bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results and drug development summary for Xanamem, a potent inhibitor of the 11β‐HSD1 enzyme
Authors: Ritchie Craig W. , Miller Tamara , Ketelbey John W. 
Published: December 2020

AbstractBackgroundXanamem™ is a potent and selective 11β‐HSD1 inhibitor. 11β‐HSD1 amplifies cortisol in brain regions, including the hippocampus. There is abundant evidence from animal and clinical studies linking elevated cortisol with hippocampal dysfunction, leading to poor learning, recall, and objective memory impairment. Thus, interventions that reduce cortisol levels may improve cognition and have long‐term benefits in reducing the risk of glucocorticoid toxicity and thereby reducing the risk of development and/or progression of dementia; Xanamem™ also has potential to treat additional indications beyond AD.MethodThe development strategy for Xanamem™ will be outlined including all pre‐clinical and clinical studies. Additionally, many independent studies have concluded that higher plasma cortisol is significantly related to lower hippocampal and gray matter volume, and that chronically elevated cortisol could exacerbate pathological processes associated with the onset and progression of AD.ResultThe development of Xanamem™ will be discussed, inclusive of: Pre‐clinical Studies; Phase II XanADu Study; Phase I XanaHES Study ‐including statistically significant results achieved in the Cogstate NTB in XanaHES; Target Occupancy program ‐ including new data on human and in vitro binding studies; Quantitative Systems Pharmacology (QSP) Modelling Outcomes ‐ including new data on QSP and PBPK models; and Complementary research endorsing the cortisol hypothesis.ConclusionXanamem™ provides a mode of action wherein it inhibits cortisol production; the results achieved to date further endorses this scientifically robust target for both symptomatic treatment and disease course modification in AD and potentially non‐AD dementias and other neurodegenerative disorders.
Effect of increased physical activity on cognitive function in individuals with mild cognitive impairment: A pilot study
Authors: Nickerson Gasong Yun , Shade Kate 
Published: December 2020

AbstractBackgroundStudies suggest physical activity reduces risk of dementia and aerobic exercise improves global cognitive function in people with Mild Cognitive Impairment (MCI). Commercial wearable activity trackers tested in neurological studies have shown excellent reliability with older adults and are valid measures of daily step count. The primary objective of this pilot study was to determine if increased physical activity improved cognitive function in individuals with MCI. The secondary objective was to evaluate the feasibility of the use of an activity tracker with individuals with MCI.MethodThis pilot was a one‐group pretest‐posttest study and included 16 community‐dwelling older adults diagnosed with MCI who met inclusion and exclusion criteria. Participants were patients of the memory clinic in Sacramento, CA during 2018‐2019. One wrist wearable activity tracker was issued to each participant, along with a free downloadable software application to pair the tracker with a device. Daily step count was measured by an activity tracker. Change in cognitive function was measured with a pretest and posttest using the Montreal Cognitive Assessment (MoCA). Timed Up and Go (TUG) assessed risk for fall as an exclusion criteria and to measure any change in physical fitness. Participants were encouraged to increase their physical activity for 12 weeks. The primary investigator contacted the participants every 2 weeks to check their progress.ResultIncreased step count was positively correlated with an improvement in cognitive function (p‐value of 0.04) with a moderate effect size (r = 0.55). The group of participants showing MoCA score improvement had a higher average daily step count than those that did not show score improvement at a confidence level of 90% (p‐value of 0.09).Conclusion5,500 steps or more per day is recommended to help improve cognitive function in individuals with MCI. It is feasible for individuals with MCI to wear an activity tracker reliably. The results of this pilot suggest the need for a randomized controlled trial with a larger sample. Further study is also recommended to identify covariates, such as activity intensity or history of regular exercise that predict improvement in cognitive function after a 12‐week intervention.
Translation and cultural adaptation of iSupport in Brazil
Authors: Oliveira Deborah , Jacinto Alessandro Ferrari , Gratao Aline Cristina Martins , Ottaviani Ana Carolina , Ferreira Camila Rafael , Monteiro Diana Quirino , Barham Elizabeth Joan , Orlandi Fabiana de Souza , de Cruz Keila Cristianne Trindade , Correa Larissa , Zazzeta Marisa , Pavarini Sofia Cristina Iost 
Published: December 2020

AbstractBackgroundMost people with dementia are living in low‐ and middle‐income countries and are being cared for at home by their families. This task can negatively affect the mental and physical health of carers. However, public health initiatives to support family carers are still scarce. This study aimed to translate and culturally adapt the iSupport programme from World Health Organization for use by carers of people with dementia in Brazil.MethodsThe translation of the programme from English to Brazilian Portuguese was conducted by a professional translator. The translated content was discussed and checked for relevance, clarity and accuracy by a multidisciplinary team of researchers in Brazil. Next, 16 focus groups (n=48) were conducted with family carers of people with dementia and health and social care professionals in Sao Carlos‐SP, Brasilia‐DF and Sao Lourenco‐MG. Discussions were aimed at exploring whether the content of the translated version of iSupport was both clear and relevant to the needs of carers of people with dementia in Brazil. Representatives of the Brazilian Ministry of Health and Alzheimer’s Associations also contributed to this assessment.ResultsOverall, all participants had positive views of the iSupport material. In addition to researchers and translators, carers and professionals helped refine the text to make it clearer and more tuned to the Brazilian context. In general, participants found the material clearly written and culturally relevant. A few changes were suggested with regards to terminology and examples given in the modules to better fit the Brazilian culture and health systems, and links to relevant web pages of the Brazilian Alzheimer Association were included. Although further information could be added, the existing material was seen as sufficient.ConclusionThe translation and cultural adaptation of iSupport included inputs from four categories of participants and showed that the programme was considered easy to understand and culturally relevant for carers of people with dementia in Brazil. The next step will be to pilot the translated and culturally adapted programme with carers in Brazil to establish its efficacy and usability.
Diagnosis of Alzheimer's disease with eye examination
Authors: Lü Yang , Qin Zhang Jin 
Published: December 2020

AbstractBackgroundTo evaluate the retinal changes in patients with Alzheimer's disease(AD) by combining pattern visual evoked potential(PVEP) and optical coherence tomography(OCT) and to study their diagnostic effects on AD.Method31 patients with AD and 37 normal elderly were involved in the study. The patients with AD were diagnosed in the First Affiliated Hospital of Chongqing Medical University between August 1, 2018 and November 30,2019, and the normal elderly were recruited from the local community. PVEP and OCT were performed on all subjects, and then the latency and amplitude of P100 wave in PVEP, the pRNFL thickness of each quadrant in OCT were recorded, and the difference between AD and HC(Health Control) was analyzed to study its diagnostic value for AD.ResultCompared with the HC group, the amplitude of P100 wave in the AD group was significantly lower (p<0.05), and there was no difference in latency of P100 wave (p>0.05);The thickness of pRNFL was significantly thinner in the nasal, superonasal, superotemporal and Inferotemporal quadrant(p<0.05), and there was no difference in the temporal and Inferonasal quadrant(p>0.05). And by ROC curve analysis, it was found that the AUC of a single parameter of either retinal function or structure was lower than the AUC of multiple parameter combinations.ConclusionThe amplitude of P100 wave combined with pRNFL thickness of superonasal and superotemporal has a high diagnostic efficiency for identifying patients with or without AD. This suggests that the combination of PVEP and OCT provides a good clinical biomarker for the diagnosis of AD.
Increased excess short‐ and long‐term mortality following infections in dementia: A prospective nationwide and registry‐based cohort study
Authors: Janbek Janet , Taudorf Lærke , Musaeus Christian Sandøe , Frimodt‐Møller Niels , Laursen Thomas Munk , Waldemar Gunhild 
Published: December 2020

AbstractBackgroundThe role of infections in dementia remains to date insufficiently explored. Studies have reported that pneumonia and sepsis were either an immediate cause of death or increased mortality in people with dementia. However, it is unknown whether association with mortality is long‐term and whether it is dependent on the type of infection. We aimed to investigate the association between several infections and the short‐ and long‐term mortality in people with and without dementia.MethodWe conducted a nationwide registry‐based prospective cohort study using data from Danish national registries. Follow up was from 1 January 2000 or the 65‐year birthday (whichever came later) until death, immigration or 31 December 2015. Primary exposure was incident dementia and a first infection post start of follow‐up. The primary outcome was all‐cause mortality. Mortality rate ratios (MRR) were calculated in all exposure groups (Dementia/Infection; Infection before or after dementia, Dementia/No Infection, No Dementia/Infection and with No Dementia/No Infection as the reference group) and stratified by sex and infection site categories. MRRs were also calculated by time since first infection and by infection site.ResultA total of 1,496,436 people were followed with a total of 12,739,135 person years. A total of 575,260 people died during follow‐up (82,573 with dementia). MRR for the Dementia/Infection group (infection after dementia) was 6.52 (95% CI: 6.43 to 6.61) times higher compared with the reference group and was higher in men. MRRs for the Infection groups in all of the site categories were markedly higher in the Dementia than No Dementia group (highest ratios for sepsis and lowest for ear infections). MRRs were highest the first 30 days after onset of first infection in the Dementia group and remained higher than the No Dementia group until 10 years after first infection (similar trends in the analyzed infection site categories).ConclusionMortality is substantially increased in people with dementia following infections of all sites. Excess mortality is both short‐ (within 30 days) and long‐term (after10 years). Our findings identify people with dementia and infections as a vulnerable group who need clinical attention.
What can lipidomics tell about patho‐mechanisms at the early phases of Alzheimer’s disease?
Authors: Sakr Fatemah A. , Dybra Martin , Gräler Markus , Teipel Stefan J. , Braeuer Anja 
Published: December 2020

AbstractBackground“Precision medicine” is an emerging concept in the field of Alzheimer’s disease research, allowing for individual risk stratification based on the specific biological/molecular signature. Hence, extensive “Omics” studies exploring different biological molecules were run in order to retrieve molecular‐cellular pathways reflecting the full spectrum of the disease. Lipidomics seems to be one promising approach, as it reveals a number of bioactive molecules regulating patho‐physiological mechanisms. In this study, we explored Lipidomics‐derived data to identify relevant predictors of diagnostic sensitivity in the early phases of AD.MethodWe used data provided by ADNI and ran initial exploratory analyses followed by a logistic regression approach with elastic‐net regularization for selecting pertinent lipids discriminating between people from the AD spectrum and amyloid negative healthy controls. We defined three different models; 1‐ null model, only lipids were included as predictors 2‐ Fixed factors adjusted model, where Age, Gender and BMI were included as covariates and 3‐ APOE4 & Fixed factors adjusted model, which were further tested by adding continuous CSF‐pTAU values.ResultIn our analysis investigating CSF‐Aβ‐ NC (n=63) and CSF‐Aβ+ MCI (n=134), the best performance was achieved by the third model with an estimated cross‐validation accuracy, area under the curve (AUC), negative (NPV) and positive predictive value (PPV) of 0.76, 0.83, 0.67 and 0.80 respectively. Analogously, on investigating individuals at preclinical stage (CSF‐Aβ+ cognitively normal, n=39) against CSF‐Aβ‐ NC, the third model was the only model with acceptable performance with estimated CV accuracy, AUC, NPV and PPV of 0.66, 0.70, 0.68 and 0.64, respectively. This performance was further improved by combining the lipids with pTAU yielding 0.72, 0.74, 0.73 and 0.72 for the accuracy, AUC, NPV and PPV, respectively. The comparison between all models’ performance is summarized in Table. 1 for theNC versus preclinical analysis and displayed in terms of AUC values in Fig. 1 for NC versus MCI analysis. Additional results will be presented at the conference.ConclusionLipid profiling can be a useful tool to reflect the pathological changes in early phases of AD. We plan to replicate these findings on a locally recruited cohort from our specialized memory clinic.
Studies on ApoE in the neurobiology of Alzheimer’s disease
Authors: Konings Sabine C. , Martinsson Isak , Gouras Gunnar K. 
Published: December 2020

AbstractBackgroundApoE4, the most important genetic risk factor for Alzheimer’s disease (AD), is mainly produced by astrocytes, to some extent by microglia, and under stress also by neurons. Under healthy conditions ApoE transports lipids from astrocytes to neurons, where it binds to receptors and is internalized. ApoE4 was reported to impair normal receptor recycling, modulates synaptic receptors and associates with enlarged endosomes in AD. ApoE4 target replacement (TR) mice in the absence of AD mutations show neuronal hyperactivity. However, precise mechanisms, cell types and targets of ApoE relating to AD remain unclear. Previous studies from our lab reported endosomal Aβ accumulation and Aβ‐induced endosome enlargement. Here we aim to elucidate the cellular mechanisms of different ApoE isoforms on neurobiological AD changes, including intraneuronal Aβ accumulation, endosomal alterations and synaptic dysfunction.MethodCortical and hippocampal mouse astrocytes and neurons are derived from ApoE KO, ApoE3‐TR and ApoE4‐TR mice. Human ApoE is obtained from various sources, including conditioned media of ApoE‐TR astrocytes or recombinant ApoE protein, among others. Wild‐type C57BL/6JRj, APP/PS1 and APP KO mouse neurons and mouse N2a cells are treated for different durations with ApoE3, ApoE4, ApoE KO or vehicle control, and analyzed by immunofluorescence, western blot and live cell calcium imaging.ResultAstrocytes from ApoE3‐TR and ApoE4‐TR mice secrete high levels of human ApoE. Recombinant ApoE3 and ApoE4 bind to neurites, seemingly preferentially to synaptic terminals of neurons. ApoE‐TR mouse neurons express endogenous human ApoE in vitro, potentially related to stress associated with culture conditions. Internalized recombinant and endogenous ApoE and internalized synthetic and endogenous Aβ show a mostly vesicular but non‐overlapping pattern of labeling.ConclusionEndogenous and internalized ApoE are present in a vesicular pattern, which however does not significantly overlap with internalized Aβ. In addition, particularly exogenous synthetic ApoE appears to preferentially bind to synapses. We hypothesize that determining the biology of ApoE within neurons, as well as its effects on endosomes, intraneuronal Aβ and synapses, can help to better understand the role of ApoE in neurons and can provide new insights on the role of ApoE in Alzheimer’s pathogenesis.
Improving patient care through a national memory clinic network
Authors: Bouwman Femke H , Pel‐Littel Ruth , Hoogendoorn Tanja , Devries Kerst , Schipper Annemieke C , Driesen Jan , VanStek‐Smits Vera CJ , Sterrenburg Anje , VanderKroon Hester , Oudega Mardien L , van Der Flier Wiesje , Hofman Cynthia 
Published: December 2020

AbstractBackgroundMemory clinics and their practising professionals may hide a treasure of clinical experience and knowledge. In addition, neuroscientists are seeking a way to bring their scientific results swiftly to clinical practice.ObjectiveTo optimize patient care in Dutch memory clinics (>100) by stimulating and facilitating its members to learn together, innovate and share knowledge and experience.MethodsIn November 2016 the Dutch Memory clinic Network (Nederlands Geheugenpoli Netwerk, NGN) was initiated after consulting the four national academic Alzheimer clinics (Amsterdam, Rotterdam, Maastricht, Nijmegen) and the Dutch Alzheimer Association (Alzheimer Nederland). The primary goal ‐ sharing knowledge – is achieved by: 1) Maintaining the NGN Website with information on educational opportunities, ongoing clinical research, guidelines, list of associated memory clinics, etc., 2) Sending out newsletters (4 times a year), 3) Organizing yearly conferences on various topics relevant to memory clinic professionals and researchers, 4) Facilitating professionals to discuss complex patients via the Siilo groups app (a protected messenger, to be used only by care professionals, checked through a national registration number: BIG).ResultsOf >100 memory clinics 77 listed themselves at the website (Fig 1). In the last nine months the website generated >4000 pageviews. Topics that are most frequently visited on the website are educational podcasts on trending topics in the field of dementia presented by clinicians several times a year. The newsletter topics vary: ‘ current research projects’, reports of recent relevant conferences, agenda of relevant conferences for memory clinics. Currently we have 430 subscribers for the newsletter. For the conference the number of attendants has increased over the past four years from 90 in 2016 till 220 in 2019. The Siilo groups app started November 2019, and currently counts 30 participants, increasing every month. Complex patients are discussed as well as news on memory clinics in the media.ConclusionWith the growing number of page views, newsletter‐subscribers, attendants at the conference and members of the Siilo groups app, the NGN serves the dense network of memory clinic professionals in the Netherlands, with the ultimate goal to improve patient care for cognitively impaired patients.
Micronutritional biological status and dementia risk
Authors: Samieri Cécilia 
Published: December 2020

AbstractBackgroundOptimal nutrition may prevent dementia; several nutrients have been associated with dementia risk, yet randomized controlled trials (RCT) testing the efficacy of nutrient supplementation for the prevention of dementia have remained largely disappointing so far. One of the reasons for the inability of RCT to demonstrate the efficacy of nutrient supplementation may be their failure to take into account basal nutritional status (as supplementation may benefit only people with nutrient deficiency). Epidemiology is a unique tool to understand and define the basal nutritional deficiencies that may primarily deserve correction with (multi)‐nutrient supplementation. We leveraged the large prospective French Three‐City (3C) cohort study, with multiple nutrient biomarkers measured at study entry and 17 years of follow‐up for the incidence of dementia, to define a micro‐nutritional biological status (MNBS) score that is associated with subsequent dementia risk.MethodWe included n=666 participants from the 3C study not demented and with blood measurements of 22 nutrients (12 fatty acids, 6 carotenoids, vitamin D, 2 forms of vitamin E, and vitamin A) at baseline, who were followed for up to 17 years for incidence of dementia. To construct our MNBS score, we: (1) defined the primary nutrients of interest, based on both literature review and 3C data; (2) defined plasma concentration thresholds, based on both existing thresholds (eg, existing recommendations, as for vitamin D) and 3C data (modeling each individual nutrient with dementia risk using Cox models with penalized splines); (3) computing a summary MNBS score and estimating its multivariable association with dementia risk.ResultOur MNBS score included 3 nutrient groups significantly associated with dementia risk in our cohort: 25(OH)D; EPA+DHA; total carotenoids. Each component was divided into 3 biological levels (low, 0 point; intermediate, 1 point; high, 2 points), and the total score ranged from 0 to 6 points (Figure 1). Each increase of 1 point of the score was associated with a 20% reduction of dementia risk (p=0.002) (Figure 2).ConclusionA biological score assessing micro‐nutritional status globally is strongly associated with dementia risk. B vitamins may increase the predictive performance of the score and will be incorporated shortly.
Long‐term safety and efficacy of lemborexant in subjects with irregular sleep‐wake rhythm disorder and Alzheimer’s disease dementia
Authors: Moline Margaret , Bsharat Mohammad , Cheng Jocelyn 
Published: December 2020

AbstractBackgroundIrregular Sleep‐Wake Rhythm Disorder (ISWRD) is a common circadian rhythm sleep disorder among individuals with Alzheimer’s disease dementia (AD‐D). The dual orexin receptor antagonist lemborexant (LEM) is approved in the US and Japan for insomnia, and is under investigation for ISWRD. Effects of LEM on clinical measures of ISWRD were evaluated in patients with mild‐moderate AD‐D in a Phase 2 proof‐of‐concept and dose‐finding clinical study (NCT03001557; E2006‐G000‐202). LEM improved circadian variables, helped consolidate nighttime sleep, and was well tolerated, over 1 month. Safety and efficacy data over the Core and long‐term open‐label Extension Phases are reported for subjects who entered the Extension Phase.MethodsThis randomized, double‐blind, multicenter, global, placebo (PBO)‐controlled parallel group study enrolled subjects (aged 60‐90y) who met DSM‐5 criteria for ISWRD and had mild‐moderate AD‐D. In the Core Phase, subjects were randomized to PBO or LEM (2.5mg, 5mg [LEM5], 10mg [LEM10], or 15mg [LEM15]) for 28 days. During the Extension Phase, eligible subjects initially received open‐label LEM10, with option of adjusting the dose to LEM5 or LEM15. Caregivers completed the Sleep Disorders Inventory (SDI), which assesses sleep‐related disturbances. SDI total score (SDI‐ts) was derived as the product of the average of the frequency ratings and the average of the severity ratings (range: 0–12 [worst]).ResultsTwenty‐five subjects entered the Extension Phase. In these subjects, treatment emergent adverse events (TEAEs) were reported in 16(64%) subjects over the Core and Extension Phases (1‐14 months). Serious TEAEs were reported in 3(12%) subjects; no deaths were reported. TEAEs led to dose adjustment in 4(16%) subjects. The most common TEAEs (incidence >10%) were nasopharyngitis (n=4;16%), fall (n=3;12%), and somnolence (n=3;12%). In subjects who received a modal dose of LEM10 (Core and Extension Phases [n=17]), mean(SD) SDI‐ts was 0.72(0.75) at baseline (n=12). Mean(SD) change from baseline (CFB) in SDI‐ts at Day 29 (n=12) was −0.14(0.63). In the Extension Phase, mean(SD) CFB in SDI‐ts was −0.37(0.50) at Day 133 (n=14) and −0.12(0.81) at Day 223 (n=12).ConclusionsIn subjects with AD‐D and ISWRD treated with LEM10, moderate improvement in SDI‐ts continued to be observed over time. LEM was well tolerated over 1‐14 months. Support: Eisai Inc.