Table 1). Independent of demographic variables and stressors experienced during COVID‐19, the rate of annual change in Aβ1‐42 predicted PTSD scores (p = .008; Table 2). This association attenuated after introducing HADS and PSS scores into the model (p = .066). We found full mediation effects of HADS and PSS scores, explaining 46% and 40% of the effect of annual change in Aβ1‐42 on PTSD scores, respectively (Figure 1).ConclusionCU older adults with longitudinal CSF Aβ1−42 increases are more vulnerable to developing PTSD symptomatology after a stressful event, such as the pandemic. Anxiety/depression is one plausible mechanism through which increases in Aβ might exacerbate PTSD symptomatology. The results suggest a window for stress regulation during stressful events to prevent further mental health worsening in people at risk for AD.
Identification of a Novel Mechanism Fostering the Alterations of Brain Energy Metabolism: a Link Between AD and T2DM
Authors: Lanzillotta Chiara , Lanzillotta Simona , Tramutola Antonella , Pagnotta Sara , Domenico Fabio Di , Paul Bindu D , Snyder Solomon , Butterfield D Allan , Perluigi Marzia , Duarte Joao MN , Barone Eugenio 
Published: December 2023

AbstractBackgroundBrain insulin resistance (bIR) is associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration both in Alzheimer’s disease (AD) and Type 2‐Diabetes Mellitus (T2DM). Our group previously demonstrated that loss of BVR‐A is an early event triggering bIR in AD. Hence, we tested the hypothesis that reduced BVR‐A levels link bIR and mitochondrial defects resulting in AD‐like neuropathology in T2DM.MethodAlterations of insulin signalling, autophagic flux, oxidative stress levels and AD hallmarks were analyzed in the hippocampus of wild‐type and the goto‐kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR‐A, similar analyses were performed in the hippocampus of WT and BVR‐A KO mice fed a high fat diet (HFD, 60% kcal from fat) for 1, 3 or 8 weeks. Additional mechanistic insights were gained by evaluating mitochondrial function (sea‐horse) and the above‐mentioned intracellular pathways in response to insulin, in neuronal cells lacking BVR‐A.ResultGK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR‐A levels along with IRS1 hyper‐activation and loss of Akt‐mediated inhibition of GSK3ß were observed in the hippocampus, consistent with the regulatory role for BVR‐A. As result, hyperactive GSK3ß accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Similar alterations in BVR‐A KO mice and in neuronal cells lacking BVR‐A were observed, reinforcing the role for BVR‐A in regulating mitochondrial bioenergetics in response to insulin. HFD regimen promoted worse outcomes in BVR‐A KO mice with respect to WT. Remarkably, gender‐differences were observed whereby female mice show earlier and greater alterations with respect to male mice.ConclusionThese results suggest that early BVR‐A loss triggers bIR and the hyper‐action of GSK3ß, that, in turn, drives the development of mitochondrial stress in T2DM brain. These alterations accelerate the impairment of energy metabolism and development of AD‐like neuropathology in T2DM.
Validating the clinical utility of AI‐guided tools for early dementia prediction
Authors: Vaghari Delshad , Lee Liz Yuanxi , Burkhart Michael C. , Montagnese Marcella , Zuhlsdorff Katharina , Giorgio Joseph , Chong Eddie , Jagust William J. , Chen Christopher Li‐Hsian , Williams Guy B , Rittman Timothy , Tino Peter , Kourtzi Zoe ,   the Early Detection of Neurodegenerative diseases initiative
Published: December 2023

AbstractBackgroundRecent advances in machine learning highlight the potential of Ai‐guided tools for early dementia prediction with major implications for timely clinical management. Yet, we still lack robust tools for predicting neurocognitive decline early in clinical practice. We have developed a predictive prognostic model based on Generalised Matrix Learning Vector Quantisation (GMLVQ) that combines multimodal biological and cognitive data to predict cognitive decline (Giorgio et al., 2020). Here we test the clinical validity of this model in predicting individualised cognitive trajectories on real‐world memory clinic data.MethodWe trained our model (Fig.1) to classify sMCI (individuals with stable MCI diagnosis within a 3‐year period; n = 290) vs. pMCI (individuals who progressed from MCI to AD within a 3‐year period; n = 120). We tested the model (out‐of‐sample validation) on a) an asymptomatic sample (Berkley Ageing Cohort: BACS, n = 187 healthy controls), b) two clinical samples: National University of Singapore (NUS; AD: n = 32, non‐AD neurodegenerative disease: n = 15, MCI moderate: n = 42, MCI mild: n = 53, Control: n = 27); Quantitative MRI in NHS Memory Clinics; AD: n = 72, MCI: n = 50, Non‐AD: n = 30, Functional/attentional memory symptoms: n = 30, other cognitive disorders: n = 10). We trained and tested the model with baseline structural MRI (medial temporal grey matter density) and cognitive data (following data harmonization across training and test samples). Using a scalar projection method, we generated a prognostic index that indicates distance from the stable prototype and classifies individuals to Clinically Stable vs. Declining (slowly vs. rapidly).ResultOur trained model on ADNI data classified sMCI vs. pMCI with 79.87% class‐balanced cross‐validated accuracy (sensitivity = 83.33%, specificity = 76.52%). For the clinical NUS and QMIN‐MC samples, most AD patients were classified as rapidly progressive compared to MCI patients that were mostly classified as stable or slowly progressive (Fig.2). In contrast, for the BACS asymptomatic sample most individuals were classified as stable. Survival analysis on the NUS sample— for which longitudinal assessments (up to 6 years) are available— validated the model predictions, showing that patients with higher model‐derived prognostic index decline faster (Fig.3).ConclusionValidating our AI‐guided tool for early dementia prediction in real‐world patient data provides evidence for its clinical utility.
Predictors of primary care psychological therapy outcomes for treatment of depression and anxiety in people living with dementia: evidence from national healthcare records in England
Authors: Bell Georgia , Baou Celine El , Saunders Rob , Buckman Joshua , Charlesworth Georgina , Richards Marcus , Fearn Caroline , Brown Barbara , Nurock Shirley , Michael Stuart , Ware Paul , Marchant Natalie L , Aguirre Elisa , Rio Miguel , Cooper Claudia , Pilling Stephen , John Amber , Stott Joshua 
Published: December 2023

AbstractBackgroundPrimary care psychological therapy services can be effective in reducing symptoms of depression and anxiety in people living with dementia (PLWD) and are recommended in national guidelines (e.g., NICE, UK). However, it is currently unknown which factors are associated with better psychological therapy outcomes in PLWD.MethodNational linked healthcare records (IAPT, HES, MHSD, HES‐ONS mortality data) were used to identify 1,522 PLWD who attended psychological therapy services across England. Associations between various factors (dementia‐specific and non‐dementia specific) and therapy outcomes on widely used anxiety (GAD7) and depression (PHQ9) measures (reliable improvement, recovery, deterioration, dropout) were explored.ResultPeople with FTD were more likely to experience a deterioration in depression or anxiety symptoms compared to people with vascular dementia (OR = 2.98, 95%CI[1.08,8.22], p = .03) and people with Alzheimer’s disease (OR = 2.95, 95%CI[1.15,7.55], p = .03). Age at dementia diagnosis did not predict any therapy outcomes after controlling for sociodemographic and clinical factors. Greater depression severity (recovery: OR = .95, 95%CI[.92,.98], p<.001; deterioration: OR = 1.73, 95%CI[1.04,2.90], p = .04), lower anxiety severity (improvement: OR = 1.06, 95%CI[1.03,1.09], p<.001; deterioration: OR = .89, 95%CI[.84,.94], p<.001; dropout: OR = 1.06, 95%CI[1.02,1.11], p = .01), lower work and social functioning (improvement: OR = .98, 95%CI[.96,.99], p = .002; recovery: OR = .98, 95%CI[.96.99], p = .002; dropout: OR = 1.03, 95%CI[1.01,1.05], p = .01), psychotropic medication use (improvement: OR = .62, 95%CI[.46,.84], p = .002; recovery: OR = .67, 95%CI[.51,.90], p = .01; deterioration: OR = 1.73, 95%CI[1.04,2.90], p = .04), being working age (improvement: OR = 2.11, 95%ci[1.10, 4.04], p = .02; recovery: OR = 2.03, 95%CI[1.10,3.73], p = .02), and fewer therapy sessions (improvement: OR = 1.10, 95%CI[1.06,1.14], p<.001; recovery: OR = 1.12, 95%CI[1.09,1.16], p<.001) were all associated with worse psychological therapy outcomes in PLWD.ConclusionPredictors of psychological therapy outcomes in PLWD were largely in line with those identified for a general population above and beyond dementia‐specific factors. Additional support and adaptations, such as more therapy sessions and regular clinical reviews, may be required to improve therapy outcomes in PLWD, particularly in those who are younger and have more severe depression.
5‐HT1A Receptor Agonist, SUVN‐N9503012 for the Treatment of Dementia and Associated Neuropsychiatric Disorders
Authors: Abraham Renny , Petlu Surendra , Thentu Jagadeesh Babu , Grandhi Venkata Ramalingayya , Raya Anji Reddy , Ganuga Narender , Medapati Rajesh Babu , Subramanian Ramkumar , Rasheed Mohammed Abdul , Nirogi Ramakrishna 
Published: December 2023

AbstractBackgroundDementia such as Alzheimer’s disease (AD) dementia is a growing unmet medical condition which involves a gradual decline in cognition and function. Few therapeutic options are available for the treatment of dementia of this type with limited efficacy.MethodsSUVN‐N9503012 was characterized for its in‐vitro affinity towards 5‐hydroxytryptamine 1A (5‐HT1A) receptors using radioligand binding and functional assays. Its pharmacokinetic properties were evaluated both in rodents and dogs. The procognitive efficacy of SUVN‐N9503012 was evaluated in combination with the current standard of care (SOC), donepezil. As dementia is a co‐morbid with depression and aggression, SUVN‐N9503012 was evaluated for its potential in treating depression and agitation/aggression like behaviors.ResultsFrom in‐vitro assays, SUVN‐N9503012 was found to be a potent and selective agonist at 5‐HT1A receptors. SUVN‐N9503012 is orally bioavailable in rats and dogs and showed adequate brain penetration in rats. SUVN‐N9503012 potentiated the procognitive effects of donepezil in rat object recognition task. SUVN‐N9503012 was also found to have antidepressant like activity in rat as well as in mice in a forced swim test. SUVN‐N9503012 was found to have anti‐aggressive like activity in a mice resident‐intruder task.ConclusionFrom the efficacy studies carried out in combination with donepezil, we conclude that SUVN‐N9503012 has procognitive like activity in animal models of learning and memory. Apart from its procognitive like effects, SUVN‐N9503012 exhibited both anti‐depressant and anti‐aggressive like properties as well.
Defining tau pathology and neurodegeneration by dual‐phase 18F‐Flortaucipir PET as diagnostic and prognostic biomarkers in a memory clinic setting
Authors: Boccalini Cecilia , Mathoux Gregory , Peretti Débora Elisa , Ribaldi Federica , Scheffler Max , Perani Daniela , Frisoni Giovanni B , Garibotto Valentina 
Published: December 2023

AbstractBackground
18F‐Flortaucipir‐PET allows visualization of tau deposits (T) representing a powerful diagnostic and prognostic tool for Alzheimer’s disease (AD). Dual‐phase 18F‐Flortaucipir‐PET can also evaluate neurodegeneration (N) through the early‐phase images. We aim to assess the diagnostic and prognostic power of visual and semi‐quantitative T assessment and the potential added value of early‐phase images.MethodWe included 245 subjects from the Geneva Memory Clinic who underwent 18F‐Flortaucipir‐PET (157 with a dual‐phase protocol). Amyloid (Aβ) status was available for 207 subjects and clinical follow‐up for 135. T positivity and a Braak staging estimate were evaluated visually and semi‐quantitatively by standardized uptake value ratio (SUVr) in AD‐related regions. N status was semi‐quantitatively defined using early‐phase images as a summary metric in the AD meta‐ROI region. Receiver Operating Characteristic (ROC) analyses were applied to compare T and N discriminative power. Linear mixed‐effects models tested the prognostic values of T alone and T combined with N (T/N profiles).ResultThe mean age of the participants was 70.49±9.13 years, 52.2% were females and 55.7% were Aβ+. 53.4% of subjects had Mild Cognitive Impairment (MCI), 19.8% had dementia and 26.7% were cognitively unimpaired. All T‐assessment modalities significantly discriminated Aβ+ MCI and demented subjects from others (AUC>0.80), Aβ+ from Aβ‐ subjects (AUC>0.85), and cognitive decliners from stable individuals at follow‐up (AUC>0.79). The discriminative power of N, assessed by early‐phase images, was lower compared to T, with AUC ranging from 0.63 in discriminating Aβ+ MCI and demented subjects from others to 0.71 for discriminating Aβ+ T+ from Aβ‐ T‐ subjects. Linear mixed‐effect models showed that T+ individuals presented a significantly faster cognitive decline than the T‐ group (p<0.001) as well as T+/N+ and T+/N‐ compared to T‐/N‐ group (p<0.001), independently from T classification methods.ConclusionOur results show a similar diagnostic and prognostic power of visual and semi‐quantitative T evaluation of 18F‐Flortaucipir‐PET, proving its high potential for clinical applicability. The N status assessment with early‐phase images did not improve the prediction of cognitive decline. Its usefulness for differential diagnosis by the topographical information provided should be investigated.