bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical stage Alzheimer’s therapy, NNI‐362 promotes TH+ neurons associated with a reversal of motor deficits in AAV‐alpha synuclein model, leaving alpha synuclein unchanged
Authors: Kelleher‐Andersson Judith , Noe Emelie , Robin Laurie , Bezard Erwan , Turner R. Scott 
Published: December 2023

AbstractBackgroundNNI‐362 is a novel small molecule identified by phenotypic screening to discover compounds that promote new neurons from human neural progenitor cells and have neuroprotective capacity. A placebo‐controlled, double‐blind Phase 1a trial examined the safety and tolerability of NNI‐362, as well as a pharmacodynamic outcome ‐ the level of plasma p‐tau181, a blood‐based biomarker specific to Alzheimer’s disease (AD) pathology. Results in animal models of other age‐related disorders suggest NNI‐362 has the potential to halt or reverse AD and PD clinically.MethodAn AAV‐alpha synuclein rat model of Parkinson’s disease (PD) (MOTAC, France) was used to examine the effects of NNI‐362 treatment. This model results in anosmia and motor phenotypes, loss of TH+ neurons, and diminished adult‐born neurons triggered by alpha‐synuclein expression in the SNpc. NNI‐362 and placebo were formulated as a lipid suspension and administered orally once daily for up to 6 weeks post‐stabilization of AAV‐synuclein expression. At 8 weeks, brains were removed, and the SNpc sectioned and stained for TH+ neurons, alpha‐synuclein, and BrdU+ adult‐born neurons. Results were compared to AAV‐GFP‐injected, vehicle‐treated rats ‐ in groups of M or F and treatment or placebo (n = 14/group, 7F/7M).ResultBrain permeable therapy NNI‐362 did not alter alpha‐synuclein levels, but promoted BrdU+ neurons in the substantia nigra. Thus, generating and protecting TH+ neurons was associated with reversing motor deficits in females. No motor deficits and no BrdU+ neuron deficits were observed in AAV alpha‐synuclein treated males (twice run model), as such no amelioration by NNI‐362 treatment.ConclusionOral NNI‐362 may be a cause‐agnostic therapeutic ‐ promoting region‐specific new neurons, TH+ neuronal protection, and behavioral improvement when induced by dopaminergic deficit, including neurogenesis deficit. After AAV‐alpha‐synuclein induction of 2 weeks, and then followed by chronic NNI‐362 treatment, both behavior and neuron numbers were no different than AAV‐GFP control levels in this clinically‐relevant experimental model of PD.
Heuristic evaluation and usability testing of a functional dementia stages app for Hispanic family caregivers
Authors: Arcia Adriana 
Published: December 2023

AbstractBackgroundHispanic family caregivers of persons with Alzheimer’s disease and other dementias are not getting the anticipatory guidance they need about how functional abilities will change as dementia progresses. Existing informational resources are overwhelming to navigate and written at a high reading level. Furthermore, professional assessment of functional abilities is not universally available. Innovative, tailored approaches are needed. Our aim was to develop and test a mobile application, the Interactive Functional Assessment Staging Navigator (I‐FASTN), to support Hispanic family caregivers’ assessment of care recipients’ functional stage of dementia in either English or Spanish.MethodWe conducted heuristic evaluation with informatics experts (N = 5, English only) and usability testing with caregivers (n = 10 English, n = 10 Spanish). Participants attempted a series of tasks with the app using a think‐aloud protocol and then rate the usability of the app using mobile app heuristics (experts) and two usability instruments (caregivers). Sessions were recorded and transcribed. For heuristic evaluation, we tabulated the number of usability problems by category: cosmetic, minor, major, and catastrophic. For usability testing, recordings, notes, and transcripts were content analyzed to extract usability problems, suggestions for improvement, desired app features, and other feedback.ResultRefinements to the app were made after each of the five evaluations to address the problems encountered. Caregivers’ mean usability scores were high (4.6 and 4.7 out of 5.0), reflecting good usability overall. Chief usability problems were a confusing tutorial and difficulty finding the app’s side menu. These will be addressed by creating a video tutorial and moving all menu items to the home screen. The app was very well received by caregivers, who indicated that the concise, illustrated content met their informational needs. However, analog alternatives are still needed by caregivers unaccustomed to using apps as they had difficulty moving on from even the simplest screens (see Figure 1a).ConclusionCaregivers are not receiving informational support in a way that meets their needs. The focus should be on providing concise information that addresses the practical aspects of caregiving, tailored to the care recipient’s functional stage.
Role of Peroxiredoxin 6 in the Development of Tau Pathology
Authors: Pankiewicz Joanna E. , Lizińczyk Anita M , Franco Leor A. , Diaz Jenny R , Gootman Alexandra , Sadowski Martin J. 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease (AD) and fronto‐temporal dementia excess of hyperphosphorylated tau (p‐tau) assembles into neurofibrillary tangles (NFTs). NFT‐bearing neurons are associated with A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD). A1 astrocytes lose their neuron‐supporting properties and along with MGnD contribute importantly to the degeneration of NFT‐bearing neurons. MGnD and A1 astrocytes also reciprocally stimulate their pathological phenotypes. Factors endowing astrocytes with resistance to A1 transformation remain unknown. Astrocytes express peroxiredoxin 6 (PRDX6) protein, which glutathione peroxidase and phospholipase 2 enzymatic activities enable repair of oxidatively damaged cell membranes and cell‐to‐cell signaling. PRDX6 upregulation has been noted in astrocytes associated with NFT‐bearing neurons in AD, yet its precise role in the development of tau pathology remains unknown. To this end we created new MAPTP301S transgenic mouse lines featuring Prdx6 haplodeficiency and hemizygous knock‐in of the overexpressing Prdx6 transgene.MethodMAPTP301S (PS19/Prdx6+/+) mice were crossed with Prdx6−/− mice and with Prdx6129X1/SvJ allele knock‐in mice, which feature wild‐type PRDX6 overexpression. Resulting lines PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg showed 0.4:1:2 ratio of brain Prdx6 mRNA level, while hTau and Gfap mRNA levels were similar. All lines were neuropathologically characterized at the age of 9.5 months.ResultBrain atrophy determined by quantifying hippocampal and lateral ventricular volumes and the hippocampal p‐tau load show inverse relations with the Prdx6 gene dose. The load of GFAP+ astrocytes and the C3+/GFAP+ ratio used as a surrogate A1 phenotype marker also vary inversely with the Prdx6 expression. The load of IBA1+ microglia show inverse relation with the Prdx6 gene dose, while the CD68+/IBA1+ index used as a surrogate marker of microglia phagocytic activity show direct correlation.ConclusionAttenuation of the pathological phenotype in PS19/Prdx6Tg line and its worsening in PS19/Prdx6+/− line evidence a neuroprotective role of PRDX6 in tau‐mediated neurodegeneration. Observed inverse relation between the Prdx6 gene dose and astrocytic C3 expression and microglia activation suggests PRDX6 endows astrocytes with resistance to A1 transition, which in turn hampers microglia activation. Analysis of astrocyte and microglia transcript from PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg lines focused on A1 and MGnD activation markers is underway.
Sleep apnea‐related hypoxemia, not sleep fragmentation, is associated with white matter hyperintensities in older adults
Authors: Berisha Destiny E , Rizvi Batool , Chappel‐Farley Miranda G. , Taylor Lisa M. , Sattari Negin , Dave Abhishek , Chen Ivy Y. , Neikrug Ariel , Benca Ruth M , Yassa Michael A. , Mander Bryce A 
Published: December 2023

AbstractBackgroundSleep apnea is a type of sleep‐disordered breathing that increases risk for Alzheimer’s disease‐related pathology potentially through cerebrovascular pathology, likely exacerbated by two features of sleep apnea: intermittent hypoxia and sleep fragmentation. White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase in aging and in AD. Here, we tested the hypothesis that apnea‐related hypoxemia severity, and not sleep fragmentation, are associated with WMH volume in older adults.MethodsThirty‐two older adults (73.4±5.3 years, 19 female, AHI = 15.2±18.9) were evaluated with overnight polysomnography (PSG). Apnea severity was quantified using the Apnea‐Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), and blood oxygen desaturation (Oxygen Desaturation Index (ODI), duration, frequency of ≥4% desaturations, and desaturation nadir) stratified by sleep stages. T1‐MPRAGE and T2‐FLAIR scans were acquired using a 3T Siemens scanner. Total WMH volumes were derived using a semi‐automated algorithm. Overnight memory retention was assessed using the change in the lure discrimination index (LDI) for the emotional version of the Mnemonic Discrimination Task.ResultsTraditional measures of apnea severity and sleep fragmentation were not significantly associated with global WMH volume. However, both max duration of oxygen desaturation events (r = 0.44, p = 0.011) and max oxygen desaturation percentage (in rapid‐eye movement (REM) and in total sleep: r = 0.48, p = 0.005, and r = 0.44, p = 0.01), were significantly associated with total WMH volume. Similar relationships were found with time spent below 90% and 80% oxygen saturation (Kendall’s tau = 0.33, p = 0.02 and tau = 0.275, p = 0.03). These relationships survived adjustment for sex, age, and hyperlipidemia and/or hypertension medication at time of PSG. Global WMH volume was also negatively associated with overnight memory retention (r = ‐0.38, p = 0.03).ConclusionsThese findings suggest that hypoxemia severity, compared to sleep fragmentation, are more strongly associated with global WMH volume. As WMH volume was associated with overnight memory retention, this may suggest a pathway in which OSA increases WMH, which is subsequently associated with tau burden, worsening sleep‐dependent memory.
Validation of early‐frame 18F‐FDG PET for CBF quantification: Comparison to simultaneous eASL measurements in memory patients
Authors: Fettahoglu Ates , Zhao Moss , Chen Kevin , Khalighi Mehdi , Zeineh Michael , Mormino Elizabeth C. , Moseley Michael , Zaharchuk Greg 
Published: December 2023

AbstractBackgroundThis study aimed to validate early [18F]‐FDG (eFDG) imaging for the quantification of cerebral blood flow (CBF), enabling dual‐marker imaging of perfusion and metabolism with a single tracer.Method19 participants with memory concerns underwent simultaneous [18F]‐FDG PET and multi delay pseudo‐continuous arterial spin labeling (eASL) MR imaging on a hybrid 3T PET/MRI scanner. eFDG‐CBF maps were generated from the first 30s, 60s, 120s and 300s after injection, and measurements were compared to ASL‐CBF using voxel‐wise cross correlation and concordance correlation for 7 regions derived from the MNI‐structural atlas.ResultHighest voxel‐wise cross‐correlation to ASL‐CBF maps were reported for 300s (5 min) eFDG (r = 0.77).Concordance correlation (CC) values were strong in all ROIs, ranging from (CC = 0.88) to (CC = 0.65) in temporal and occipital regions respectively. Mean of measurements in all ROIs were in good agreement between eFDG and ASL CBF maps, with a reported voxel‐wise mean absolute error of ±6.73 ml/100g/min between two maps.ConclusionBy simultaneous measurement of hemodynamics across modalities with a TOF‐enabled PET/MRI, we were able to demonstrate that eFDG PET is a reliable measure in mapping CBF based on strong inter‐modality correlation with ASL‐CBF, irrespective of pathophysiological variations in memory patients.
Trends in the prevalence of dementia in LMIC: findings from 10/66 studies in Latin America and the Caribbean.
Authors: Llibre‐Rodriguez Juan J. , Acosta Daysi , Guerra Mariella , Sosa‐Ortiz Ana Luisa , Velazquez Ivonne Z. Jimenez , Salas Aquiles , Llibre‐Guerra Jorge J , Prince Martin J ,   10/66 Dementia Research Group
Published: December 2023

AbstractBackgroundPopulation ageing will lead to a dramatic increase in dementia prevalence globally. Recent evidence suggest a decline in dementia incidence in High Income Countries due to increasing education levels and improvements in cardiovascular health. Although, most of the increase will occur in low and middle‐income countries (LMICs), there are no recent estimates of dementia prevalence and incidence in LMICs. The present study aimed to examine new trends on dementia prevalence and incidence in Latin‐America and associations of socioeconomic determinants and cardiovascular risk factors.MethodSample size included older adults from Latin America (Cuba, Dominican Republic [DR], Puerto Rico [PR], and Mexico) drawn from the 10/66 Dementia Research Group study. We compare wave 1 (2003‐2006) with wave 3 (2016‐2019) of 10/66 studies. The main outcome was dementia prevalence relative to previous waves. Dementia diagnosis was determined according to 10/66 dementia criteria. All the 10/66 waves used the same standardized assessments and protocols.ResultDementia prevalence is stable Cuba, standardized dementia prevalence rates was 12.4% in wave I and 10.1% in wave III. Relative to wave I, Dominican Republic (wave I 11.5% vs wave II 13.6%), Peru (wave I 9.2% vs wave II 16.8%) and Mexico (wave 1 8.3% vs wave 2 17.1%) experience a significant increase in dementia prevalence. Despite, improvements in levels of education, increases in dementia prevalence were associated with higher rates of cardiovascular disease and cardiovascular risk factors, including diabetes, hypertension, obesity and heart disease in the later‐born cohorts. Self‐reported stroke is also rising.ConclusionThe prevalence of dementia in the older Latin American and Caribbean population is high and increasing relative to the previous decade. These findings may inform health promotion efforts within dementia national plans adopted recently in some Latin American countries
Falls Risk Profile in Community Dwelling Adults with Moderate‐Severe Cognitive Impairment
Authors: Ho Yun Ying , Chong Elizabeth Gar Mit 
Published: December 2023

AbstractIntroductionIt is well established that older adults with cognitive impairment are more likely to fall. Injurious falls lead to functional decline and higher level of mortality. The Centers for Disease Control and Prevention, USA further concluded 20% falls resulted in serious injuries which were either fractures and/or head injuries.MethodologyThis paper aimed to evaluate the relationship between characteristics of fallers with moderate cognitive impairment and osteoporosis. A single center cross sectional study with universal sampling was performed for all patients who attended the transdisciplinary falls clinic in a large tertiary center in Klang Valley from January 2015 till January 2023. Anonymised data was collected from the existing falls database. Subjects with MMSE score 0‐18 were categorised as having moderate‐severe cognitive impairment.ResultsDuring the study period, a total of 185 older adults were assessed with 96 females (51.9%) and 35 (18.9%) with moderate‐severe cognitive impairment. They were all community dwellers. All those with moderate‐severe cognitive impairment had previous history of falls. 91.3% subjects with mild or no cognitive impairment had fallen before. Those who stayed alone (0 out of 21 subjects) were less likely to have moderate‐severe cognitive impairment (p value 0.037). Subjects with moderate‐severe cognitive impairment had lower hip T‐score (mean ‐2.23, SD1.93, p = 0.026), Mechanisms were more likely due to slipping (25.7%, p = 0.03) and less likely because of losing balance (22.9%, p = 0.006). The Berg Balance Scores were numerically higher 42.2 (SD32.3) but did not achieve statistical significance (p = 0.652). These fallers were less likely to fall out of home (11.4%, p = 0.017). 34.3% fallers with moderate‐severe cognitive impairment required assistance to ambulate (p = 0.034). There was no difference for the following parameters: age, gender, ethinicity, multi‐morbidities, polypharmacy, sensory impairment, history of falls, recurrent falls, frequencies of any injuries sustained including fractures or intracranial hemorrhage, admission for falls and presence of osteoporosis.ConclusionThis study suggested that community dwelling older adults with moderate‐severe cognitive impairment had similar falls risk profile comparing to their counterparts. Clinicians should be more vigilant in screening for falls risk in this population and be proactive in managing their bone health.
The association between gut microbiota and postoperative delirium in patients
Authors: Zhang Yiying 
Published: December 2023

AbstractBackgroundPostoperative delirium is one of the most common postoperative complications in older patients. Its pathogenesis and biomarkers, however, remain largely undetermined. Majority of human microbiota is gut microbiota and gut microbiota has been shown to regulate brain function. Therefore, this study aimed to determine the association between gut microbiota and postoperative delirium in patients.MethodOf 220 patients (65 years old or older) who had a knee replacement, hip replacement, or laminectomy under general or spinal anesthesia, 86 participants were included in the data analysis. The incidence (primary outcome) and severity of postoperative delirium was assessed for two days. Fecal swabs were collected from participants immediately after surgery. The 16S rRNA gene sequencing was used to assess gut microbiota.ResultUsing principal component analyses along with a literature review to identify biologically plausible mechanisms, and three bacterials were studied for their associations with postoperative delirium. Of the 86 participants [age 71.0 (69.0‐76.0, 25%‐75% percentile of quartile), 53% female], ten (12%) developed postoperative delirium. Postoperative gut bacteria Parabacteroides distasonis (Odds Ratio [OR] 2.13, 95% Confidence Interval (CI): 1.09 ‐ 4.17, P = 0.026) was associated with postoperative delirium after adjusting for age and sex. The association between delirium and both Prevotella (OR: 0.59, 95% CI: 0.33 – 1.04, P = 0.067) and Collinsella (OR: 0.57, 95% CI: 0.27 – 1.24, P = 0.158) did not meet statistical significance.ConclusionThese findings suggest that postoperative gut microbiota (e.g., Parabacteroides distasonis) may serve as biomarkers in the pathogenesis of postoperative delirium, pending confirmative studies.
Psychotropic Medications in People with Alzheimer’s Disease in Care Homes
Authors: Alotaibi Talal A , Smith Mathew , Lane Emma , Kidd Emma J 
Published: December 2023

AbstractIntroductionDepression in Alzheimer’s disease (AD) is difficult to treat and our preliminary data in care homes, captured from electronic medicines administration records (eMAR) suggested that residents with AD were receiving multiple psychotropic drugs. We are investigating the psychotropic burden of AD residents to determine whether treatment is appropriate. We report here demographic characteristics of all care home residents.MethodsSecondary cross‐sectional, pseudonymised data for residents in care homes were collected by eMAR from 2014‐2020. SQLPRO Studio was used to interrogate the database and mediations were classified using the BNF. Residents with archived records, aged >105 years, with unclear gender or stopped medication status were excluded.Results9060 residents living in 310 care homes across the UK were included. 29% and 71% were male and female, respectively. 38% were ‘youngest‐old’ (65 ‐ 85 years) with 62% ‘oldest‐old’ (85 ‐ 105 years). The mean number of active medications per resident was 10.36 (SD 4.9). ‘Youngest‐old’ males and females had 11.11 (SD 5.2) and 10.54 (SD 5.1) active medications, respectively versus 10.56 (SD 4.9) and 9.99 (SD 4.7) active medications in the Oldest‐old.The top three classes of active mediations were for the nervous (28%), gastrointestinal (19%) and cardiovascular (14%) systems. For the nervous system, the largest classes were analgesics (44%) and antidepressants (17%).Residents administered psychotropic medications were 30.5% male and 69.5% female with 44.5% for ‘youngest‐old’ and 55.5% for ‘oldest‐old’ residents. The medications comprised antidepressants (48.7%), antipsychotics (13.8%) and anxiolytics (6.5%). The mean number of active psychotropic medications per resident was 1.54 (SD 0.794).ConclusionsMost care home residents were female and ‘oldest‐old’ agreeing with the 2011 census and showing the study population is representative of care home residents. Nervous system medications were the largest class with antidepressants the highest psychotropic class and largely prescribed to the female ‘oldest‐old’.
The potential cost‐effectiveness of roflumilast drug treatment in mild cognitive impairment
Authors: Handels Ron , Grimm Sabine , Blokland Arjan , Possemis Nina , Ramakers Inez H.G.B. , Sambeth Anke , Verhey Frans R.J. , Vos Stephanie J. B. , Joore Manuela , Prickaerts Jos , Jönsson Linus 
Published: December 2023

AbstractBackgroundEvidence is needed on the value of new (pharmacological) health technologies in their early stage of development, to support stakeholders (industry, regulators, payers, and health care providers) in decision‐making linked to their further development and introduction in routine care. Early health‐technology assessment supports stakeholders by providing insight into the size and uncertainty of the expected benefits new technologies may have. This can facilitate early guidance on positioning in clinical practice and research recommendations. Our objective was to provide a pragmatic example of the potential cost‐effectiveness of roflumilast treatment in addition to usual care versus usual care alone if prevention of progression to dementia is in part realized in a population of patients diagnosed with a mild cognitive impairment (MCI) at a memory clinic.MethodThe IPECAD open‐source decision‐analytic model was used to simulate the natural disease progression of MCI and dementia and estimate the quality‐adjusted life years (QALYs) and care costs, comparing roflumilast treatment added to usual care with usual care alone. In this model roflumilast proof of concept evidence on a visual 30‐word verbal learning test (0.39 z‐score) was translated using a published risk equation model to a relative risk of 0.93 for developing dementia. The treatment was assumed symptomatic with no effect on mortality.ResultMore lifeyears were spent in MCI in the roflumilast strategy compared with usual care, with 0.2 increment lifeyears (95%CI: 0.0 to 0.6) (see figure 1), and 0.04 incremental lifetime QALYs (95%CI: 0.00 to 0.11) and k€1.3 adjusted societal costs (95%CI: ‐6.3 to 5.5) (see figure 2). This resulted in an incremental cost‐effectiveness ratio of k€34 per QALY (see table 1). Roflumilast was estimated to have a 37% probability of being cost‐effective (net health benefit 95% interval ‐0.27 to 0.42), with uncertainty mainly driven by extrapolating the word learning surrogate outcome to the patient‐relevant outcome of dementia onset, and the efficacy estimate (see figure 3).ConclusionThe potential cost‐effectiveness of roflumilast treatment is uncertain, driven by uncertainty in treatment efficacy and extrapolation to postponing dementia onset. We believe the results indicate a potential for roflumilast and provide several recommendations to consider investing in its future research.