bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large‐scale analysis of heart‐brain interactions through personalisation of a mechanistic cardiovascular model
Authors: Banus Jaume , Lorenzi Marco , Camara Oscar , Sermesant Maxime 
Published: December 2020

AbstractBackgroundHeart and brain are linked by means of pathophysiological and physiological mechanisms sharing several risk factors (Doehner, W. et al. 2018). Clinical evidence supports a common underlying cardiovascular pathophysiology relating cardiac function and brain damage (Moroni, F. et al. 2018). Nevertheless, heart and brain have usually been studied independently and until now the lack of databases combining data from both has prevented to properly study their relationship. Computational cardiovascular models can complement statistics imposing prior knowledge using a mechanistic approach, and can help us to estimate non‐observable parameters key for the cardiac function such as cardiac contractility or aortic compliance, which cannot be measured in‐vivo.Methodextending the approach presented in (Mollero, R. et al. 2018) we propose to constrain the personalisation of a cardiovascular model to ccount for the relationships between cardio‐vascular parameters and brain‐volumetric features extracted from imaging data. We applied our framework in a cohort of more than 3400 subjects and in a pathological subgroup of 59 subjects diagnosed with atrial fibrillation (AF).ResultsWe observed an association between non‐observable parameters such as aortic stiffness or peripheral resistance with brain‐volumetric features such as white matter hyperintensities (WMH) and brain ventricles volume. Moreover, we observed differences in the estimated parameters between AF subjects and control groups linking AF with WMH and cardiac remodeling (Seko, Y. et al. 2018).ConclusionOur methodology allows to study the influence of the brain features in the estimation of the cardiac function parameters, and to identify significant differences associated to specific clinical conditions, such as between atrial fibrillation and white matter damage.
Integrated dementia care centers in Southern Taiwan: Experiences from Chi Mei Medical Center
Authors: Chou Chih‐Ho 
Published: December 2020

AbstractBackgroundTaiwan is facing a social crisis of super‐aged society. In response to the increasing burden, Taiwan launched the Dementia Plan and Action Plan 2.0, which is a part of Long‐term Care Service Network in 2018. The integrated Dementia Care Centers (IDCC) and Support Centers for People with Dementia and their Families (SPDF) were funded under this plan. We reported the executive experiences of IDCC and SPDF in our institution.MethodWe recruited patients with mild to moderate dementia or diagnosed MCI from (1) who received ambulatory care from our hospital and (2) who was referred from neighborhood hospital/clinics. Patients with severe medical comorbidities or disability were excluded. We analyzed those received follow‐up for more than 12 month or died within the period. Age, gender, clinical diagnosis, education, baseline cognitive assessment, dementia severity (CDR), medical treatments, behavior and psychological symptoms(BPSD), long‐term care services usage, 12‐month‐follow‐up cognitive assessment and CDR were analyzed.ResultWe recruited 453 subjects in the first year. Among the recruited patients, 121 women and 72 men completed 12‐month follow‐up. The average age was79.2 (SD=8.4) in women, and 80.0(+7.5) in men respectively. Moderate or above disease severity was more common among in women. Low educational level was more in women than men (57.9% vs 22.2%). Alzheimer’s disease (AD)was the most common diagnosis. Thirty‐six patients had a least one documented BPSD or took antipsychotic agents during the observation period. Most patients at mild to moderate stages, the primary caregiver were their spouses or offspring. More than a half of severe patients needed to hire a foreign caregiver. Only 25.2% patients requested long‐term care services. The most commonly used service were day‐care facilities.ConclusionOur analysis demonstrated that senility and late diagnosis were still challenging in Taiwan society. The causes of low utilization of long‐term care services were quite diverse and heterogeneous among geographical regions. How to reduce the caregiver burden and improve the efficiency of long‐term care services needs further optimization and communication.
Venular amyloid and its relationship with cerebral amyloid angiopathy in TGF344AD rats
Authors: Bishay Jossana , Beckett Tina , Lai Aaron Y. , Hill Mary E. , McMahon Dallan , Simpson Craig , Hynynen Kullervo , McLaurin JoAnne 
Published: December 2020

AbstractBackgroundIn Alzheimer’s Disease (AD), the amyloid‐beta peptide (Aβ) aggregates and deposits in the form of amyloid plaques within the brain parenchyma. Overproduction of Aβ is less common in sporadic AD cases, suggesting that impairment in Aβ clearance contributes to disease pathology. In AD, failure of the perivascular drainage pathway leads to Aβ deposition in the walls of cerebral blood vessels, resulting in cerebral amyloid angiopathy (CAA). The association between amyloid deposits with arterioles and capillaries is known, however, amyloid deposits present in venules is still controversial.MethodA TgF344‐AD rat model overexpressing the human APPswe and PS1ΔE9 mutations was used as it recapitulates the typical hallmarks of AD in humans, including Aβ plaque formation, CAA, tau pathology, frank neuronal loss, and cognitive deficits. At 7, 10, 13, and 16 months of age, brain sections were examined by immunofluorescence staining and image analyses for amyloid deposits around all blood vessels using Thioflavin S staining. Further identification of deposits with Aβ specific antibodies, 4G8 (17‐28), MOAB2 (1‐4), and anti‐Aβ1‐40/42, were used to confirm Thioflavin results. Amyloid aggregates were isolated from parenchymal plaques, CAA, and venular amyloid using a laser capture microdissection (LCM) microscope and sent for mass‐spectrometry (MS) to identify the presence of Aβ.ResultResults suggest as an increase in CAA is detected, venular amyloid starts to accumulate, with disease progression. Confirmation with antibodies that span the Aβ sequence, 4G8, MOAB2, anti‐Aβ1‐40/42, identify amyloid deposits in both venules and arterioles. Furthermore, LCM‐MS technique identified presence of Aβ in cortical plaques and CAA samples.ConclusionCorrelation with venular amyloid deposition and CAA suggests an important interplay between these vascular pathologies with AD progression. Understanding venular amyloid and its relationship with CAA can play a role in studying mechanisms involved in neurovascular dysfunction of AD.
Alzheimer’s disease‐related necroptotic pathology: An exclusive presence of the necrosome in granulovacuolar degeneration inclusions in human and transgenic mouse brains
Authors: Koper Marta J. , Van Schoor Evelien , Ospitalieri Simona , Vandenberghe Rik , Vandenbulcke Mathieu , von Arnim Christine , Tousseyn Thomas , Reichwald Julia , Rabe Sabine , Staufenbiel Matthias , Balusu Sriram , De Strooper Bart , Thal Dietmar Rudolf 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by pathological processes such as β‐amyloid (Aβ) plaques, neurofibrillary tangles (NFT), cytoplasmic granulovacuolar degeneration (GVD) lesions and neuronal loss that underpin cognitiveand behavioral alterations. Necroptosis, a programmed form of cell death defined by the assembly of the necrosome complex composed of phosphorylated proteins (pRIPK1, pRIPK3 and pMLKL), has recently been shown to be involved in AD.MethodTo determine the neuropathological characteristics and distribution pattern of the necrosome components, we performed a comprehensive immunohistochemical analysis of brains of AD, pathologically defined preclinical AD and non‐AD control cases. A similar analysis was carried out to investigate necroptosis‐related proteins in transgenic mouse models of Aβ and Tau pathology.ResultsWe identified all three activated necrosome components (pRIPK1, pRIPK3 and pMLKL) in GVD inclusionswithin neurons of the hippocampal subfields CA1, CA2/3, CA4, dentate gyrus, subiculum, entorhinal cortex, temporal cortex, hypothalamus, amygdala and frontal cortex of symptomatic and preclinical AD patients. The three necrosome proteins colocalized with standard GVD markers, such as pTDP‐43 and CK1δ, and similarly to these markers detected GVD lesions. Necrosome‐associated GVD neurons inversely correlated with neuronal density in the early affected hippocampus and in the late affected frontal cortex. Necroptosis‐specific GVD lesions showed strong positive associations with AD‐defining parameters, showing the strongest correlation and partial colocalization with Tau pathology. Moreover, we analyzed brain tissues of transgenic mice carrying mutated APP, Tau or both transgenes. We found morphologically comparable GVD lesions positive for the necroptosis components in the subiculum, hippocampus and entorhinal cortex of 12‐month‐old APP23xTAU58 mice. We confirmed mouse necrosome‐positive GVD inclusions by CK1δ immunoreactivity.ConclusionThe presence of the necrosome in GVD inclusions points to a specific form of necroptosis in AD that can be modelled in APPxTAU transgenic mice, possibly indicating Tau and/or Aβ as drivers of this pathology. Necrosome‐positive GVD granules represent a potential protective system sequestering the necrosome complex, which could interfere with or delay necroptosis‐related neuronal death.
Effects of a liver APOEε4‐genotype on synaptic integrity, gliosis and insulin signaling in the brain
Authors: Giannisis Andreas , Patra Kalicharan , Edlund Anna K. , Rosa Andrés De La , Nieto Lur Agirrezabala , Gras Joan Benedicto , Moussaud Simon , Bengtsson Tore , Fu Yuan , Bu Guojun , Bial Greg , Foquet Lander , Hammarstedt Christina , Strom Stephen , Kannisto Kristina , Ellis Ewa , Nielsen Henrietta M. 
Published: December 2020

AbstractBackground
APOEε4 is the strongest genetic risk factor for AD[1]. Although plasma apoE does not cross the blood‐brain‐barrier[2], altered plasma apoE levels have been linked to increased risk of AD[3] and to unfavorable CSF Aβ42 and tau levels[4]. Translation of results from studies of apoE in rodents to the human situation is difficult due species‐specific difference for instance in lipid metabolism[5]. Here we have studied the effects of a humanized APOEε4 liver[6] on synaptic integrity, insulin signaling and gliosis in a mouse model that reproduces the human plasma profile and that retains its endogenous apoE expression in the brain.MethodTissue samples from the cortex, hippocampus, cerebellum and thalamus were obtained from FRGN mice with humanized APOEε2/ε3 (n=4) versus APOEε4/ε4 (n=8) livers, and from APOEε3/ε3 (n=3) and APOEε4/ε4 (n=3) TR mice. Using established protocols[7], nuclei‐ and synaptosome‐enriched, and synaptosome‐depleted fractions were generated and analyzed for contents of markers relating to synapse integrity, gliosis and insulin signaling using western blotting. Levels of apoE4 were assessed in plasma from FRGN mice with humanized APOEε4/ε4 livers.ResultCortical and hippocampal levels of endogenous apoE, cortical levels of tubulin‐βIII, AMPAR, NMDAR, bassoon, mTOR, pAkt and a‐synuclein as well as hippocampal levels of synaptophysin, EAAT2, GFAP, NMDAR, pmTORS2448 and pIRS616 were reduced in FRGN mice with humanized APOEε4/ε4 versus APOEε2/ε3 livers (p≤0.05). Several of these findings were recapitulated in brain tissues from APOEε4/ε4 versus APOEε3/ε3 TR mice (p≤0.05). In both mouse models we observed a shift of a‐synuclein content from the synaptosomal (reduction) to the extra‐synaptosomal (increase) compartment (p<0.05). Altered expression levels of synaptic markers were also found in the thalamus and to a lesser extent in the cerebellum. Plasma levels of apoE appeared lower in the humanized APOEε4/ε4 liver mice and correlated positively to cortical levels of endogenous apoE but negatively to various markers of synaptic integrity and insulin signaling mainly in the hippocampus.ConclusionWe here provide the first evidence of a profound and negative effect of a liver APOEε4 phenotype in a human‐like setting, on key markers related to brain synaptic integrity, insulin signaling and glial cells involved in neuroinflammation.
Strategic corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy
Authors: Freeze Whitney M. , Zotin Maria Clara Zanon , Warren Andrew D. , van der Weerd Louise , Gurol M. Edip , Viswanathan Anand , Greenberg Steven M , Reijmer Yael D. , van Veluw Susanne J. 
Published: December 2020

AbstractBackgroundCerebral amyloid angiopathy (CAA) is highly prevalent in Alzheimer’s disease (AD) and is associated with hemorrhagic and ischemic brain lesions. CAA is increasingly recognized as an important independent cause of cognitive impairment. However, the mechanisms underlying cognitive impairment in these patients are poorly understood. We hypothesized that lesions in the corpus callosum (CC), because of their strategic location, are associated with widespread reductions in microstructural white matter integrity and worse cognitive performance, specifically in the domains of attention/information processing speed and executive functioning.Method57 individuals meeting the modified Boston criteria for probable CAA underwent 3T MRI, including a DTI scan, and neuropsychological testing. Microstructural white matter integrity was quantified by means of fractional anisotropy and mean diffusivity. Test scores on individual neuropsychological tests were converted into Z‐scores and averaged into the following cognitive domains: memory, attention/information processing speed, language, executive functioning, and visuospatial processing. CC lesions were defined as hemorrhagic (microbleeds or larger bleeds) and ischemic (microinfarcts, lacunar infarcts, and FLAIR hyperintensities). Associations between CC lesion presence, microstructural white matter integrity, and cognitive performance were examined with multiple regression models, corrected for age, sex, education (when cognition was the dependent variable), and history of large ICH. False discovery rate corrections for multiple comparisons were applied.ResultDemographic and imaging characteristics of cases with and without CC lesions are outlined in table 1. Sixteen cases (28%) had one or two CC lesions (n=18 lesions). Most lesions were located in the splenium (n=8), followed by the genu (n=7) and the midbody (n=3) of the CC. In multivariate regression models, presence of CC lesions was associated with reduced microstructural white matter integrity on DTI within the CC and in the total white matter. Interestingly, cases with CC lesions performed significantly worse on the domains of attention/information processing speed, and executive functioning compared to those without CC lesions, but no differences were found for the other domains (table 2).ConclusionBecause of their strategic location, focal CC lesions may significantly contribute to cognitive impairment in CAA, potentially through their negative impact on the microstructural white matter integrity beyond the lesion core (i.e., Wallerian degeneration).
An ABCA7 partial deletion and a GRN variant in a semantic variant of primary progressive aphasia patient
Authors: Antonell Anna , Ramos‐Campoy Oscar , Balasa Mircea , Borrego‐Écija Sergi , Montagut Núria , Falgàs Neus , Tort‐Merino Adrià , Olives Jaume , Fernández‐Villullas Guadalupe , Bosch Beatriz , Sanchez‐Valle Raquel , Lladó Albert 
Published: December 2020

AbstractBackground
ABCA7 gene (ATP‐binding cassette transporter A7) loss‐of‐function mutations are related to increased risk of suffering Alzheimer’s disease (AD). On the other hand, mutations in GRN (Progranulin) gene are causative of frontotemporal dementia (FTD).MethodsThe proband was a patient diagnosed from semantic variant of primary progressive aphasia. Age at onset was at 50 years‐old, presenting progressive cognitive decline with an important language loss. The MRI showed a left temporal atrophy. AD CSF biomarkers were normal and no familial history of dementia was reported. Next generation sequencing was performed with Illumina NextSeq500. Single nucleotide variants were detected using GATK and copy number variants using ExomeDepth algorithm. Sanger sequencing was performed for GRN variant confirmation and MLPA technique for ABCA7 deletion validation. C9orf72 repeat expansion was studied with a repeat primed PCR and fragment analysis. Biological samples from his mother and a brother were obtained. Commercial ELISA kit was used to measure serum PGRN levels (Adipogen).ResultsPatient showed an ABCA7 partial deletion (exons 17‐47) plus 4 contiguous genes, of a total of 105 kb in size (hg19 chr19:g.1048865_1154298). Deletion was confirmed in the proband and discarded in the proband’s mother and brother by MLPA. Patient and his mother (asymptomatic at 81 yo) were also carriers of a reported GRN variant, p.(Asp33Glu; rs63750742). Progranulin serum levels were normal in the patient and his family members. C9orf72 screening was negative.ConclusionsThe patient harbored two genetic alterations in genes related to dementia risk, although it is unlikely that any of them alone could be responsible of the FTD phenotype. ABCA7 deletion should be de novo or father inherited. ABCA7 protein truncating variant at exon 14 (p.Arg578fs), which has a similar protein consequence, is relatively frequent in control population, although has showed a 1.8‐fold enrichment in AD patients. Moreover, GRN variant does not seem to be pathogenic or low penetrance because proband’s mother is unaffected and serum progranulin levels are normal. In conclusion, these variants per se are likely not sufficient to cause the disease, but rather risk variants of intermediate to high penetrance along with other factors.
Functional ultrasound imaging can detect vascular changes in tau P301S mouse model of Alzheimer’s disease
Authors: Rytkönen Jussi , Shatillo Artem , Dudek Mateusz , Puoliväli Jukka , Oksman Juho , Parkkari Teija , Miszczuk Diana , Yang Cindy , Braithwaite Steven P , Minami S. Sakura 
Published: December 2020

AbstractBackgroundTauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. Evidence suggests that tauopathy mouse models develop changes in blood vessel morphology, density and altered cerebral blood flow, which could be linked to cognitive deficits in Alzheimer’s Disease. Here we assess changes in neurovascular coupling in Tau P301S mouse model (MAPT P301S, PS19) using functional ultrasound (fUS) and its relationship to histological changes and cognitive deficits.MethodHemizygous (HE) P301S mice and their wild type littermates (n=20) were used in the study. fUS imaging of the brain was performed at 6 and 7 months of age, including resting state functional connectivity (RFC), somatosensory stimulation and acetazolamide challenge (ACZ, 30 mg/kg). At 7 months contextual fear conditioning (CFC) and radial arm water maze (RAWM) tests were used to assess behavioral impairments. At study end, brains were histologically assessed for microgliosis and synaptic density.ResultAt 6 months of age, fUS imaging showed differences between genotypes in all measurements. Resting state imaging showed a reduction in RFC of sensory‐motor cortex of HE animals. Chemical stimulation showed strong vascular reaction in HE mice after ACZ challenge. Somatosensory stimulation resulted in lower response in HE mice compared to WT. The fUS data at 7 months had a lower signal‐to‐noise ratio compared to 6 months, but similar trends were observed. In RAWM HE mice made less errors and displayed a trend toward increased latency in finding the platform compared to WT. The progression pattern of HE animals during CFC differed from WT counterparts. Significant increases in microgliosis by CD68 immunostaining were observed in HE mice, accompanied by a significant reduction in synapse density.ConclusionfUS is a powerful tool for functional imaging of preclinical CNS disease models. Here we confirmed vascular changes in P301S mouse model accompanied by mild decline in cognition and significant effects on neuroinflammation and synaptic density.
Frailty as a risk factor for incident dementia and cognitive decline: Data from the longitudinal InveCe.Ab study
Authors: Davin Annalisa , Cereda Cristina , Ardemagni Deborah , Mimmi Maria Chiara , Abbondanza Simona , Vaccaro Roberta , Poloni Tino Emanuele , Medici Valentina , Colombo Mauro , Guaita Antonio 
Published: December 2020

AbstractBackgroundFrailty is a frequent and potentially reversible age‐related syndrome. Current evidence supports the associations between Frailty, cognitive impairment and dementia. The aim of the study is to estimate the predictive role of Frailty syndrome in incident dementia and cognitive impairment, as well as the modulation of genetic‐psycho‐social factors, such as APOEɛ4 polymorphism and loneliness in a non‐demented Italian cohort of elderly individuals.MethodData are from a cohort of 1,321 persons aged 70‐74 years old, living in Abbiategrasso (Milan, Itay): the InveCe.Ab study (Guaita et al. 2013; clinical trials.gov NCT01345110). The sample took place in 2009 with follow‐ups in 2012 and 2014. Frailty was measured by Frailty Index (FI). The FI was then separated into Frail (FI>0.25), pre‐Frail (FI = 0.08‐0.25) and non‐Frail (FI < 0.08) groups. Dementia was defined using the DSM‐IV‐TR. Global cognition was assessed by the Mini Mental State Examination (MMSE), Comorbidity by Cumulative Illness Rating Scale (CIRS).ResultFrailty was associated with cumulative incidence of dementia (p<0.001), MMSE score at baseline (p<0.001), difference in MMSE score between 2009 and 2014 (p 0.005), CIRS (p<0.001).After four follow‐up years, 4.6% developed Dementia. In the longitudinal regression models adjusted for age, gender, level of education and loneliness, APOEɛ4 carrier status, Frailty was associated with incident dementia (OR=7.75,95% CI 3.26‐18.41), with higher risk of dementia for frail men compared to women (OR=13.79, 95% CI 4.11–46.21; OR= 4.63, 95% CI 1.32‐16.26, respectively). In linear regression models, adjusted for the same variables, Frailty also showed a significant association with the decrease of MMSE score in follow‐up only in males (male: β ‐0.131,95% CI ‐7.16 – ‐0.15; females: β‐0.085, 95% CI ‐5.60 – 0.19). Other covariates, such as loneliness, were independently associated with the outcomes. However, the interaction term for loneliness and frailty was not significant in predicting incident dementia.Conclusionin our large population sample, Frailty is associated with cognitive impairment and cognitive decline. These results suggest that Frailty syndrome, especially if accompanied by other genetic‐psycho‐social characteristics such as loneliness, could be considered by clinicians as a red flag for early detection of cognitive disorders.