bluuebunny/crossref_metadata_2025_split huggingface dataset:
The incidence of dementia‐related psychosis in people with dementia: Results from a survey of 302 U.S. healthcare providers
Authors: Chen Jeanny , Bell Stephen , Brain Cecilia 
Published: December 2020

AbstractBackgroundIn the U.S., the incidence of dementia‐related psychosis (i.e., hallucinations and delusions) among people with dementia has been estimated at 30%.1‐15 However, it is hypothesized that the lack of a diagnostic code and approved medications for dementia‐related psychosis has resulted in considerable under‐recognition of the symptoms. It is possible that the actual incidence of dementia‐related psychosis is much higher than 30%.Method302 U.S. healthcare providers (HCPs)—physicians, nurse practitioners, and physician assistants—completed an online survey in which they were asked to estimate the percentages of their patients with dementia who have (a) hallucinations and/or delusions; (b) neuropsychiatric symptoms not including hallucinations or delusions (e.g., aggression, agitation, depression, sleep disturbances, anxiety); or, (c) no neuropsychiatric symptoms. Survey respondents were also asked to provide medical chart data for the last 8 (n=2416) treated patients with dementia and neuropsychiatric symptoms. HCPs were asked several questions about each chart, including which specific neuropsychiatric symptoms the patient had at the last consultation. As part of the data analysis, the percentage of the 2416 charts in which the patient had hallucinations, or delusions, or both, was computed.ResultThe mean percentages of patients with dementia who had: (a) hallucinations and delusions; (b) neuropsychiatric symptoms not including hallucinations or delusions; and, (c) no neuropsychiatric symptoms, were (a) 44%, (b) 36% and (c) 20% respectively. When asked in the survey to only consider the dementia population with any neuropsychiatric symptoms the HCPs’ estimate of delusions and hallucinations was 55% (calculated as 44%/(44%+36%)). Based on the medical charts, 57% of patients with dementia and neuropsychiatric symptoms had hallucinations and/or delusions, which is close to the HCP’s estimate of 55%.ConclusionU.S. HCPs estimate that 44% of their patients with dementia have hallucinations and/delusions—an incidence much higher than the previously assumed one‐third. Results from a large sample of medical charts attest to the accuracy of the HCPs' estimate.
RIN3 Binds to BIN1 and CD2AP to increase APP‐CTFS in early endosomes
Authors: Shen Ruinan , Wu Chengbiao 
Published: December 2020

AbstractBackgroundAbout one‐third of the genes related to Alzheimer’s disease (AD) identified by GWAS encode proteins that function predominantly in the endocytic pathways. Among them, the Ras and Rab Interactor 3, RIN3 is a guanine nucleotide exchange factors (GEFs) for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD (LOAD) and sporadic early onset AD (sEOAD). However, how RIN3 is linked to AD pathogenesis is currently undefined.MethodsQuantitative PCR and immunoblotting were used to measure gene expression levels in mouse brain, cultured basal forebrain cholinergic neuron (BFCNs) or PC12 cells. Immunostaining was used to define subcellular localization of RIN3 and visualize endosomal changes in cultured primary BFCNs and PC12 cells. Recombination RIN3‐flag‐tagged protein was purified from HEK293T cells and was used to define RIN3‐interactomes by mass spectrometry. Live imaging of primary neurons was used to examine axonal transport.ResultsExpression of RIN3 was upregulated in the brain tissues of young APP/PS1 mice. The increase was specific for the hippocampus and cortex since RIN3 expression level did not show an increase in either the olfactory bulb or the cerebellum. RIN3 mRNA level was also found to be elevated in embryonic day (E18) 18 in primary basal forebrain cholinergic neurons (BFCNs) cultured from APP/PS1 mouse. Concomitant early endosome enlargement was seen in these BFCNs. We have demonstrated that RIN3 interacted with two other AD risk factors: BIN1(bridging integrator 1) and CD2AP (CD2 associated protein). Both BIN1 and CD2AP were recruited to early endosomes through binding to the proline rich domain (PRD) of RIN3. Overexpression of RIN3 or CD2AP promoted APP cleavage to increase APP carboxyl terminal fragments (CTFs) in PC12 cells, while upregulating RIN3 or BIN1 neuronal isoform increase phosphorylated Tau level. The effect of upregulation of RIN3 expression to increase APP CTFs was ameliorated by a dominant negative Rab5 construct (Rab5S34N). Increased expression of RIN3 impaired axonal trafficking of both APP and BACE1.ConclusionRIN3 is significantly unregulated and correlated with endosomal dysfunction in APP/PS1 mouse. Through interacting with BIN1 and CD2AP, increased RIN3 expression alters axonal trafficking and procession of APP.
Treatment patterns and needs for dementia‐related psychosis described by patients and care partners (caregivers): An observational, prospective study to describe the patient experience
Authors: Brandt Teresa , Frangiosa Theresa , Biggar Virginia , Taylor Angela , Keller Bill , Abler Victor 
Published: December 2020

AbstractBackgroundWe aimed to describe current treatment patterns and unmet needs of persons with DRP from a patient and care partner (CP) perspective.MethodsThis observational, non‐interventional, prospective study used a mixed‐methods approach with qualitative interviews and a quantitative online survey. Persons with DRP and CP of persons with DRP reported the effectiveness of current treatments using a visual analog scale (VAS) of 0 (“not at all well”) to 5 (“extremely well”) and ranked benefits of an ideal treatment. CP burden was outside the scope of this study.ResultsThe qualitative interview was completed by 1 patient and 15 CP. Current treatments included atypical antipsychotics, antidepressants, anxiolytics, and benzodiazepines. Participants commonly indicated a need to improve patients’ ability to know what is real vs not real. The online survey was completed by 26 patients and 186 CP on behalf of patients under their care. Common treatments used included atypical antipsychotics (27% of patients, 41% of CP) and psychological/ behavioral therapy (23% of patients, 8% of CP). Many participants reported no current treatment (42% of patients, 42% of CP). Participants reported that current treatment methods were less than moderately helpful in treating patients’ most impactful symptoms with a median VAS score of 2.0/5 reported by patients and CP (mean VAS score [standard deviation] = 2.33 [1.0] for patients [n=15], mean [standard deviation] VAS score = 2.4 [1.3] for CP [n=104]). Discontinuation of a treatment was reported by 11 patients and 115 CP, most commonly due to a side effect (27% of patients, 31% of CP), doctor’s recommendation (27% of patients, 14% of CP), or lack of symptom improvement (9% of patients, 28% of CP). Participants ranked the ability to distinguish what is real vs not real (35% of patients, 49% of CP) and overall symptom improvement (42% of patients, 23% of CP) as the most important benefits of an ideal treatment (Figures 1 and 2).ConclusionsPatients and CPs reported either not taking any DRP treatments or that current treatments were associated with side effects along with limited efficacy. There is an unmet need for safe and effective treatments for DRP.
Cytoplasmic expression of TDP‐43 decreases global translation both in vitro and in vivo
Authors: Charif Santiago Elias , Luchelli Luciana , Vila Antonela , Blaustein Matías , Igaz Lionel Muller 
Published: December 2020

AbstractBackgroundTDP‐43 is a major component of cytoplasmic inclusions observed in neurodegenerative diseases like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To further understand the role of this predominantly nuclear RNA‐binding protein in disease‐related mRNA/protein metabolism and proteostasis, we used a combined approach with cellular and animal models that overexpress a cytoplasmic form of human TDP‐43 (TDP‐43‐ΔNLS), recapitulating ALS/FTD features.MethodHEK293 cells were transfected with empty vector or hTDP‐43‐ΔNLS followed by a method for labeling de novo translation, surface sensing of translation (SUnSET), based on puromycin (PURO) incorporation. We also assessed whether cytoplasmic TDP‐43 regulates global translation in vivo using a transgenic TDP‐43‐ΔNLS mouse model. Brain cortices from control and transgenic mice were subjected to polysome profiling and western blotting. Lastly, cellular level analysis of ongoing protein synthesis was performed by applying the SUnSET method in acute thick brain slices from control and TDP‐43‐ΔNLS mice. Immunofluorescence for TDP‐43 and PURO was performed and signal intensity was measured.ResultOur in vitro approach showed that, while control cells displayed robust puromycilation, TDP‐43‐ΔNLS positive cells exhibited reduced ongoing protein synthesis when compared to control groups. In vivo results from polysome profiling revealed a shift towards light (non‐polysomal) fractions as compared to wild‐type littermates, indicating a decrease in global mRNA translation. Cellular level analysis of ongoing protein synthesis showed that slices from control mice incubated with PURO exhibited robust cytoplasmic PURO signal in layer 5 neurons from motor cortex, and normal nuclear TDP‐43 levels similar to control (‐PURO) neurons. Slices from TDP‐43‐ΔNLS mice incubated with PURO exhibited high cytoplasmic expression of TDP‐43 and a reduction in puromycilation respect to control mice. Quantification of neuronal staining intensity revealed a significant decrease in PURO incorporation in transgenic vs. control mice.Conclusion
In vitro and in vivo results indicate that cytoplasmic TDP‐43 can decrease global translation and potentially cause functional/cytotoxic effects as observed in ALS/FTD. We provide in vivo evidence (by two independent and complementary methods) for a role of mislocalized TDP‐43 in the regulation of global protein synthesis, with implications for understanding the molecular changes underlying the clinic‐pathological manifestations of TDP‐43 proteinopathies.
Employing an in vitro biosensor assay to investigate tau seeding kinetics within cases of sporadic Alzheimer disease and in a model of tauopathy
Authors: Kamath Tarun V , Commins Caitlin , Klickstein Naomi , Oakley Derek , Hyman Bradley T , Dujardin Simon 
Published: December 2020

AbstractBackgroundTauopathies such as Alzheimer’s disease (AD) are characterized by tau aggregation in the brain (Kovacs, 2015). Recent studies have suggested that tau aggregation occurs via the trans‐synaptic spread of certain tau species and subsequent aggregation via contact between these seeds and non‐aggregated tau (Mudher et al., 2017). Tau seeds can be isolated from many sources, including the brains of humans with tauopathies and tau‐transgenic mice (Clavaguera et al., 2009; Holmes et al., 2014; Iba et al., 2013; Kaufman et al., 2016). Here, we aimed to understand if the kinetics of tau seeding could inform us on the properties of initial seeds.MethodBrain extracts containing tau seeds from 32 patients with sporadic AD and the rTg4510 mouse model of tauopathy were incubated with a well‐described FRET‐biosensor tau seeding assay. The cells were imaged for 48 hours and analyzed for aggregate count and morphology.ResultAggregate formation followed a logistic function over time, with a lag phase, exponential rise phase, and plateau phase. We investigated the properties of these phases by increasing the concentration of tau seeds added to the assay, which led to a parallel increase in the magnitude of the plateau phase and slope of the exponential rise phase, until a ceiling. Across cases of sporadic AD, the length of the lag phase was inversely correlated with the magnitude of the plateau phase. Finally, when initiating aggregation using tau seeds from the rTg4510 mouse, aggregation was several fold higher in the plateau phase than any case of sporadic AD, with significantly altered aggregate morphology which was not observed across the human AD aggregates.ConclusionThe definition of a strain of tau has long been dominated by structural variation – aggregates with different morphologies are thought to be of different strains (Sanders et al., 2014; Kaufman et al., 2016). We present here an alternative method of classifying aggregates based not just on morphology but on aggregation kinetics which we believe reflect biochemical and biophysical properties. This analysis reveals that contrary to previous reports, within cases of sporadic Alzheimer’s disease, there may exist multiple strains of tau leading to variations in aggregate formation kinetics.
Association of APOE genotype and lipid lowering with cognitive function in a randomized placebo‐controlled trial of Evolocumab
Authors: Korthauer Laura E , Giugliano Robert , Guo Jianping , Sabatine Marc , Sever Peter , Keech Anthony , Pedersen Terje , Kurtz Christopher , Ruff Christian , Mach Francois , Ott Brian R 
Published: December 2020

AbstractBackgroundAPOE encodes a cholesterol transporter, and the ε4 allele is associated with higher cholesterol levels, ß‐amyloid burden, and risk of Alzheimer’s disease (AD). A recent pooled re‐analysis of clinical trials (Geifman et al., 2017) found that long‐term use of cholesterol‐lowering medications may lower rates of cognitive decline in patients with mild to moderate AD, with potentially greater therapeutic efficacy for ε4/ε4 carriers. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. The purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab, LDL cholesterol level, and cognitive function.MethodOf 16,174 APOE‐genotyped patients (25.8% with one ε4 allele; 2.3% with two ε4 alleles) from FOURIER, a randomized, placebo‐controlled trial of evolocumab added to statin therapy, 13,481 completed the Everyday Cognition Scale (ECog) to report subjective cognitive changes from the end of the trial compared to its beginning (scores ≥2 reflect subjective decline). A subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial.ResultThere was a dose‐dependent relationship between APOE ε4 genotype and subjective memory decline on the ECog in the placebo arm (p = .009; ε4/ε4 carriers vs. non‐carriers: OR = 1.38, 95% CI [.98,1.95]) but not the evolocumab arm (p = .77, OR = 1.14, 95% CI [.81,1.60]). However, the genotype x treatment interactions were not significant, likely due to a limited number of ε4/ε4 carriers. After adjustment for demographic and medical covariates, APOE genotype did not significantly moderate the relationships between treatment arm or post‐baseline LDL cholesterol level on CANTAB performance (p’s>.05) in the subset examined.ConclusionAPOE genotype did not significantly moderate the relationship between evolocumab treatment and cognitive function, although analyses were limited by the low population frequency of the ε4/ε4 genotype. This supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol‐lowering medications in people at genetic risk for Alzheimer’s disease.
Engaging rural older minority adults in dementia research during a pandemic‐associated quarantine
Authors: Wiese Lisa Kirk , Lingler Jennifer , Williams Ishan Canty , Schoenberg Nancy E , Galvin James E 
Published: December 2020

AbstractBackgroundRural‐dwelling individuals are at heightened risk for dementia syndromes as they age. Recognizing that faith institutions are bulwarks in rural communities, we partnered with churches to design research that aims to improve knowledge of, and promote screening for, dementia. Since recruitment began just as COVID‐19 emerged, in‐person recruitment ceased. We developed a virtual protocol to train health educators and engage rural, racially diverse congregants.MethodGuided by Schoenberg’s (2011) “Faith Moves Mountains” model, health educators were trained via videoconferencing, using Alzheimer’s Association online English/Spanish resources. Educators approached 35 congregants to administer telephone‐based teaching, pre‐post tests of dementia knowledge, and dementia screening.ResultsThirty rural older adults responded to faith health educator tele‐recruitment and intervention. Pre‐post knowledge surveys showed significant improvement (r=.67, p=.04). Thirteen (43%) completed dementia screening, followed by referral to a memory telehealth clinic.ConclusionThis faith‐based model shows promise for reaching isolated rural residents facing dementia risk.
Fluid biomarkers of Alzheimer’s disease in the Systolic Blood Pressure Intervention Trial
Authors: Pajewski Nicholas M , Elahi Fanny M , Ix Joachim H , Nasrallah Ilya M , Reboussin David M , Tamura Manjula Kurella , Wright Clinton B , Hinman Jason , Miller Lindsay M , Sudduth Tiffany L , Wilcock Donna M , Williamson Jeff D 
Published: December 2020

AbstractBackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive treatment (systolic blood pressure (SBP) target <120 mm Hg) reduces the risk for mild cognitive impairment and slows the progression of white matter lesions detected via magnetic resonance imaging (MRI) as compared to standard treatment (SBP<140 mm Hg). However, it is unclear what pathway(s) mediate this effect.MethodWe measured plasma beta‐amyloid 40 (Aβ40), beta‐amyloid 42 (Aβ42), total tau, and neurofilament light (NfL) at baseline and during follow‐up (median follow‐up = 3.8 years) in a subgroup of participants 60 years or older that also participated in SPRINT’s MRI imaging substudy (N=542). We modeled changes in each AD biomarker using robust linear mixed models.ResultThe average baseline age of this subgroup of SPRINT participants was 69.8 ± 7.1 (standard deviation) years; with a mean SBP of 138.2 ± 17.0 mm Hg; and 42.1% were female. At baseline, the strongest plasma biomarker correlations were with age (Spearman’s rho = 0.27 for Aβ40 and 0.43 for NfL, both P<0.001) and estimated Glomerular Filtration Rate (eGFR; rho ranged from –0.21 for Aβ42 to ‐0.42 for NfL, all P<0.001). We observed larger increases in each AD biomarker for participants that experienced ≥30% decline in eGFR during follow‐up, which occurs more frequently with intensive treatment. There were no significant between‐group differences for Aβ40, Aβ42, or total tau, however intensive treatment was associated with larger increases in NfL during follow‐up (mean change per year (MCPY) = 2.6 pg/ml, 95% CI: 1.8‐3.3), as compared to standard treatment (MCPY = 1.6 pg/ml; 95% CI: 1.3‐1.8). This difference was explained by changes in eGFR (between‐group difference in MCPY adjusting for eGFR = 0.04 pg/ml; 95% CI: ‐0.76 ‐ 0.84).ConclusionIn this pilot study of SPRINT participants, after accounting for kidney function, intensive treatment was not associated with significant changes in fluid biomarkers of AD. Our results highlight the need for future studies of blood‐based AD biomarkers to account for renal function, especially within the context of hypertension and vascular disease.
The role of ABI3 in human induced pluripotent stem cell‐derived microglia
Authors: Rolova Taisia , Zhang Fuping , Koskuvi Marja , Koistinaho Jari 
Published: December 2020

AbstractBackgroundMicroglia are the main immune cells of the central nervous system clearing invaded pathogens, damaged cells and toxic aggregates, thus maintaining tissue homeostasis. However, in Alzheimer’s disease (AD), microglia do not perform their job that well anymore. Recent genome‐wide association studies (GWAS) have strongly implicated microglia in AD pathogenesis. One of the genetic variants recently identified is rs616338/p.S209F in ABI3 gene (OR 1.43), which is stronger expressed in microglia than other types of brain cells. ABI3 (ABI family member 3) is a structural component of WAVE2 complex known to regulate formation of lamellipodia, membrane ruffling and phagocytosis. However, the role of ABI3 and its functional difference from a similar protein ABI1 in microglia is not clear.MethodWe have used CRISPR/Cas9 technique to generate a knockout iPS line (ABI3 KO) producing truncated protein that lacks Src‐homology 3 domain crucial for the regulation of actin remodeling. We have further differentiated ABI3 KO line and the original isogenic control line (WT) into microglia according to the previously published protocol of McQuade et al (2018).ResultWe have found that ABI3 KO microglia exhibited significantly lower uptake of zymosan‐conjugated pHrodo beads, lower expression level of scavenger receptor MSR1 and higher expression level of glucose transporter SLC2A1 as compared to the WT control. ABI3 KO cells were also significantly less responsive to ADP in Transwell migration assay although the mRNA expression of P2RY12 receptor was higher in the KO cells. The protein level of WAVE2 was similar but the level of ABI1 was strongly increased in ABI3 KO cells suggesting a compensatory effect. ABI3 deficiency did not significantly affect secretion of Aβ42, phosphorylation of TAU at Ser214 and phosphorylation of APP at Thr668 in co‐culture with human iPS‐derived neurons harboring Swedish mutation in APP.ConclusionIn conclusion, ABI3 deficiency in microglia significantly impaired phagocytosis and ADP‐induced migration but did not have an effect on AD‐like pathology in co‐culture with diseased iPS‐derived neurons.
Quality of life of informal caregivers for elderly people with dementia: A comparative study
Authors: Laranjeira Carlos 
Published: December 2020

AbstractBackgroundThe provision of informal care to the elderly with dementia, presenting a complex, demanding nature and with evident repercussions, affects the health, Well‐being and Quality of Life of the informal caregiver (CG). Thus, the main aim of this study was to assess the Quality of Life and Subjective Well‐being of informal caregivers of demented (non‐institutionalized) elderly, through two contrasting groups: Group A, of CG of elderly with little dependence diagnosed with mild dementia; and Group B, of CG of elderly dependents diagnosed with severe dementia.MethodThis was a quantitative, cross‐sectional and comparative study design. The initial sample consisted of 65 informal caregivers of the elderly with a confirmed diagnosis of dementia. Information was collected regarding demographic characteristics and diagnosis; the functional capacity of the elderly in activities of daily living (Barthel Index); the global cognitive judgments of satisfaction with one's life (SWLS); and finally, the levels of Quality of Life (WHOQOL‐BREF).Result69% of the participants are female, aged between 53 and 89 years old (M=66.5; SD=9.4), being mostly elderly (59.7%) and with low levels of education. Male CG have a slightly more positive perception of the general facet of Quality of Life and the environment domain, compared to the female CG. The results obtained indicate that informal caregivers belonging to Group A have a more positive perception of Quality of Life and Subjective Well‐Being, compared to informal caregivers who constitute Group B, in all domains.ConclusionThe profile of informal caregivers who make up the samples of the two groups under analysis is similar to that reported by studies researched in the existing literature. It should be noted that the multidisciplinary intervention model is basic, involving several health professionals who direct action plans according to the specific needs of demented elderly and their CG, covering all levels of care and biopsychosocial needs.