bluuebunny/crossref_metadata_2025_split huggingface dataset:
The use of genetic risk prediction to study prodromal Alzheimer’s disease in the PISA study
Authors: Lupton Michelle K. , Fazlollahi Amir , Ceslis Amelia , Fripp Jurgen , Rose Stephen , Salvado Olivier , Robinson Gail , Guo Christine , Breakspear Michael , Martin Nick 
Published: December 2020

AbstractBackgroundNeuropathology accumulates for decades prior to the onset of cognitive decline in Alzheimer’s disease (AD). Interventions to modify the course of the disease have the greatest potential to avert neuronal death and later disease burden if they are introduced during this crucial window. Our prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) aims to characterise the natural history of AD at its prodromal phase. Using genetic risk prediction we have identified middle‐aged and older Australians at high risk of dementia to enable the discovery of biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease conversion.MethodWe utilized APOE genotype and polygenic risk scores (PRS) to identify individuals at high and low risk of AD. We have leveraged our extensive in‐house cohorts, comprising ∼15,000 individuals aged 40‐70 years with available genome wide genotyping data to generate a genetically enriched cohort for investigating prodromal markers for AD. Online surveys and cognitive testing are used to collect information from a national sample currently totally nearly 3,000 participants. Subjects (N = 400) from a defined at‐risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment and/or early AD) have taken part in onsite visits for lifestyle monitoring, cognitive testing, blood sample donation, MRI and PET imaging.ResultA high prediction accuracy for AD with an AUC of 78.2% can be achieved by a prediction model including APOE genotype, and PRS (containing GWAS association SNPs with P value <0.5) with the PRS adding significant predictive value over APOE alone. The association of genetic factors with baseline imaging and neuropsychological phenotypes will be presented as well as multivariate analysis investigating the influence of genetic risk on inter‐individual phenotypic relationships.ConclusionThe PISA study is an at risk AD cohort enriched by genome‐wide risk prediction, aiming to validate early markers of prodromal Alzheimer’s disease that can be utilized in middle age. This study will help elucidate changes in early prodromal AD risk variants observed in middle age, and evaluate which measures show the earliest changes.
Montreal Cognitive Assessment 5‐minute protocol is accurate in screening for mild cognitive impairment in the rural African population
Authors: Masika Golden Mwakibo , Yu Doris S.F. , Li Polly W.C. , Wong Adrian , Lin Rose S.Y. , Lee Diana T.F. 
Published: December 2020

AbstractBackgroundThe prevalence of dementia in Tanzania, as in other developing countries is progressively increasing.1 Yet the screening instruments for the pre‐clinical stage of the diseases are lacking. This study examined the diagnostic accuracy of the Montreal Cognitive Assessment‐5‐minutes protocol (MoCA‐5‐min) among older adult in the rural Tanzania.MethodsAfter cultural adaptation following Brislin’s approach,2 the MoCA‐5‐min and the IDEA cognitive screening were concurrently administered to community‐dwelling older adults (n=202) in Chamwino district and 40 re‐evaluated at 6 weeks. Exploratory factor analysis (EFA) using principal component method and oblique rotation was performed to determine the underlying factor structure of the scale. The concurrent and the diagnostic accuracy of the MoCA‐5‐min were examined by comparing its score with IDEA cognitive screening and the psychiatrist’s diagnosis using DSM‐V criteria respectively.ResultsThe EFA found that all the MoCA‐5‐min items highly loaded into one component, with factor loading ranging from 0.550 to 0.879. The intraclass correlation coefficient for 6 weeks test‐retest reliability was 0.85. Its strong significant correlation with the IDEA screening (Pearson's r = 0.614, p < 0.001) demonstrated a good concurrent validity. Using the psychiatrist’s rating as a gold standard, the area under the curve (AUC) was 0.861, (95% CI = 0.799 – 0.922) (Figure 1). With the optimal cut‐off score for MCI at 22, the sensitivity was 80% and specificity was 74%. As for dementia, at a score of 16 the sensitivity was 90% and specificity was 80%, whereas the AUC was 0.910, (95%CI = 0.852 – 0.967) (Figure 2). Upon stratifying the sample into different age groups, the optimal cut‐off scores tended to decrease with the increase in age (Table 1).ConclusionThe MoCA‐5‐min is reliable and provides a valid and accurate measure of cognitive decline among older population in the rural settings of Tanzania. The use of varying cut‐off scores across age groups may ensure a more precise discriminatory power of the MoCA‐5‐min. References: 1. WHO. Dementia: Key facts [Internet]. World Health Organization ‐ Fact Sheets. 2019 [cited 2019 Nov 11]. p. 1–5. Available from: https://www.who.int/news‐room/fact‐sheets/detail/dementia. 2. Brislin RW. Back‐translation for cross‐cultural research. J Crosss Cult Psychol. 1970;1(3):185–216.
Alzheimer’s disease risk factor mutations in patients diagnosed with Creutzfelt‐Jakob disease
Authors: Bagyinszky Eva , Farrer Lindsay A. , Farrell John , Van Vo Giau , Shim KyuHwan , An Seong Soo , Kim SangYun 
Published: December 2020

AbstractBackgroundCJD is a fatal neurodegenerative disease without successful therapy. Many variants in PRNP gene was established as causative gene for Creutzfeldt‐Jakob disease, but it does not define all CJD cases. Pathological overlap may be possible between CJD and AD.MethodIn this study, 40 DNA Korean CJD patients were analyzed by whole exome sequencing and their in‐depth analyses. Complex genetic screening analyses were performed on genes, associated with neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD). Rare and possible damaging variants were filtered, and analyzed with pathway analysis tools, such as ClueGo or STRING.ResultSix PRNP variants were identified among patients. The majority of possible CJD patients did not reveal strong genetic correlations with PRNP, APP, PSEN1 and PSEN2 genes. Instead significant numbers of variants were identified from the genes, which were previously indicated as risk factors in other neurodegenerative diseases, including Alzheimer’s disease.ConclusionSuch involvements of risk genes of AD and PD could suggest few common disease pathways among the various neurodegenerative diseases. Further studies will be carried out on assess their involvement in CJD and its disease progression.
Vitamin B12 may prevent Aβ oligomer‐induced neurotoxicity in Alzheimer's disease
Authors: Kimura Atsushi Michael , Tsuji Mayumi , Yasumoto Taro , Oguchi Tatsunori , Mori Yukiko , Yano Satoshi , Kinnno Ryuta , Nakamura Shiro , Inoue Tomio , Teplow David B. , Kiuchi Yuji , Ono Kenjiro 
Published: December 2020

AbstractBackgroundExcessive accumulation of β‐amyloid peptide (Aβ) is one of the major mechanisms that cause neuronal death in Alzheimer's disease (AD). We’ve previously shown protofibrils, one of the accumulated Aβ oligomers, are implicated to play a major role. Vitamin B12 (VB12) is an important micronutrient required for brain development and has received attention because of its ability to improve cognitive status in Mild Cognitive Impairment(MCI).However, the protective effects of VB12 against Aβ oligomer‐induced neurotoxicity remain unclear. Recently, we found blood VB12 levels in AD patients are significantly associated with some of the major cognitive functions. Besides, it was associated with left hippocampal blood flow.The purpose of this study was to clarify the mechanism of the protective effect of VB12 against the Aβ oligomer‐induced neurotoxicity.MethodAβ(1‐42) oligomer was eluted using size exclusion chromatography. Neuronal damage was induced in human neuroblastoma cells (SH‐SY5Y) using 5 μM Aβ oligomer. SH‐SY5Y cells were treated with VB12 (50 μM) for 30 min ‐3 hours in combination with Aβ oligomer. Cytotoxicity of Aβ oligomer‐exposed cells was assessed by the 3‐[4,5‐dimethylthiazole‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) and mitochondrial membrane potential (MMP) analyses. Oxidative stress was evaluated by measuring products of reactive oxygen species (ROS), mitochondrial ROS and phospholipid peroxides of plasma cell membranes.ResultAβ oligomers (1, 2.5, 5 and 10 μM) exposure decreased cell viability in a dose‐dependent manner. However, treatment with VB12 significantly recovered the cell viability that was reduced by treatment with Aβ oligomer. MMP significantly decreased with Aβ oligomer and the decrease was significantly suppressed with treatment with VB12, indicating that mitochondria were involved in the neuronal damage induced by Aβ oligomer exposure. Aβ oligomer increased intracellular ROS, mitochondrial ROS and phospholipid peroxides of the plasma membrane, and the increase in Aβ oligomer‐induced oxidative stress was reduced by VB12 treatment.ConclusionThese results suggested that the collapse of mitochondria induced by oxidative stress associated with Aβ oligomer exposure was suppressed by treatment with VB12. VB12 may be provided as a therapeutic agent for the prevention of neuronal damage and as a candidate for the treatment of cognitive impairments in AD patients.
Characterising mild behavioural impairment in Asian mild cognitive impairment and cognitively normal individuals
Authors: Wong Fennie , Ng Kok Pin , Yatawara Chathuri , Low Audrey , Ismail Zahinoor , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundMild Behavioural Impairment (MBI) is a neurobehavioral syndrome characterized by later‐life emergent and sustained neuropsychiatric symptoms that is associated with higher risk of incident cognitive decline and dementia. While MBI is common in both subjective and mild cognitive impairment (MCI), most findings are based on Caucasians and the literature of MBI among Asians remains sparse. Here, we aim to investigate the frequency of MBI and its relationship with cognition, sleep and mood symptoms among cognitively intact (CN) and MCI Asians.Method162 subjects (80 CN and 82 MCI) with a Clinical Dementia Rating of 0 or 0.5 were recruited from an outpatient neurology clinic (National Neuroscience Institute, Singapore). All subjects were administered a comprehensive neuropsychological assessment, the Pittsburgh Sleep Quality Index (PSQI) and the MBI‐checklist (MBI‐C). The presence of MBI was determined based on published cut‐offs of 6.5 for MCI and 8.5 for CN. Regression models evaluated the relationships between MBI and cognition, sleep and mood.Result29 out of 162 subjects (17.9%) had MBI (28.0% of MCI and 7.5% of CN). Subjects with MBI had poorer global cognition (p=.029) and attention/working memory (p=.049). Specifically, we found that interest and impulse control subdomains of the MBI‐C were associated with poorer performance on the global cognition tests. In addition, those with MBI had sleep‐related daytime dysfunction (p=.008), poorer GDS and DASS scores (p<.01 or p<.001).ConclusionMBI in common among our Asian cohort and is associated with poorer cognitive performance, sleep and mood symptoms. Our findings further support the utility of MBI in clinical practice to identify individuals with early presentation of neurodegenerative diseases so as to provide a window of opportunity for early interventions to improve clinical outcomes.
Which pre‐analytical confounder matters the most in the comparison of two cohorts? Tubes and storage fill volume put to the test
Authors: Bastard Nathalie Le , Nadal Alicia , Armengol Elisenda , Torres Soraya , Estellés Teresa , Illán‐Gala Ignacio , Huyck Els , Parnetti Lucilla , Lleó Alberto , Alcolea Daniel 
Published: December 2020

AbstractBackgroundThe tubes used for collection and storage and their fill volumes have been identified as critical elements for standardized CSF collection as they have proven to significantly influence recovery of CSF biomarker levels and β‐amyloid1‐42 (Aβ1‐42) in particular. The aim of the current study was to compare different collection protocols in terms of CSF biomarker recovery to assess the potential impact on studies establishing cut‐off values.MethodTwo pre‐analytical protocols, used in two experienced CSF biomarker testing sites in Europe, were compared by exchanging the collection and storage tubes. In addition, two different fill volumes were tested for the largest storage tube. In total, six protocols were compared of which protocol 1 and 2 represent the routine practice in the respective sites (Table 1). Twelve consecutive patients were sampled according to all six protocols and the order of the protocols was sequentially assigned per patient. CSF biomarker analyses were done using the LUMIPULSE G platform and related assays. A linear mixed effects model was applied using R.ResultProtocols 1 and 3, both of which used storage tube 1 with a 0.5 mL fill volume, resulted in significantly lower CSF Aβ1‐42 and CSF Aβ1‐42/Aβ1‐40 ratio compared to all other protocols (p<0.001). Compared to protocol 6, which gave the highest recovery for the Aβ markers, the relative difference in Aβ1‐42 was ‐13.9% (95% CI: ‐16.1% to ‐11.6%) for protocol 1 and ‐14.8% (95% CI: ‐17.1% to ‐12.6%) for protocol 3. For the Aβ1‐42/Aβ1‐40 ratio, this resulted in a difference of ‐6.7% (95%CI: ‐8.8% to ‐4.5%) and ‐6.3% (95%CI: ‐8.5% to ‐4.1%) for protocol 1 and 3, respectively. No significant differences were observed for total Tau and hyperphosphorylated Tau.ConclusionIn the current study, and with the tubes studied in these protocols, CSF biomarker recovery did not depend on the tubes in which the samples were collected or stored. However, fill volume did have a significant impact on the Aβ1‐42 levels and the Aβ1‐42/Aβ1‐40 ratio, implying that the combination of tube plus fill volume is a factor that needs to be taken into account when comparing studies calculating cut‐off values.
Neurodegeneration in medial temporal lobe subregions propagates within distinct functional networks in the AD continuum
Authors: de Flores Robin , Das Sandhitsu R. , Xie Long , Wisse Laura , Shah Preya , Yushkevich Paul A. , Wolk David A. 
Published: December 2020

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks: the anterior‐temporal (AT) and the posterior‐medial (PM) systems. As neurodegeneration is thought to occur along specific networks, our aim was to evaluate whether atrophy in perirhinal (PRC) vs parahippocampal cortices (PHC) ‐ two MTL nodes of the AT vs PM systems, respectively ‐ covary over time with distinct brain regions reflecting the AT vs PM networks.MethodLongitudinal T1‐weighted images (up to 3 scans, span: 1.73±0.49 years) of 117 Ab‐ Cognitively Normal elderly (CN), 65 Ab+ CN, 148 Ab+ MCI and 19 Ab+ AD individuals from ADNI were included. Annualized atrophy rates of PRC and PHC were estimated with an unbiased deformation‐based morphometry method. Whole‐brain cortical thickness annualized atrophy rates were estimated using ANTs. Voxel‐wise correlations between MTL measures and whole‐brain maps were performed to highlight structural covariance patterns [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01]. Functional connectivity analyses (seed‐based) were employed to define the AT and PM networks [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01] in an independent sample of 68 CN older adults. The overlap between structural covariance patterns and the AT and PM networks was visually inspected. T‐maps from the voxel‐wise correlations were used to calculate goodness of fit (GOF) indices with the AT and PM networks (GOF=tinside‐toutside).ResultFunctional connectivity analyses revealed two distinct networks: the AT network encompasses the amygdala and the temporopolar cortex extending posteriorly to inferior and middle temporal gyri while the PM network encompasses the posterior cingulate cortex, the precuneus, the cuneus, the angular and occipital gyri and the right insula (Figure 1‐a). PRC structurally covaried with the amygdala and the left temporopolar cortex, overlapping with the AT network (Figure 1‐b,c). In contrast, PHC covaried with the posterior cingulate cortex, the precuneus, the cuneus and the angular and occipital gyri, overlapping with the PM network (Figure 1‐b,d). PRC covariance showed best GOF with the AT system (1.10 vs ‐0.50 for PM) and PHC covariance showed best GOF with the PM system (0.92 vs ‐0.33 for AT).ConclusionOverall, MTL atrophy propagates within two distinct networks over time, recapitulating the typical atrophy pattern in AD.
PENSA study: Study design, recruitment profiles and participant inclusion in multimodal intervention studies
Authors: Fauria Karine , Forcano Laura , Knezevic Iva , Minguillón Carolina , Menezes‐Cabral Sofia , Gispert Juan Domingo , Sánchez‐Benavides Gonzalo , Soldevila‐Domenech Natalia , Boronat Anna , Cuenca Aida , Puig‐Pijoan Albert , Mateus Julian , de la Torre Rafael , Molinuevo Jose Luis ,   PENSA Study Group
Published: December 2020

AbstractBackgroundA large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer benefits. The PENSA Study is a clinical trial aiming at preventing cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline (SCD). The proposed clinical trial design will evaluate the efficacy of epigallocatechin‐3‐gallate (EGCG) in the context of a personalized medicine approach including a multimodal intervention looking at improving person‐centered outcomes in this population.MethodWe have established a randomized, double‐blind, multimodal personalized clinical trial with 200 participants (60‐80 years; APOE‐ε4 allele carriers; fulfilling SCD criteria with 2 additional SCD plus supportive features) with 4 arms of 50 participants each (Fig 1). Recruitment is primarily achieved through web‐based forms capturing information about participants’ subjective cognitive status. Those participants a priori eligible will be tested for APOE status, and carriers of the APOE‐ε4 allele will be invited to the study. The intervention lasts for 12 months and the multimodal lifestyle approach will include physical activity, dietary, and mental health promotion interventions.ResultThe trial’s primary efficacy outcome is a modified ADCS‐PACC score. The secondary efficacy outcome will be evaluated by Functional neuronal connectivity (fcMRI) and structural connectivity (MRI). Exploratory outcomes include Microbiota composition, Dietary patterns (metabolomics), additional cognitive performance scores and plasma AD biomarkers assessment.ConclusionThe multimodal intervention approach of PENSA is expected to slow down cognitive decline and improve brain connectivity in a population of APOE‐e4 participants with SCD. The study also intends to evaluate several underlying mechanisms that could explain the efficacy of the intervention in slowing down cognitive decline such changes in brain connectivity, gut microbiota composition, AD biomarkers and biological ageing predictors. Further, this trial will give us information regarding participants’ retention and compliance, and therefore feasibility of this kind of high‐demanding engagement prevention studies.
Visual mental imagery in mild cognitive impairment: A pilot study
Authors: Vita Antonella Di , D'Antonio Fabrizia , Boccia Maddalena , Lisi Stefania , Savino Chiara Di , Piccardi Laura , Guariglia Cecilia , Lena Carlo 
Published: December 2020

AbstractBackgroundVisual Mental Imagery (VMI), the ability of seeing with the mind eyes, has shown to be related with autobiographical memory deficits inAlzheimer's disease (AD) (El Haj et al., 2019). Hippocampus, affected by AD neuropathology since early stages, plays a pivotal contribution to the recollection of previous memories in service of VMI; however, little is known about VMI in Mild Cognitive Impairment (MCI). Basing on the current model of VMI and findings that the various processes and contents of VMI decline differently in physiological ageing (Piccardi et al. 2015), we investigated whether VMI is involved by MCI analyzing which processes and specific contents are compromised to evaluate the possible role of deficit in VMI as early neuropsychological marker of dementia.MethodTwelve amnestic‐MCI patients (mean age = 75.42, SD = 5.68; mean education=10.92, SD=4.17) and eleven healthy controls (HC) (mean age = 71.09, DS = 8.40; mean education = 13.18, SD = 4.64), matched for Age and Education, were enrolled. VMI was extensively assessed in all patients and controls by means of 1) an adapted version of The Complete Visual Mental Imagery Battery (CVMIB; Palermo et al., 2016), including tasks evaluating the generation, maintenance, inspection and transformation of different types of visual mental images (i.e. objects, buildings and faces), and 2) the O’Clock test (Grossi et al.,1994) that allows to disentangle the possible role of perceptive difficulties in the VMI task’s performance.ResultParametric and non‐parametric analyses revealed that MCI performed worse than HC in all CVMIB’s tasks except transformation (i.e. Mental Rotation and Folding tasks) and for the generation of VMI of faces. VMI deficits seem not attributable to perceptual difficulties due to the absence of deficits in the Perceptive task of the O’Clock Test (see Figure 1).ConclusionPresent preliminary results suggest that VMI is impaired since the early phase of cognitive decline and an extensive assessment of VMI, taking into account the different components and contents of VMI, may be used to better characterize MCI neuropsychological profile as well as early neuropsychological marker of dementia.
Evaluation of genetic risk for Alzheimer’s disease in the Hong Kong Chinese population
Authors: Zhou Xiaopu , Chen Yu , Lai Nicole Chit Hang , Li Yuen Tung , Kwok Timothy C.Y. , Mok Vincent C.T. , Zhang Yulin , Ma Shuangshuang , Liu Saijuan , Chen Yuewen , Tong Estella Pui‐Sze , Ip Fanny C.F. , Mok Kin Y. , Hardy John , Fu Amy K.Y. , Ip Nancy Y. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a leading cause of mortality in the elderly. Although genome‐wide association studies (GWASs) have identified dozens of genetic risk factors in the Caucasian population, their associations with AD in the Chinese population have not been thoroughly investigated.MethodA TaqMan‐based single‐nucleotide polymorphism genotyping assay was implemented to evaluate Caucasian GWAS risk variants in a Hong Kong Chinese AD cohort (n = 732). Logistic regression analysis was performed to examine the associations between these risk variants and AD, adjusting for age and gender.ResultSeveral Caucasian AD candidate loci including SORL1(rs11218343) and ABCA7(rs4147929) were associated with AD in the Hong Kong Chinese AD cohort.ConclusionKnown Caucasian AD GWAS candidates can contribute to AD risk in the Chinese population. This suggests that AD pathogenesis might share general mechanisms in both Asian and Caucasian populations.