bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long noncoding RNA MALAT1; A novel and potential therapeutic target for Alzheimer’s disease
Authors: Khan Mohammad Moshahid , Tripathi Manish , Xiao Jianfeng 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the most common form of dementia, characterized pathologically by amyloid plaques and neurofibrillary tangles. Despite considerable advances in the knowledge of AD pathogenesis, we know little about preventing or delaying the ongoing neurodegenerative process, indicating that there remain critical gaps in our understanding of disease mechanisms and opportunities for new treatment approaches. Long noncoding RNAs (lncRNAs) are larger than 200 nucleotides, structurally resemble mRNAs but do not encode proteins. LncRNAs participate in regulation of several physiological and pathophysiological processes by modulating gene expression and have been documented in several neurodegenerative diseases. Among them, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant and evolutionary conserved lncRNA and regulates a subset of genes involved in synaptic plasticity, cognitive function and memory.MethodTo test the hypothesis that lncRNA MALAT1 plays an important role in AD pathology, we quantified expression levels of lncRNA MALAT1 in the brains of age‐matched AD patients and cognitively normal controls (Non‐AD) by QRT‐PCR and RNAScope in situ hybridization assays, respectively. We further examined the lncRNA MALAT1 expressions and AD‐related neuropathology in the brains of 5XFAD transgenic mouse model of AD and their WT littermates using dual RNAScope/Immunofluorescence technique.ResultWe observed reduced expressions of lncRNA MALAT1 in the hippocampus of AD brains compared to the non‐AD control brains. Next, we found marked reduced expression of lncRNA MALAT1 in the brain of 5xFAD mice compared to non‐transgenic mice. Interestingly, decreased expression levels of lncRNA MALAT1 are correlated with AD‐related neuropathology and memory deficits in 5xFAD mice.ConclusionThese findings provided compelling evidence that AD is associated with altered expression of lncRNA MALAT1 which may influence several pathways related to neural damage and memory deficits in AD. Because expression patterns, interacting proteins, pathways, and biological functions of lncRNA MALAT1 are remain largely unexplored in AD, understanding how lncRNA MALAT1 regulates AD‐related neuropathology may allow development of effective therapies for this incurable disease.
Physiotherapist And Physiotherapy Student Knowledge, Confidence, Attitudes, And Beliefs About Providing Care For People With Dementia: A Mixed‐Methods Systematic Review
Authors: Quick Stephen M , Snowdon David A , Lawler Katherine , Soh Sze_Ee , McGinley Jennifer L , Callisaya Michele L 
Published: December 2023

AbstractBackgroundClinical care for people with dementia as a primary diagnosis, or as a co‐morbidity, can be complex. Physiotherapists play a key role in the care of people living with dementia in multiple settings. The aim of this systematic review was to understand the attitudes, beliefs, knowledge and confidence of physiotherapists and physiotherapy students when working with people living with dementia.MethodsThis was a mixed‐methods systematic review that included qualitative and quantitative studies. Participants were physiotherapists working in any clinical specialty (e.g. gerontology, orthopaedic, neurological), and physiotherapy students who had completed at least 5 weeks of clinical placement. The phenomena of interest were attitudes, beliefs, knowledge and confidence when working with people with dementia in any setting. Eleven databases were searched. Data synthesis followed a convergent integrated approach according to Joanna Briggs Institute methodology for mixed methods systematic reviews.ResultsFifteen studies were included (9 quantitative and 6 qualitative studies). Seven key themes evolved. Five related to the belief that (1) working with people with dementia is complex and challenging; (2) opportunities for education in dementia care are lacking; (3) working with people with dementia is a specialized area of practice; (4) there are unsupportive systems for working with people with dementia; and (5) people with dementia deserve rehabilitation, but their potential to improve is less certain. One theme related to knowledge (lack of knowledge in some areas of dementia care), and one theme related to confidence (lack of confidence in working with people with dementia).Discussion/ConclusionPhysiotherapists and physiotherapy students have low levels of knowledge and confidence in areas including cognition, communication and management of behavioural symptoms. Given that higher levels of knowledge and confidence may be associated with more positive attitudes and beliefs, dementia education needs of physiotherapists at all levels needs to be addressed.
Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Zhang Shengwei , Evia Arnold M , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B).Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.
Synergistic role of white matter changes and CSF biomarkers in amnestic and non‐amnestic AD phenotypes
Authors: Fernandez Paulo Eduardo Lahoz , Liger Ivy , Curti Nayara Christina de Lima , Bond Marisa Macedo Kuenzer , Falcão Mariana Braga , Bertolucci Paulo Henrique Ferreira 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is pathologically diagnosed based on abnormal amyloid and tau pathology but is also related to additional pathologic processes. (1) The cognitive symptoms are not directly associated with AD pathology but are the consequence of a complex mechanism, showing discordance between clinical symptoms and CSF biomarkers. (2) Previous evidence suggests a range from the synergistic role of white matter signal abnormality (WMSA) and CSF biomarkers on AD to no relationship between the two. (1) We aimed to analyze the CSF biomarker profiles, and brain MRI changes in AD patients with different phenotypes.MethodCSF was collected by lumbar puncture from 40 individuals with AD. We analyzed CSF levels (Aβ‐42, Aβ‐40, t‐tau, p‐tau, tau / Aβ‐42, and Aβ‐42/40) in two different samples. The clinical characteristics included: AD phenotype (amnestic or non‐amnestic), age, gender, education, and age‐onset. We used the brain MRI scales: MTA (mesial temporal lobe atrophy), and Fazekas, for white matter signal abnormality (WMSA), considering pathological changes (≥ 2).ResultPreliminary results in 16 patients showed that most of the patients with CSF typical AD pattern presented an amnestic phenotype, revealing WMSA changes. The patients with no CSF changes showed little or no WMSA changes in both clinical presentations. The amnestic phenotype showed more MTA changes in patients with typical AD CSF pattern, and no difference was found between the phenotypes in patients with no CSF changes.ConclusionIt can be a positive relation between cerebrovascular diseases, WMSA changes, and CSF pathological changes in AD, regardless of the phenotype, supporting that Aβ pathology may lead to secondary vascular damage including white matter lesions.References: 1. Lindemer ER, Greve DN, Fischl B, Salat DH, Gomez‐Isla T. White matter abnormalities and cognition in patients with conflicting diagnoses and CSF profiles. Neurology. 2018 Apr 24;90(17):e1461‐9.2. Alexopoulos P, Roesler J, Thierjung N, Werle L, Buck D, Yakushev I, et al. Mapping CSF biomarker profiles onto NIA‐AA guidelines for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2016 Oct;266(7):587‐97.
Cognitive function in older adults with hearing loss; outcomes for treated versus untreated groups at 3‐year follow‐up.
Authors: Sarant Julia Z , Harris David , Maruff Paul , Schembri Adrian , Lemke Ulrike , Launer Stefan , Phillips Jocelyn , Nixon Grace , Canagasabey Manasi , Anderson Charlotte , Davine Ella 
Published: December 2023

AbstractBackgroundHearing loss has been identified as the largest potentially modifiable risk factor for dementia and affects 50% adults aged 50‐64 years, and 70% aged 70 years and older. The quality of evidence the effect of hearing aid use on cognition in older adults is currently poor due to methodological limitations. Few studies have objectively studied these outcomes beyond 6‐12 months. This prospective longitudinal observational cohort study investigated the effects of hearing aid use on cognitive performance in older adults over 3 years.Method183 first‐time hearing aid users aged 60 years and older with mild to severe hearing loss were assessed using gold standard measures before hearing aid fitting, with subsets of this group re‐assessed after 18 and 36 months as they reached these timepoints. Outcomes for the treatment group were compared with those of participants of a large longitudinal cohort study of community‐living older adults (AIBL) using the same measures. Objective assessment measures included cognitive function, hearing loss, hearing aid use, genetic phenotyping, and speech perception. Subjective measures included hearing disability, mood, quality of life, social isolation, and loneliness.ResultThe treatment group showed good hearing aid compliance, significant improvement in speech perception (quiet and noise) and decreased self‐reported listening disability despite further significant hearing loss over the 3‐year follow‐up. There was significant improvement in cognitive performance from baseline for the treatment group versus the comparative group for working memory, attention, psychomotor function, and visual learning. Comparatively, AIBL participants showed statistically significant decline across all cognitive functions.ConclusionOlder adults with untreated hearing loss are expected to decline cognitively at 2‐5 times the rate of adults without hearing loss. Comparatively, cognitive performance in treated participants in this study instead improved after 3 years of hearing aid use, while the comparative group declined. These results suggest that treatment of hearing loss with hearing aids may delay cognitive decline.
Specific Association of Worry and Amyloid‐β Deposition in Cognitive Unimpaired Older Adults
Authors: Lee Soyoung , Siddiqi Shan , Donovan Nancy J 
Published: December 2023

AbstractBackgroundAnxiety symptoms are common in cognitively unimpaired (CU) older adults prior to the onset of cognitive impairment. Evidence suggests that anxiety symptoms may be sequelae of amyloid‐beta (Aβ) deposition in early Alzheimer’s disease (AD) and/or anxiety may potentiate the pathophysiologic process. Despite this pivotal role, the specific components of anxiety associated with high brain Aβ in CU older adults are relatively unknown. It was previously reported that Aβ deposition is associated with a global anxiety score measured by State‐Trait Anxiety Inventory‐6 (STAI‐6) but not depression measured by Geriatric Depression Scale (GDS) total scores. Here, we examined the specific associations of individual anxiety symptoms with Aβ.MethodOlder adult participants were screened for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (“A4 study”) and underwent assessments of anxiety (STAI‐6), depression (GDS), cognitive performance (MMSE and Preclinical Alzheimer Cognitive Composite /PACC), subjective cognition (Cognitive Function Instrument/CFI) and cortical Aβ deposition using Florbetapir PET standardized uptake value ratio (SUVR). Linear regression models estimated associations of STAI‐6 items, “calm,” “tense,” “upset,” “relax,” “content,” and “worry,” with Aβ deposition, adjusting for multiple potential confounders.ResultThe sample (n = 4486) were older adults ages 65 ‐ 85 (mean [SD] age, 71.29 [4.67] years, included 2647 women (59%) and 1323 (29.5%) who were classified as Aβ+. STAI‐6 total score ranged from 6 ‐ 24 (Mean 9.9 [3.1]). A significant positive association was found between the anxiety item measuring “worry”, and Aβ, adjusting for age, sex, education, marital status, depression (GDS), objective cognition (MMSE or PACC), and subjective cognition (CFI) [Table 1]. There were other significant (negative) associations between items measuring “calm” and “relax” and Aβ in similar regression models. Only the association of “worry” with Aβ remained significant after further adjustment for global anxiety measured by the total STAI‐6 score.ConclusionIn a large, well‐characterized sample of CU older adults, worry was significantly and most strongly associated with Aβ, independent of psychosocial factors, subjective and objective cognition and global anxiety. These findings suggest that self‐reported worry may have unique explanatory value in the clinical assessment of CU older adults at high risk of AD and cognitive impairment.
Xanamem shows pro‐cognitive activity with clinically meaningful effect sizes across 3 independent, placebo‐controlled clinical trials
Authors: Hilt Dana , Rolan Paul , Taylor Jack , Miller Tamara , Jaros Mark , Harrison John E , Ritchie Craig W , Woodward Michael 
Published: December 2023

AbstractBackgroundXanamem® is a brain‐penetrant inhibitor of 11‐beta hydroxysteroid dehydrogenase type 1, which converts intracellular cortisone to cortisol and is highly expressed in brain regions such as the hippocampus. Elevated plasma and CSF cortisol is strongly associated with cognitive decline.MethodEffects of Xanamem on cognition were assessed in 3 independent, placebo‐controlled, double‐blind trials. The XanaHES (n = 42, 20 mg) and XanaMIA (n = 105, 5 & 10 mg) Phase 1b trials used the computerised Cogstate system to assess cognition in normal, older volunteers. The XanADu‐X biomarker extension study (n = 72, 10 mg) explored clinical and cognitive outcomes in subgroups (n = 34 each) of the XanADu Phase 2a AD trial with higher (H) or lower (L) plasma p‐Tau181 in a new prospective analysis. To compare the results across trials, we focus on the cognitive effect sizes measured by the Cohen’s statistic (treatment effect vs. placebo / pooled baseline standard deviation).ResultXanamem was safe and well‐tolerated with no treatment‐related SAEs and the predominantly mild AEs were generally equally distributed between Xanamem and placebo. In XanaHES and XanaMIA, a pattern of clinically significant improvements was observed in attention and working memory compared to placebo in the Xanamem groups, with Cohen’s d ranging up to 1.27. Improvements from baseline were observed in both Xanamem and placebo in domains of episodic memory and executive function without a treatment difference. In XanADu, Xanamem demonstrated clinically significant benefit with a Cohen’s d of 0.41 on the CDR‐SB compared to placebo in the H group but not in the L group. In both L and H groups improvements in executive function were seen favouring Xanamem (Cohen’s d = 0.34 and 0.26, respectively) and the MMSE (Cohen’s d = 0.32 and 0.16, respectively). There were no improvements observed on original XanADu primary outcome measures of ADAS‐Cog14 and ADCOMs.ConclusionXanamem displays activity in multiple domains of cognition including attention, working memory, and executive function with clinically meaningful effects in normal subjects and in patients with p‐Tau‐elevated mild AD. These data suggest Xanamem may be both a pro‐cognitive drug and disease‐modifying agent and guide design of future trials.
Prevalence of Cognitive Domain Impairments in Mild Cognitive Impairment Subtypes in the NACC Database
Authors: Lerner Alan J. , Appleby Brian , Elkasaby Mohamed , Leverenz James B , Malone Joseph , Miller‐Scott Lindsay J , Murphy Tamara B , Ogrocki Paula K. , Pillai Jagan A. , Duffy Charles 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD. In this study, we explore frequencies of domain impairment by MCI subtype, and frequency of each combination of (memory ±) all combinations of Language, Attention, Executive and Visuospatial impairment in the NACC database. This is of practical importance for both localization of amyloid or tau deposition as well as relative localization of areas of deficit.MethodUsing the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with sub‐typing. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. 9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD.ResultFigure one shows the distribution overall of domain specific impairment by MCI subtype. Except for ASD, Executive function was the most common domain affected, and visuospatial was the least common. NAMD had higher percentages affected for all domains compared to AMD. In Figure 2, all combinations of language, executive, attention and visuospatial are compared. The most frequent combination was Language‐Executive, and the least common combination was Language‐Attention‐Visuospatial. The mean absolute percentage difference between AMD and NAMD was 2.2%. The Spearman’s rho of AMD vs. NAMD was 0.845.ConclusionWithin an MCI subtype, there is substantial variability in the frequency of individual domains. However, comparison of AMD and NAMD shows striking uniformity in frequency of combinations of individual domains with very correlation. The latter findings suggests that Amnestic and Nonamnestic multidomain subtypes may be closely related in pathophysiology but show greater heterogeneity within a MCI subtype.
Volumetric and cognitive findings in transient global amnesia: results of the FORGOT cohort
Authors: Hernández Micaela A , Chaves Hernan , Allegri Ricardo Francisco , Calandri Ismael Luis 
Published: December 2023

AbstractBackgroundTransient global amnesia (TGA) is a sudden onset syndrome of episodic amnesia with unclear pathophysiology. Although expected to last less than 24 hours, different studies described persistent cognitive impairment primarily in memory and executive functions. We aim to analyze the cognitive performance and cortical volume of patients after a TGA as contributing factors to its pathophysiology.MethodCase‐control study of matched TGA subjects (n = 50) and normal controls (NC) (n = 50). All were studied with brain MRI with volumetric T1 sequences (in TGA subjects performed 1.4 months after the episode (SD±3.4)). Voxel‐based morphometry (VBM), region‐based morphometry (RBM) and surface‐based morphometry (SBM) steps were performed using an extension of the software package SPM12. All subjects were evaluated with a modified UDS3 neuropsychological battery. TGA patients were assesed 3 months after the event to avoid confusors. A deficit in each cognitive domain was diagnosed when individuals scored below ‐1.5 SD for normal values for age, sex and education. Anxiety, depression and cognitive complaints were also assessed. For VBM and RBM, a two‐sample independent t‐test was modeled and estimated with TIV, sex, and age as covariates. For SBM, a two‐sample independent t‐test without covariates was modeled and estimated. We applied the FDR method for multiple comparison corrections and defined a p<.05 threshold for statistical significance.ResultAmong 50 patients with TGA, 54% were female. Mean age was 66 (±9). No significant differences were found in VBM analysis. In the RBM test, we observed reduced volume in the left accumbens nucleus (figure 1) and in SBM, reduced cortical thickness on the right temporal pole and ventromedial visual area 2 (figure 2). No differences were found among cognitive performance between TGA and control patients (table 1).ConclusionThe absence of abnormalities in cortical volume and cognitive failure beyond three months of the event affirms the transient nature of the episode and dispells the association with a neurodegenerative disease as a predisposing factor. SBM abnormalities in distant regions may suggest a network disruption beyond the hippocampus.