bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan
Authors: Lao Patrick J. , Sedaghat Amirreza , Edwards Natalie C. , Lippert Rafael V. , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L. , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M. 
Published: December 2023

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.MethodAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.ResultTotal WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).ConclusionIn adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.
White matter hyperintensities associate with pathological stages of neurodegenerative disease
Authors: Jonkman Laura E. , Lin Chen‐Pei , Frigerio Irene , Noteboom Samantha , Bouwman Maud M.A. , Reijner Niels , Preziosa Paolo , Boon Baayla D.C. , Bouwman Femke H. , Rozemuller Annemieke J.M. , Steenwijk Martijn D. , Barkhof Frederik , van de Berg Wilma D.J. 
Published: December 2023

AbstractBackgroundWhite matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and a‐synuclein (a‐syn).MethodIn‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and a‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.ResultCompared to controls, WMH load was higher in AD (p<0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016). In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p<0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak a‐syn stage (r = 0.27, p0.018). Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p<0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04). Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak a‐syn stage (r = 0.60,p<0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).ConclusionWMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.
Polyphenol intake beneficially associates with inflammation and cognitive performance, and is mediated by MRI‐derived features
Authors: Dryer‐Beers Elliot R , Matthews Paul M , Frost Gary S , Griffin Jennifer 
Published: December 2023

AbstractBackgroundEarly changes to cognitive performance and neurophysiological biomarkers offer insights into one’s future risk of developing Alzheimer’s disease or other dementias. Evidence suggests a link between polyphenol intake and reduced incidence of age‐associated cognitive decline and neurodegeneration. These relationships may be driven by the effect of dietary polyphenols on inflammation and degeneration of critical neurological structures and systems. These relationships are challenging to assess, as few cohorts allow cohesive assessment of polyphenol intake, systemic inflammation, neurophysiological measures and cognition.MethodPolyphenol intake was assessed in two UK cohorts: The Airwave Health Monitoring Study and UK Biobank (UKB). Diet diary and questionnaire data were integrated with polyphenol composition data from Phenol‐Explorer to allow for testing of associations between polyphenol intake, blood biomarkers of inflammation, and cognitive performance. 9008 Airwave participants and 209,163 UKB participants were included in a cross‐sectional analysis. C‐reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation, and cognitive assessments included reaction time (milliseconds) and fluid intelligence (score /13). Neuroimaging assessments included grey matter volumes and white matter integrity, and were considered individually and using PCA.ResultLinear regressions showed inverse associations between total polyphenol intake and CRP: ß ‐0.00702 (Airwave) and ß = ‐0.00672 (UKB), both P <0.001, as well as fibrinogen: ß ‐0.00221; P = 0.038 (Airwave only), in addition to biomarker associations with polyphenols at the compound group level. Regarding cognition, linear regressions revealed beneficial associations between total intake and performance in fluid intelligence tests: ß 0.00657; P = 0.009 (Airwave) and ß 0.00715, P <0.001 (UKB), and reaction time ß ‐0.0000977; P = 0.020 (UKB). Mediations of the polyphenol‐fluid intelligence relationship were detected for IDPs including grey matter volumes of hippocampal‐associated regions, and white matter integrity measured using ISOVF.ConclusionWe described polyphenol intake in two large, contemporary UK cohorts, and discovered associations between higher intake and improved inflammatory markers and cognitive performance, as well as mediations of the polyphenol‐cognition relationship by physical neurological markers. This contributes to evidence supporting the health benefits of dietary polyphenols, clarifies the physiological pathways through which they may act, and highlights their relevance when considering preventative interventions for neurodegeneration.
Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum
Authors: Spotorno Nicola , Strandberg Olof , Stomrud Erik , van Westen Danielle , Hansson Oskar 
Published: December 2023

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aß‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.MethodMean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aß‐negative/tau‐negative, Aß‐positive/tau‐negative, and Aß‐positive/tau‐positive based on CSF levels of Aß42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.ResultAnalyses of MD revealed widespread differences in rates of change already between Aß‐negative/tau‐negative and Aß‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aß accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aß early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps<0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aß‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.ConclusionMean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.
Cerebral perfusion is not altered after 24 weeks of daily anthocyanin consumption in a population population of individuals at increased risk for dementia
Authors: Kallevag Oystein 
Published: December 2023

AbstractBackgroundPreliminary research suggests that anthocyanin‐consumption may improve memory, with a positive influence on the blood vessels as a possible contributing factor to these effects (1). We investigate the potential of long‐term consumption of anthocyanins to improve regional cerebral perfusion in a population of individuals at increased risk for dementia.MethodFrom 2018 to 2020 we performed a 24‐week randomised, doubleblind, placebo‐controlled study on 87 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR) (2. Anthocyanins were given in Medox® capsules that contained 80 mg natural purified anthocyanins, and the dosage was 4 capsules daily (i.e., 320mg/d of anthocyanins). Cerebral perfusion was measured non‐invasively with ASL‐MRI at baseline and after 24 weeks of daily anthocyanin‐consumption. The MRI‐scans analyzed using the FMRIB Software Library (FSL v 6.0.1; Analysis Group, Oxford, UK).ResultThe mean age in the anthocyanins group was 69.8 (± 5.5) years and the placebo group was 69.1 (± 6.0) years. When corrected for FWER, the anthocyanin > placebo analysis did not reveal any significant increased regional cerebral perfusion. There were no clusters found. When extracting maximum intensity, the lowest p‐value present was 0.839. When corrected for FWER, the placebo > anthocyanin analysis did not reveal any significant increased regional cerebral perfusion. The lowest p‐value present was 0.889 located in the right temporal pole.ConclusionOur results show no significant differences in cerebral perfusion found between the control and experimental group after 24 weeks. The data does not provide evidence for, in a population of older adults with risk of developing dementia, a daily dose of 320 mg anthocyanin ingested over a period of 24 weeks to affect cerebral perfusion to a level measureable by ASL‐MRI. • Kent K, Charlton K, Roodenrys S, Batterham M, Potter J, Traynor V, et al. Consumption of anthocyanin‐rich cherry juice for 12 weeks improves memory and cognition 23 in older adults with mild‐to‐moderate dementia. Eur J Nutr. 2017;56(1):333‐41. • Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.
Synapse dysfunction and astrocyte reactivity are associated independently of amyloid‐β and tau pathologies
Authors: Rohden Francieli , Bellaver Bruna , Ferreira Pamela C.L. , Aguzzoli Cristiano Schaffer , Lussier Firoza Z , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Zalzale Hussein , Leffa Douglas Teixeira , Abbas Sarah , Cabrera Arlec , Lemaire Peter Charles , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundBiomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.MethodCerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aß and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.ResultDemographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, ß = 0.1076; SYT1: p<0.0001, ß = 0.0024; SNAP‐25 long: p<0.0001, ß = 0.0008) as well as postsynaptic markers (Ng: p<0.05, ß = 0.0066) independently of Aß and tau burden (Figure 1).ConclusionOur biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aß and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.
CSF total tau is more closely associated with synaptic dysfunction than overt neurodegeneration
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Ferrari‐Souza João Pedro , Zalzale Hussein , Lussier Firoza Z , Rohden Francieli , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundCSF total tau (t‐tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we hypothesize that CSF t‐tau is more closely related to synaptic loss than over neurodegeneration.MethodWe evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t‐tau, SNAP25long and Neurofilament Light (NfL), Amyloid‐beta (Aß) positron emission tomography and magnetic resonance imaging, and clinical assessments. We used increased SNAP25long as an index of synaptic dysfunction (S+) and reduced hippocampal volume as neurodegeneration (N+). S and N positivity were determined using a cutoff anchored in young CU individuals. Linear regression models were used to test the association between CSF t‐tau, SNAP25long and NfL levels and hippocampal volume, adjusted for age, sex, and cognitive status. ANCOVA was employed to inspect CSF t‐tau levels across the groups 1) S‐N‐; 2) S+N‐; 3) S‐N+; 4) S+N+, adjusted for age, sex, cognitive status, and Aß burden.ResultWe found that a model with the addition of SNAP25long to the covariates explained 65% of the variance (p‐value<0.0001) of CSF t‐tau. Alternatively, hippocampal volume (R2 = 0.2187; p‐value<0.0001) and NfL (R2 = 0.3671; p‐value<0.0001) alone or in combination explained less than 40% of the variance of CSF t‐tau (R2 = 0.3597; p‐value<0.0001) (Figure 1). Interestingly, we observed an increase of CSF t‐tau in the S+N‐ group but not in the S‐N+, further supporting that CSF t‐tau is abnormal in the presence of synaptic dysfunction rather than neurodegeneration. Additionally, Loess regression lines confirm a larger magnitude of change of synaptic dysfunction as a function of t‐tau, compared with neurodegeneration (Figure 3).ConclusionOur results suggest that CSF t‐tau may reflect synaptic loss rather than neuronal degeneration. This has implications for the interpretability of results obtained with CSF t‐tau in biomarker studies.
Distinct Neural Correlates of Anxiety and Depression in Subjective Cognitive Decline versus Healthy Aging, a Microstructural Diffusion MRI Study
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana 
Published: December 2023

AbstractBackgroundA common criticism of considering Subjective Cognitive Decline (SCD) as a preclinical stage of Alzheimer’s Disease is that it may be explained by depression or anxiety1. We used NODDI, a diffusion microstructural model2, to explore the pathophysiology of depression and anxiety in SCD versus controls.Method325 participants in the Cam‐CAN study 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the NODDI metric Intracellular Volume Fraction (ICVF) were completed using MRTrix3, AMICO and MATLAB. The hippocampal cingulum bundle and fornix regions of interest (ROIs)4 were extracted from the ICBM‐DTI‐81 atlas. Depression and anxiety were assessed using the Hamilton Anxiety and Depression Scale (HADS). Linear regression models were completed in R. Gender and age were included as nuisance variables.ResultThere were no differences in gender or age distribution between cohorts, however participants with SCD were more depressed and anxious on average (Table 1). There was a significant interaction effect between depression and cohort in the fornix (Figure 1), as well as between anxiety and cohort in the hippocampal cingulum (Figure 2). In post‐hoc analyses, only the SCD group showed a correlation between depression and ICVF in the fornix (Figure 1) while only controls showed a correlation between anxiety and ICVF in the hippocampal cingulum (Figure 2), indicating different pathophysiology underlying psychiatric symptoms in the two groups.ConclusionAnxiety and depression appear to be associated with different microstructural features in SCD versus controls, suggesting anxiety and depression in SCD is a phenomenon distinct from anxiety and depression in healthy aging. Future work will explore the relationship between anxiety and depression and risk of conversion to mild cognitive impairment. • Mitchell AJ, Beaumont H, Ferguson D, et al. Acta Psychiatrica Scandinavica. 2014;130(6):439‐51. • Daducci A, Canales‐Rodriguez EJ, Zhang H, et al. Neuroimage. 2015;105:32‐44. • Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25. • Kantarci K. Frontiers in Aging Neuroscience. 2014;6.