bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medial temporal lobe subregional atrophy in ageing and Alzheimer’s disease: A longitudinal study
Authors: Chauveau Lea , Kuhn Elizabeth , De la Sayette Vincent , Chetelat Gaël , de Flores Robin 
Published: December 2021

AbstractBackgroundMedial temporal lobe (MTL) subregions are sensitive to Alzheimer’s disease (AD) but also to normal ageing. To enhance the clinical utility of this biomarker, we need to improve our understanding of the differential effects of age versus AD by i) encompassing the full clinical range from cognitively unimpaired (CU) to dementia, ii) including all MTL‐subregions with up‐to‐date approaches and iii) using longitudinal designs to assess atrophy more sensitively. This study aimed to fill these gaps.MethodLongitudinal T1‐weighted MRI of 209 CU participants aged from 19 to 85 were used to estimate age‐related trajectories using polynomial best‐fit from model selection. AD‐related changes were compared i) across the Alzheimer’s continuum in 121 participants divided into amyloid‐β negative (Aβ‐, controls) and Aβ+ CU elderly, Aβ+ mild cognitive impairment (MCI) and AD demented patients; and ii) between 19 MCI‐to‐AD dementia converters and 34 non‐converters. All participants were followed up to 47 months. MTL‐subregions (hippocampus [HPC] ‐anterior[a] and posterior[p]‐, entorhinal cortex [ERC], Brodmann area [Ba] 35 and 36 ‐as perirhinal cortex [PRC] components‐, and parahippocampal cortex [PHC]) were segmented using a new longitudinal pipeline (LASHiS) and manually corrected when necessary. Statistical analyses were performed using mixed models.ResultAdult lifespan models highlighted both linear (PRC, Ba35, Ba36, PHC) and non‐linear (HPC, aHPC, pHPC, ERC) trajectories (Figure 1). Aβ+ MCI and AD patients showed steeper volume decline over time in most subregions compared to controls. No significant differences between controls and Aβ+ CU or between Aβ+ MCI and AD patients were observed (Figure 2). MCI‐to‐AD dementia converters showed significant greater volume decline only in hippocampal subregions compared to non‐converters (Figure 3).ConclusionOur results emphasized the benefits of studying MTL‐subregions to distinguish age‐related changes from AD. MTL‐subregions were unequally vulnerable to the detrimental effects of ageing, and subregions displaying a late‐onset decline were particularly involved in AD from the MCI‐stage. However, none of these biomarkers detected changes at the preclinical stage (Aβ+ CU). Finally, our results suggested that hippocampal volumes could constitute reliable predictors of MCI‐to‐AD dementia conversion. Together, these findings provide a better understanding of MTL alterations, which is crucial for the definition of AD‐specific biomarkers.
Sildenafil reduces the incidence of Alzheimer’s disease
Authors: Cheng Feixiong , Fang Jiansong , Zhang Pengyue , Zhou Yadi , Chiang Chien‐Wei , Pieper Andrew A. , Cummings Jeffrey L. 
Published: December 2021

AbstractBackgroundThere is an urgent need for effective therapeutic treatments for patients with Alzheimer’s disease (AD).MethodTo address this need, we developed an endophenotype molecular network‐based methodology for AD drug repurposing and then validated network‐based predictions using state of‐the‐art pharmacoepidemiologic analysis of 7.23 million U.S. commercially insured individuals. We conducted five comparison analyses: (i) sildenafil (n = 116,412) vs. a matched control (n = 460,356), (ii) sildenafil vs. diltiazem, (iii) sildenafil vs. losartan, n = 664,265), (iv) sildenafil vs. glimepiride, and (v) sildenafil vs. metformin, n = 723,082). We estimated the un‐stratified Kaplan‐Meier curves and conducted propensity score stratified log‐rank tests and the Cox regression model.ResultWe found that sildenafil usage was significantly associated with a 69% reduced risk of AD, compared with matched non‐sildenafil users (hazard ratio [HR] =0.31, 95% confidence interval [CI] 0.25‐0.39, P < 1 × 10‐8) after 6 years of follow‐up. Propensity score‐stratified cohort studies reveal that sildenafil usage is significantly associated with a 65% reduced risk of AD compared to diltiazem (HR 0.35, 95% CI 0.29‐0.44, P < 1 × 10‐8), a 55% reduced risk compared to losartan (HR 0.45, 95% CI 0.35‐0.55, P <1 × 10‐8), a 64% reduced risk compared to glimepiride (HR 0.36, 95% CI 0.28‐0.45, P <1 × 10‐8), and a 63% reduced risk compared to metformin (HR 0.37, 95% CI 0.30‐0.45, P <1 × 10‐8). Sildenafil usage was significantly associated with reduced likelihood of AD across all five drug cohorts in individuals (Figure 1) with coronary artery disease (CAD), hypertension (HT), and type 2 diabetes (T2D), and in individuals after excluding CAD, HT, and T2D. Age‐specific subgroup analyses showed that sildenafil was significantly associated with reduced likelihood of AD across all five drug cohorts in both mid‐older (65‐74 years) and older individuals (75‐100 years). In vitro experiments show that sildenafil downregulates GSK3β and CDK5 in human microglia cells, supporting a possible mechanism for its beneficial effect in AD.ConclusionThis study supports a proof‐of‐concept of endophenotype‐based drug discovery and identifies that sildenafil is a promising drug candidate for prevention and treatment of AD.
Results of the first‐in‐human, randomized, double‐blind, placebo‐controlled phase 1b study of lumbar intrathecal bolus administrations of antisense oligonucleotide (ISIS 814907; BIIB080) targeting tau mRNA in patients with mild Alzheimer’s disease
Authors: Mummery Catherine J , Junge Candice , Kordasiewicz Holly B , Mignon Laurence , Moore Katrina M , Yun Chris , Baumann Tiffany L , Li Dan , Norris Daniel A , Crean Rebecca , Graham Danielle , Huang Ellen , Ratti Elena , Lane Roger M 
Published: December 2021

AbstractBackgroundISIS 814907 (BIIB080) is an antisense oligonucleotide (ASO) that hybridizes to a complementary nucleotide sequence of mRNA of the human microtubule‐associated protein tau (MAPT) gene, preventing production of tau protein. Accumulation of hyperphosphorylated tau is associated with cognitive decline and brain atrophy in Alzheimer’s Disease (AD). The placebo controlled period of the Phase 1b multiple ascending dose (MAD) study of ISIS 814907 in patients with mild AD is complete and the open‐label long term extension (LTE) is ongoing in the UK, Canada, Germany, Sweden, Netherlands and Finland (EudraCT: 2016‐002713‐22; NCT03186989).MethodsThe study is divided into 2 parts. Part 1 is the MAD study, comprising a 3‐month Treatment Evaluation (TE) Period and a 6‐month Post‐Treatment (PT) Period. Part 2 is the open‐label LTE, comprising a 12‐month TE Period and a 4‐ or 6‐month PT Period. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal (IT) bolus administrations of ISIS 814907 or placebo. Male or female patients aged 50‐74 years with mild AD and confirmed amyloid positivity (via CSF) at Screening were considered eligible. The primary objective was to assess safety and tolerability of multiple IT bolus administrations of ISIS 814907. The secondary objective was to evaluate CSF pharmacokinetics (PK). Exploratory objectives include assessment of plasma PK, target engagement and disease biomarkers, genotype and clinical endpoints relevant to AD.ResultsAll subjects (N=46) completed the MAD TE Period and 43 subjects completed the PT Period. All AEs were mild/moderate in severity. No serious AEs occurred in subjects receiving ISIS 814907. Dose‐dependent mean reduction from baseline in CSF total tau and phospho‐tau was observed in the TE period and continued in the PT period. CSF total tau and phospho‐tau reductions were comparable.ConclusionsIT bolus administration of multiple ascending doses of ISIS 814907 over 3 months was well‐tolerated in patients with mild AD. The robust lowering of CSF total tau and phospho‐tau warrants further investigation for the treatment of AD.
Trajectories of gait and cognitive decline in aging, and as a function of parental longevity and the motoric cognitive risk syndrome
Authors: Jayakody Shanika Oshadi , Ayers Emmeline , Verghese Joe , Barzilai Nir , Milman Sofiya , Weiss Erica , Blumen Helena M. 
Published: December 2021

AbstractBackgroundAccelerated gait decline in aging often precedes mild cognitive impairment, Alzheimer’s disease, and related dementias. The relative trajectories of gait and cognitive decline are poorly understood, particularly, in older adults who are a) more resilient to cognitive impairment because they are offspring of parents with exceptional longevity (OPEL) and, b) at increased risk for cognitive impairment and dementia because of the Motoric Cognitive Risk (MCR) syndrome. MCR is a pre‐dementia syndrome, characterized by slow gait and subjective cognitive complaints. We examined trajectories of gait and cognitive decline in older adults overall, and as a function of parental longevity and MCR.MethodLonGenity study participants (n=1,095; M Age=75.4±6.7 years) were followed for up to 12 years (M =6.6±3.4 years). Participants were of Ashkenazi Jewish descent and free of dementia at baseline. 53% were OPEL and 9% had MCR. Gait speed was measured on an instrumental walkway. Standardized performance on 13 different cognitive tests were examined separately, and as a composite global cognition score. Linear mixed‐effects models adjusted for baseline age, sex, education, cognitive impairment, and parental longevity were used to examine trajectories of gait and cognition over time – and as modified by parental longevity and MCR.ResultGait speed and performance on all cognitive tests (except phonemic fluency and digit span) declined with time. Gait speed (β= ‐0.076; 95% CI= ‐0.083‐0.070) declined faster than cognitive tests, including figure copy (β= ‐0.041; 95% CI= ‐0.050‐0.031), digit symbol substitution (DSST; β= ‐0.036; 95%CI= ‐0.041‐0.031), and trail‐making test interference (β= ‐0.032; 95%CI= ‐0.024‐0.040). Global cognition, DSST, and logical memory declined at a slower rate in OPEL. Figure copy performance declined at a faster rate in MCR.ConclusionThese findings suggest that 1) gait declines faster than most cognitive functions in aging, 2) OPEL are more resilient to cognitive decline in general, and processing speed/attention and memory in particular, and 3) individuals with MCR are more susceptible to visuo‐spatial and executive function decline. This study adds important knowledge of trajectories of gait and cognitive decline in aging, and identifies a protective factor and a risk factor of age‐related cognitive decline.
Hippocampal connectivity in illiterate adults from Brazil
Authors: Resende Elisa de Paula França , Rosen Howard J , Friedlaender Clarisse Vasconcelos , Lara Vivian Proença , Santiago Ana Luisa Carvalho , Silva Lênio Lúcio Gávio , Brown Jesse A , Maciel Francisca , Grinberg Lea T , Caramelli Paulo 
Published: December 2021

AbstractBackgroundThe role of hippocampal connectivity for good memory performance is well known in persons with high educational level. However, it is understudied the role of hippocampal connectivity in illiterate populations.MethodsThirty‐nine illiterate adults underwent resting state functional MRI and an episodic memory test (Free and Cued Selective Reminding Test). We correlated the hippocampal connectivity at rest with the free recall scores. Analyzes were corrected for head motion and physiological BOLD signal.ResultsParticipants were most female (66%) and black (79%) and the mean age was 49 years‐old (±13.9). The mean score on free recall was 27.2 (±10.7) out of 48 points. We found a significant correlation between the hippocampus and the right parahippocampal gyrus, right insula and right basal ganglia. However, we did not find an association between the hippocampal connectivity and the memory scores.ConclusionsIlliterate adults have a significant correlation between the hippocampus and the right insula and basal ganglia. The lack of association with memory scores might be associated with low brain reserve in this group of individuals.
Childhood trauma and social resources moderate relationships between perceived discrimination and late‐life cognition in older African Americans
Authors: Pugh Erika , Divers Ross , Calamia Matthew 
Published: December 2021

AbstractBackgroundPerceived discrimination (PD) is a common stressor for African Americans (AA) that has been linked to poorer cognition in old age, although factors that increase or decrease this association remain understudied. For example, a history of childhood trauma, for which African Americans are at greater risk, may affect later cognition by making individuals more stress reactive. In contrast, there may be other factors (e.g. socioeconomic status, access to cognitively stimulating resources) that buffer the negative association between PD and cognition. The purpose of this study was to examine these possible moderators of the association of PD with cognition in a sample of older AAs (n = 583),MethodData was obtained from the Minority Aging Research Study (MARS), a longitudinal, epidemiologic cohort study of cognitive decline and risk of AD in older (65+) AAs. Moderation analyses were conducted to identify the potential effects of childhood trauma and protective factors on the relationship between PD and cognition,ResultChildhood trauma, specifically greater parental violence, increased the negative association between PD and perceptual speed. Additionally, both early childhood socioeconomic status and access to resources that support cognitive activities throughout one’s life decreased the negative association between PD and both global cognition and working memory,ConclusionIn sum, experiencing childhood trauma significantly impacts the effects of PD on cognition in older AAs, representing a key target for interventions. Protective factors, particularly access to cognitively stimulating resources throughout one’s life, may represent an actionable target for promoting cognitive wellbeing in older AAs.
Fluid intelligence and its neural correlates in early onset mild cognitive impairment
Authors: Carbone Chiara , Bardi Elisa , Corni Maria Giulia , Fiondella Luigi , Salemme Simone , Vinceti Giulia , Tondelli Manuela , Molinari Maria Angela , Chiari Annalisa , Zamboni Giovanna 
Published: December 2021

AbstractBackgroundFluid intelligence refers to the ability of abstract reasoning, problem‐solving and other mental activities considered to be independent from learned knowledges and experience. It has been demonstrated that fluid intelligence is compromised in Mild Cognitive Impairment (MCI), but it also declines with ageing. We tested if fluid intelligence is also affected when MCI occurs before 65 years of age (i.e., in early‐onset MCI) and studied its specific functional and structural brain correlates independently from the effect of ageing.MethodEighty‐five subjects with early‐onset MCI (cognitive symptoms onset < 65 years) underwent extended neuropsychological assessment including Raven’s Coloured Progressive Matrices (RCPM), a culture‐free non‐verbal relational reasoning task that is considered a proxy of fluid intelligence. They also underwent multimodal Magnetic Resonance Imaging (MRI) protocol on a 3T scanner including high‐resolution T1 and sequences acquired at rest for functional MRI (fMRI). Performance at RCPM was related to regional grey matter volume using Voxel Based Morphometry (VBM) and to functional connectivity of resting‐state networks (RSNs) known to be related to cognition using independent component analysis.ResultsThe median RCPM score was 27 (range 8‐36, with 36 being the maximum obtainable score). Among all 85 patients, only 11.8% (N=10) performed below the age and education‐corrected cut‐off. These patients also had significantly lower scores in almost all the remaining neuropsychological tests, suggesting that they were in a more severe stage of MCI (i.e., close to conversion). VBM results showed that, across all patients, decreased performance on RCPM was associated with focal atrophy in right fronto‐temporal and bilateral parietal areas (Figure 1). FMRI acquired at rest showed that better performance on RCPM was associated with lower functional connectivity in areas of the anterior DMN and with higher functional connectivity in areas of the left fronto‐parietal RSN (also indicated as the working memory RSN).ConclusionIn patients with early‐onset MCI fluid intelligence is relatively preserved, associated with lower atrophy in right fronto‐temporal and bilateral parietal regions, and with decreased functional connectivity in the anterior DMN and increased in the left fronto‐parietal network.
Remote diagnosis of dementia using AI methods on clock drawing images
Authors: Amini Samad , Zhang Lifu , Hao Boran , Gupta Aman , Song Mengting , Karjadi Cody , Au Rhoda , Paschalidis Ioannis 
Published: December 2021

AbstractBackgroundDetection of any form of cognitive impairment is challenging and the subjects have to undergo numerous evaluations and clinical tests. Hence, it would be of great importance to design a reliable and accessible procedure by which patients may get diagnosed for dementia remotely. The capability of the Clock Drawing Test (CDT)as an effective cognitive assessment tool has motivated us to develop an online diagnostic tool by leveraging artificial intelligence techniques.MethodDigital pen recordings of 3,263 normal subjects and 160 with dementia in the Framingham Heart Study (FHS) were collected, where all subjects have completed two analog clock drawings, one drawn on command and the other by copying. Using the idea of transfer learning, we first modified and trained a Convolutional Neural Network (CNN) pre‐trained on the ImageNet dataset to extract high level features of the CDT images, which generated a score associated with the likelihood of dementia for each patient. The proposed method integrates the scores of the CDT images and other demographic information. Therefore, the generated scores for both command and copy CDTs along with age were used to train a logistic regression model to classify individuals as demented or normal.ResultWe have evaluated the performance of the developed models by applying 5‐fold cross validation on the FHS dataset. On the test dataset, the model (modified pre‐trained CNN) based on command CDT images yielded an AUC of 0.81±0.043. The logistic regression model using age and the generated scores of command and copy CDTs, yielded an average AUC and average F1 score of 0.92±0.008 and 0.94±0.008, respectively.ConclusionOur method need not necessarily have access to digital biomarkers or clinical tests since the CDT can be completed using pen and paper, capturing the image using a smartphone. Hence, our method offers a cost‐effective and accurate screening tool to diagnose dementia and related diseases remotely.
Whole genome shotgun metagenomic sequencing to identify differential abundant microbiome features between dementia and mild cognitive impairment (MCI) in AD subjects
Authors: Jeong Sohyun , Huang Li‐Kai , Tsai Ming‐Ju , Liao Yi‐Tyng , Lin Yow‐Sien , Chang Chi‐feng , Chi Wei‐Kuang , Hu Chaur‐Jong , Hsu Yi‐Hsiang 
Published: December 2021

AbstractBackgroundPrevious studies demonstrated differential abundances of gut microbiota between Alzheimer’s disease (AD) and normal controls (NCs). However, gut microbiota distribution between dementia and amnestic mild cognitive impairment (aMCI) in AD subjects lacks clear data. With whole‐genome shotgun metagenomic sequencing (WGS), we aimed to identify differentially abundant microbiota as well as metabolic pathways between dementia and aMCI in AD subjects.MethodFecal samples from AD subjects were collected at Shuang‐Ho Hospital, Taipei Medical University, Taiwan and analyzed by WGS technique. 16S rRNA sequencing data from NCs were acquired from Taiwan Microbiome Database. Mini‐Mental State Examination (MMSE) and clinical dementia rating (CDR) scores, food frequency questionnaire, and other principal characteristics were collected along with fecal samplings. Alpha and β diversities were estimated by Chao1 and Shannon indices, and PCoA, respectively. We applied univariate tests (t‐test/Mann‐Whitney) and other modeling approaches (HAllA, MaAsLin, DESeq2, and LEfSe) to identify differential microbial biomarkers.ResultA total of 48 AD (38 dementia and 10 aMCI) and 50 NC samples were analyzed. Alpha diversities at the taxonomy level of Family, Class, and Genus were significantly different between AD and NC. With the results commonly confirmed in the MaAsLin (age and sex‐adjusted) and other models, we found significantly increased abundances of phyla Firmicutes and Actinobacteria; but decreased abundances of Bacteroides and Acidobacteria in AD subjects (Figure 1). There was no significant difference in both α and β diversities between dementia and aMCI in AD subjects. However, lower MMSE (higher CDR) scores in the AD subjects were associated with higher abundances of strains in Blautia hydrogenotrophica, Anaerotruncus colihominis and Gordonibacter pamelaeae. In addition, metabolic pathway analyses by HAllA demonstrated microbial glucose and S‐Adenosyl‐L‐methionine (SAMe) pathways were associated with cognitive function scores (Table 1) and more enriched in aMCI (not significant).ConclusionWe identified significantly higher strains in AD subjects with lower MMSE (higher CDR) scores suggesting that these microbes may have deleterious effects to cognitive function. In addition, the findings of higher enrichment of microbial glucose and SAMe metabolism in aMCI compared to dementia may implicate their beneficial roles in cognitive function in AD subjects.