bluuebunny/crossref_metadata_2025_split huggingface dataset:
The dementia policies in Australia relating to the COVID‐19 pandemic
Authors: Goh Anita MY , Dow Briony 
Published: December 2021

AbstractBackgroundAustralia has a population of 26 million, and on January 28th 2021, 28,794 COVID‐19 infections and 909 deaths. 685 deaths were at residential aged care facilities, and data from the Australian Bureau of Statistics revealed that 72.7% of the people who died of the coronavirus in Australia (up to 31 August 2020) had at least one pre‐existing chronic condition listed on their death certificate, with dementia the most common (noted on 41% of death certificates). This presentation will present and discuss the key Australian dementia policy interventions implemented during the pandemic.MethodA scoping review of published academic, media, policy papers, white papers, and grey literature was conducted. We extracted relevant information pertaining to policies relating to dementia care during the COVID‐19 pandemic.ResultThe Australian government is managing the COVID‐19 outbreak as a health emergency, and have developed and funded a comprehensive response. For the older population and those with ADRD, the key policies include the National Health Plans, specific plans for people with disabilities, telehealth expansions, mental health and wellbeing pandemic response plans, home delivery of prescriptions, the establishment of an Aged Care Health Emergency Response Operations Centre, and a National COVID‐19 Aged Care Plan. In Victoria, the Victorian Aged Care Response Centre was established. The Pfizer/BioNTech vaccine will be given to priority groups from February 2021, which include aged care and disability care residents and workers (people with dementia account for 52% of all residents in aged care facilities).
Strict policies were put in place for aged care facility visitations, and for the aged care workforce, such as the use of personal protective equipment and limiting staff to work in only one facility. Advocacy bodies were also key, and Dementia Australia and Dementia Support Australia, for example, developed advice to support people experiencing behavioural and psychological symptoms of dementia during the pandemic.ConclusionThere are currently no active cases in residential aged care in Australia, zero locally acquired cases for several weeks, with the (minimal) new cases emerging from the hotel quarantine system. Health policies have managed to limit the spread of COVID‐19 infection in Australia.
Use of neural precursors as a therapy to alleviate Alzheimer’s disease neuropathology and cognitive impairment
Authors: Ruiz Nazaret Gamez , Morales Rodrigo , Gutierrez Antonia , Moreno‐Gonzalez Ines 
Published: December 2021

AbstractBackgroundCurrent treatments for Alzheimer´s disease (AD) only ameliorate the symptoms, but none of them delays or halts disease progression. In recent years, stem cells have received growing attention as a potential therapy for brain disorders. Patients’ self‐derive stem cells offer the possibility to avoid rejection and a more personalized treatment. However, there is an urgent need to replace the conventional intracerebral stem cell therapy for a less invasive method to avoid some of the technical challenges. Our recently published results indicate that peripheral treatment with neural precursors (NPs) ameliorates clinical symptoms by reducing the disease‐associated neuroinflammation in a mouse model of Parkinson’s disease. Therefore, we hypothesize that intravenous administration of NPs could be considered as a non‐invasive therapy to ameliorate memory impairment in mouse models of AD.MethodNPs derived from mesenchymal stem cells and induced pluripotent stem cells were intravenously injected into APP/PS1 and P301S mice before and after brain pathology is stablished. At the age of 7 months old, experimental and control animals were subjected learning and memory tasks and brain analyzed.ResultNP‐treated mice demonstrated a significant decreased of cognitive impairment compared to PBS‐injected animals as well as improved motor coordination in P301S mice. Histological analysis showed that although amyloidogenic deposits were slightly reduced, microglial activation decreased after the treatment.ConclusionThe preclinical analysis of NPs peripheral inoculation suggests that these cells could be considered as a potential treatment to reduce AD‐related pathology.
Delivering probes and clinical candidates to test precision medicine therapeutic hypotheses
Authors: Watterson Daniel Martin , Roy Saktimayee M , Van Eldik Linda J , Arancio Ottavio 
Published: December 2021

AbstractBackground. There is a need for selective clinical candidates that allow testing of explicit precision medicine hypotheses emerging from diverse clinical data acquisition, analysis and archiving initiatives. Candidates that target pathophysiology progression mechanisms would offer the potential for disease modification. Appropriate clinical candidates would, ideally, facilitate clinical hypothesis testing in order to find the right drug at the right dose at the right time for the right patient. In this regard, we developed a discovery and development platform focused on altering pathophysiology progression mechanisms and delivers novel small molecule candidates with good bioavailability, safety profiles and potential for evaluation in proof‐of‐concept clinical trials.MethodSynaptic dysfunction and neuroflammation are pathophysiology progression mechanisms. Our discovery starts with molecular scaffolds emerging from pharmacoinformatic analysis of prior CNS drugs and their clinical utility. Medicinal chemistry diversification is driven by chemoinformatics related to small molecule drug properties in biological systems and by pharmacoinformatics related to pharmacology and toxicology potential. Campaigns can target single molecular entities (e.g., a serine/threonine protein kinase), pathways (e.g., cytokine biosynthesis dysfunction) or combinations (e.g., serotonin receptor linked dysfunction). Efficient medicinal chemistry approaches include diversifications based on [Target:Inactive Molecular Fragment] complexes or us of SOSA variations (systematic optimization of side activities). Best‐in‐class candidates emerge from IND‐enabling preclinical safety pharmacology and tractability of GMP production and delivery.ResultsMW150, MW189 and MW151 are example deliverables that continue to exhibit utility in human subjects. MW150 is a highly selective CNS S/T protein kinase inhibitor deliverable entering phase 2a safety trials for AD patients. MW150 exhibited selectivity in hierarchal kinome‐wide and large scale functional GPCR screens and absence of activity in standardized screens related to ADMET liabilities. Preclinical safety testing according to FDA/ICH guidelines provided the foundation for regulatory approval of clinical trial initiation. MW189 and MW151 are clinical trial stage deliverables where design and synthesis of a curated small chemical library was based on SOSA rationale and functional vetting was based on attenuation of cytokine biosynthesis dysfunction.ConclusionOverall, the platform continues to be validated for delivery of novel small molecule candidates for human studies.
Selective targeting of intracellular, misfolded, pathogenic TDP‐43 with rationally designed intrabodies
Authors: Zhao Beibei , Louadi Sarah , Dijkstra Anke A. , Plotkin Steven S , Kaplan Johanne , Cashman Neil R 
Published: December 2021

AbstractBackgroundCytoplasmically mislocalized aggregates of TDP‐43 have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) through direct toxicity, loss of function of normal TDP‐43, induction of misfolding of other neuronal proteins, and prion‐like, cell‐to‐cell propagation of disease. We generated monoclonal antibodies (mAbs) selective for the misfolded form of TDP‐43 and derived single chain intrabody constructs to allow for intracellular targeting of pathogenic TDP‐43 without interfering with physiological forms of TDP‐43 important for normal cell function.MethodMonoclonal antibodies (mAbs) were generated by immunization with an unfolded N‐terminal domain (NTD) linear epitope predicted to become exposed in cytoplasmically mislocalized aggregates of TDP‐43 but otherwise buried in natively folded TDP‐43. The selectivity of mAbs for pathogenic, aggregated TDP‐43 was assessed by immunocytochemistry (ICC) of HEK293FT cells transfected with mutant TDP‐43 (DNLS‐TDP‐43) and by immunohistochemistry (IHC) on patient samples. Single chain (scFv) intrabody constructs were derived from selective antibodies and HEK293FT cells were co‐transfected with plasmids encoding intrabodies and misfolding DNLS‐TDP‐43. The selective interaction of expressed intrabodies with cytoplasmic DNLS‐TDP‐43 aggregates was assessed by ICC, and clearance of the aggregates was evaluated by western blot analysis of cell lysates.ResultICC showed mAb reactivity with cytoplasmic aggregates of transfected DNLS‐TDP‐43 but not endogenous wild‐type nuclear TDP‐43. IHC of ALS and FTLD CNS sections confirmed immunoreactivity specifically with pathogenic TDP‐43 in patient samples. Similarly, co‐transfection of DNLS‐TDP‐43 and scFv intrabody constructs showed intracellular interaction of intrabodies with misfolded cytoplasmic aggregates of TDP‐43 but not with normal, nuclear TDP‐43. In agreement with a lack of interference with normal TDP‐43, the robust expression of intrabodies did not affect cell viability. Intracellular clearance of the aggregates was observed in western blots of the cell lysates and was enhanced by the inclusion of a lysosomal targeting signal in the intrabody constructs.ConclusionImmunization with an NTD epitope of misfolded TDP‐43 gave rise to mAbs selective for pathogenic vs physiologically important forms of TDP‐43. Intrabody constructs derived from these mAbs were able to promote clearance of intracellular pathogenic TDP‐43 without toxicity to the cells.
Local neurodegeneration and global connectivity adaptation across the FTD‐AD spectrum
Authors: Brown Jesse A. , Lee Alex Jihun , Pasquini Lorenzo , Friedberg Adit , Rabinovici Gil D. , Kramer Joel H , Tempini Maria Luisa Gorno , Rosen Howard J. , Miller Bruce L. , Seeley William W. 
Published: December 2021

AbstractBackgroundNeurodegenerative diseases involve weakened functional connectivity in disease‐targeted brain areas. Equally important but overlooked is the hyperconnectivity that appears in other brain areas (Hillary and Grafman, TICS 2017). Hyperconnectivity has been attributed to processes like disinhibition, imbalance, compensation, and reserve. It is critical to understand the neuroanatomical mechanism underlying hyperconnectivity because this functional process may accelerate subsequent disease progression. We performed structure‐function mapping for patients across subtypes and stages of the frontotemporal dementia‐Alzheimer’s disease atrophy spectrum. Our goal is to develop a comprehensive model relating diverse focal atrophy patterns to corresponding brain‐wide functional connectivity reconfigurations.MethodWe studied patients with Alzheimer’s disease (AD), behavioral variant FTD (bvFTD), semantic and nonfluent variant primary progressive aphasia (svPPA/nfvPPA), cortical basal syndrome (CBS), and healthy controls (HC). We included subjects who received a clinical diagnosis at the UCSF Memory and Aging Center and had structural and task‐free functional MRI scans (n=281). Each subject’s gray matter atrophy map was measured using voxel‐based morphometry volume loss in 273 ROIs. Functional connectivity matrices (273x273) were derived for each subject. We combined data for all patients and controls into a structural data matrix (281x273) and a functional data matrix (281x37128). We then performed partial least squares regression to find components that maximized the covariance between structure and function.ResultThe first PLS component captured the relationship between global atrophy burden and a distributed pattern of functional connectivity loss in unimodal cortical areas and enhancement in subcortical‐cortical pathways (r=0.64; Figure 1). The second PLS component showed svPPA‐like anterior temporal atrophy corresponding to atrophy‐proximal connectivity deficits, with enhancements in contralateral frontoparietal areas (r=0.67). The third PLS component revealed a spectrum from anterior (bvFTD) to posterior (AD), contrasting frontal‐insular atrophy, connectivity deficits, and parietal connectivity enhancements versus parietal atrophy, connectivity deficits, and frontal connectivity enhancements (r=0.51).ConclusionSpecific atrophy subtypes across the FTD‐AD spectrum associate with proximal functional connectivity reductions. Intriguingly, these subtypes also exhibit concomitant functional connectivity enhancements in more distal areas. The enhancements are of the same magnitude as the deficits and may represent a general principle of functional “load‐shifting” (Jones et al, Brain 2016) away from disease‐targeted areas.
Self and informant‐rated mild behavioral impairment and genetic risk for AD: The respondent matters
Authors: Creese Byron , Arathimos Ryan , Brooker Helen , Corbett Anne , Aarsland Dag , Lewis Cathryn , Ballard Clive , Ismail Zahinoor 
Published: December 2021

AbstractBackgroundLate‐life onset neuropsychiatric symptoms (NPS) have received increasing attention in recent years because of their prognostic potential for neurodegenerative disease. As focus intensifies, appropriate measurement will be critical. The emergence of Mild Behavioral Impairment ‐ which describes late‐life onset apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness, and psychosis ‐ and the MBI‐Checklist (MBI‐C), developed to capture these symptoms in accordance with the ISTAART‐AA MBI criteria, has been a step forward. Previous work has demonstrated only modest correlation between proxy informant and self‐rated MBI‐C responses, but the significance of these differences in responses is not yet understood. Moreover, there is relatively less work examining non‐affective late‐life NPS. To explore both of these factors, we examined the relationship between genetic risk for Alzheimer’s disease and the five MBI domains in a sample of cognitively normal older adults.MethodGenetic and clinical data from 2,529 cognitively normal participants aged ≥65 in the PROTECT study were analysed. MBI was evaluated using the MBI‐C; individual domain scores were calculated, and participants dichotomised into domain ‘present’ or ‘absent’. Polygenic risk scores (PRS) for Alzheimer’s disease were used as predictors in binary logistic regression models with the MBI domains, each rated by self and by proxy, as separate outcomes. To evaluate whether AD PRS was associated with depression, the most commonly considered NPS in older adults, we also tested the association between AD PRS and PHQ‐9 score (>=5 or <5).ResultAD PRS was associated with a greater risk of apathy and impulse dyscontrol in proxy MBI‐C ratings but not in self‐report MBI‐C ratings (OR: 1.2 [95% CI: 1.06‐1.40], p=0.004; OR: 1.12 [95% CI: 1.01‐1.24], p=0.03, respectively). There was no association between AD PRS and PHQ‐9 symptoms.ConclusionProxy informant and self‐reported MBI‐C elicit different associations in analysis of AD genetic risk. These findings suggest that even in cognitively normal older adults, proxy informant ratings are important to consider in the evaluation of NPS and risk of dementia. There was no association between PHQ‐9 symptoms and AD PRS, highlighting the importance of the multi‐domain MBI‐C as a specific tool to capture late‐life NPS as risk factors for dementia.
Interactions between dietary patterns and genetic factors in relation to incident dementia among 70‐year‐olds
Authors: Samuelsson Jessica , Najar Jenna , Wallengren Ola , Wetterberg Hanna , Fässberg Madeleine Mellqvist , Zetterberg Henrik , Blennow Kaj , Lissner Lauren , Rothenberg Elisabet , Skoog Ingmar , Zettergren Anna 
Published: December 2021

AbstractBackgroundGenetic and lifestyle factors influence the risk of developing dementia. Diet is one of the modifiable lifestyle factors thought to affect risk, but it is unclear whether there is an interplay with genetic risk factors in relation to incident dementia.MethodData was derived from the population‐based Gothenburg H70 Birth Cohort Studies based in Sweden, including 602 dementia‐free 70‐year‐olds (born 1922 or 1930; 64% women) with dietary and genetic data followed for incident dementia until 2016. Two dietary patterns were derived with reduced rank regression analysis, one healthy (e.g., fruits, vegetables, fish) and one western (e.g., full‐fat dairy products, refined bread, red and processed meat). Genetic risk was determined by APOE ε4 status and four non‐APOE AD‐polygenic risk scores (AD‐PRSs). Gene‐diet interactions in relation to incident dementia were analysed with cox regression models. If an interaction at a p‐value threshold of p< 0.20 was detected, stratified analyses were performed. Analyses were adjusted for sex, energy intake, birth year, age at examination, educational level, physical activity level, cardiovascular risk factors and 10 principal components (to correct for population stratification).ResultThere was an interaction between APOE ε4 status and a healthy and a western dietary pattern in relation to incident dementia (p=0.13 and p=0.07), while no interactions were found between AD‐PRSs and dietary patterns. Those with higher adherence to a healthy dietary pattern had a reduced risk of dementia (HR 0.77; 95% CI 0.64–0.94, p=0.008) among ε4 non‐carriers, but not among ε4 carriers. There was a borderline association between a western dietary pattern and an increased risk of dementia among ε4 carriers (HR 1.25; 95% CI 0.97–1.61, p=0.08), while no association was observed among ε4 non‐carriers.ConclusionThe results suggest an interplay between APOE ε4 status and adherence to dietary patterns in relation to incident dementia. The findings from this study could be of importance for dementia prevention strategies and for future intervention studies investigating the effect of dietary patterns in relation to dementia incidence.
Can we improve clinical trial design in Alzheimer’s disease? The participants point of view
Authors: Ottenhoff Lois , Vijverberg Everard G.B. , Visser Leonie N.C. , Verrijp Merike , Prins Niels D. , van der Flier Wiesje M , Sikkes Sietske A.M. 
Published: December 2021

AbstractBackgroundPivotal to clinical trial success is the recruitment and retention of participants. To improve both, it is important to know which trial features increase willingness to enroll and are appreciated by participants. We examined experiences of trial participants, and their suggestions on how to optimize clinical trial design.MethodIn this mixed‐methods study, we included participants via the Dutch Brain Research Center (11 different international sponsor‐initiated Alzheimer’s disease trials). An online study‐specific questionnaire was distributed among current and past participants addressing four topics; participant’s motives to enroll, experienced burden, preferred frequency of visits, and attitudes towards participation. Subsequently, we organized three focus groups to gain more in‐depth understanding of negative and positive aspects of trial design. Audio recordings from focus group interviews were transcribed verbatim and analysed by thematic content analysis by two independent raters.ResultsThe questionnaire was completed by 71 participants (age 69±6.5, 54% female, 19 cognitively normal, 19 Mild Cognitive Impairment (MCI), and 33 Alzheimer’s dementia). To benefit future generations was most frequently (34%) reported as a motive for enrolment, Figure 1. The lumbar puncture (40%) and memory assessments (15%) were most often experienced as being of high burden. The most frequently mentioned features to increase the likelihood and willingness to enroll were a low probability to get allocated to the placebo group (27%), and the possibility to obtain personal test results (21%). Negative trial experiences according to focus group participants (N=12, 8 cognitively normal, 4 MCI) included the themes ‘not obtaining their own results during or at the end of a clinical trial’ and ‘no follow up enquiries after participating in the trial’. Among the positive aspects were ‘professionalism’, ‘accuracy’ and ‘empathy of research staff’.ConclusionOur findings provide input for how priorities of participants can be used in clinical trial design to optimize recruitment and ensure trial success. Relevant factors include expectation management and careful planning of high burden assessments, provision of individual feedback and prioritizing professionalism and empathy throughout conduct of the trial. Thus selection of experienced and well‐equipped trial centres is a key component.
Lifelong music practice as reserve factor: Associations with cognition and brain structure in older adults
Authors: Wirth Miranka , Böttcher Adriana , Höppner Angela , Fabel Klaus , Köbe Theresa , Teipel Stefan J , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Laske Christoph , Spottke Annika , Jessen Frank , Düzel Emrah , Wagner Michael , Roeske Sandra 
Published: December 2021

AbstractBackgroundRegular music practice is suggested to be protective against age‐related cognitive decline and Alzheimer’s disease (AD) 1. This study investigated associations between music making during the entire life, late‐life cognitive performance and gray matter (GM) structure in the DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE, DRKS‐ID: DRKS00007966).MethodCognitively unimpaired participants (age: ≥60 years including normal controls, participants with subjective cognitive decline, and first‐degree relatives of AD patients) were included in this study. Frequency of music practice over lifetime was self‐reported by each participant using the Lifetime of Experiences Questionnaire (LEQ 2). A group with regular lifelong music practice (n=72) was identified and compared to a control group (n=72) that did not practice any music during life. The control group was selected to match for age, sex, education, crystallized intelligence, socioeconomic status and diagnostic group. Multivariate analyses included group comparisons on late‐life cognition using composite scores 3, GM volumes in the entire cortex and in combined posterior AD regions (adjusted for TIV) and interaction effects.ResultLifelong music practice was associated with better late‐life performance in global cognition (Fig. 1, left side), working memory, and executive function (p’s < 0.05). A similar effect was not seen for episodic memory. No significant direct associations were found between lifelong music practice and GM volumes in the cortex and within AD regions. Global cognition (Fig. 1, right side), working memory, and executive functions were enhanced in those individuals with both lifelong music practice and greater cortical GM volume (p’s < 0.05).ConclusionRegular music making over life may help preserve late‐life cognitive performance in executive function and working memory, mirroring existing findings 4. This cognitive benefit appears to be related to superior ability to recruit brain resources, rather than greater brain reserve per se. Music practice could represent an enrichment strategy that may to a certain degree provide cognitive reserve in older age. References: (1) Verghese J, et al. N Engl J Med 2003. (2) Valenzuela MJ, Sachdev P. Psychol Med 2007. (3) Wolfsgruber S, et al. Neurology 2020. (4) Mansens D, et al. Aging & Mental Health 2018.