bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity of objective and subjective sleep features to tau and Aβ burden in healthy older adults
Authors: Winer Joseph R. , Morehouse Allison , Fenton Laura E. , Harrison Theresa M. , Baker Suzanne L. , Jagust William J. , Walker Matthew P. 
Published: December 2020

AbstractBackgroundImpaired sleep is a risk factor for Alzheimer’s disease (AD) as well as a symptom of AD pathological progression. Recent work has established associations between disrupted sleep electrophysiology and AD pathology before the onset of AD symptoms. However, it is not understood how real‐life sleep features, both objective and subjective, are associated with tau and Aβ burden in the context of early AD.MethodWe compared objective and self‐reported measures of sleep quantity and quality to 18F‐FTP tau PET and 11C‐PIB Aβ PET in healthy older adults (N=80, age 78.9 ± 6.9, 65% female). Objective sleep was assessed using 7 nights of at‐home wristwatch actigraphy, with analyses focusing on sleep duration, efficiency, fragmentation and timing (midpoint). Subjective sleep was assessed using the Pittsburgh Sleep Quality Index. 18F‐FTP SUVRs (80‐100 min, inferior cerebellar gray reference) were calculated for each subject in a composite ROI of temporal cortical regions. A global cortical 11C‐PIB DVR (0‐90 min, cerebellar gray reference) was also calculated.ResultShorter average sleep duration was associated with significantly greater cortical Aβ (Figure 1A; r=‐.23, p=0.04). In contrast, worse sleep efficiency, rather than duration, was associated with greater tau burden (Figure 1B; r=‐.24, p=.03). Of clinical interest, neither self‐reported sleep duration or efficiency were associated with tau and Aβ burden. Indeed, greater tau and Aβ burden were associated with worse accuracy in self‐reported estimation of sleep, relative to objective amount (Figure 2; r=0.23, p=0.04).ConclusionThese findings suggest that specific actigraphy‐based measures of sleep, assessed in the ecological at‐home setting, are differentially predictive of tau and Aβ burden. This dissociation may reflect distinct effects of these anatomically segregated pathologies in early stages of AD and their respective impact on different aspects of sleep‐regulating brain networks. Of translational relevance, participants’ own subjective sleep estimates did not predict tau or Aβ burden, suggesting that objective sleep assessments may be more clinically appropriate, reflecting real‐life behavior patterns in the context of aging. Finally, the severity of both tau and Aβ burden predicted the degree of inaccuracy in participants’ assessment of their own sleep duration, the underlying neural mechanisms of which remain unclear.
Impact of intrathecal cell therapy with autologous stromal cells on short‐term memory binding in early Alzheimer’s disease: One‐year follow‐up assessment
Authors: Guinea Sara Fernández , Zurita Mercedes , Mucientes Jorge , García Estefanía , Marqués Javier González , Parra Mario A. , Vaquero Jesús 
Published: December 2020

AbstractBackgroundWe had previously reported that the administration of autologous stromal cells (ASCs) therapy to two patients with mild AD dementia led to a global increase in cerebral glucose metabolism which was accompanied by significant improvement of visual short‐term memory binding (VSTMB), a function known to be a marker of AD. We suggested that intrathecal administration of autologous ASCs could be considered a new therapeutic strategy for AD dementia (Vaquero et al., 2019). We were interested in investigating the post‐intervention durability of such cognitive improvements.MethodsWe studied two AD patients with cerebral beta‐amyloid neuritic plaques detected with 18FFDG‐PET. The patients received every three months 100 million of ASCs by intrathecal route, until a total dose of 300 million. None received any other medication for its disease at the time of receiving cell therapy. Clinical and neuroimaging studies were performed previous and after the therapy, including brain glucose metabolism by 18F‐FDG‐PET and assessment with the visual short‐term memory binding task (VSTMBT). This task has been proposed as a preclinical marker of AD. It requires subjects to detect whether or not two combinations of shape and colour change across two sequential arrays. Here we report on the assessment of these patients one year after the therapy. We compared them with 4 AD patients who did no undergo stem cell therapy.ResultsSingle case statistics revealed that benefits drawn by treated patients from the therapy remained a year after. Using a more taxing version of the VSTMB test (memory load of 3 items) we observed that, after the therapy, the chance that an untreated AD patient would show more impairment was 75.45% (p= 0.24) for Case 1 and 89.23% (p=0.11) for case 2. This chance remained after 1 year post‐treatment for Case 1 (75.45%, p=0.24) and increased for Case 2 (96.89%, p=0.031).ConclusionImprovements of memory functions known to be marker for AD in patients who underwent stem cell therapy remained stable after one year post‐intervention. This offers a new therapeutic strategy for AD.
Associations between age, sex, menopause and cardiometabolic risk profiles with brain structure: A latent class analysis
Authors: Than Stephanie , Moran Christopher , Beare Richard , Vincent Amanda , Srikanth Velandai K 
Published: December 2020

AbstractBackgroundOlder age and female sex are both risk factors for the development of dementia. This may be related to menopause, a midlife event associated with an increased incidence of cardiometabolic conditions for women. We aimed to identify latent groups of cardiometabolic risk, explore their interactions with age, sex and menopause, and examine the associations with imaging biomarkers of dementia.MethodCross‐sectional study of participants with cardiometabolic and structural brain magnetic resonance imaging data from the UK Biobank, a community‐based cohort of men and women over 40 years of age in the United Kingdom. We applied latent class analysis to age, sex, menopausal status and available cardiometabolic measures using poLCA in R. Information criteria determined the best model fit. We then used logistic regression to examine class‐dependent associations with brain volumes.ResultData were available for 1824 postmenopausal women, 233 premenopausal women and 2165 men (median age 63.3, range 44.6‐78.0 years). LCA identified 4 distinct classes: an “unhealthy” group of men and postmenopausal women (22.5%), a “hypertensive group” of men and postmenopausal women (10.4%), a “healthy” group of postmenopausal women (31.9%), and a younger “healthy” reference group of men and premenopausal women (35.2%). Mean total brain volume was greatest in the reference group (1517 mL ± 71.6), followed by the “healthy” postmenopausal group (1516 mL ± 70.7), the “hypertensive group” (1493 mL ± 70.8), and the “unhealthy” group (1475 mL ± 69.2).ConclusionOlder age and menopause are associated with reduced brain volumes. Differences in cardiometabolic risk profiles appear to moderate these associations.
Protein‐protein interaction networks of genes associated with different cognitively defined subtypes of late‐onset Alzheimer's disease in five white populations identify novel candidate genes
Authors: Mukherjee Shubhabrata , Mez Jesse , Trittschuh Emily H. , Saykin Andrew J. , Gibbons Laura E. , Sanders R. Elizabeth , Fardo David W. , Crane Paul K. 
Published: December 2020

AbstractBackgroundWe previously defined late‐onset Alzheimer's disease (AD) subgroups using cognitive profiles (memory, executive functioning, language, and visuospatial ability) for individuals with Clinical Dementia Rating < 2 in five White populations. This approach results in six subgroups: those with no domain with a substantial relative impairment; those with an isolated substantial relative impairment in one of four domains, and those with multiple domains (mixed) with substantial relative impairments. We performed gene network analysis to find unique and overlapping genes to enhance our understanding of AD heterogeneity.MethodWe performed genome‐wide association studies (GWASs) for each of the AD subtypes against cognitively normal elderly adjusting for age, sex, and population substructure using PLINK v1.9 in each population and meta‐analyzed results using METAL. We excluded the AD‐Executive function group because of small sample size. For each of the subtypes, we performed gene‐wide association analyses using VEGAS v2 and combined results with human protein‐protein interaction (PPI) data using a dense module searching method to identify candidate gene modules. This approach searches the entire interactome and exhaustively evaluates the combined effects of multiple genes to identify networks of interacting genes with low p‐values for the phenotype of interest. We performed gene network analysis for AD using Stage 1 GWAS summary statistics reported in the 2019 IGAP GWAS of AD paper and compared genes in the top module for AD to the top module for each AD subtype.ResultThe top gene network module for AD and AD subtypes were enriched for genes in Chromosome 19. Ubiquitin C (UBC) was the hub gene in each of the top modules (See Figure 1). Very few genes were common across the different subtypes and with AD, and except for UBC, all of them reside in Chromosome 19 (See Figure 2).ConclusionNetwork analyses using PPI data identified novel candidate genes for cognitively‐defined AD subtypes, which supports the AD heterogeneity idea. Further functional enrichment analysis is needed to determine whether these candidate loci may provide targets for interventions to ameliorate AD.
Neurodegenerative substrate of behavioral changes in Alzheimer’s disease
Authors: Ringman John M , Pawar Sanjay , Montoya Lucy , Ge Xinting , Qiao Yuchuan , Shi Yonggang 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD) and, with advancing disease, are a major cause of disability and the principal cause of institutionalization. With the advent of tau imaging with PET, we can directly interrogate the neurodegenerative changes associated with behavioral changes in AD.MethodWe performed flortaucipir PET scans in persons carrying autosomal dominant AD (ADAD) mutations and with late‐onset AD (LOAD). The Neuropsychiatric Inventory (NPI) was administered to knowledgeable study partners and the frequency x severity scores calculated for each behavioral domain. All underwent scans with flortaucipir using 110‐minute uptake time and 30‐minute dynamic scanning. PET scans were first normalized to T1 space and then corrected for partial volume effects using Mueller‐Gaertner approach. SUVRs for PET scan were calculated using the whole cerebellum grey matter as a reference. Regional average SUVRs were finally obtained for each ROI mapped from the Desikan‐Killiany Atlas. NPI scores for each domain were correlated with SUVRs using Pearson’s correlations.ResultWe included 24 participants (53% male, mean MMSE = 21, CDR = 0.8, CDR SOB = 4.6) with ADAD mutations (mean age = 38) and 6 participants with LOAD (mean age = 60). Strong (p’s < 0.01) correlations were found for affective behaviors (apathy>depression>anxiety) and tau SUVRs in the anterior cingulate gyrus and medial orbitofrontal lobe. The highest correlations were found between apathy and tau signal in these areas (r = 0.67, p < 0.001).ConclusionChanges in affect correlated strongly with tau pathology in the medial and orbital frontal lobes. This is consistent with previous studies implicating a role or these areas in apathy and depression. These findings enhance our understanding of the pathology underlying affective symptoms in AD and suggest a role of tau PET in identifying those at the greatest risk for these debilitating symptoms.
Diagnosis and management of neuropsychiatric symptoms in early Alzheimer’s disease in the memory clinic setting
Authors: Eikelboom Willem S. , Coesmans Michiel , Singleton Ellen H. , Ossenkoppele Rik , van Swieten John C. , van den Berg Esther , Papma Janne M. 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) are highly prevalent in early Alzheimer’s disease (AD) and are associated with poor clinical outcomes. Although non‐pharmacological interventions are considered first‐line treatment for NPS in AD, they are rarely implemented into the memory clinic. Here, we present the protocol of our intervention study aimed to structure and standardize the detection and treatment of NPS in AD in the memory clinic, and provide preliminary data from our control group to obtain more insight in the current memory clinic care as usual (CAU) of NPS in AD.MethodWe are currently enrolling a control group that receives CAU at six memory clinics in and around Rotterdam, the Netherlands. From spring 2020 onwards, a second wave of subjects will undergo the Describe, Investigate, Create, Evaluate (DICE) method in order to standardize and structure the management of NPS in AD. Primary outcomes are the quality of life of patients and their caregivers measured by the Qol‐AD. Secondary outcomes include NPS change, caregiver burden, the experiences of the participants that underwent the DICE method, and the cost‐effectiveness of the intervention. We conducted interviews with physicians to investigate the CAU for NPS in the memory clinic.ResultTo date, 26 community‐dwelling patients have been enrolled in the control group together with their caregivers (n=19 AD dementia, n=7 mild cognitive impairment due to AD, mean [SD] Mini‐Mental State Examination = 23.5 [3.6]). Most common NPS presented at baseline were depression (80.8%), apathy (65.4%), and irritability (61.5%). Although we found heterogeneity in the CAU of NPS between participating sites, most memory clinics do not routinely screen for NPS (2/6 sites) and/or to carry out an elaborate assessment of NPS and its potential underlying causes (2/6 sites).ConclusionPreliminary data on the CAU indicate a high prevalence of NPS that are currently not routinely investigated nor treated in the memory clinic. Early recognition and thorough assessment of NPS seem important first steps to facilitate the use of non‐pharmacological treatments for these symptoms in AD. Our intervention study aims to facilitate an early diagnosis and adequate management of NPS in early AD in the memory clinic.
Cerebral hemodynamics using BOLD MRI in MCI
Authors: Hajjar Ihab , Henley Brandon 
Published: December 2020

AbstractBackgroundAlterations in cerebral hemodynamics are a key factor in the onset and progression of Alzheimer’s disease (AD). In this report we describe we describe a procedure to measure multiple cerebral hemodynamic features using magnetic resonance imaging (MRI) with simultaneous multi‐dimensional physiological signals.MethodsWe assembled an MRI‐compliant system that records continuous systemic blood pressure, pulse rate, respiratory rate and end‐tidal CO2 synchronized with the MRI image acquisitions of resting state blood oxygenation level depend (BOLD) MRI. We employed the concept of Principal Dynamic Modes (PDMs) to model the effect of three determinants: mean arterial blood pressure (MABP), end‐tidal CO2 (ETCO2), and pulse rate (PR) to quantify cerebral autoregulation (CA), CO2 vasoreactivity (CVR), and pulse rate reactivity (PRR). BOLD images were acquired at rest and during an 8% 2‐minute CO2‐challenge. Data were collected as part of the baseline assessment of the participants in the Brain Stress Hypertension and Aging cohort which includes those with normal cognition and mild cognitive impairment (MCI).ResultsThe hemodynamic set up was well tolerated and successful analysis of data were obtained from 129 participants ( age 65, 80 women, 60 African Americans, 79 MCI). There was a significant correlation between the PDM‐based calculation of CVR and that obtained during CO2 challenge (R2 = 5.19%, p = .016). There was also a significant correlation between PDM‐based measure of CA and the ratio of sit‐to‐stand change in MABP to PR (R2 = 6.86%, p = .005). Relative to those with normal cognition (NC), CA was reduced in MCI in the parietal lobe, CVR was reduced in MCI in the occipital and temporal lobes, and PRR was reduced in multiple lobes lobes. Reduced CVR and PRR was associated with worse cognitive scores.ConclusionsThe employed acquisition and analysis of MRI hemodynamic procedures is well‐tolerated, and identified cerebral hemodynamic alterations in MCI, related to PR and ETCO2 changes. These offer a potential for collection of hemodynamics during routine MRI in cognitive disorders.
APOE‐ε4 shapes temporo‐parietal network properties in middle‐aged, cognitively unimpaired individuals: A graph theory analysis
Authors: González‐de‐Echávarri José Maria , Cacciaglia Raffaele , Falcon Carles , Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M , Grau‐Rivera Oriol , Operto Greg , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , Minguillón Carolina , Fauria Karine , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA study
Published: December 2020

AbstractBackgroundThe allele ε4 of the APOLIPOPROTEIN E gene (APOE‐ε4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). However, the underlying mechanisms are not well understood. Our objective was to assess the effect of the APOE‐ε4 allele dose on brain functional connectivity networks in cognitively unimpaired middle‐age individuals, using resting‐state functional magnetic resonance imaging (rs‐fMRI) and graph theory.MethodThis research included resting state 3 tesla functional Magnetic Resonance Imaging (rs‐fMRI) data from 349 cognitively unimpaired subjects from the ALFA+ cohort study, in which clinical, genetic and AD core cerebrospinal fluid biomarkers (Aβ42 and p‐tau), measured using Elecsys® immunoassays (Roche Diagnostics) data were also collected. The sample was composed of 127 men and 222 women with a mean age of 60.2 years, 32 homozygous ε4, 123 heterozygous ε4 and 164 non‐carriers. The CONN toolbox (matlab toolbox) was used to preprocess and analyze the fMRI images with the default pipelines and adjusting by age, sex and years of education. ROI‐to‐ROI bivariate correlations were performed using cortical ROIs of Harvard‐Oxford atlas to compute each subject adjacency matrix. After thresholding and binarizing these results, graph theory was used to analyze the differences between APOE‐ε4 groups and false discovery rate (p‐FDR= 0.05) was applied.ResultsWe observed APOE‐ε4 allele‐dose dependent effects on multiple network properties, including reduced degree centrality, reduced global efficiency and increased average path length located in temporo‐parietal nodes: left temporo‐occipital fusiform cortex, occipital fusiform gyrus, right lateral parietal cortex, temporal pole and posterior superior temporal gyrus. In addition, increased betweenness centrality of the precuneus was also observed. (Figure 1). These results survived after adjusting the model for Aβ42 and p‐tau values.Conclusion
APOE‐ε4 allele modulates the functional integration among cortical nodes within temporo‐parietal networks, which typically present structural and metabolic alterations in AD. Importantly, these effects survived after adjustment by AD core biomarkers, suggesting that they were selectively mediated by APOE genotype. The inclusion of neuropsychological data shall clarify whether this distinctive network configuration may represent a network vulnerability or underlie compensatory strategies.
Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer’s and Parkinson's disease patients: Possible biomarkers for early diagnosis
Authors: Angelantonio Silvia Di , Pizzarelli Rocco , Pediconi Natalia , Rosito Maria , Greco Federica Lo , Grimaldi Alfonso , Giubettini Maria 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid‐beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure therefore, the actual challenge is to define new biomarkers and non‐invasive technologies to measure neuropathological changes in vivo at pre‐symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non‐invasive rapid detection of AD biomarkers.MethodHuman retinal slices from AD (n=20) and PD (n = 10) patients and age matched controls (n=20/10) were purchased from Human Eye Biobank for Research, St Michael Hospital, Toronto, Canada. Immunofluorescence analysis was perfomed using primary antibodies to detect protein aggregates, neurodegeneration and glial activation: anti‐βAmyloid; anti‐Cleaved‐Casapase3; anti‐PhosphoTau; anti‐Iba1; anti‐GFAP; anti‐C3d; anti‐IL‐1β; anti‐αsynuclein; anti‐TH, anti‐TuJ1.ResultIn all AD patients we detected retinal Aβ and pTau immunoreactivity and both in the inner and outer layers; Aβ plaques number, in a region of 400 mm2, was significantly higher in AD patients compared to controls (p<0.01). pTau immunoreactivity (AT100 clone) was significantly higher in the AD retina compared to age matched controls as quantified by fluorescence intensity in each field of view (p<0.005). Analysis GFAP staining showed a marked astrogliosis localized at the level of the ganglion cell layer both in AD and PD retinas. Astrogliosis may arise also as a consequence of aging however, the amount of astrocyte activation was more pronounced in the AD and PD retina compared to controls, as quantified by fluorescence intensity in each field of view. Similarly microglia cell density was increased in AD and PD patients retina compared to age matched controls. C3 and Il1β were enhanced in bot AD and PD retina, suggesting a detrimental glial activation.ConclusionThese observations further support the possibility that ocular biomarkers could be used for early detection of AD associated neurodegeneration.
LangAware: A robust ML‐based platform for the quick and accurate assessment of neurodegenerative diseases
Authors: Rentoumi Vassiliki , Paliouras George , Mougias Antonis A. , Kotrotsou Irene , Garrard Peter 
Published: December 2020

AbstractBackgroundAlthough Alzheimer's disease (AD) is associated with changes in spoken language, these have seldom been subjected to systematic analysis on a large scale. We evaluated the effectiveness of LangAware to detect the language indicators that are coupled with early AD, thus assisting with diagnosis. We evaluated LangAware using recordings of speech samples obtained from AD patients and matched healthy controls (NC) derived from various elicitation tasks in two languages, English and Greek*.MethodEnglish and Greek datasets were analyzed employing feature selection techniques to choose the most prominent multi‐level linguistic analysis features differentiating the AD from the NC group in both languages. The platform’s diagnostic performance was evaluated on its ability to classify "unseen" audio recordings employing these salient features.ResultEvaluation results indicated that LangAware achieved equally high classification scores for both English and Greek. Most significantly, these scores were achieved by employing a custom set of LangAware‐developed cross‐linguistic markers.ConclusionThe current evaluation verified the robustness of the platform’s predictive models using audio datasets in two languages. Based on the findings, we conclude that LangAware could provide a time and cost‐effective platform for cognitive screening across languages and across tasks pertaining to neurodegenerative diseases in a range of clinical settings. Such findings also advocate in favor of the robustness of LangAware platform in pursuing cognitive assessment on spontaneous speech across languages. *Peter Garrard and Antonis A. Mougias contributed to this work by providing data for the evaluation of the LangAware platform.