bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perceived neighborhood safety and aesthetic quality are associated with cognitive change over time
Authors: Hyun Jinshil , Qin Jiyue , Katz Mindy J. , Derby Carol A. , Wang Cuiling , Sliwinski Martin J. , Lipton Richard B. 
Published: December 2022

AbstractBackgroundIdentifying factors that contribute to cognitive decline is critical to the design of interventions to help older adults maintain independence. Although several studies have investigated associations between neighborhood characteristics and cognitive decline, these studies have not properly considered practice‐related cognitive gains (i.e., retest effects), which may hamper accurate estimation of aging‐related cognitive decline over time. This study examined whether subjective neighborhood characteristics were associated with longitudinal changes in processing speed, an early marker of cognitive aging and impairment, after accounting for retest effects.MethodThe analysis sample includes 316 individuals enrolled in the Einstein Aging Study (mean age = 78; 67% females; 46% non‐Hispanic Whites, 40% non‐Hispanic Blacks). Neighborhood characteristics, including perceived neighborhood safety, aesthetic quality, and social cohesion, were measured at enrollment from self‐reports (range = 1 poor to 5 excellent). Processing speed was assessed using the brief, smartphone‐administered Symbol Search Test, and was completed 6 times per day for 16 days. The 16‐day protocol was repeated every year for three years. Double negative exponential models were used to estimate the relation of neighborhood characteristics to asymptotic performance (i.e., fastest response time) at baseline and asymptotic change (the rate in which asymptotic performance changes across years).ResultResults suggested that perceived neighborhood safety was associated with better (i.e., faster) baseline asymptotic performance after controlling for demographic information and individual‐ and neighborhood‐level socioeconomic status (Table 1). A one‐point increase in perceived safety was associated with a 115 millisecond faster asymptotic response time at baseline. Neighborhood safety and aesthetic quality were associated with greater decline in asymptotic response time: asymptotic response time decreased by 42 milliseconds (for safety) and 60 milliseconds (for aesthetic quality) per year for a one‐point increase in safety and aesthetic quality (Figure 1).ConclusionPerceived neighborhood characteristics were associated with both baseline cognitive performance and rates of cognitive change for a three‐year period among community‐dwelling older adults. It is possible that a disordered neighborhood environment may act as a chronic stress leading to long‐term cognitive decline. Future studies need to examine psychosocial and behavioral mechanisms to identify targetable area for intervention.
Improving Vascular Functions by Bioreactive Nanoparticles for Treatment of Alzheimer’s Disease
Authors: Park Elliya , Li Lily Yi , He Chunsheng , Abbasi Azhar Z. , Ahmed Taksim , Foltz Warren D. , Rauth Andrew M. , Fraser Paul , Henderson Jeffrey T. , Wu Xiao Yu 
Published: December 2022

AbstractBackgroundDeveloping effective disease‐modifying treatment for Alzheimer’s disease (AD) remains a tremendous challenge due to its multifactorial nature involving multiple pathologic signaling pathways in addition to ineffective drug delivery through the blood‐brain barrier (BBB).1 With this in mind our group has developed multifunctional bioreactive nanoparticles (Ab‐TP‐MDNPs), consisting of anti‐amyloid β antibody (Ab) linked to brain‐penetrating terpolymer (TP) and manganese dioxide (MnO2) nanoparticles (MDNPs), that are shown to reduce oxidative stress in AD brains.2 Given the early occurrence of oxidative stress, hypoxia, and vascular dysfunction in AD brains,3,4 we investigated the therapeutic effects of Ab‐TP‐MDNPs on reducing neuroinflammation and vascular dysfunction in an AD mouse model.MethodA transgenic mouse model of AD (TgCRND8 species) and wildtype littermates (WT) were treated with intravenous (i.v.) injection of Ab‐TP‐MDNPs (twice/week, 100 µmol Mn/kg b.w.) or vehicle for 2‐weeks. Oxidative and inflammatory biomarkers were examined using immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA). Vascular function before and after the treatment was studied via high resolution magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was assessed using FAIR (flow‐sensitive alternating inversion recovery) technique. BBB permeability was measured via T1 mapping re‐acquisition prior to and following i.v. injection of gadolinium‐diethylenetriamine penta‐acetate (Gd‐DTPA) at 1.2 mmol/kgResultAb‐TP‐MDNPs treatment significantly decreased inflammatory cytokines and activation of microglia and astrocytes markers (reactive microglia: hippocampus by 69% and cortex by 59%, reactive astrocytes: hippocampus by 32% and cortex by 33%). In addition, Ab‐TP‐MDNPs treatment improved CBF (cortex by 19% and subcortex by 35%) and vessel leakage by 29% in the cortex of AD mouse brains.ConclusionAb‐TP‐MDNPs treatment reduced neuroinflammation and vascular dysfunction in an AD mouse model. These findings suggest a new multimodal strategy for AD treatment and encourage further development of such approach for complex neurologic diseases.Reference:1.	Panza F, Lozupone M, Logroscino G, Imbimbo BP. Nature Reviews Neurology. 2019;15(2):73‐88.2.	He C, Ahmed T, Abbasi AZ, et al. Nano Today. 2020;35:100965.3.	Sweeney MD, Montagne A, Sagare AP, et al. Alzheimer’s & Dementia. 2019;15(1):158‐167.4.	Nortley R, Korte N, Izquierdo P, et al. Science. 2019:eaav9518.
The effects of sub‐threshold depression and anxiety symptoms on fluid cognitive performance in older adults: an exploratory analysis
Authors: Farris Kristen M , Parsey Carolyn M , Hanson Angela J 
Published: December 2022

AbstractBackgroundClinical anxiety and depression have well‐understood cognitive effects, but less is known about sub‐threshold symptoms. This study explored differences in cognition between older adults with sub‐threshold symptoms of depression or anxiety in comparison to those with no symptoms and investigated whether the COVID‐19 pandemic or APOE4 carrier status contributed to these symptoms.Method72 older adults (age 64.33±6.3) completed the Patient Health Questionnaire (PHQ‐9), Generalized Anxiety Disorder scale (GAD‐7), and NIH Toolbox Cognition Battery (NIHTB‐CB). Participants were split into a Pre‐COVID Group (participation before March 2020) and a Post‐COVID Group. Subjects were also split based on their mood assessment scores. Those who scored 0 on the PHQ‐9 (“None” Group) were separated from those who scored 1–4 (“Some” Group). The same process was performed for the GAD‐7 assessment. Age‐corrected NIHTB‐CB scores were compared between groups for both mood assessments by ANCOVA using SAS Studio software, adjusting for education level.ResultThere were no significant differences in PHQ‐9 or GAD‐7 scores between Pre‐ and Post‐COVID groups, nor did mood symptoms differ by APOE4 status (p’s>.05). The PHQ‐9 “Some” Group produced higher scores on the Fluid Cognition Composite than the “None” Group (111.11±2.24 and 102.57±2.81, respectively; p = .023). This was driven by significantly better performances on Pattern Comparison (PC; p = .014) and a trend of better performance on Dimensional Change Card Sort task (DCCS; p = .054). Reaction times were also faster for the “Some” Group on DCCS (p = .002) and PC (p = .002) tasks. No significant differences were found for GAD‐7 subgroupings.ConclusionAnxious and depressive symptoms did not differ between COVID‐19 or APOE4 groups. While sub‐threshold anxiety did not affect cognition, those with some depressive symptoms performed better on fluid cognitive measures, specifically tests of processing speed, than those with no symptoms. Further analysis exploring the relationship between components of these two mood assessments and fluid cognitive performance is warranted.
HMGB1‐Mediated Senescence and Brain Inflammation Contributes to Cognitive Dysfunctions
Authors: Gaikwad Sagar , Kayed Rakez 
Published: December 2022

AbstractBackgroundHigh mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein, which is excessively released by glial cells during aging and Alzheimer’s Disease (AD). The extracellular HMGB1 serves as a key initiator of neuroinflammation, which is linked to exacerbated cognitive impairments in AD. Importantly, aging ‐ the strongest risk factor for AD is characterized by a chronic, low‐grade inflammation known as inflammaging. Evidence suggests that senescent cells (SC) accumulate with aging and are characterized by an apoptosis‐resistant, arrested cell cycle with a distinct “inflammatory” phenotype also known as senescence‐associated secretory phenotype (SASP). However, the precise etiology of inflammaging in tauopathies remain largely unknown.MethodWe used brain tissues from AD patients and hTau mouse model and performed immunoflourescence, microscopy, astrocyte cell cultures, pharmacological inhibition of HMGB1 in vitro and in vivo in a hTau mouse model to examine role of HMGB1 in senescence, brain inflammation and cognitive dysfunctions. We scored cellular senescence, inflammation, tau pathology (phospho‐tau, tau oligomers, neurofibrillary tangles), Synaptic and postsynaptic proteins, and cognitive functions (Y‐maze and novel‐objective recognition tests).ResultIn this study, we demonstrate that (1) HMGB1 release is linked to advanced age in hTau tauopathy mice. (2) HMGB1 release is a hallmark of senescent cells both in mice and humans. (3) Astrocytes display a senescence‐like phenotype in the brains of patients with AD. (4) Pathological tau oligomers (TauOs) exposure triggers astrocyte senescence through HMGB1 release, which mediates paracrine senescence in adjacent cells and potentiates inflammatory SASP. (5) Inhibition of HMGB1 release using ethyl pyruvate (EP) and glycyrrhizic acid (GA) results in decreased astrocyte senescence and neuroinflammation. (6) Importantly, despite the developed tauopathy and cognitive deficits in 12‐month‐old hTau mice, EP+GA treatment significantly decreased SCs loads in the brain, reduces inflammaging, and thus ameliorated cognitive deficits. Collectively, our data suggest that HMGB1 release promotes inflammaging, and cellular senescence, which could represent an important pathomechanism in the progression of aging‐related diseases, including AD. Future studies are warranted to develop safe and effective therapeutic strategies to control inflammaging and enhance healthy lifespan in patients with tauopathy.ConclusionThe data suggests that HMGB1 release is a key pathomechanism in AD.
Characteristics of Cognitive Function Changes and Related Factors in Individuals with Cognitive Impairment during the Pandemic of COVID‐19
Authors: Choi Jin‐Hui , Kim Hyegeum , Seo Wan‐Seok , Koo Bon‐Hoon , Sung Hyung‐Mo , Cheon Eun‐Jin , Kim Ji Yean , Jeong Hyun‐Seok , Kim Younggyo 
Published: December 2022

AbstractBackgroundThis study aimed to explore the characteristics and factors related to changes in cognitive function in vulnerable individuals with cognitive impairment affected by the coronavirus disease 2019 (COVID‐19) pandemic.MethodAmong patients who visited a local university hospital with subjective cognitive complaints, those who had been tested for cognitive function at least once after the onset of COVID‐19 and tested regularly at least three times within the last 5 years were included. Finally, 108 patients were included in this study. They were divided into groups according to whether the Clinical Dementia Rating (CDR) was maintained/improved and deteriorated. We investigated the characteristics of the changes in cognitive function and related factors during COVID‐19.ResultWhen comparing CDR changes before and after COVID‐19, there was no significant difference between the two groups (p = .317). Alternatively, the main effect of the time when the test was conducted was significant (p<.001). There was also a significant difference in the interaction between the groups and time. When the effect of the interaction was analyzed, the CDR score of the maintained/improved group significantly decreased before COVID‐19 (1st–2nd) (p = .045). After COVID‐19 (2nd–3rd), the CDR score of the deteriorated group was significantly higher than that of the maintained/improved group (p<.001). MMSE recall memory and changes in activity during COVID‐19 were significantly associated with CDR deterioration.ConclusionMemory dysfunction and decreased activity during the COVID‐19 pandemic are strongly related to the deterioration of cognitive impairment.
Resilience and Reserve mechanisms underlying clinical‐cognitive progression in Dominant Inherited Alzheimer’s Disease.
Authors: Llibre‐Guerra Jorge J , Ma Yinjiao , Aschenbrenner Andrew J. , Xiong Chengjie , Hassenstab Jason J. , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Perrin Richard J. , Morris John C. , McDade Eric , Bateman Randall J. 
Published: December 2022

AbstractBackgroundPrevention of Alzheimer’s dementia may encompass both avoiding the AD pathological processes (resistance) and coping with AD pathology (resilience). Increasing evidence implicates resistance/resilience factors (e.g., level of education, socio‐economic status [SES], physical activity [PA]) occurring through life as potential modifiers of age at symptom onset (AAO) and rate of cognitive decline to dementia. The extent to which life course factors may influence disease progression in Dominantly Inherited Alzheimer’s Disease (DIAD) remains unknown.MethodsWe aimed to examine the influence of life‐course factors on clinical‐cognitive decline and MRI hippocampal volume in individuals with DIAD enrolled in the Dominantly Inherited Alzheimer Network. A total of 310 mutations carriers (195 asymptomatic and 111 symptomatic [CDR>0]) self‐reported education, work complexity, SES, and PA at baseline and completed longitudinal clinical‐cognitive measures, CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau), structural MRI and Aβ‐PET imaging. The influence of life‐course risk factors on AAO, cognitive performances, and hippocampal volume were analyzed using linear mixed models.ResultIn mutation carriers (MC), adjusting for age, PiB‐PET SUVR, and sex, lower clinical disease severity as measured by CDR‐SB was associated with higher levels of education (p = 0.04), PA (p = 0.01) and SES (0.002). Similarly, MC with higher educational levels (p = 0.02) and SES levels (p = 0.001) exhibited larger hippocampal volume despite no differences in PiB‐PET SUVR. Longitudinally, MC with higher levels of education, PA, and SES showed better performance and slower cognitive decline in memory and executive function prior to symptom onset (CDR>0), but a similar decline rate after symptom onset.ConclusionLife‐course factors, like higher education, PA, and SES may promote brain resistance and clinical resilience to AD pathology in DIAD. A model of cognitive reserve in DIAD may help to identify how social and behavioral factors influence the progression of AD pathophysiology and explain how a variety of factors may enhance resistance to pathology, delay AAO, and cognitive decline rate.
Differential modulation of amyloid‐beta levels by psychotropic medications in an in vitro model of Alzheimer’s disease
Authors: Aleksynas Robertas , Sastre Magdalena 
Published: December 2022

AbstractBackgroundPreclinical studies suggest that psychotropic drugs (e.g. antidepressants, benzodiazepines) can affect amyloid‐β (Aβ) levels, yet mechanisms remain unclear. We aimed to determine the effects of common psychiatric drugs on Aβ generation and clearance in an in vitro model of Alzheimer’s disease (AD).MethodThe effects of a range of psychotropic drugs on Aβ generation and clearance were assessed in N2a/APP695swe cells, a neuroblastoma cell line overexpressing APP with the Swedish mutation. Cells were incubated for 24h with either fluoxetine (selective serotonin reuptake inhibitor (SSRI); 1‐10μM), venlafaxine (serotonin‐norepinephrine reuptake inhibitor (SNRI); 0.1‐10μM), mirtazapine (α2‐adrenergic antagonist; 1‐25μM), phenelzine (monoamine oxidase inhibitor (MAOI); 10‐50μM) or nordiazepam (benzodiazepine (BNZ); 1‐25μM). Aβ42 levels were quantified in conditioned media using an enzyme‐linked immunosorbent assay (ELISA). Amyloid precursor protein (APP) processing was studied using western blots (WBs), including expression of different secretases, full‐length APP, C‐terminal fragments (CTFs) in membrane preps and APP soluble‐α in media. Neprilysin and insulin degrading enzyme (IDE) expression was quantified as major Aβ clearance factors.ResultsCertain drugs increased Aβ levels; in particular, Venlafaxine (SNRI) and nordiazepam (BNZ) elevated Aβ42 at 10 µM, due to increased amyloidogenic APP cleavage. Conversely, the anti‐depressant drug fluoxetine (SSRI; 10 µM) reduced Aβ42, concomitant with reduced β‐secretase (BACE1) and presenilin‐2 expressions. Mirtazapine (α2‐adrenergic antagonist) and phenelzine (MAOI), on the other hand, did not modulate Aβ levels.ConclusionCertain psychotropic medications, i.e. nordiazepam (BNZ) and venlafaxine (SNRI) can increase Aβ levels, while fluoxetine (SSRI) can reduce them. This results from the effects of these drugs on Aβ generation rather than clearance. This is important, as the administration of these drugs could affect AD‐risk.
A Text Message Intervention to Support Latino Dementia Family Caregivers (CuidaTEXT): Feasibility study
Authors: Perales Jaime 
Published: December 2022

AbstractBackgroundLatino family caregivers experience disproportionately poor health outcomes and access to caregiver support. We aimed to test the feasibility, acceptability, and preliminary efficacy of CuidaTEXT: a tailored text message intervention to support Latino dementia family caregivers.MethodCuidaTEXT is a six‐month, bilingual, and bidirectional intervention tailored to caregiver needs (e.g., education, problem‐solving, resources). We enrolled 24 Latino caregivers in a one‐arm trial, and assessed feasibility, acceptability, and preliminary efficacy within six months.ResultRecruitment took 61 days and enrollment took 20. None of the participants unsubscribed from CuidaTEXT, and 83.3% completed the follow up survey. Most participants (85.7%) reported reading most text messages thoroughly. Participants reported high levels of satisfaction with the intervention (3.6 on a scale from 1 to 4). CuidaTEXT helpfulness was high (3.5‐3.8 on a 1 to 4 scale). Compared to baseline, at six months caregiver behavioral symptom distress (0‐60) decreased from 19.8 to 12.0, and depression (0‐30) from 8.8 to 5.4 (p<0.05).ConclusionCuidaTEXT demonstrated high levels of feasibility, acceptability, and preliminary efficacy among Latino caregivers. The next logical step is CuidaTEXT’s efficacy‐testing.
Interferon hypersensitivity in the brain of a Down syndrome preclinical model
Authors: Mumford Paige , Farrell Clíona , Salih Dervis , Tybulewicz Victor L , Fisher Elizabeth , Wiseman Frances K 
Published: December 2022

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21). People with DS have altered neuroinflammation, including abnormal microglial morphology and elevated cytokines. The peripheral immune system is also different in DS, including an over‐activated interferon response likely due to four genes encoding interferon receptors being located on Hsa21. How this affects neuroinflammation is unknown. The “ex vivo” model system of organotypic brain slice cultures (OBSCs) derived from mouse brain can be used to model neuroinflammation. We created OBSCs from a DS preclinical mouse model containing three copies of the interferon receptor genes, and treated them with interferon‐β to investigate if this model had a hyper‐sensitive interferon response in the brain.MethodThe Dp(16)2Tyb (Dp(16Mis18a‐Runx1)2TybEmcf, MGI 5703800) mouse strain was used, which has the region Mis18a‐Runx1 on mouse chromosome 16 in three copies, containing ∼33 Hsa21 orthologous genes including the four interferon receptor genes. Cortico‐hippocampal OBSCs were prepared from Dp(16)2Tyb pups at age P8‐P9, grown in culture and treated at DIV14 with interferon‐β for 24‐hours. Slices were used for western blotting or qPCR, and conditioned media used for ELISAs.ResultDp(16)2Tyb OBSCs treated with interferon‐β had a significantly elevated response to treatment compared to treated wild‐type littermates, with higher expression of interferon‐stimulated genes in slice tissue and higher levels of CXCL10 protein secreted into the conditioned media.ConclusionWe found that Dp(16)2Tyb OBSCs displayed a hypersensitive interferon response. The apparent candidate genes for this interferon hypersensitivity are the four interferon receptor genes encoded on Hsa21. How this interferon hypersensitivity effects neuroinflammation in the presence of amyloid pathology is unknown. Next, we will cross the Dp(16)2Tyb with the AppNL‐G‐F mouse model of amyloid pathology to investigate how interferon hypersensitivity alters neuroinflammation in response to amyloid pathology.
Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Cognition in Alzheimer’s Disease
Authors: Fang Cheng , Hernandez Priscilla , Liow Kore , Chen Michael , Zetterberg Henrik , Blennow Kaj , Maccecchini Maria L. 
Published: December 2022

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of amyloid precursor protein, tau and alpha‐synuclein, our drug restored axonal transport, lowered inflammation, and protected nerve cells from dying in animal models. Buntanetap’s reversal of the toxic cascade leading to nerve cell death did preserve and/or restore full function in 7 different animal models of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodIn a double blind, placebo controlled Phase2a study, early AD patients were randomized into 80mg Buntanetap (n = 10) or placebo (n = 5) QD for 25±2 days. We evaluated the safety, pharmacokinetics of Buntanetap, biomarkers, and its efficacy.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both healthy volunteers and AD/PD patients. In our recent double‐blind, placebo controlled Phase2a study, patients randomized to either 80mg QD Buntanetap or placebo we measured biomarkers in AD patients and showed that Buntanetap can lower neurotoxic proteins, improve axonal integrity and synaptic function, and lower inflammation. Buntanetap has also improved AD patients’ cognitive functions as measured by ADASCog11 and WAIS coding test after 25±2 days treatment.ConclusionThese encouraging data support our further development of Buntanetap as a potential treatment for Alzheimer’s disease. We are planning three double‐blind, placebo‐controlled studies, a short 3‐month dose‐finding trial and two long‐term 12‐ and 18‐month trials in early and moderate AD patients.