bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter lesions are associated with CSF biomarkers of neuroinflammation in prodromal Alzheimer’s disease
Authors: Gertje Eske Christiane , Janelidze Shorena , van Westen Danielle , Palmqvist Sebastian , Hansson Oskar , Mattsson Niklas 
Published: December 2020

AbstractBackgroundPrevious studies have shown that cerebrospinal fluid (CSF) levels of different biomarkers of neuroinflammation and cerebrovascular dysfunction are increased in Alzheimer’s disease (AD), even during its preclinical and prodromal stages. However, little is known about associations between inflammatory markers and signs of cerebrovascular injury such as white matter lesions (WML) detected with magnetic resonance imaging (MRI) so far.Method582 cognitively unimpaired (CU) elderly and 279 patients with mild cognitive impairment (MCI) from the Swedish BioFINDER cohort were included. CSF samples were analyzed for interleukin (IL)–6, IL‐7, IL‐8, IL‐15, IL‐16, interferon‐gamma induced protein‐10 (IP‐10), monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule 1(ICAM‐1), vascular adhesion molecule 1 (VCAM‐1), placental growth factor (PIGF), and fms‐related tyrosine kinase 1 (Flt‐1) as well as vascular endothelial growth factor (VEGF). WML volumes were determined from MRI for all subjects.ResultMore WML was associated with higher levels of IL‐6 (β=0.311, p=0.002), higher levels of IL‐8 (β=0.001, p=0.001), higher levels of PIGF (β=0.007, p<0.001), lower levels of sFLT1 (β=‐0.017, p<0.001) and higher levels of VEGF (β=0.092, p<0.001) in all patients. In the CU group more WML was associated with higher levels of PIGF (β=0.007, p<0.001) and lower levels of sFLT1 (β=‐0.018, p<0.001), whereas in MCI more WML volume was associated with higher levels of IL16 (β=0.118, p<0.001), higher levels of PIGF (β=0.007, p<0.001), and higher levels of VEGF (β=0.105, p=0.003). The associations with PIGF were seen independent of beta‐amyloid‐status. However, the other associations were mainly seen in beta‐amyloid‐negative subjects (N=179 CU and N=164 MCI). Associations were still significant after corrections for multiple comparisons. No associations were found between WML volume and IL‐7, IL‐15, IP‐10, MCP1, ICAM‐1, and VCAM‐1.ConclusionNeuroinflammation is associated with cerebrovascular injury in prodromal stages of AD, especially the markers of the VEGF family widely expressed in the vascular system.
Cognitive decline and cerebral vasoreactivity in asymptomatic patients with severe internal carotid artery stenosis
Authors: Marijana Lisak Marijana , Špiljak Bruno 
Published: December 2020

AbstractBackgroundThe aim of the study was to correlate cognitive decline and cerebral vasoreactivity in 150 asymptomatic right‐handed patients with severe ≥70 % unilateral internal carotid artery (ICA) stenosis and to evaluate the role of intracranial collateral circulation during cognitive testing.MethodsCognitive assessment was performed by means of Montreal Cognitive Assessment (MoCA) and Mini Mental State Exam (MMSE) scales. Cerebrovascular reactivity (CVR) and intracranial collateral circulation were evaluated by means of breath holding index (BHI) and transcranial color Doppler (TCD) sonography.ResultsThe results were compared with 150 right‐handed controls matched for demographic variables and vascular risk factors. Patients with severe unilateral ICA stenosis had MMSE scores within a normal range, but MoCA scores were lower than normal. By examining the side of the observed stenosis, it has been noted that patients with left‐sided ICA stenosis had lower MoCA scores in categories of language and episodic memory performance, while patients with right‐sided ICA stenosis had lower MoCA scores in a category of visual–spatial skills. All patients had BHI values lower than normal. Subjects with a single intracranial collateral artery recruited had slightly better cognitive results than the patients with two or more collateral arteries activated.ConclusionsResults of the study showed that altered cerebrovascular reactivity and cerebral hypoperfusion might be responsible for the reduction of specific cognitive functions ipsilateral to the ICA stenosis, therefore BHI and MoCA might be useful tools when screening for cognitive decline in asymptomatic patients with severe ICA stenosis.
Screening for gene mutation in early onset Alzheimer’s disease and frontotemporal dementia: Report from a Serbian tertiary referral center
Authors: Stojmenovic Gorana Mandic , Stefanova Elka , Novakovic Ivana , Dobricic Valerija , Stojkovic Tanja , Kostic Vladimir S. 
Published: December 2020

AbstractBackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age. Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are two most common forms of degenerative EOD. Our aim was to screen for known gene mutation status in consecutive degenerative EOD patients.MethodTwo hundred and eight consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. Patient from AD spectrum were tested for APP, PSEN1, GRN, MAPT and C9ORF72 gene mutation and FTD patients for GRN, MAPT, C9ORF72, VCP, ANG gene mutation.ResultGene mutations were identified in 3.9% of our AD patients: 2.3% patients had mutations in the PSEN1 gene and 1.5% patients in the APP gene. There was no MAPT, GRN and C9ORF72 mutations carriers in our AD cohort. Genetic mutations have been demonstrated in 10.3% of patients with FTD. The most frequent was the hexanucleotide expansion in C9ORF72 (6.4% of all FTD patients), following mutations in GRN, VCP and ANG with the same frequency of (1.3% FTD for each gene). No patient was a MAPT mutation carrier.ConclusionGene mutations were rare causes in our AD cohort. The frequency of carriers was higher in FTD patients‐ mutations were identified in C9ORF72, GRN, VCP and ANG genes. No MAPT mutation carriers were identified in our cohort of patients with degenerative EOD.
Ultrasensitive blood biomarkers to predict cognitive decline and diagnose Alzheimer’s disease in the absence of AT(N) classification as the reference standard
Authors: Simrén Joel , Leuzy Antoine , Karikari Thomas K , Hye Abdul , Mattsson Niklas , Hansson Oskar , Schöll Michael , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kloszewska Iwona , Soininen Hilkka , Lovestone Simon , Aarsland Dag , Westman Eric , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J ,   AddNeuroMed Consortium
Published: December 2020

AbstractBackgroundIn recent years, blood biomarkers for Alzheimer’s disease (AD) have attracted much interest. Technological advances have allowed quantification of markers for neurodegeneration (NfL), neurofibrillary tangles (p‐tau181) and amyloid‐β pathology (Aβ42, Aβ42/Aβ40), which perform well in cohorts stratified by cerebrospinal fluid and positron emission tomography (PET) biomarkers. Here, we aimed to investigate i) the diagnostic performance of blood biomarkers in the absence of CSF/PET modalities; ii) how these markers change longitudinally and relate to cognitive decline.MethodsWe evaluated cross‐sectional data for 307 participants (100 cognitively unimpaired (CU, Clinical dementia rating (CDR) score = 0) elderly and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) (CDR=0.5) and 106 AD dementia (CDR>0.5)) from the European multicentre AddNeuroMed cohort. 237 participants (76 CU, 161 CI) had longitudinal plasma biomarker and cognitive data (MMSE). Single molecule array (Simoa) assays were performed for NfL, t‐tau, Aβ42, Aβ40 and GFAp (all time‐points, single batch). P‐tau181 was measured using an in‐house Simoa assay. Cross‐sectional analyses were conducted using a generalized linear model for age‐adjustment, an ANOVA to compare biomarkers across groups, and correlation analysis to examine biomarker concentrations in relation to MMSE. Longitudinal analyses were performed using linear mixed models.ResultsAt baseline, neuronal and astrocytic biomarkers were increased (p‐tau181, NfL, t‐tau, GFAp; P<0.001), whilst the amyloid marker (Aβ42/Aβ40 ratio) was decreased (P<0.001) in AD compared with CU. Significant differences were also observed between AD and MCI for p‐tau181, Aβ42/Aβ40, GFAp (P<0.001) and NfL (P<0.05). P‐tau181 (P<0.001) and NfL (P<0.05) were increased in MCI compared with CU. ROC curves revealed high accuracy for p‐tau181 in separating AD from CU (AUC=0.921) and MCI (AUC=0.816), and in separating CU from CI (AUC=0.843). Linear mixed models showed increases in all five measures in both CU and CI subjects; when assessing change in MMSE, the strongest associations were seen for GFAp in CU (standardized‐β=‐0.27, P<0.001) and for p‐tau181 in CI subjects (standardized‐β=‐0.34, P<0.001).ConclusionThese results suggest that blood biomarkers have diagnostic potential for AD in the absence of AT(N) classification, and that longitudinally, levels of p‐tau181 have potential as a biomarker of cognitive decline.
Molecular events regulating axonal structure and function during injury
Authors: Devoto Victorio Martin Pozo , Lacovich Valentina , Carna Maria , Feole Monica , Texlova Katerina , Stokin Gorazd Bernard 
Published: December 2020

AbstractBackgroundAxonal swellings (AxS) are focal enlargements of axons found in a range of biological and pathological settings, including traumatic brain injury. However, the development of AxS and their effects on axonal homeostasis are poorly understood. Here, using a novel in vitro experimental paradigm we describe cytoskeletal and molecular events responsible of AxS formation and its consequences to axonal homeostasis.MethodHuman neuronal progenitor cells were seeded into microfluidic chambers and terminally differentiated to neurons. In these chambers, axons grow into microchannels, which are crossed by a perpendicular channel that is connected to a syringe pump. A negative flow caused by the syringe pump subjects axons to bending stress. After full characterization of the axonal response to the stress, we established a protocol that causes injury without reaching axotomy. Detailed morphometric and structural analysis were performed to validate axonal injury.ResultStructural analysis of the AxS showed disarrangement of microtubules and neurofilaments, with a disrupted periodicity of Actin and BII‐Spectrin rings underlying the axolemma. The functional impact of these changes was evidenced by the significant dysregulation observed in the axonal transport of APP vesicles during and after injury. Axonal membrane and calcium levels changes were analysed in real‐time, showing an increase in calcium levels that was concomitant to the formation of focal membrane enlargement. To understand the main source of axoplasm calcium increase during injury, extracellular and different intracellular stores of calcium were blocked. Activation of CaMKII derived from the local increase of Ca in the axon can lead to the regulation of multiple targets. We reasoned that myosins (one of CaMKII targets) could be regulating axolemmal changes by exerting a contraction force on the actin rings underlying the axolemma. By pharmacological and molecular intervention we uncover a physiological role of myosins in the regulation of the axonal shaft structure and the AxS formation.ConclusionWe created a unique cell culture paradigm to study the response of axons to physical injury and provide novel insight into mechanisms responsible for axonal shaft structure and the formation of AxS.
An hiPSC‐based genetic screening system to model aggregation of tau protein allows the identification and validation of possible targets for Alzheimer’s disease therapies
Authors: Reinhardt Peter , Guillen Nathalie , Untucht Christopher , Ried Janina S. , Manos Justine , Geist Daniela , Korffmann Juergen , Cik Miroslav , Lakics Viktor 
Published: December 2020

AbstractBackgroundOne of the hallmarks of Alzheimer's Disease (AD), as with some other neurodegenerative diseases, is the misfolding and aggregation of proteins, such as amyloid‐beta and tau. Tau pathology is also believed to propagate trans‐synaptically from neuron to neuron. Either prevention of propagation, or the removal of aggregated tau, is a potential approach for AD modification.MethodDeubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling. We hypothesize that the modulation of the ubiquitin‐proteasome system with DUB inhibitors will lead to decreased tau aggregation either directly (by inhibiting the removal of ubiquitin from tau thereby increasing its degradation) or indirectly (via modulation of other relevant pathways, like autophagy). To select relevant DUBs, we developed a phenotypic assay to assess the effect of knocking down ∼100 DUBs on the clearance of tau aggregates in hiPSC – derived neurons, assayed using high content image analysis.ResultWe show that addition of recombinant tau seeds to hiPSC – derived cortical neurons expressing a fluorescent tau reporter construct, leads to formation of tau aggregates, which we can robustly and reproducibly reduce by knocking down specific DUBs.ConclusionThe DUB enzymes revealed in our phenotypic screen have been validated in confirmatory studies and have the potential to become novel targets for the treatment of AD. In collaboration with Mission Therapeutics we will develop selective, potent DUB inhibitors for preclinical target validation.
What older adults do with results from a community‐based dementia screening program
Authors: Galvin James E , Tolea Magdalena I , Chrisphonte Stephanie 
Published: December 2020

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD), and mild cognitive impairment (MCI) are often under‐recognized in the community. Primary care providers are often responsible for the detection, diagnosis, and treatment of ADRD as the number of dementia specialists are not sufficient to meet the growing demands. MCI/ADRD screening could offer benefits such as early treatment, research participation, lifestyle modification, and advanced care planning. To date, there are no clear guidelines regarding the benefits vs. harms of dementia screening or what individuals who completed screening will do with their results.MethodsA community‐based study was conducted to evaluate acceptability of MCI/ADRD screening, and how older adults would make use of the results and information provided to them. Measures of cognition, physical health, functionality, and mood were collected. Participants met with a health professional, were given screening results with recommendations, and then contacted 60 days later to determine what was done with the results.ResultsParticipants (n=288) had a mean age 71.5+8.3y, mean education 13.3+4.8y, and were 70% female, 67% White, 26% Black, 48% Hispanic. After 60 days, 75% of participants were contacted; 54% shared results with family, 32% shared results with health care providers (HCPs), and 52% initiated behavioral change. Among participants sharing results, 51% reported HCPs did not follow‐up on the results, and 18% HCPs did not show any interest in the screening. Behavioral changes included lifestyle modification (58%), social engagement (10%), cognitive stimulation (5%) and advanced care planning (4%). Predictors of behavioral change were lower comorbidities (OR=0.62, 95%CI:0.39‐0.96), higher A1C (OR=3.24, 95%CI:1.32‐7.95), poorer self‐perceived emotional health (OR=4.67, 95%CI:1.17‐18.67) and increased age (OR=1.14, 95%CI:1.01‐1.29).ConclusionMCI/ADRD screening was well‐accepted in a diverse community sample. Participants showed interest in sharing the results with their family and HCPs and many attempted behavioral change. While HCPs did always not act on screening results, 25% ordered further testing and evaluation. Future efforts are needed to (1) increase self‐efficacy of older adults to discuss screening results with their HCPs, and (2) educate HCPs on the value of early detection of MCI/ADRD. Community dementia screening programs can increase MCI/ADRD detection, improving patient‐centered outcomes and medical decision‐making.
Functional changes and expression of inducible NO synthase in dentate gyrus of rats during modeling of depression and the possibility of their pharmacological correction
Authors: Ekova Maria , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Volotova Elena 
Published: December 2020

AbstractBackgroundDepression is seen as the most common cause of disability, and is associated with chronic stress and neuroinflammation. The signaling pathway for the synthesis of nitric oxide plays a crucial role in the neurobiology of mild stress and depression.Methods3 groups were formed: group 1 — control rats (n = 10), group 2 — rats with experimental depression (n = 10), group 3 — rats with experimental depression (n = 10) receiving a compound with the laboratory cipher RSPU‐189 (salifen). The depressive state in animals was caused by exposure to stressful stimuli such as vibration, loud sound and pulsating bright light for 7 days (daily for 30 minutes). The experiment used rats at the age of 12 months. We evaluated the neuropsychiatric state of animals and expression of iNOS in the dentate gyrus.ResultsIn animals of the 2 group, symptoms of depressive behavior were observed, having a pronounced phenomenological similarity to the clinical picture of depression: anxiety, behavioral correlates of despair, inactivity, anhedonia, as well as a decrease in tentative research activity. The use of salifen in rats of group 3 leveled these changes. When evaluating the results of immunohistochemical studies in rats with experimental depression, in contrast to animals of the control group, an increase in the expression level of iNOS‐IRM in granule cells and neuropil in inner polymorphic layer of dentate gyrus was noted. Pharmacological correction of experimental depression by salifen showed a decrease in the expression of iNOS‐IRM to values close to the expression level in the control group of animals.ConclusionsWhen modeling a depressive state in rats of adulthood, an increase in iNOS expression in dentate gyrus is observed, the use of salifen leads to the correction of revealed changes, which may be associated with GABAergic modulation of neurotransmission in the hippocampus. The reported study was funded by RFBR and Administration of Volgograd region according to the research project № 19‐415‐340004∖19.
Neuropsychiatric symptoms correlated with functional trajectories among people living with Alzheimer’s disease dementia and Lewy body dementia
Authors: Borda Miguel German , Aarsland Dag , Oppedal Ketil , Giil Lasse Melvær , Vik‐Mo Audun Osland , Alves Guido , Tovar Diego , Gonzalez Maria Camila , Brønnick Kolbjørn 
Published: December 2020

AbstractIntroductionFunctionality is one of the most important markers of wellbeing in older adults. People with dementia lose functionality mainly because of cognitive impairment. However, little has been outlined regarding the independent association of Neuropsychiatric symptoms (NPS) on functional decline in this population, especially in those diagnosed with Lewy body dementia (LBD). The aim of our work is to study the association of NPS at time of dementia diagnosis and 5‐year longitudinal course with the 5 years’ trajectory of functional decline in people with Alzheimer´s disease (AD) and LBD.MethodsThis is a secondary analysis of the Dementia Study of Western Norway (DemWest) including a total of 196 patients with newly diagnosed AD (n=111) and LBD (n=85). Baseline information on NPS was obtained using the Neuropsychiatric Inventory (NPI), and activities of daily living (ADL) was assessed yearly during five years using the rapid disability rating scale (RDRS). The longitudinal functional trajectories were analyzed using linear mixed modeling, adjusting by Age, cognition, sex and comorbidity.ResultsTotal NPI score at diagnosis was associated with functional decline for AD (Est 0.007 SE 0.002 p‐value 0.0014) but not for LBD (Est 0.002 SE 0.003 p‐value 0.4258). NPI score longitudinal course was associated with the functional decline trajectory in AD (Est 0.004 SE 0.001 p‐value 0.0002) and LBD (Est 0.005 SE 0.002 p‐value 0.0070).ConclusionNPS independently predicted the rate of functional decline in people with AD and LBD despite their cognitive status. These results highlight the relevance of early detection and intervention of NPS, which may also reduce functional decline.
Diffusion tensor imaging (tractography) in elderly people with mixed dementia and mild Alzheimer's disease
Authors: Mimenza Alberto Jose , Navarro Sara Gloria Aguilar , Albán Paulina Bombón , Samudio Alejandra , Ortega Jhonatan Ruvalcaba , Meléndez Oscar Marrufo , Funes José A Avila 
Published: December 2020

AbstractBackgroundCerebral tractography is a Magnetic Resonance Imaging technique that allows you to visualize the white matter fascicles that connect different parts of the brain. It is based on the diffusion of water in biological tissues, through which fiber tracts are evaluated in a three‐dimensional space, which allows to obtain the Anisotropy Fraction (FA) and Medium Diffusivity (DM). Tractography allows correlating the integrity of these pathways with cognitive function. The objective of our study was to identify anatomical regions with alterations in AF in mixed dementia compared to AD.Method16 patients were included; 8 with Mixed Dementia (DMix) and 8 with Alzheimer's Disease (AD). Mean, standard deviations and frequencies were used, as well as Chi‐square and Mann‐Whitney tests. A linear regression model was used to determine the association between Tractography and performance in cognitive domains, adjusted for age and educational level.ResultsThe mean age of the participants was 85 ± 7.9 years (p ≤.57), 69% were women (p ≤.10) and the educational level was 11 ± 6.0 years (p ≤.87). Participants with AD had a worse cognitive performance (NEUROPSI: 68.5 ± 11.6 points, p ≤.02) compared to the DMix group. When analyzing by cognitive domains, patients in the DMix group had a worse performance in phonological verbal fluency (7.0 ± 3.5 words, p ≤.05). Regarding neuroimaging, significant differences were observed in participants with DMix in the Anisotropy Fraction (AF) in the following tracts: right cerebral peduncle (0.5557 ± 0.0121, p ≤.05), left cerebral peduncle (0.5476 ± 0.0121, p ≤0.01), right external capsule (0.3346 ± 0.0163, p ≤0.01) and left cingulate gyrus (0.3756 ± 0.0241, p ≤0.05) and mean diffusivity in the right thalamic posterior radiation (0.0010 ± 0.0000, p ≤ 0.03) and left external capsule (0.0012 ± 0.0001, p ≤0.03).ConclusionTractography allows quantifying and differentiating anatomical regions with myelin damage in mixed dementia compared to AD.
Effects of cognitive rehabilitation intervention based on sensory activities on the perception, depression, and quality of life of the elderly with dementia in a care facility
Authors: Lee Hey Sig , Yang Min Ah 
Published: December 2020

AbstractBackgroundWe want to find out how the intervention of cognitive rehabilitation group programs based on sensory activities can affect the cognitive function, depression and quality of life for the elderly with dementia living in the facility.MethodIn this study, the cognitive rehabilitation group program based on the sensory activity of 20 cycles is applied to 10 the elderly with dementia facility to determine if it is effective by pre‐ and post‐evaluation of cognitive function, depression and quality of life. Cognitive function is evaluated as MMSE‐DS, depression as S‐GDS‐K, and quality of life as WHOQOL‐BREF.ResultAs a result of this study, the MMSE‐DS score increased by 3.20, the S‐GDS‐K score decreased by 4.32, and the WHOQOL‐BREF score increased by 7.05.ConclusionTherefore, sensory activity‐based cognitive rehabilitation programs are effective for the elderly with dementia living in the facility.