bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulating SORL1 expression affects endolysosomal trafficking function in hiPSC‐derived models of Alzheimer's disease
Authors: Knupp Allison , Mishra Swati , Martinez Refugio A. , Young Jessica E. 
Published: December 2020

AbstractBackgroundThe SORL1 gene encodes for the protein SorLA, a sorting receptor involved in retromer‐related endosomal traffic. Many SORL1 genetic variants increase Alzheimer’s disease (AD) risk, and rare loss‐of‐function truncation mutations have been found to be causal of AD. SORL1 is expressed in neurons and glia of the central nervous system and loss of SORL1 has been reported AD tissue.MethodTo model the causal loss‐of‐function mutations, we used CRISPR/Cas9 technology to deplete SORL1 in human induced pluripotent stem cells (hiPSCs) to test the hypothesis that loss of SORL1 (SORL1 KO) contributes to AD pathogenesis by leading to dysfunction in endo‐lysosomal trafficking. In contrast, certain SORL1 variants may be acting in a protective capacity to help prevent AD pathogenesis. To model protective variants, we used a PiggyBac Transposon system to test the hypothesis that overexpression of SORL1 (SORL1 OE) protects against AD pathogenesis and endo‐lysosomal trafficking dysfunction.ResultsWe report that loss of SORL1 in hiPSC‐derived neurons leads to early endosome enlargement, a cellular phenotype that is indicative of ‘traffic jams’ and is now considered a hallmark cytopathology AD. We validate defects in endo‐lysosomal traffic in SORL1 KO neurons by showing decreased localization of amyloid‐precursor protein (APP) to the degradative pathway. We confirm decreased function of the degradative pathway in SORL1 KO neurons through experiments using pH‐sensitive pHrodo dyes. Conversely, in SORL1 OE neurons we show nominal early endosome morphology, reduced localization of APP to the degradative pathway, and increased functionality of the degradative pathway. Finally, we determined that defects in endo‐lysosomal trafficking caused by loss of SORL1 affect synapse function by analyzing SORL1 KO neurons on multielectrode arrays.ConclusionCollectively, these findings clarify where and how SORL1 links to AD. Moreover, our data, together with recent findings, underscores how sporadic AD pathways that regulate endosomal trafficking, and autosomal‐dominant AD pathways that regulate APP cleavage, independently converge on AD’s defining cytopathology.
Vascular and Alzheimer’s pathology: A mixed affair
Authors: Schneider Julie A 
Published: December 2020

AbstractBackgroundIn‐vivo indicators of the central pathologies that define Alzheimer’s disease (AD) have transformed research in dementia. The AT(N) framework was proposed to standardize nomenclature when using these biomarkers in the research setting of suspected Alzheimer’s dementia. However, in‐vivo amyloid and tau biomarkers provide an incomplete picture of the brain in persons living with Alzheimer’s dementia, a heterogeneous syndrome that not only includes prominent episodic memory impairment, but often deficits in multiple other cognitive domains, motoric abilities and behavior.MethodPresentation of human data from autopsy studies that support a role for vascular pathology in accelerating neurodegeneration and worsening cognitive impairment.ResultBrain vascular disease is extraordinarily common in the aging brain with and without AD pathology and contributes to cognitive impairment. In spite of the prevalence of vascular pathology, most persons have no history of stroke. Vascular brain pathologies include but are not limited to small and large vessel diseases and macro and microscopic tissue injuries. Each vascular pathology adds to cognitive impairment and lowers the threshold for Alzheimer's dementia. In some studies, vascular pathologies contribute to about 1/3 of association between age and dementia. Changes in endothelial cells, the blood brain barrier and the neurovascular unit are also implicated. Moreover, vascular risk factors and vessel diseases may promote or interact with amyloid and/or tau to accelerate tissue injury.ConclusionPreventing and treating cognitive impairment requires an integrated understanding of beta‐amyloid, hyperphosphorylated tau, and the vascular pathologies and processes that lead to tissue injury, neurodegeneration, and ultimately cognitive decline.
The features of BECN1 expression in the pyramidal layer of rat hippocampus in chronic cerebral ischemia
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Kurkin Denis , Ekova Maria 
Published: December 2020

AbstractBackgroundBECN1 is a member of the Bcl‐2 protein superfamily, belonging to the BH3‐proteins subfamily, which performs many functions, including cross‐regulation of autophagy and apoptosis. BECN1 acts as regulator of the formation and maturation of autophagosomes, the development of neurodegenerative processes in the hippocampus and cerebellum in a BECN1‐knockout mice.MethodChronic cerebral ischemia modeled in rats by limiting cerebral blood flow with applying ligatures to the carotid arteries. The cognitive sphere, the preservation of reflexes, the ability to remember new objects, the degree of neuronal injury, and the level of BECN1 expression in the pyramidal layer of the hippocampus were evaluated. Immunohistochemical study was performed using polyclonal antibodies to BECN1, visualized using diaminobenzidine.ResultThe most pronounced changes were found in the pyramidal layer of the CA1, where neurons with signs of damage were identified along with unchanged neurons. Dystrophic changes in the pyramidal cells were of different severity, determined by a significant increase in the number of hyperchromic neurons, and in most of them total hyperchromia of the nucleus and cytoplasm was observed, a large number of shadow cells were formed. An immunohistochemical study of the hippocampus using antibodies to BECN1 revealed a uniform positive cytoplasmic reaction, mainly of low intensity. A significant increase in expression was found in the CA1, where the relative area of the immunoreactive material increased by 1.1% compared with the control (p <0.001) and reached 1.5%.ConclusionBECN1 is involved in the cross‐regulation of autophagy and apoptosis. According to modern concepts, BECN1 localized intracellularly in the complex with homologs‐proteins of the Bcl‐2 family. With dissociation of the Bcl‐2/BECN1 complex and an increase in free BECN1, autophagy is induced. The observed increase in the expression of BECN1 in CA1 indicates the inclusion of BECN1‐dependent autophagy in this zone in chronic cerebral ischemia.
Preliminary feasibility of technology use in an internet‐delivered intervention: Improving sleep in older adults with mild cognitive impairment
Authors: Mattos Meghan K , Barnes Laura , Davis Eric M , Manning Carol A , Mostafavi Moeen , Quigg Mark S , Perez Hillary , Sollinger Ann , Ritterband Lee M 
Published: December 2020

AbstractBackgroundIndividuals with mild cognitive impairment (MCI) experience more sleep disturbances than individuals without MCI, and improving sleep in this at‐risk group may delay progression to Alzheimer’s disease. Internet‐based interventions may promote access to treatments for sleep disorders, such as insomnia. However, preliminary studies examining technology use and compliance are needed prior to undertaking large‐scale interventions in this population.MethodOlder adults (≥55 years old) with MCI are recruited from hospital‐based memory and sleep disorders clinics and enrolled in a single‐arm intervention pilot study. An existing Internet‐delivered cognitive behavioral therapy for insomnia (CBT‐I)called Sleep Healthy Using the Internet for Older Adult Sufferers of Insomnia and Sleeplessness (SHUTi OASIS) collects daily sleep diary data and delivers the automated intervention over nine weeks. Wrist‐worn actigraphs are used to collect subject objective sleep data over two 14‐day periods, pre‐ and post‐intervention. SHUTi OASIS sends daily morning emails to remind subjects to complete the sleep diary and wear the actiwatch at night. There are only two in‐person study visits over the 4‐5 month study duration. Care partners are invited to enroll in the study to share their experience observing or assisting their loved one. Descriptive statistics for technology use are presented for the baseline study period.ResultSeven subjects are enrolled in the ongoing study and are, on average, 76.0±5.4 years of age, mostly female (4/7), with an average MoCA of 22.7±3.1 (19‐28).Four care partners, all spouses, are enrolled. All subjects with MCI completed 10 sleep diaries over 14 days, most accessing the SHUTi OASIS program daily. Actiwatch data show that subjects wore the actiwatch between 5‐14 days.ConclusionConsistent daily or every other day sleep diary entry may be in response to viewing the automated e‐mail reminders and immediately logging into SHUTi OASIS to complete their daily entry. Although subjects were accepting of wrist‐worn actigraphy, there was inconsistent wear time at night, which may be related to the early‐morning timing of e‐mail reminders. Incorporating technology for subjective and objective sleep data collection in this population is promising, and future work should consider frequency and timing of reminders with multimodal technology use.
Supporting people with dementia and their family caregivers through a home‐based, dyadic, multisensory stimulation intervention: A feasibility study
Authors: Kor Patrick Pui Kin , Yu Clare , Liu Justina Yat Wa , Cheung Daphne Sze Ki , Kwan Rick Yiu Cho , Leung Angela 
Published: December 2020

AbstractBackgroundMultisensory stimulation interventions are commonly used to support people with dementia (PWD). Major attention has only been paid to their beneficial effects on PWD. This study examined the preliminary effects of a home‐based, dyadic, multisensory stimulation intervention on both PWD and family caregivers (CG).MethodIn this quasi‐experimental study, 72 PWD‐caregiver dyads received either a 15‐week home‐based, dyadic, multisensory stimulation intervention (n=36) or the usual care (n=36). The intervention was delivered 3 times per week (30 minutes each time) by the CG. It consisted of various multisensory stimulation activities (i.e., tasting food, listening to music, singing). Weekly telephone follow‐ups and sharing sessions were also provided. The following outcomes were measured at baseline, immediately post‐intervention, and at the 3‐month follow‐up: the positive aspect of caregiving, stress, depression, burden, and quality of life (QoL) of the CG; and the cognitive function and Behavioral and Psychological Symptoms of Dementia (BPSD) of the PWD. A process evaluation was conducted through focus groups involving 13 pairs of dyads.ResultIntervention feasibility was established with a high completion rate of 82% (≥60 out of the 90 minutes per week) and a low attrition rate of 5.56%. The average duration of weekly training was 62.5 minutes (S.D.=18.4). The results of the generalized estimating equation indicated that the intervention group experienced a statistically significant improvement in the positive aspect of caregiving (B=‐4.68, 95% confidence interval [CI]=‐7.71, ‐1.65, p=0.002), stress (B=1.75, CI=0.45, 3.06, p=0.009), burden (B=4.86, CI=2.20, 7.52, p<0.001), and QoL (B=‐2.05, CI=‐3.05, ‐1.05, p<0.001) of the CG; and in the BPSD (B=1.80 CI=0.55, 3.05, p=0.005) of the PWD at the post‐test, compared to the controls. Sustainable effects in QoL, positive aspect of caregiving, and BPSD were demonstrated at the 3‐month follow‐up. Focus groups conducted immediately after the intervention revealed three major themes: Impacts on the dyadic relationship, Impacts on the PWD, and Difficulty of implementation.ConclusionThis study showed that the intervention is acceptable to PWD‐caregiver dyads in Hong Kong. The program not only benefited the PWD but also the caregivers and the dyadic relationship. Further testing of this program with a larger and more diverse sample is needed.
Translational potential of mouse CSF biomarkers in Alzheimer’s disease: Association of CSF neurogranin with tau, NFL and amyloid pathology in APP knock‐in mouse models
Authors: Smailovic Una , Delac Ljerka , Liman Victor , Kvartsberg Hlin , Winblad Bengt , Jelic Vesna , Höglund Kina , Zetterberg Henrik , Blennow Kaj , Nilsson Per 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by early and progressive synaptic dysfunction and loss that are closely related to cognitive impairment in AD patients. Neurogranin (Ng) has emerged as a potential marker of synaptic dysfunction, with cerebrospinal fluid (CSF) levels specifically increased in AD. In order to investigate the translational potential of CSF Ng, the present study investigated its alterations and relationship to AD‐related pathology (Aβ42, tau and neurofilament light; NFL) in both CSF and brain tissue of novel App knock‐in mouse models.MethodsCSF and brain tissue were sampled from 12‐months old wild type (WT), AppNL‐F/NL‐F and AppNL‐G‐F/NL‐G‐F mice. CSF and brain (cortex and hippocampus) Ng, Aβ42, t‐tau and NFL protein levels were analyzed using new ultra sensitive digital enzyme‐linked immunosorbent assays on the Simoa platform. Differences in expression of Ng in the brain tissue and its relation to amyloid plaques in App knock‐in mice were investigated by immunohistochemistry (IHC).ResultsCSF Ng, t‐tau and NFL levels were significantly increased in App knock‐in compared to WT mice (p < 0.05). CSF Ng negatively correlated with Ng levels in the cortex and Aβ42 levels in the CSF and positively correlated with CSF t‐tau and NFL levels (p < 0.05). Loss of neurogranin in the dendrites of hippocampal CA1 region of App knock‐in mice was closely associated with the localization of Aβ plaques in double IHC stainings.ConclusionsApp knock‐in mice exhibit synaptic degeneration that is associated with AD neuropathology and remarkably comparable to findings from clinical studies. CSF Ng is potential translational marker of synaptic degeneration in AD.
A‐posteriori‐derived dietary patterns and cognitive function in the SUN project
Authors: Muñoz‐García Mariana I , Martinez‐Gonzalez Miguel Angel , Razquin Cristina , Fernández‐Matarrubia Marta , Guillen‐Grima Francisco , Toledo Estefanía 
Published: December 2020

AbstractBackgroundDementia affected an estimated 44 million persons in 2016 and it is projected to affect 132 million by 2050. Drugs to cure or delay the progression of the disease are not available and are proving difficult to develop. Thus, prevention of cognitive function decline is extremely relevant. Diet is a key and pertinent target for primary prevention, but firm recommendations for dementia prevention are not available yet. Our aim was to address the association between empirically derived dietary patterns (DP) and changes in Spanish Telephone Interview for Cognitive Status (STICS‐m) scores over 6 years in a Mediterranean cohort.MethodA total of 803 participants from the ‘Seguimiento Universidad de Navarra’ (SUN) Project sub‐study of cognitive function were analyzed using principal component analysis to derive DP. The derived DP were associated with change in STICS‐m scores over 6 years, through adjusted multiple linear regression models.ResultTwo main DP were identified. The first resembled a Western diet (WDP)— high in sugar, fat, processed foods and red meat— and the second one a Mediterranean diet (MDP)— high in vegetable, fruit, nuts, fish and olive oil (table 1). Baseline characteristics of participants are shown in table 2. Highest adherence to the WDP (tertile 3 vs tertile 1) was associated with a non‐significant decrease in STICS‐m after 6 years of ‐0.65 points (95% CI ‐1.36, 0.06, p‐value=0.07) (figure 1). On the other hand, results for the MDP were showed a 0.73 point increase in STICS‐m after 6 years (95% CI 0.18, 1.27, p‐value=0.008), comparing tertile 3 vs tertile 1 (figure 2).ConclusionA healthy, prudent, Mediterranean‐like DP was associated with less decline in cognitive function and, thus, could help to lower dementia incidence. Western‐type diets could be associated with a faster decline in cognitive performance and higher dementia incidence. Our results are compatible with previous studies in other populations and can have an impact in future public health recommendations to decrease the risk of developing dementia.
Cognitive impairment in physicians suffering burnout syndrome: A matter of moral Injury
Authors: Martino Gabriel Gerardo , Rojas Galeno , Zuin Daniel , Persi Gabriel Gustavo , Leis Adriana , Macri Ana Macarena , Camino María Victoria , Parisi Virginia Laura , Silva Nahuel Pereira , Gatto Emilia , Aldinio Victoria , Guillen Jonathan Cubas , Boccazzi Julián Fernández 
Published: December 2020

AbstractBackgroundBurnout syndrome (BOS) is frequently described in physicians, being characterized by exhaustion and long‐term loss of interest generally at work. It is associated with lower effectiveness, lower job satisfaction, and a decrease in commitment to work. It’s been recently hypothesized that BOS could lead to cognitive impairment (CI), leading to serious consequences for health care professionals. Primary objective: to determine the impact that BOS has on subjective memory (SM) in physicians compared to general population in other occupations (OthOcc). Secondary objective: to compare how BOS is linked to anxiety, depression and SM impact in physicians and OthOcc.MethodWe performed an observational multicenter cross‐sectional study using a custom‐made survey (using Maslach Burnout Inventory [MBI], Hospital Anxiety and Depression Scale, and a SM scale of our own elaboration), sent digitally, distributed nationally. Risk of BOS (BOS‐R) was defined when 1‐2/3 MBI subscales were altered and BOS when all 3 were. Statistical analysis was performed with parametric and non‐parametric tests.ResultWe obtained 215 responses (111 physicians and 104 OthOcc). The average age of the physicians, was 34.23 years, women were 62.16% (n=69). In physicians, prevalence of BOS‐R was 62.16% (n=69) and of BOS was 20.72% (n=23); 33.33% (n=37) presented anxiety; and 9.91% (n=11), depression. We found a relationship between BOS‐R/BOS and lower SM scores (p=0.011). Physicians had worse SM scores when compared to OthOcc, being the mean for physicians with BOS‐R 11.32 (SD 6.36) and for OthOcc 9.75 (SD 6.54); for physicians with BOS 11.52 (SD 6.56) and for OthOcc 8.23 (SD 4). Physicians with BOS‐R/BOS presented anxiety (p<0.001) and depression (p=0.001), OthOcc also presented anxiety (p=0.019) and depression (p=0.001).ConclusionThe impact of BOS in physicians is alarming, and is associated with cognitive impairment and anxiety/depression. It has serious personal consequences, negatively affecting health care quality. We believe physicians are suffering what has been coined as ‘moral injury’, something beyond BOS, that is also affecting our health care system and our patients.
Association of tau tangle burden with depressive symptoms in community‐dwelling older adults: A longitudinal study
Authors: Gatchel Jennifer R. , Marshall Gad A. , Locascio Joseph J. , Yang Hyun‐Sik , Donovan Nancy J. , Buckley Rachel F. , Properzi Michael J. , Quiroz Yakeel T. , Rabin Jennifer S. , Vannini Patrizia , Amariglio Rebecca , Chhatwal Jasmeer P. , Rentz Dorene , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Hanseeuw Bernard J 
Published: December 2020

AbstractBackgroundDepressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid‐β and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults.Method252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau (18F‐Flortaucipir) and amyloid‐β (11C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time.ResultBaseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11).ConclusionBaseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
White matter texture abnormalities are associated with delusional severity in a cognitively mixed sample of older adults
Authors: Venkatesh Saanika , Bahsoun Mohamad‐Ali , Arezza Giordano , Digregorio Justin , Schweizer Tom A. , Churchill Nathan W , Munoz David G. , Fischer Corinne E. , Khademi April 
Published: December 2020

AbstractBackgroundDelusions in older adults correlate with white matter lesion burden [1], though the relationship with white matter texture (WMT) is unclear. White matter texture is the tissue organization in normal‐appearing brain matter (NABM) related to overall diffusion capabilities.MethodUsing NPI‐Q scores from the ADNI data set, a cognitively mixed sample of patients with delusions was extracted. Delusional severity was ranked from 1‐3 (1 being the lowest severity) based on the NPI‐Q scores along with downloads of FLAIR MRI volumes for each subject. Subjects and volumes were analyzed in each severity group. Normal‐appearing brain matter of FLAIR images were extracted with validated in‐house brain extraction and intensity standardization algorithms [2]. Volume texture maps representing the correlation in the NABM for each FLAIR image were generated as per Khademi et. al [3].ResultBoxplots for the NABM texture measures are shown for groups 1, 2 and 3 in Figure 1. Subjects with high delusional severity (group 3) had the most noticeable change in WMT relative to lowest delusional severity (group 1). Group 3 had a higher spatial correlation value of 6.0947 e+03 +/‐ 592.6178 than group 1 with values of 5.7630 e+03 +/‐ 832.5040. A higher value indicates more spatial correlation among pixels. This suggests that there are larger regions that are smooth in Group 3 compared to Group 1, indicating less WM “structure” in the more severe delusion group.ConclusionThe severity of delusions in a cognitively diverse sample of older adults correlates with abnormalities in white matter texture, though further research is required to further validate our findings. References: [1] K. Misquitta, M. Dadar, D. L. Collins and M. C. Tartaglia and Alzheimer’s Disease Neuroimaging Initiative, White matter hyperintensities and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment, bioRxiv, 2019. [2] A. Khademi, B. Reiche, G. Arezza, Method and System for Standardized Processing of MR Images, PCT Patent Application No. PCT/CA2018/051606, Filed.US. December 2018. [3] A. Khademi, D. Hosseinzadeh, A. Venetsanopoulos and A. Moody, "Nonparametric statistical tests for exploration of correlation and nonstationarity in images," 2009 16th International Conference on Digital Signal Processing, Santorini‐Hellas, 2009, pp 1‐6.