bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of the Medtep digital health platform in the framework of a multimodal intervention in patients with subjective cognitive decline (PENSA Study)
Authors: Soldevila‐Domenech Natalia , Forcano Laura , Otero Eduard , Boronat Anna , Lorenzo Thais , Pizarro Nieves , Knezevic Iva , Fauria Karine , Minguillon Carolina , Molinuevo Jose Luis , Panisello‐Royo Josefa M , de la Torre Rafael ,   PENSA Study Group
Published: December 2020

AbstractBackgroundCurrent evidence suggests that multimodal interventions with diet, physical activity and cognitive training could prevent cognitive decline in individuals at preclinical stages of Alzheimer’s disease. However, maintaining subject compliance is a critical challenge for the success of studies that involve intensive behavioral changes. The PENSA Study is a clinical trial that aims to prevent cognitive decline in 200 older adults (60‐80 years) APOE‐ɛ4 carriers with subjective cognitive decline. A personalized multimodal intervention will combine with a dietary supplement enriched with epigallocatechin gallate (7mg/kg) during 12 months. To continuously monitor the adherence to the intervention and to motivate participants in engaging in healthy promoting behaviors, a digital health platform provided by Medtep has been incorporated in the PENSA Study.MethodsThe Medtep App collects daily information on participant’s diet, mood and social activities using ecological momentary assessments, and registers the attendance to gymnasium, cognitive stimulation and psychoeducational sessions. It also integrates measures of physical activity, heart rate, sleep quality and cognitive performance collected from an activity tracker and a cognitive training telematic platform. Researchers can control the progression of each participant and automatically personalize the intervention according to their characteristics and progression.ResultsDuring the two weeks prior to the intervention starting date, the information collected is used to establish a reliable lifestyle pre‐treatment measure and to provide each participant with a personalized plan on diet and physical activity. Throughout the intervention, participants receive personalized goals and recommendations, as well as a monthly report with feedback on their behaviors. To this end, several indexes or scores have been created based on participants’ adherence and progression on Mediterranean diet, physical activity, cognition, sleep and social health.ConclusionsThe use of Medtep in the PENSA study is expected to improve participants’ adherence and motivation to the intervention as they might be more aware of what they are expected to do, their strengths and weaknesses, and their progression throughout the study. Furthermore, it will be useful for researchers to track intervention compliance, to make improvements in the intervention throughout the study and to better understand longitudinal changes in behaviors and their impact on cognition.
Hippocampal subfield volume differences are independent of age in teenagers and young adults with Down syndrome
Authors: Koenig Katherine A , Oh Se‐Hong , Stasko Melissa , Lissemore Emma , Roth Elizabeth , Birnbaum Anne , Scheidemantel Thomas , Taylor Hudson , Roizen Nancy , Ruedrich Stephen , Leverenz James B , Costa Alberto 
Published: December 2020

AbstractBackgroundDown syndrome (DS) leads to a range of well‐described physiological and neuroanatomical characteristics, including a disproportionate decrease in corrected sizes of the hippocampus [1]. In young adults with DS, we previously reported decreases in the size of bilateral CA1 and dentate gyrus in comparison to age‐matched controls [2]. Here we compare hippocampal subfield volumes in teenagers and young adults with DS to age‐matched healthy controls, and assess the relationship of volume differences to age.MethodSample: 34 teenagers and non‐demented adults with DS (mean age (years) 24.5 ± 6.5, range 15‐35; 22 males) and 27 age‐matched healthy controls (HC; mean age (years) 24.9 ± 6.1, range 15‐36; 17 males). MRI: All participants were scanned under an IRB‐approved protocol on a Siemens 7T Magnetom scanner. Using a whole‐brain MP2RAGE (0.75mm3 isotropic voxel size), hippocampal subfield volumes were calculated and corrected for intracranial volume using the Automated Segmentation of Hippocampal Subfields (ASHS) software (Figure 1). Linear regression used to assess group and age differences in the subiculum, CA1, CA3, dentate gyrus, tail and total volumes.ResultIndividuals with DS had disproportionately smaller bilateral CA1, CA3, dentate gyrus, and total hippocampal volumes, all of which were significant for group but not for age (Table 1). Volume of the right tail was the only region that was significantly age‐dependent (0.0039) in the full sample. However, when broken down by group, this relationship was only significant in individuals with DS (r = ‐0.410, p < 0.0168), not in controls (r = ‐0.308, p < 0.1180). In the DS group alone, age did not have a significant effect on any other subfield volume.ConclusionIn agreement with previous reports, we find a disproportionate decrease in hippocampal volume in persons with DS, driven by CA1, CA3, and the dentate. Although individuals with DS show early neuropathology associated with dementia onset, the majority of subfield volumes were not associated with age in this sample of teenagers and young adults. This work was supported by Alzheimer’s Association, Alana USA Foundation (Contract 200381), and the National Institute of Aging (P30 AG062428 01), with technical support by Siemens Medical Solutions.
Investigating markers of NLRP3 inflammasome activation in neurodegenerative diseases
Authors: Tang Hao , Harte Michael 
Published: December 2020

AbstractBackgroundIncreasing evidence implicates neuroinflammation in the pathogenesis of various neurological and psychiatric disorders. This is particularly true in neurodegenerative diseases. The NLRP3 inflammasome is a critical component of the innate immune response and its activation is implicated in neurodegenerative disease by emerging studies from both in vitro inflammatory assays and in vivo preclinical models.MethodPost‐mortem samples were obtained from The Manchester Brain Bank and The Multiple Sclerosis and Parkinson’s Tissue Bank (London). Tissue collections comprised of age and sex matched non‐neurodegenerative controls and Alzheimer’s disease (AD) (temporal lobe; control: Braak stage 0‐II, mild AD: Braak stage III‐IV, severe AD: Braak stage V‐VI. N=40 per group) and Parkinson’s disease (PD) (frontal cortex and substantia nigra, control & PD, N=20 per group per region). Gene expression (mRNA) of NLRP3 and associated proinflammatory markers (AIF1, HLA‐DRA, PYCARD, CASP1, IL1B, IL18 and GFAP), were determined in brain tissues by RT‐qPCR. Aβ42 protein level was assessed in the AD cohort by ELISA.ResultsGFAP (a marker for activated astrocytes) was up‐regulated in severe AD patients compared with controls. This was not significantly related to carriage of the APOE ε4 allele and remained significant in both sex subgroups. Aβ42 protein was upregulated in severe AD group and higher in APOE ε4 carriers. GFAP correlated with Aβ42 but not with the expression of any of the NLRP3‐related proinflammatory markers, which themselves were not significantly changed in the neurodegenerative disease cohorts.ConclusionThe results indicate that a relative increase in gene expression of the NLRP3 system as an inflammatory marker in neurodegenerative diseases may not be apparent, despite an increase in GFAP in severe AD. Although our data are contrary to previous findings from in vitro and in vivo preclinical studies, they are similar to other two post‐mortem human brain studies. It may be that data from animal models and in vitro studies, in which inflammatory processes are usually generated acutely with abundant stimuli, are not representative of the chronic neuroinflammation associated with neurodegenerative diseases. Future research with greater cell‐specificity and closer examination of protein function in this pathway in well‐characterised human cohorts is urgently needed.
Proteomic analysis of cognitive impairment in responders traumatized by the World Trade Center disaster
Authors: Luft Benjamin , Clouston Sean , Kotov Roman , Bromet Evelyn , Kuan Pei‐Fen 
Published: December 2020

AbstractBackgroundWTC responders, particularly those with long‐term PTSD, have an increased incidence of mild cognitive impairment (MCI), a prognostic marker of later dementia. In this study, we used proteomics to interrogate the interaction between PTSD and MCI in a cohort of disaster responders.MethodThe sample included 181 responders to the World Trade Center (WTC) disaster, including 73 with probable PTSD, 61 with MCI, and 81 WTC traumatized controls with neither condition. 34 responders had comorbid PTSD and MCI. PTSD was measured with the Posttraumatic Stress Disorder Checklist (PCL; cut‐point >44). MCI was defined according to NIA‐AA criteria using the Montreal Cognitive Assessment (MoCA; cut‐point <23). In total, we profiled 282 proteins with known involvement in relevant biological processes using the Olink Proseek Multiplex Platform. Specifically, we focused on markers of neurodevelopmental processes, cellular regulation, immunological function, cardiovascular disease, inflammatory processes, neurological diseases. Differential expression analysis was conducted to identify protein biomarkers of PTSD, MCI, and co‐occurring PTSD/MCI.ResultsIn total, 46 unique proteins were identified from the combined list of PTSD and MCI associated proteins. Thirty‐seven proteins were differentially expressed in PTSD versus exposed controls at p < 0.05; nine were significant after correcting for multiple comparisons using the false discovery rate (FDR < 0.1). Twenty‐five proteins were differentially expressed in MCI versus exposed controls (p < 0.05); 6 attained an FDR < 0.1. After controlling for PTSD, effect size directions for these 25 MCI‐related proteins were unchanged; 13 remained significant at p < 0.05.ConclusionThe current study identified several novel protein biomarkers for PTSD and MCI, which were associated with disease burden characterized by co‐occurrence of the phenotypes. Results indicated that half of the proteins associated with PTSD, and vice versa proteins associated with MCI were found in comorbid PTSD and MCI. The results suggest that identification of protein biomarkers might be useful in development of a plasma‐based assay for early detection of MCI in traumatized patients, especially those showing signs of MCI.
Salience network functional connectivity associates with levels of social interactions in healthy and mild cognitively impaired older adults
Authors: Pruitt Patrick J , Damoiseaux Jessica S , Dodge Hiroko H ,   Michigan Alzheimer's Disease Center
Published: December 2020

AbstractBackgroundOlder adults are at high risk for both cognitive decline and social isolation. A higher level of social interaction, however, confers a protective effect against cognitive decline, and intervention studies have demonstrated the efficacy of social interactions to enhance cognitive function. The biological mechanism of this enhancement is unclear. Here we evaluate the association between social interaction and the functional connectivity of the salience (SN) and default mode (DMN) networks, two large‐scale brain networks implicated in social and cognitive function.MethodMichigan Alzheimer's Disease Center at University of Michigan (Ann Arbor, MI, USA) collected data on the Lubben Social Network Scale (LSNS‐6), which indicates levels of social interaction, and resting‐state functional MRI data for 62 older adults with normal cognition (NOR; mean age +/‐ SD = 69.72 years +/‐ 6.24) and 51 mild cognitively impaired (MCI; 71.61 years +/‐ 8.57) participants. We evaluated the association between SN or DMN functional connectivity (DV) and level of social interaction using a linear regression model with age and sex as covariates.ResultNOR and MCI participants did not differ in age (t=‐1.31, p=0.19), level of social interactions (t=1.47, p=0.14), or SN connectivity (t=1.86,p=0.065), but MCI did have lower DMN connectivity (t=2.839, p=0.005). Level of social interaction associated positively with SN connectivity (t=2.34, p=0.02, rp
=0.218). The Lubben items most strongly associated with SN connectivity were: “How many relatives do you feel at ease with that you can talk about private matters?” (rp
=0.268, p=0.004) and "How many relatives do you feel close to such that you could call on them for help?” (rp
=0.284, p=0.003).ConclusionOur data support an association in older adults between greater salience network connectivity and higher levels of social interaction, driven by quality of family interactions. Notably, an association with level of social interaction was not found for default mode network connectivity, suggesting the association found with salience network is not a global network effect. This finding highlights salience network functional connectivity as a meaningful outcome measure for social interventions on cognition in older adults.
COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients
Authors: Raha Debasish , Broce Sean , Haditsch Ursula , Rodriguez Leo , Ermini Florian , Detke Mike , Kapur Shirin , Hennings Dave , Roth Theresa , Nguyen Mai , Holsinger Leslie J. , Lynch Casey C. , Dominy Steve 
Published: December 2020

AbstractBackgroundWe identified the bacterial pathogen, Porphyromonas gingivalis (Pg), and its protease virulence factors, gingipains, in the brain of patients with Alzheimer’s disease (AD). Gingipain levels in AD brains were shown to significantly correlate with AD diagnosis and tau and ubiquitin pathology. The neurodegeneration and AD‐like pathology in Pg infected mice were blocked after oral administration of COR388, an orally bioavailable, brain penetrant small‐molecule that irreversibly inhibits lysine‐gingipain. Since ApoE4 is the greatest genetic risk factor for sporadic AD, we investigated if ApoE proteins are targets of gingipain proteolysis.MethodIn vitro proteolysis of recombinant ApoE proteins, Mass Spectrometry (MS) analysis of gingipain cleavage sites, and detection of ApoE proteolytic fragments in brain and CSF.ResultApoE proteins were cleaved by gingipains rapidly, and ApoE4 was a preferred substrate over ApoE3. Gingipain inhibitors blocked ApoE proteolysis. MS analysis confirmed higher susceptibility of ApoE4 to gingipain cleavage. MS analysis enabled the identification of cleavage sites and the majority of these sites were concentrated near the carboxy‐terminal of the protein. MS analysis performed on low‐molecular‐weight (LMW) fragments of ApoE4 from a human AD brain, homozygous for the APOE4 allele, identified peptide fragments from this same region. Western blot analysis of AD CSF revealed a higher level of LMW ApoE proteolytic cleavage products in AD CSF than non‐AD CSF. A significant decrease in LMW ApoE fragments in CSF was detected in AD subjects following 28 days of administration of COR388 compared to placebo in a Phase1b clinical study.ConclusionOur data suggest that gingipain proteases may mediate ApoE proteolysis in the brain, with higher susceptibility of ApoE4, providing a link between P. gingivalis infection and the APOE4 allele, a major risk factor in AD. Based on the literature, fragmentation of ApoE4 by gingipains would be likely to reduce synaptic maintenance and regulation of immune response as well as aggravate toxicity to cells through the generation of fragments. COR388, a small‐molecule inhibitor of lysine‐gingipain, is currently being tested in a large Phase 2/3 clinical study in subjects with mild‐to‐moderate AD.
Disrupted brain dynamics across the Alzheimer’s disease spectrum is related to tau accumulation
Authors: Botha Hugo , Graff‐Radford Jonathan , Gunter Jeffrey L. , Schwarz Christopher G. , Senjem Matthew L. , Vemuri Prashanthi , Przybelski Scott A. , Wiste Heather J. , Machulda Mary M. , Fields Julie A. , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Lowe Val J. , Jack Clifford R. , Jones David T. ,   the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

AbstractBackgroundRecent evidence has implicated brain networks in the pathophysiology of Alzheimer’s disease (AD). However, the phenotypic variability in AD, inter‐individual differences in tau PET uptake patterns, and dynamic nature of functional connectivity have been relatively neglected. In this talk, I will discuss our recent work linking measures of dynamic brain organization to spatially independent tau PET patterns defined in a phenotypically diverse cohort.MethodsWe identified all Mayo Clinic participants with concurrent amyloid PET (PiB), tau PET (AV1451) and task‐free fMRI (impaired participants were all Aβ+). We used independent component analysis (ICA) to identify spatially independent patterns of tau PET uptake. For the fMRI data, we used a Hidden‐Markov Model (HMM) design to identify distinct patterns of activity/connectivity (‘states’). The ICA and HMM parameters were used to project/segment an independent cohort (ADNI) and subsequent longitudinal timepoints for the Mayo cohort. Multilevel Bayesian regression models were fit in Stan to explore the association between phenotype, component load and brain state.ResultsThe optimal HMM model identified 10 brain states (Figure 1). The optimal ICA decomposition identified 42 tau PET components, of which 13 were potentially related to AD pathobiology (Figure 1). Component loads and brain state dwell time differed between diagnostic groups in both Mayo and ADNI cohorts. One state was much more likely to occur in AD in both cohorts (State 8). Cross‐sectionally, State 8 dwell time was associated with higher tau loads, while higher baseline dwell‐time was predictive of ∆tau in participants with at least 2 timepoints (Figure 2).ConclusionWe found links between dynamics of functional connectivity, tau deposition, and cognitive impairment across the AD spectrum using two different cohorts and longitudinal data. Specifically: 1) our method for characterizing tau PET uptake was able to capture the magnitude and spatial pattern of binding across diverse phenotypes; 2) Our data supports a role for dynamic brain connectivity in cognitive impairment due to Alzheimer’s disease; 3) Dynamic connectivity appears to be directly related to AD pathobiology as measured by tau PET. Incorporating the time‐varying nature of connectivity will be important in future studies of connectome‐based disease progression in AD.
Apolipoprotein E genotype and the relationship between chitinase 3‐like protein 1 and postoperative delirium: Potential gene‐protein interactions
Authors: Vasunilashorn Sarinnapha M. , Inouye Sharon K. , Ngo Long H. , Fong Tamara G. , Jones Richard N. , Dillon Simon T. , Libermann Towia A. , O'Connor Margaret , Arnold Steven E. , Xie Zhongcong , Marcantonio Edward R. 
Published: December 2020

AbstractBackgroundDelirium and Alzheimer’s disease (AD) are common causes of late‐life cognitive impairment with clear epidemiologic links; however, the pathophysiology underlying these links remains unclear. Our recent work suggests that Apolipoprotein E (APOE) ɛ4, the strongest genetic risk marker for AD, does not confer significantly increased risk of delirium in older surgical patients. However, APOE ɛ4 status did modify the relationship of C‐reactive protein (CRP) with delirium, with increased risk for delirium in ɛ4 carriers with high levels of CRP. We now examine whether APOE genotype modifies the established association between inflammatory marker chitinase‐3‐like protein‐1 (CHI3LI/YKL‐40) and postoperative delirium.MethodsWe examined patients without dementia age≥70 undergoing major non‐cardiac surgery in the SAGES: Successful AGing after Elective Surgery study. We collected blood, extracted DNA, and performed APOE genotyping using allele specific polymerase chain reaction assays, considering APOE ɛ4 vs. non‐ɛ4 carriers. Plasma YKL‐40, measured on postoperative day 2 (POD2) by ELISA, was examined using sample‐based quartiles (Q1‐Q4). Delirium status was determined with daily interviews rating the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and stratified by APOE ɛ4 carrier status, to determine whether APOE modifies the association between YKL‐40 and delirium.ResultsAmong the 557 patients (mean age 76.7 [standard deviation 5.2], 58% female, 81% orthopedic), 19% were APOE ɛ4 carriers. Postoperative delirium occurred in 24%. The YKL‐40‐delirium relationship differed by APOE status. Among APOE non‐ɛ4 carriers, we found a significant relationship between YKL‐40 and delirium (relative risk [RR] (95% confidence interval [CI] for YKL‐40 Q4 vs. Q1: 2.6(1.4‐4.9) and Q3 vs. Q1: 2.3(1.2‐4.5); p‐trend<.01). Among APOE ɛ4 carriers, YKL‐40 was not significantly associated with delirium (RR(95% CI) for YKL‐40 Q4 vs. Q1: 2.0(0.6‐6.6) and Q3 vs. Q1:1.1(0.3‐3.5); p‐trend = 0.37).ConclusionsAPOE non‐ɛ4 carriers may have increased risk of delirium conferred by post‐surgical inflammation specific to the type 2 immune response (high POD2 YKL‐40). These results differ from our prior results with CRP, and raise the intriguing possibility that differing APOE genotypes may interact at different points in the inflammatory pathway leading to delirium.
TGF344‐AD rats exhibit cognitive reserve despite continual Aβ and tau accumulation
Authors: Morrone Christopher D. , Lai Aaron Y. , Hill Mary E. , McLaurin JoAnne 
Published: December 2020

AbstractBackgroundPatient to patient variability in Alzheimer’s disease progression complicates treatment efficacy. Furthermore, the presence of Aβ pathology does not always indicate cognitive impairments. Epidemiological evidence of cognitive reserve suggests some individuals exhibit enhanced neuronal and behavioural resilience, protecting against neurodegeneration and cognitive decline. However, Alzheimer’s disease models typically exhibit a correlation between accumulation of pathology and behavioural impairments, making cognitive reserve difficult to investigate preclinically.MethodTgF344‐AD rats recapitulate the amyloid cascade with a long‐term accumulation of Aβ and tau pathology leading to significant neurodegeneration and behavioural impairments. TgF344‐AD rats were assessed for cognitive and neuropathological alterations compared to age‐matched non‐transgenic littermates, across disease progression at 4, 6, 9, 12 and 15 months of age. Latency to escape and complexity of search strategies utilized in the Barnes maze spatial and reversal phases were assessed to determine learning, long‐term memory, and executive function. Neuropathological assessment included GABAergic and total neuronal counts, and quantification of Aβ and tau pathology.ResultTgF344‐AD rats demonstrate deficits in spatial memory and executive function beginning at 6 months which are not exacerbated at 9 or 12 months, but are at 15 months of age. GABAergic and total neuronal counts in the hippocampus and entorhinal cortex of TgF344‐AD rats exhibit a similar trend, with deficits not progressing between 9 and 12 months of age. Conversely, Aβ and tau pathology accumulate continually across disease progression. Non‐transgenic rats exhibit slight, yet consistent age‐related decline in cognitive and neuronal measures.ConclusionDisease‐bearing TgF344‐AD rats exhibit cognitive reserve before robust cognitive decline at 15 months, despite consistent increases in Aβ and tau deposition. Maintenance, and in certain hippocampal subregions a recovery, of neuronal loss at 12 months support this observation, and suggest the involvement of compensatory mechanisms such as hippocampal neurogenesis. Understanding the mechanisms underlying cognitive reserve in Alzheimer’s disease will help explain patient variability in disease progression and elucidate novel regenerative therapeutic targets.