bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional network alterations in early‐onset Alzheimer’s disease studied with resting‐state fMRI
Authors: Sala‐Llonch Roser , Contador José , Pérez‐Millan Agnés , Falgàs Neus , Ruiz‐Peris Mariona , Tort‐Merino Adrià , Balasa Mircea , Olives Jaume , Castellví Magdalena , Juncà Jordi , Borrego‐Écija Sergi , Bosch Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Sanchez‐Valle Raquel , Lladó Albert 
Published: December 2020

AbstractBackgroundChanges in functional connectivity (FC) networks have been extensively reported in late onset Alzheimer’s Disease (AD), being the default mode network (DMN) the key system to be affected. However, it remains unclear if FC in early‐onset AD (EOAD) would show a similar pattern than late onset AD.MethodWe studied 48 EOAD patients (mean age=57.40±5.53 years) and 31 healthy controls (CTR, mean age=58.22±3.94 years) who underwent resting state functional magnetic resonance imaging (rs‐fMRI) in a 3T MRI scanner. We used group independent component analysis to identify the main resting state networks (RSNs). We studied group‐differences in the spatial extent of these networks, in the amplitude of their temporal oscillations and in the temporal correlation between pairs of networks, using FSLNETS. We also evaluated the discrimination capability of FC patterns by using a support vector machine (SVM) classifier.ResultWe identified 17 RSNs that were further classified into DMN, visual, motor, executive, salience and cerebellum systems. The network spatial maps' vertex‐wise analysis shows regional increases of some executive networks in EOAD (p<0.05, FWE corrected), suggesting increased aberrant local connectivity surrounding the main RSN nodes. In the temporal domain, we find decreases in amplitude in the posterior DMN and the salience network (p<0.05, corrected), and increases in the anterior DMN and the cerebellum networks. With the study of correlations between networks we describe a pattern of altered inter‐network connectivity that involves both increases and decreases of connectivity. Importantly, the entire pattern of network correlations discriminated AD from CTR subjects with an accuracy of 83.5%.ConclusionOur results suggest that EOAD is characterized by a complex pattern of FC alterations involving alterations in the amplitude of the main RSNs and in the way that they interconnect. Increase in connectivity in short‐range connections surrounding the main nodes might be a consequence of the decreases of larger connections between nodes. Alterations in the salience network differ from the late onset AD literature. Overall, the entire FC pattern gives a good classification rate suggesting that it might be a good biomarker for EOAD.
The impact of control conditions on the interpretation of multi‐sensory technology interventions
Authors: Perion Jennifer , Steiner Victoria , McBride Kimberly , Saltzman Barbara , Kinney Jennifer 
Published: December 2020

AbstractBackgroundMulti‐sensory interventions utilizing technological elements (e.g. projectors, robotics) create opportunities for increased engagement and well‐being among nursing home residents with dementia. When evaluating multi‐sensory technology, researchers often employ a control condition to measure differences in positive and negative affect. A study’s quality may be compromised when researchers fail to provide sufficient details about control conditions, or when inappropriate control activities are chosen.MethodUniversity research databases were searched for peer‐reviewed studies that utilized multi‐sensory technology aimed at reducing problem behaviors among nursing home residents with moderate‐to‐severe dementia. Articles were limited to experimental or quasi‐experimental designs published since 2007. A descriptive analysis of the methodologies used in the relevant articles was conducted.ResultEleven articles met the selection criteria. A review of the reported design and data collection procedures for the studies revealed three common practices that may impact interpretation of the data. Usual care: Five of the eleven studies (45%) included observation of participants’ routine activities for comparison; however, only two provided more than a sentence to describe the control activities, while the other three simply stated that participants spent an equivalent amount of time engaged in “usual care.” Recall of behaviors: Three studies (27%) relied on nursing staff recall of behaviors reported pre‐ and post‐intervention. Direct observations were not recorded, and the residents’ normal routines were not described. No control: Three studies (27%) introduced novel non‐technological activities such as personalized gardening for comparison to the intervention. No control activity was included in the study design.ConclusionA review of eleven studies conducted to evaluate innovative multi‐sensory technology revealed a lack of consistent design and reporting practices. Publications providing scant details regarding normal routines or a definition of “usual care” create difficulties for researchers who may wish to evaluate, replicate, or improve upon the intervention. Additionally, using a novel non‐technological activity for comparison may also affect engagement and the ability to draw accurate conclusions about the intervention’s efficacy. Researchers who wish to determine the effectiveness of multi‐sensory technology interventions with nursing home residents should carefully select and fully justify the choice of control conditions.
Assessment of the integrity of the noradrenergic nucleus locus coeruleus during normal ageing by neuromelanin‐3T MRI
Authors: Galgani Alessandro , Lombardo Francesco , Hana Hlavata , Daniele Della Latta , Ghicopulos Irene , Coi Alessio , Martini Nicola , Marchi Daniele , Keilberg Petra , Tognoni Gloria , Siciliano Gabriele , Ceravolo Roberto , Pavese Nicola , Fornai Francesco , Bonuccelli Ubaldo , Giorgi Filippo Sean 
Published: December 2020

AbstractBackgroundThe pontine nucleus Locus Coeruleus (LC) provides noradrenergic innervation to the whole brain. It is involved in neuronal homeostasis, sleep/wake cycle and in specific cognitive functions. Several data suggest a degeneration of LC in neurodegenerative disorders. Recent post‐mortem studies showed that LC is not affected by ageing (Theofilas et al., 2017, Alzheimers Dement. 13:236‐46). Using a neuromelanin‐sensitive 3 Tesla MRI protocol, we assessed LC integrity in healthy elderly subjects, exploring also the occurrence of age‐related modifications and evaluating any correlation with cognitive performance.Method60 healthy volunteers aged 60‐80y, equally distributed by sex and age, underwent 3‐Tesla brain MRI (Signa‐GEH), including neuromelanin (NM)‐sensitive FSE T1‐weighted sequences for LC study, which were evaluated by two independent operators, using a semi‐automatic software (modified from Garcia‐Lorenzo, 2013, Brain, 136:2120‐9). Results were expressed with the parameter VOX, that is the total amount of MRI‐voxels positive for LC‐signal. Then, subjects were submitted to a full neuropsychological assessment, including evaluation of verbal and visuo‐spatial memory, attention and executive functions. A test‐retest reliability verification was performed, comparing the variability intra and inter‐operator.ResultWe did not observe any significant age or gender‐related variation of the parameter VOX; no correlation was detectable between VOX values and cognitive tasks performances; our protocol showed a good intra‐ and inter‐observer reproducibility.ConclusionOur results are in line with recent neuroanatomical post‐mortem data which did not describe any age‐related modification of LC in cognitively healthy subjects; the small variability among subjects we observed for selected cognitive functions did not correlate with significant variations of MRI LC signal. Assessing the LC integrity in healthy elderly subjects is a necessary preliminary step for studies evaluating LC involvement in neurodegenerative disorders, as Alzheimer’s Disease, in which LC degeneration might be a key‐point in the pathogenesis (Kelly et al., 2017,Acta Neuropathol Commun. 5:8). (Funding: Ministero della Salute PE‐2013‐02359574; P.I.:FSG).
Relationship between multimodal neuroimaging biomarkers and white matter hyperintensities across the Alzheimer’s disease spectrum: A region‐of‐interest‐ and voxel‐based study
Authors: Gaubert Malo , Lange Catharina , Garnier‐Crussard Antoine , Bougacha Salma , Gonneaud Julie , De Flores Robin , Tomadesso Clémence , Mézenge Florence , Landeau Brigitte , De la sayette Vincent , Chetelat Gael , Wirth Miranka 
Published: December 2020

AbstractBackgroundWhite matter hyperintensities (WMH) are a frequent marker of cognitive impairment and Alzheimer’s disease (AD). Although WMH have been commonly linked to cerebrovascular disease, recent studies suggest an association between AD pathology and regional WMH distribution. The objective of this study was to investigate the relationship of AD neuroimaging biomarkers of Aß burden, hypometabolism and GM atrophy with regional WMH distribution in older adults across the cognitive continuum at two different levels: regions of interest (ROIs) and voxel.MethodFLAIR MRI (1), AV45‐PET (2), FDG‐PET (3) and T1 MRI (4), were acquired in 155 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD in the IMAP cohort (Caen, France). WMH were segmented using FLAIR MRI with the SPM12‐based lesion‐segmentation‐tool (Schmidt, 2017). Standard pipelines were applied to WMH probability maps and all other images (2‐4) resulting in maps normalized in MNI space. Mean AV45‐SUVR, mean FDG‐SUVR and total GMV were extracted within AD signature templates (Besson et al., 2015). Moreover, regional WMH were computed in multiple ROIs based on previous recommendations (Wardlaw et al., 2013). The associations between AD biomarkers levels and regional WMH distribution were assessed using linear regression models at ROI and voxel levels, adjusting for age, sex, education and blood pressure. Uncorrected p<.05 and p<.005, respectively for ROI‐ and voxel‐wise analyses, were applied.ResultFor the ROI analysis (Table 1), mean AV45‐SUVR was not significantly associated with regional WMH. Mean FDG‐SUVR was negatively related with regional WMH, including periventricular region and corpus callosum (body and splenium). Finally, GMV in the AD signature was found to be significantly associated with WMH in all ROIs (Table 1). For the voxel‐based analyses, the results are comparable (Figure 2B.‐D.). Notably, a positive association was found between the mean AV45 SUVR and the splenium part of the corpus callosum (Figure 2.D).ConclusionOur findings confirm that AD neuroimaging biomarkers of Aß burden, hypometabolism and GM atrophy are associated with regional WMH, including periventricular regions and posterior parts of the corpus callosum. These associations might reflect either involvement of vascular damage in AD pathogenesis or contribution of AD pathology to white matter damage.
1H‐MRS signature in Alzheimer disease in Down syndrome
Authors: Barroeta Isabel , Montal Victor , Carmona‐Iragui Maria , Pegueroles Jordi , Vilaplana Eduard , Bejanin Alexandre , González‐Ortiz Sofía , Altuna Miren , Benejam Bessy , Alcolea Daniel , Videla Laura , Valldeneu Sílvia , Fernandez Susana , Videla Sebastián , Blesa Rafael , Clarimon Jordi , Lleó Alberto , Fortea Juan 
Published: December 2020

AbstractBackgroundDown syndrome(DS) is a genetically determined form of Alzheimer's Disease(AD). Proton magnetic resonance spectroscopy(1H‐MRS) allows in vivo assessment of brain biochemistry. Few studies have assessed 1H‐MRS metabolites for tracking AD in DS. Our objective was to assess the changes in the myo‐inositol(mI)–a glial marker‐ and N‐acetyl‐aspartate(NAA)‐ a neuronal marker‐ in 1H‐MRS and its correlation with cortical thickness and AD biochemical biomarkers in the AD continuum in DS.MethodCross‐sectional study. DS subjects were classified into asymptomatic (aDS) and symptomatic: prodromal AD(pDS) and AD dementia(dDS).Participants underwent a single‐voxel 3TMRS in the posterior cingulate/precuneus and a 3Tstructural MRI. mI, NAA and total creatine (TCr) metabolites levels were quantified using Tarquin. Cortical thickness (CTh) values were computed using Freesurfer. Aβ1‐42, total tau, phosphotau, and NFL levels were determined in plasma using a SIMOA platform and in CSF using Lumipulse. For a subset of subjects, amyloid plaques were spatially mapped using Florbetapir‐PET (PET‐FBP). We performed ANCOVA analyses with Tukey posthoc corrections to assess the mI/TCr and the NAA/TCr between‐groups differences. We computed the vertex‐wise correlation between mI/TCr, NAA/TCr and CTh. We used linear regression to assess relationship between MRS metabolites and PET‐FBT and AD biochemical biomarkers.ResultWe included 83 adults with DS(61aDS, 15pDS and 7dDS) and 25 euploid healthy controls (HC). The three DS subgroups showed significant (p<0.05) increases in mI/TCr when compared to HC. Moreover, we found a gradient of increases of mI/TCr in the DS subgroups (aDS>pDS=dDS). The dDS subgroup showed significant (p<0.05) decrease in NAA/Cr compared to HC and aDS. mI/TCr levels were negatively correlated with CTh in the medial and lateral temporal regions, bilaterally. NAA/TCr levels revealed a similar pattern of positive correlations with Cth but more widespread. mI/TCr levels were positively correlated with PET‐FBP and plasmatic NfL in the DS symptomatic group. NAA/TCr level were negatively correlated with CSF tTau and plasmatic NfL in the DS symptomatic group.ConclusionThere is a gradient of increases of myo‐inositol in the AD continuum in DS which correlate with atrophy in temporal regions, increased PET‐FBP, and plasma NfL. Our data reveals a 1H‐MRS signature in AD in DS and supports myo‐inositol as a potential glial marker.
Small molecule inhibitors of apolipoprotein E4‐catalyzed amyloid‐β fibrillization as novel therapeutics for Alzheimer’s disease
Authors: Johnson Noah R. , Wang Athena Ching‐Jung , Coughlan Christina M. , Lucero Esteban M. , Viltz Lisa , Allen Cody , Markham Neil , Chial Heidi J. , Potter Huntington 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative illness initiated by fibrillization of the amyloid‐beta (Aβ) peptide in the brain. Genetic factors can increase the risk for developing AD, especially in individuals who carry the ε4 allele of the apolipoprotein E (APOE) gene. Having one copy of APOE4 doubles the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than ten‐fold. ApoE4 acts as a catalyst to accelerate the polymerization rate of Aβ into neurotoxic oligomers and filaments; thus, inhibiting this enzymatic process is a promising therapeutic approach to preventing AD. We therefore developed an ApoE4‐Aβ fibrillization assay for high‐throughput drug screening of small molecule compounds.MethodA design of experiments (DOE) approach was employed to optimize the ApoE4‐Aβ fibrillization assay. A series of fractional factorial and surface response designs were used to determine the concentrations of Aβ, ApoE4, and thioflavin T that yielded the greatest rate and amount of Aβ fibrillization. The optimized assay was then used to screen two small molecule libraries representing more than 3,000 compounds, most of which are drugs or natural compounds that have already been tested in humans for other indications. Hit compounds were next evaluated for cytotoxicity and inhibition of Aβ neuropathology in primary mouse neurons expressing human Aβ and exposed to human ApoE4 over nine days in culture.ResultA primary screen of two small molecule libraries identified 31 hit compounds that significantly inhibited ApoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Primary hit compounds were then tested in primary mouse neurons, where six compounds were validated as non‐cytotoxic and were effective at inhibiting Aβ neuropathology. One of the six lead compounds (epigallocatechin gallate) had been studied previously as a potential therapy for neurodegenerative disease, thus validating the overall screening approach.ConclusionSix small molecule compounds were identified as novel inhibitors of ApoE4‐catalyzed Aβ fibrillization in high‐throughput screens. Three are FDA‐approved drugs for indications unrelated to AD. We are currently performing preclinical evaluations of these compounds in AD rodent models to determine their therapeutic potential for the treatment of AD.
Lifespan diffusion MRI reveals regional abnormalities in the 5xFAD model of Alzheimer’s disease
Authors: Jullienne Amandine , Lee Jeong Bin , Yassa Michael A. , Territo Paul R , Obenaus Andre , Consortium MODEL‐AD 
Published: December 2020

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human data. We undertook lifespan diffusion magnetic resonance imaging (dMRI) to fully characterize the temporal alterations in brain structure and circuits in 5xFAD.MethodAll 5xFAD mice are compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12mo. Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm2/sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AD) and mean (MD) diffusivity parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed to quantitate amyloid β (Aβ) load. Histology and immunohistochemical analyses verified neuroimaging findings.ResultOur preliminary results focus on CA1 and the subiculum of the hippocampus and show tract differences between WT and 5xFAD females at 8 months of age. DTI metrics in these tracts are also affected by sex and genotype. For example, FA is decreased by ∼30% in 5xFAD females compared to WT females at 8 months. AV45‐PET were able to detect increasing Aβ plaque load with age in 8‐12mo old 5xFAD mice when compared to WT and was verified by immunohistochemistry.ConclusionPhenotyping of mouse models using dMRI can identify altered brain connectivity and regional tissue features. The data support that increasing Aβ deposition results in altered dMRI metrics that can be readily translated to the clinic.
Rates of cognitive decline during the preclinical phase and their use in predicting future dementia
Authors: Payton Nicola Maria , Marseglia Anna , Grande Giulia , Fratiglioni Laura , Kivipelto Miia , Bäckman Lars , Laukka Erika J 
Published: December 2020

AbstractBackgroundCognitive deficits can occur years or even decades before a clinical diagnosis of dementia, with a rate of decline which differs from that in normal aging. This study aimed to investigate differences in trajectories of cognitive decline in multiple cognitive domains in the preclinical dementia phase, and whether early rates of decline can be used to predict dementia.MethodRepeated neuropsychological assessments were conducted for 1652 participants (age ≥60 years) from the Swedish National Study on Aging and Care–Kungsholmen (SNAC‐K). In this sample, 220 developed dementia and 1432 remained dementia free or died without dementia over 12 years. Piecewise linear mixed models were used to compare rates of cognitive decline between people who developed dementia and those who remained dementia free. Individual rates of decline from baseline over six years follow‐up were extrapolated from the mixed models for episodic memory, semantic memory, verbal fluency, and perceptual speed. Fast decliners were identified as those whose rate of decline was >1.5SDs faster than the mean of the no‐dementia group. Multinomial logistic regressions were used to estimate the association between domain‐specific rate of decline and dementia at 9 or 12 year.ResultSignificantly faster decline was observed in all cognitive domains in those who developed dementia vs. those who did not. In piecewise linear mixed‐models, participants in a preclinical dementia phase showed disproportionally accelerated decline as they neared the time of diagnosis in all cognitive domains except episodic memory, where decline was more linear. Being a fast decliner was associated with increased dementia risk and being a fast decliner in at least two cognitive domains further increased the risk of dementia. For the individual domains, however, only rate of decline in verbal fluency added independent variance above that of baseline scores.ConclusionThe preclinical dementia phase is associated with accelerated cognitive decline, especially in the last 6 years prior to diagnosis. Using early rates of decline (12‐6 years before diagnosis) add some information in the prediction of future dementia and can help identify individuals at increased risk of developing the disease.
Gamma power increased in Alzheimer's disease patients in comparison to healthy controls during recognition of facial expressions
Authors: Güntekin Bahar , Yıldırım Ebru , Kıyı İlayda , Fide Ezgi , Uzunlar Hakan , Calısoglu Pervin , Yirikogullari Harun , Akturk Tuba , Yener Görsev 
Published: December 2020

AbstractBackgroundSeveral researchers have reported the impairment of recognition of facial expressions in Alzheimer’s disease (AD) patients. AD had reduced theta and alpha responses compared to healthy controls during the recognition of facial expressions (Güntekin et al. 2019). Gamma responses also have a crucial role in the recognition of facial expression in healthy young adults (Güntekin and Başar 2014). AD had increased late gamma responses compared to healthy controls during working memory paradigms (Başar et al. 2017). The present study aims to analyze the gamma responses during the recognition of facial expressions in AD and healthy controls. We hypothesized that if the increase of late gamma responses is a general phenomenon in AD patients independent of the stimulation type, we expect to find increase gamma responses in AD patients in comparison to healthy controls.MethodEEGs of 40 healthy controls (HCs) and 41 AD patients were recorded during their perception of three different facial expressions (angry, happy, neutral). Event‐related power spectrum and phase locking were analyzed for three different gamma bands (30‐35 Hz, 35‐ 40Hz, 40‐48 Hz) in two different time windows (0‐200 ms, 200‐400 ms).ResultThe group difference between AD patients and HCs was not significant for the phase‐locking values. AD patients had higher gamma power responses compared to healthy controls in 200‐400 ms time window for 30‐35 Hz(p=0.016), 35‐40 Hz(p=0.018) and 40‐48 Hz (p=0.039). The only significant group difference for the early time window (0‐200 ms) was found for 35‐40 Hz (p=0.046). The figure shows topographical plots of gamma (35‐40 Hz) power for 200‐400 ms time window in patients (upper part) and healthy controls (lower part) for angry, happy and neutral facial expressions.ConclusionThe present study showed that the increase of late (200‐400 ms) gamma were independent of stimulus type in AD patients. The increase of gamma power in a 200‐400 ms time window was found in AD patients compared to healthy controls for all three facial expressions. The facial expression recognition in AD patients was differentiated from healthy controls by increased gamma power. Acknowledgments: This work (grant number 218S314) was supported by TUBITAK.