bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of multimodal non‐pharmacologic interventions on cognitive function for people with dementia: Systematic review
Authors: Sharew Nigussie Tadesse , LAM Simon Ching , Habtewold Tesfa Dejenie , Leung Angela Yee Man 
Published: December 2021

AbstractIntroductionDementia is a progressive brain degeneration characterized by a progressive deterioration in cognition and independent living capacity (Sobral, Pestana, & Paúl, 2015). Fifty million people are living with dementia globally. This number will be projected to grow to 82 million by 2030 and 152 million by 2050 (Alzheimer's Disease International, 2020. Since dementia is complex syndrome, multimodal non‐pharmacologic interventions (MNPIs) are highly recommended (Dannhauser et al., 2014; Graessel et al., 2011; Han et al., 2017; Yang et al., 2019). Currently, there is little available evidence to determine which multimodal interventions are effective for cognitive function improvement.MethodA comprehensive search was done in PubMed, EMBASE, CINHAL, Web of Science and Medline international databases. The inclusion criteria of this review were; concerned adults with primary diagnosis of dementia, measured cognitive function outcome, used two or more type of interventions, published in English language and employed controlled trial study design. The quality appraisal of the studies was done by Cochrane risk of bias assessment tools for randomized controlled trail and non‐randomized controlled trial studies (Sterne et al., 2016; Sterne et al., 2016).ResultsFourteen RCTs and five non‐RCT studies were included in the systematic review. Nearly ninety percent of studies resulted in an improvement or maintenance of cognitive function among people with dementia. Integrated, multicomponent and dyadic based interventions implemented for longer duration resulted in improve cognitive function of people with dementia. The combination of three modes of non‐pharmacologic intervention that includes exercise, music, and cognitive training with intervention design of more than three sessions per week for at least 12 ‐ 48 weeks is recommended.ConclusionThis study showed that multimodal non‐pharmacologic interventions might improve cognitive functions among people with dementia. Future high quality randomized controlled trail studies with repeated‐measured design on the combined effect of physical exercise, music and cognitive training on cognitive function for people with dementia is recommended.
Improved functional connectivity after a 6‐month ketogenic supplementation in mild cognitive impairment
Authors: Roy Maggie , Edde Manon , Fortier Melanie , Croteau Etienne , Castellano Christian‐Alexandre , St. Pierre Valerie , Vandenberghe Camille , Morin Marie‐Christine , Langlois Francis , Bocti Christian , Fulop Tamas , Descoteaux Maxime , Cunnane Stephen 
Published: December 2021

AbstractBackgroundKetones, the brain’s alternative fuel to glucose, bypass the brain glucose deficit in mild cognitive impairment (MCI). The BENEFIC trial conducted in MCI showed improved measures of cognition in multiple domains after a 6‐month ketogenic intervention [Fortier et al. 2019]. Functional connectivity in the dorsal‐attention network (DAN) deteriorates early in MCI, and prior to changes in the ventral‐attention network [Zhang et al. 2015]. We aimed to assess whether improved cognitive outcomes in the BENEFIC Trial were linked to improved brain functional connectivity.MethodParticipants in this 6‐month intervention were randomized to a placebo (n= 15) or ketogenic medium chain triglyceride (kMCT; n= 17) drink. A neurocognitive battery and brain imaging were performed pre‐ and post‐intervention. Functional connectivity was computed from resting‐state functional magnetic resonance images. Independent component analysis (FSL Melodic) was used to segment seven major resting‐state networks (DAN, ventral‐attention, frontoparietal, limbic, somatomotor, default‐mode and visual) [Yeo et al. 2011]. Regional cortical ketone (11C‐acetoacetate) and glucose (18F‐fluorodeoxyglucose) metabolic rates were also quantified using positron emission tomography (PET).ResultChanges (post ‐ pre) in DAN functional connectivity was significantly higher in the kMCT group vs placebo (P= 0.024). After correction for age, sex, education, ApoE status and intracranial volume, the significant difference between groups was still present, with a large effect size (partial h2= 0.16; P= 0.043; Figure 1). Connectivity in no other networks was significantly different between groups. Changes in attention and processing speed composite Z‐score (r= 0.42; P= 0.021) and specific tests targeting attention (Trail Making visual scanning and number sequencing conditions) were significantly associated with the increased DAN functional connectivity. Change in ketone uptake specifically in DAN cortical regions (Figure 2C) was significantly higher in the kMCT vs placebo group (P= 0.001) and was directly associated with the improved DAN functional connectivity, with a large effect size (r= 0.69; P= 0.002; Figure 3).ConclusionWe show that a 6‐month ketogenic intervention improves DAN functional connectivity in MCI, an improvement that is directly linked to increased energy (ketone) supply to the DAN. The beneficial effect of ketones on cognition in MCI may be linked to improved DAN connectivity.
E2F4DN‐based gene therapy recovers long‐term potentiation and hippocampal‐dependent memory in homozygous 5xFAD mice
Authors: Sánchez‐Puelles Cristina , Perea Gertrudis , Frade Jose María 
Published: December 2021

AbstractBackgroundNeuronal cell‐cycle reentry, followed by DNA duplication (tetraploidization), precedes and recapitulates Alzheimer´s disease (AD) neuropathological hallmarks (Arendt et al., 2010; López‐Sánchez et al., 2017). E2F4 is expressed by neurons and becomes phosphorylated in APP/PS1 mice and in Alzheimer patients. We have demonstrated that the phosphorylation of two conserved Thr residues of E2F4 is necessary to induce neuronal tetraploidization and cognitive loss in AD (Lopez‐Sanchez and Frade, 2017; López‐Sánchez et al., 2017). Thus, it was developed a therapy consisting in neuronal expression of a dominant negative form of E2F4 (E2F4DN), not phosphorylatable. This therapy has been patented (US9567384B2, EP2783696B1, JP6100276B2), and is licensed by Tetraneuron. Initial stages of AD are proposed to be linked to alterations in synapse function, responsible for the cognitive deficits observed in AD (Knafo et al., 2016). Thus, we hypothesized that viral expression of E2F4DN could correct the synaptic dysfunction associated to AD.MethodHippocampal primary cultures were prepared and neurons were transduced with a viral vector containing E2F4DN. Through whole‐cell recordings spontaneous synaptic activity (sEPSC) was analyzed (control n=15, E2F4DN n=21). Afterwards E2F4DN was expressed in vivo (AAV‐E2F4DN intravenous administration) in six‐week old homozygous 5xFAD and WT mice and behavior and electrophysiology was achieved (6‐months‐old). Cognition was analyzed in not injected (n=7) and injected WT (n=5) and not injected (n=19) and injected 5xFAD (n=5) mice through novel‐object location and contextual fear conditioning test. Synaptic function was evaluated by electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in CA3‐CA1 synapses in acute slices from WT (not injected n=10, injected n=7) and 5xFAD mice (not injected n=11, injected n=8), both basal transmission and LTP (3xTBS) was examined.ResultWe demonstrated that E2F4DN does not alter basal properties of hippocampal neurons in culture. Intravenous administration of AAV‐E2F4DN improves basal synaptic transmission and reverts LTP inhibition, observed in not injected 5xFAD mice. Furthermore, this LTP recovery leads to cognitive improvement. 5xFAD mice treated with our therapy present a notably improvement in two hippocampal‐dependent memory tasks compared to not injected 5xFAD mice.ConclusionE2F4DN‐based gene therapy represents a promising approach for AD treatment with capacity to prevent cognitive decline associated to the disease.
The use of the Cognitive Change Questionnaire by community health workers as dementia screening method
Authors: Feitosa Raul Raposo Pereira , Frota Norberto Anizio Ferreira , Maia Fernanda Martins , Feitosa Esther De Alencar Araripe Falcao 
Published: December 2021

AbstractBackgroundThe Cognitive Change Questionnaire (CCQ) was a tool developed in Brazil to evaluate cognitive changes (1). This work evaluates the applicability of the CCQ by Community Health Workers (CHW), as a way of screening for dementias.MethodThis study is being carried out in a small city in the state of Ceara, Brazil. Community health workers received training on what is dementia and how to apply the CCQ. The CHW is applying the CCQ to all individuals in the municipality, aged 60 or over, approximately 2,273 individuals, and 500 individuals have been evaluated so far. After the application of the test, all individuals considered altered will be evaluated by physicians specialized in cognitive neurology. Part of the negatively screened patients will also be chosen, at random, for evaluation by specialist doctors.ResultThe main result to be measured will be the sensitivity values of the test as a way to screen elderly patients with dementia. As a secondary data, the prevalence of dementia will also be obtained.ConclusionIt is expected that the application of the QCC by CWH will be an excellent screening tool for dementias and, therefore, improve the identification and care of these patients. 1. Damin AE, Nitrini R, Brucki SMD. Cognitive Change Questionnaire as a method for cognitive impairment screening. Dement Neuropsychol. 2015;9(3):237–44.
Relationship between platelet derived growth factor receptor‐β and Alzheimer’s biomarkers in a racially diverse, high‐risk cohort
Authors: Butts Brittany , Miners Scott , Kehoe Patrick G. , Hu William T. , Huang Hanfeng , Verble Danielle D. , Zetterberg Henrik , Zhao Liping , Wharton Whitney 
Published: December 2021

AbstractBackgroundWith the increasing prevalence of Alzheimer’s disease (AD), there is an increased need for systematic research targeting preclinical pathophysiologic mechanisms of AD development for high‐risk, racially diverse, populations. Neurovascular dysfunction and blood brain barrier (BBB) breakdown likely occur early in AD pathology, however their relationship to AD biomarkers in preclinical populations are not well known. Soluble platelet derived growth factor receptor‐β (sPDGFRβ), a novel CSF biomarker of BBB‐associated capillary pericyte damage, is shed from injured human pericytes and is associated with AD pathology. Here we tested the hypothesis that sPDGFRβ is related to CSF AD biomarkers and CSF markers of vascular dysfunction in a cohort of Black/African American (B/AA) and non‐Hispanic White (NHW) participants.MethodCognitively unimpaired, middle‐aged (45‐65 years) adults with a parental history of AD were enrolled. CSF was collected at baseline and 2 years for measurement of sPDGFRβ, AD biomarkers (Aβ and tau), and markers of vascular dysfunction (ACE activity, and VCAM‐1).ResultParticipants (N=70) were mostly female (69%), well educated (81% college or greater), and 34% identified as B/AA. Forty‐eight percent were ApoEε4 positive. At both baseline and 2 years sPDGFRβ was positively correlated with P‐tau (r=.380, p=.003; r=.356, p=.008), T‐tau (r=.466, p<.001; r=.485, p<.001), Aβ40 (r=.439, p=.001; r=.454, p=.001), ACE‐1 activity (r=.363, p=.003; r=.272, p=.041), and VCAM‐1 (r=.511, p<.011; r‐=.401, p=.002) and negatively correlated with Aβ42/40 (r=‐.282, p=.024; r=‐.399, p=.002), controlling for age, sex, race, and education. At both time points, AAs had lower sPDGFRβ, P‐tau, T‐tau, and Aβ40 and higher Aβ42/40 compared to NHWs.ConclusionsPDGFRβ was associated with tau hyperphosphorylation (P‐tau) and neurodegeneration (T‐tau) in a cohort of cognitively unimpaired middle‐aged adults at risk for AD. Pericyte loss may relate to disease pathology early in AD development in at‐risk individuals, providing a potential mechanistic target for early intervention and prevention strategies. sPDGFRβ was associated with ACE‐1 and VCAM‐1, suggesting a potential role for endothelial activation in early BBB breakdown. As we found differences in AD biomarkers by between AA and NHW participants, reference ranges for these biomarkers may vary by race. More research is needed examining pre‐clinical disease pathways in diverse populations.
Developing interdisciplinary participatory practices to disrupt the status quo in dementia research
Authors: Sood Garima , Gawryluk Jodie , Couture Daisy , Raber Caylee , Puurveen Gloria 
Published: December 2021

AbstractBackgroundIn dementia research, there is a growing emphasis on generating meaningful research collaborations with people with lived experiences (PWLE). This brings attention to different participatory methods that have the ability to shift perspectives in research and deepen engagement with both PWLE and researchers. However, how participatory methods are realized in practice across the research process requires further investigation; as such, the purpose of this study was to:1) Explore existing interdisciplinary practices, tools and strategies that promote partnership with PWLE to amplify lived experiences and foster inclusivity; and2) Identify gaps and opportunity spaces to further develop person‐centred and collaborative research tools and practices.MethodThe Alzheimer Society of B.C., Emily Carr University’s Health Design Lab and researchers from the University of Victoria and the University of British Columbia partnered at the 2021 Dementia Lab conference to conduct two virtual participatory workshops. The workshops gathered 38 participants including researchers, interdisciplinary creatives, designers and PWLE. Participants were invited to share their experiences in dementia research and their vision of how to foster best‐practices. Design methods such as envisioning, imagining, visualizing and drawing were adopted to facilitate dialogue and bring out tacit knowledge held by participants.ResultsInductive analysis of workshop data revealed that interdisciplinary practices are adopted in different dementia‐related projects to foster collaboration with PWLE, which contributes to levelling out epistemological hierarchies. The following four overlapping themes emerged from the analysis: 1) Relationships of reciprocity: Translating research findings into community support and ensuring participants are invited to participate in knowledge making and sharing. 2) Pace: Developing research strategies, objectives and methods that allow for a slower pace to afford generative and person‐centred outcomes. 3) Power dynamics: Shifting hierarchical power relations in research activities. 4) Generative and continuous practices: Embedding continuity of knowledge and ongoing relationships into research projects to ensure that acquired knowledge can be continually nourished, adopted and updated.ConclusionBy centring perspectives of people with lived experiences of dementia and fostering interdisciplinary collaborations, generative and person‐centred research practices can propel a shift in the status quo of dementia research, while empowering people living with dementia.
Combination of baicalein and trans‐chalcone synergistically reduces amyloid beta and its toxicity in yeast
Authors: Dhakal Sudip , Macreadie Ian George , Adhikari Benu , Ramsland Paul 
Published: December 2021

AbstractBackgroundThere has been a long quest to uncover effective therapeutic strategy to prevent or cure AD as current strategies only support as palliative care. This study utilizes unmodified and genetically modified Saccharomyces cerevisiae as model organisms to screen and find potential natural bioactive compounds that can reduce the levels of amyloid beta and associated toxicity.MethodsEleven selected naturally occurring bioactive compounds namely mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans‐chalcone at specific concentration (50µM) were screened for their ability to change intracellular green fluorescent protein (GFP) tagged Aβ42 levels, in vivo anti‐amyloid properties using thioflavin‐S fluorescent dye and induce heat stress response using the yeast heat stress reporter that expresses mCherry red fluorescent protein under control of a heat shock promoter containing heat shock elements (HSEs). Furthermore, the two compounds with highest activity in all three screens were combined together in varying concentrations of each to study the underlying combination ability to reduce GFP‐Aβ42, their effect on growth, turnover of native Aβ42 and reactive oxygen species.ResultsThe bioactive compounds reduced intracellular GFP‐Aβ42 levels (except mangiferin) and intracellular amyloid fibrils (except resveratrol and EGCG) in yeast models significantly with highest effect shown by baicalein and trans‐chalcone. Among the bioactive compounds, quercetin, rutin, rosmarinic acid, baicalein and trans‐chalcone significantly induced heat stress reporter with highest effect demonstrated by baicalein and trans‐chalcone. Furthermore, the combinations of baicalein and trans‐chalcone showed synergistic ability to reduce GFP‐Aβ42. Although some of the combinations were found growth inhibitory, a combination of 50μM trans‐chalcone and 30μM baicalein was found to be cytoprotective as well as an effective reducer of GFP‐Aβ42. In addition, the combination of the two compounds showed synergy in reducing ROS in yeast cells expressing native Aβ42 and reduced the Aβ42 protein levels by nearly 80%.ConclusionThe findings of the study suggest that the combination of baicalein and trans‐chalcone can be a therapeutic strategy to cure or at least prevent AD. However, further studies are recommended to ascertain that similar cytoprotective activity is observed in humans and optimization of dosage to observe best effect.
Proteomic analysis of Parkinson’s disease patient cohorts show similarities in mechanism to Alzheimer’s disease
Authors: Winchester Laura M. , Lawton Michael , Barber Imelda S. , Evetts Samuel , Ryan Brent , Wade‐Martins Richard , Ben‐Shlomo Yoav , Hu Michele , Grosset Donald G. , Nevado‐Holgado Alejo J. , Lovestone Simon 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease and Parkinson’s Disease (PD) share similarities in phenotype and an overlap between disease subtypes and diagnostic testing which implies a link between some of the neurodegenerative processes.Here, we report the initial results for proteomic assays on two longitudinal PD cohorts demonstrating dementia‐like protein dysregulation signatures as well as PD specific signatures in the largest proteomics collection of PD patients to date.MethodWe used aptamer‐based technology (SOMAmer assay, SomaLogic®) to measure 4003 proteins in 1599 serum samples collected from two observational longitudinal cohorts: Oxford Parkinson’s Disease Centre Discovery cohort (OPDC) and the UK Tracking Parkinson’s cohort. Clinical measures of disease progression included the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part III (UPDRS) and Montreal Cognitive Assessment (MoCA) adjusted for education years. The sample set included 319 controls.We performed dysregulation analysis on log2 transformed data using linear models corrected for age, gender, and cohort. Enrichment analysis was implemented in the R library clusterProfiler using the KEGG and GO databases. Comprehensive co‐expression analysis was performed using WGCNA.ResultInitial pathway analysis showed that the main significantly dysregulated protein pathways of case status were the Complement and coagulation cascades (p = 0.0086) and Protein digestion and absorption (p =0.0152). The Fat digestion and protein absorption pathway was enriched for dysregulated proteins associated to the UPDRS measure (p = 0.00142). Using co‐expression analysis we identified a module of 625 proteins with a significant relationship to disease status (p = 3.20x10‐07) and the movement (p = 2.35 x10‐05) and cognition (p = 0.005) endophenotypes. This module was enriched for proteins involved in axon guidance in addition to the complement and coagulation cascades and protein digestion and absorption found in initial analyses.ConclusionUsing a comprehensive profiling analysis of protein expression in two unique longitudinal PD cohorts we demonstrate the overlap between neurodegenerative disease types as well as highlight unique PD associations with potential mechanistic links to gut processes. This will have implications for further analysis of these PD cohorts for further mechanistic analysis and more importantly biomarker detection.
Single and multiple ascending dose studies in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme
Authors: Lowe Stephen L , Goldsmith Paul , Phipps Krista M , Kevin Donnelly B , Biglan Kevin , Mancini Michele , Nuthall Hugh Norman , Mergott Dustin J. , Kielbasa William 
Published: December 2021

AbstractBackgroundLY3372689, an OGA enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report the safety and pharmacokinetics (PK) of LY3372689 after single and multiple oral doses in healthy volunteers (HV).MethodThe single ascending dose (SAD) and multiple ascending dose (MAD) studies were single center, subject‐ and investigator‐blind, placebo‐controlled and randomized. In the SAD study [NCT03819270], 6 LY3372689 dose levels up to 16 mg and placebo were evaluated. In the MAD study [NCT04106206], LY3372689 (1, 3 and 7 mg) or placebo was given once daily (QD) for 14 days. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma pharmacokinetics (PK) was assessed in the SAD and MAD studies.ResultIn the SAD, 23 HV (15 males, 8 females; 22 – 63 years) participated, of which 18 HV completed. In the MAD, 40 HV (5 males, 35 females; 29 – 65 years) participated in the study, of which 39 HV completed. LY3372689 was generally well tolerated up to the highest dose in each study, and no serious AE were reported. In the SAD, 40 treatment‐emergent AEs (TEAEs) were reported, which were mostly mild in severity. The most common TEAEs were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. In the MAD, 42 TEAEs were reported, all of which were mild in severity. The most reported TEAE was headache. In both studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. Following QD dosing of LY3372689, the tmax and t1/2 was about 1 hour and 6 hours, respectively, and LY3372689 exposure accumulation was minimal. Renal clearance was not a major contributor of LY3372689 elimination.ConclusionLY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials.