bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease
Authors: Monge‐Argilés José Antonio , García‐Ayllón María‐Salud , García Victoria Monge , Rueda Francisco Navarrete , Robles Jorge Manzanares , Gasparini‐Berenguer Ruth , Leiva‐Santana Carlos , Sáez‐Valero Javier 
Published: December 2020

AbstractBackgroundPrevious studies have indicated the potential of cerebrospinal fluid (CSF) α‐synuclein (α‐syn) to be an additional biomarker for improving differential diagnosis of Alzheimer’s disease (AD). We evaluated α‐syn diagnostic performance across a well‐characterized patient cohort with long‐term follow‐up.MethodCSF α‐syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n= 25), 27 MCI cases due to AD (MCI‐AD; n= 32), 24 MCI cases due to Lewy body disease (MCI‐LBD; n= 24) and control subjects (Ctrl; n= 18). Levels of central core AD‐CSF biomarkers Aβ1‐42, T‐tau and P‐tau 181 were measured using enzyme‐linked immunosorbant assay (Innotest, Innogenetics/Fujirebio). Determination of α‐syn levels in CSF were performed using the LEGEND MAXTM human α‐synuclein ELISA kit (BioLegend).ResultCSF α‐syn levels discriminate between the four groups. There were higher α‐syn levels in MCI‐AD patients and lower levels in MCI‐LBD patients. The combination of P‐tau and α‐syn resulted in a specificity of 99% and a sensitivity of 97% for AD. MCI‐AD patients with early psychotic symptoms (n= 9) displayed a trend towards a decrease in P‐tau and α‐syn compared to the MCI‐AD patients without psychotic symptoms (n= 23).ConclusionAdding CSF α‐syn to central core AD biomarkers improves an early differential diagnosis of MCI‐AD from other forms of MCI.
Biomarker‐based definition of limbic‐predominant long‐lasting amnestic mild cognitive impairment
Authors: Tondo Giacomo , Carli Giulia , Santangelo Roberto , Mattoli Maria V , Presotto Luca , Filippi Massimo , Magnani Giuseppe , Iannaccone Sandro , Cerami Chiara , Perani Daniela 
Published: December 2020

AbstractBackgroundPrevious studies described amnestic Mild Cognitive Impairment (aMCI) subjects with slow rate of cognitive decline, benign disease course associated to FDG‐PET brain hypometabolism in the medial temporal lobe structures. Clinical and post‐mortem studies suggested the presence of both Alzheimer’s disease (AD) and non‐AD pathology. The identification of aMCI with a benign course has relevant consequences both for prognosis and treatment. The aim of this study was to define the role of in vivo biomarkers to predict prognosis in a large population of aMCI with long‐lasting disease course.MethodWe selected 80 aMCI (Cohort1) using the following criteria: observational time of disease duration ≥4 years; available baseline and follow‐up clinical and neuropsychological evaluations; baseline CSF analysis measuring amyloid‐β42, total‐tau and phosphorylated‐tau; FDG‐PET assessed for individual brain hypometabolism by a validated SPM procedure on a voxel‐by‐voxel basis, showing a selective medial temporal involvement, thus a non‐AD brain pattern. In addition, we selected 42 aMCI due to AD with similar baseline clinical features and biomarker measurements, and both CSF positive for amyloidopathy and FDG‐PET showing the typical AD temporo‐parietal brain hypometabolism (Cohort2).Result
Cohort1 had mean disease duration of 8.45±3.37 years, range 4‐19 years, no decline in MMSE in most subjects, only 7% conversion to AD dementia at the clinical follow‐up. In Cohort2, 81% of aMCI converted to AD. The FDG‐PET single subject analysis predicted progression in Cohort2, or stability in Cohort1 with high accuracy (AUC=0.88), sensitivity (0.85) and specificity (0.90). Within Cohort1, the CSF biomarkers showed great variability; none of the CSF biomarkers was able to predict stability or conversion. According to the AT(N) classification, in Cohort1, 54% of subjects showed an AD profile and 46% a non‐AD profile. These two groups did not show any difference in cognitive and neuropsychological features at follow‐up, showing comparable stability.ConclusionThe specific brain hypometabolism pattern in Cohort1 is associated with clinical stability and slow rate of memory deficit progression. Nor CSF biomarkers, neither the AT(N) classification, can predict prognosis in this population. These findings underline the key role of FDG‐PET brain metabolism as a fundamental biomarker in the diagnostic and prognostic challenge of aMCI.
Digital Trail Making Test‐Black and White: For android and iOS
Authors: Simfukwe Chanda , Baek Min Jae , Kim SangYun , An Seong Soo 
Published: December 2020

AbstractBackgroundThe pen‐paper version Trail Making Test‐Black and White (TMT‐B&W) method was developed previously, the collection of pen‐paper based results and its analyses may increase time‐consumption and create workloads for administrators/subjects while performing the trial test and afterward. To increase the efficiency of the data, collections, and analyses, the touch‐screen based digital Trail Making Test‐Black and White (dTMT‐B&W) based on Android tablets/iPad was developed to enhance the pen‐paper based TMT‐B&W.MethodThe dTMT‐B&W was developed using a Massachusetts Institute of Technology (MIT) and Thunkable X application inventor software, a visual online programming environment with the Android/iOS development tools, which are used to build fully functional apps for Android/iOS smartphones and tablets. The dTMT‐B&W is designed with self‐administration and additional features that help in easy data collection and analysis within much less time. The dTMT‐B&W was designed to run on a 10.5 inch Samsung Galaxy Tab A and 12.9 inches iPad Pro touchscreen tablets. The dTMT‐B&W, designed to be consistent with the pen‐paper based TMT‐B&W as possible, uses black and white circles with numbers arranged in sequential order consisting of two parts: Part‐A and Part‐B, where the subject is instructed to push buttons in black and white circles to connect them as quickly as possible while maintaining the accuracy and time. Paper‐based TMT‐B&W, a subject has to connect randomly distributed black & white circles with numbers distributed on a sheet of paper in ascending order in two parts as quickly as possible without lifting the pen or pencil from the paper sheet.ResultThe dTMT‐B&W was successfully developed as an Android/iOS application with some well‐improved features that were embedded into the design to look as similar to the original pen‐paper TMT‐B&W test as possible in order to establish equal convergent validity.ConclusionThe dTMT‐B&W can measure the same aspects of cognition as the pen‐paper based TMT‐B&W more easily. Furthermore, dTMT‐B&W’s additional features and data may be able to help administer other cognitive methods not obtained by the pen‐paper TMT‐B&W.
Whole exome sequencing analysis identifies genes and pathways in sporadic early‐onset Alzheimer’s disease
Authors: Bagaria Jaya , An Seong Soo , Nho Kwangsik , Bagyinszky Eva , Kim SangYun 
Published: December 2020

AbstractBackgroundSporadic early‐onset Alzheimer’s disease (EOAD) patients (onset age < 65 years) do not harbor a known causative variant and have a heritability estimated to be 92‐100% (Barber et al. 2016). Here we performed whole exome sequencing (WES) to identify functional exonic variants in sporadic EOAD.MethodDNA was extracted and sequenced from blood samples of 109 Korean patients with EOAD or Mild Cognitive Impairment (MCI) younger than 65 years of age. Short‐read sequences from WES were mapped to the NCBI reference human genome (build 37) using BWA and GATK. All the variants were annotated with ANNOVAR. PolyPhen‐2 and SIFT were used to predict potential impact on protein structure or function of missense variants. After quality control procedures for samples and variants, we performed a case‐control association using PLINK on 109 Korean patients and 405 East Asia population from the 1000 Genomes Project.ResultThe genetic association analysis in a case‐control study design identified several sporadic EOAD susceptibility genes with missense variants with minor allele frequency (MAF) greater than 1%. A common exonic variant in LILRB2 had a significant p‐value of 1.036 × 10e ‐11 with MAF 0.11 compared with MAF = 0.395 in East Asian and MAF = 0.160 in cognitively normal Korean population (source: KRGDB genome browser). A common exonic variant in HLA‐DQB2 was also identified with a p‐value of 2.252 × 10e ‐08 with MAF 0.197 compared with MAF = 0.413 in East Asian and MAF = 0.34 in KRGDB. A common exonic variant in LIPC showed a marginal significance with a p‐value of 4.537 × 10e ‐05 with MAF = 0.0688 compared to MAF = 0.208 in East Asian and MAF = 0.12 in KRGDB. Other common exonic variants were found in TNR, ITGAX (p‐values < 5.00xe ‐056. The protein‐protein interaction network analysis using STRING showed that LILRB2 has a direct interaction with ADAM10 and ITGAX, HLA‐DQB2 has a direct interaction with ITGAX that has a direct interaction with ADAM10, and LIPC has interactions with APP, SORL1 and CLU, which are known AD risk genes.ConclusionWhole‐exome sequencing analysis identified exonic variants associated with sporadic EOAD. Studying these genes and their pathways might lead us to a better understanding of the genetic architecture of sporadic EOAD.
Four years’ experience in an early‐onset dementia clinic in Barcelona
Authors: Contador José , Tort‐Merino Adrià , Balasa Mircea , Falgàs Neus , Olives Jaume , Castellví Magdalena , Juncà Jordi , Borrego‐Écija Sergi , Bosch Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Sanchez‐Valle Raquel , Lladó Albert 
Published: December 2020

AbstractBackgroundEarly‐onset dementia (EOD; <65 years) raises both diagnostic and social/health care challenges. Services for dementia are often designed for the elderly and might have difficulties supplying EOD needs. Clinical and epidemiological data are needed for care planning.MethodWe aim to describe the demographic and the clinical characteristics of all the new referrals to our EOD clinic during the last 4 years (2016‐2019). Clinical charts were reviewed retrospectively. Both, sporadic and genetic cases were included in the analysis. We evaluate the type of symptoms, type and frequency of ancillary tests requested and final diagnosis.ResultsWe evaluated 477 new early‐onset patients [mean age at consultation (MAC) 54.6 years (SD=±9.6), 56% female] during this period. The aim of the first visit was genetic counseling in 17.8% [MAC 48.3(±13.3), 55.3% female] and evaluation of sporadic cases in 82.2% [MAC 56(±8), 56.1% female] [Figures 1 & 2]. Among sporadic cases, memory complains were the main symptom (67.1%), followed by behavioral (13%) and language disturbance (11.2%). Complete neuropsychological evaluation was performed in 61.2%, CSF biomarkers in 30.9%, PET‐FDG in 22.4%, PET‐amyloid in 12.5% and genetic testing in 10.5%. Subjective Cognitive Decline (SCD) was diagnosed in 51.8% of these sporadic cases [MAC 54.2(±8), 63.5% female, Mean MMSE 27(±4)], while an abnormal cognition was found in the 48.2% [MAC 58(±7.5), 48.1% female, Mean MMSE 23(±6)]. Regarding EOD causes, 54% was due to neurodegenerative dementias [MAC 60(±5.5), 47.1% females, MMSE 22(±6)] and 46% to non‐neurodegenerative [MAC 55.5(±8.8), 49.4% female, Mean MMSE 25(±5)]. EOD mean time to diagnosis was 3.1 years (±3.75) with no differences between groups (p=0,207). In neurodegenerative dementias, AD constitutes 51% [MAC 61.6(±4), 51.9% female, Mean MMSE 20(±6)] and Frontotemporal lobular degeneration (FTLD) 34.3% [MAC 58.5(±5.3), 45,7% female, Mean MMSE 24(±5)].ConclusionSCD is a frequent diagnosis among new referrals to EOD clinics. AD is the most frequent neurodegenerative EOD, followed by FTLD. Non‐neurodegenerative causes of EOD are frequent and heterogeneous. Long delay until diagnosis suggests that new care policies are needed to identify EOD in early stages.
Operationalization of the ATN classification scheme in preclinical AD: Findings from EPAD V500.0 data release
Authors: Ingala Silvia , de Boer Casper , Masselink Larissa A , Vergari Ilaria , Lorenzini Luigi , Blennow Kaj , Chetelat Gael , Perri Carol Di , Ewers Michael , Fox Nick C. , Gispert Juan Domingo , Molinuevo Jose Luis , Terrera Graciela Muniz , Mutsaerts Henri J.M.M. , Ritchie Craig W. , Schmidt Mark E. , Vermunt Lisa , Waldman Adam , Wink Alle Meije , Wolz Robin , Wottschel Viktor , Scheltens Philip , Visser Pieter Jelle , Barkhof Frederik ,   EPAD Consortium
Published: December 2020

AbstractBackgroundThe goal of this study is to assess neuropsychological and radiological characteristics according to the ATN scheme in the EPAD Longitudinal Cohort Study (EPAD‐LCS) after establishing data‐driven cut‐offs for classification.MethodATN cut‐off values were determined in a deeply phenotyped cohort of 500 nondemented elderly individuals. Amyloid and p‐tau in the cerebrospinal fluid were quantified with Roche Elecsys assays. Hippocampal volume was calculated using LEAP pipeline. The intersection poin of two‐component Gaussian mixture models was used to establish cut‐off values for CSF amyloid ß42 (A) and p‐tau (T). Age‐adjusted w‐scores were used to establish a cut‐off value for neurodegeneration (N). Only subjects classified as healthy controls (A‐T‐N‐) or in the Alzheimer spectrum (A+T‐N‐, A+T+N, A+T+N+) were included. Multinomial regression was performed to test whether significant differences among the ATN groups could be detected with the EPAD Neuropsychological Examination (ENE) after correcting for age, sex, years of education, and site of data collection.ResultOut of the initial sample of 500 study participants, n=38 did not fulfil EPAD inclusion criteria, n=34 did not have CSF or MRI biomarkers, and n=49 were not either healthy controls or in the Alzheimer spectrum and were thus excluded. Cut‐offs were 1025 pg/mL for CSF amyloid ß1,42 (A), 24 pg/mL for CSF p‐tau (T), and age‐adjusted hippocampal volume w‐score below ‐2 standard deviations for neurodegeneration (N). Out of the n=376 sample, 229 individuals were classified as healthy controls (A‐T‐N‐), 102 as showing only amyloid pathology (A+T‐N‐), 45 showing amyloid and tau pathologies (A+T+N‐), and 3 A+T+N+ were eliminated [Table 1]. The ENE battery distinguished healthy controls (A‐T‐N‐) from individuals with preclinical AD (A+T+N‐), and individuals with Alzheimer pathological changes (A+T‐N‐) from individuals with preclinical AD (A+T+N‐).ConclusionWe proposed a data‐driven framework of cut‐offs for classifying preclinical AD patients in the ATN scheme. The ENE battery scores were in line with the expected cognitive decline in the AD spectrum and increasing vascular burden was shown with progression along the AD spectrum. Potential applications include the selection of patients for secondary prevention trials, preclinical disease modelling and monitoring responses to disease‐modifying therapies.
A phase 1B multiple ascending dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of a medium chain triglyceride supplement in Alzheimer’s disease
Authors: Nygaard Haakon B , Kent Brianne A , Stager Sam , Slack Penelope , DeMarco Mari L , Castellano Christian‐Alexandre , Rauscher Alexander , Cunnane Stephen , Feldman Howard H 
Published: December 2020

AbstractBackgroundImpaired brain glucose metabolism is a prominent and early feature across neurodegenerative disorders, including Alzheimer’s disease (AD). Elevating brain ketones to bypass this metabolic failure is an emerging therapeutic strategy, with promising results in AD and Mild Cognitive Impairment (MCI). The Medium Chain Triglyceride Intervention in AD (MINT‐AD) is a randomized, placebo‐controlled Phase 1b trial investigating the pharmacokinetics and pharmacodynamics of a ketogenic supplement in Alzheimer’s disease (AD). It also explores outcome measures to support the development of larger ketogenic trials for this disorder.MethodPatients (n=32) with a clinical diagnosis of with mild‐moderate AD (MMSE 16‐26) were randomized at 4:1 to twice daily medium chain triglyceride drink (MCT – 60% C8, 40% C10) prepared as a 12% emulsion in lactose‐free milk, or placebo. A total of four dose groups were recruited, with doses ranging from 5 grams twice daily up to 25 grams twice daily, for a total of 18 days (including 8‐day drug titration). Primary outcome measures were safety, tolerability and pharmacodynamics effects of MCT supplementation on plasma ketones, and the pharmacokinetics of the MCT supplement. Exploratory outcome measures included N‐acetyl aspartate and glutamine/glutamate MR spectroscopy, functional resting brain connectivity, brain blood flow (arterial spin labeling), continuous actigraphy, ambulatory sleep EEG, and cognitive measures.ResultA total of 30 participants (94%) completed the study, with 2 subjects discontinuing early. MCT supplement up to 25 grams twice daily was safe and well tolerated in patients with mild‐moderate AD. Peak plasma ketones was seen around 4 hours post MCT ingestion. Exploratory cognitive and imaging measures are currently being analyzed and will be presented.ConclusionKetogenic MCT supplementation is safe and well tolerated in AD, with reasonably predictable pharmacokinetic and ketogenic properties. These data exploring a larger dose range should inform dose selection in future trials with MCT supplementation.
Improved brain energetics and cognition after a 6‐month ketogenic intervention in mild cognitive impairment: Final results of the Benefic Trial
Authors: Cunnane Stephen , Fortier Melanie , Castellano Christian‐Alexandre , Pierre Valerie St. , Morin Marie‐Christine , Langlois Francis , Cuenoud Bernard , Delannoy Carla , Bocti Christian , Fulop Tamas 
Published: December 2020

AbstractBackgroundKetones can partially substitute for glucose as a brain fuel and may be beneficial for cognition in older people. The objective of the randomized, placebo‐controlled Benefic Trial (NCT02551419) was to assess whether counteracting the brain energy (glucose) deficit with a ketogenic medium chain triglyceride (kMCT) supplement could improve cognitive performance in mild cognitive impairment (MCI).MethodsA cognitive battery was used to screen for MCI and cognitive outcomes after the intervention. Cognitive outcomes pre‐ and post‐intervention were obtained for the active arm (15 g kMCT twice/day in a lactose‐free skim milk emulsion; n=39 completers) and placebo arm (non‐ketogenic vegetable oil of equivalent energy value and formulation as for the kMCT; n=44 completers). Brain ketone and glucose PET were done before and at the end of the 6‐month intervention on a sub‐group of both arms (n=19/group).ResultsSeveral cognitive domains improved post‐intervention in the kMCT group (p≤0.01; ANCOVA; age and education as covariates). Specifically, Trial 1 of the Free and Cued Recall Test showed a +1 word improvement on kMCT (+0.5 Δ Z‐score), correct answers on the Verbal Fluency Test increased by 2 words on kMCT (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), correct answers on the Boston Naming Test increased by 1.1 on kMCT only, time taken on the Stroop Colour Naming Test decreased by 1 sec on the kMCT (p=0.09), and errors on the Trail Making Test decreased by 0.9 on kMCT but increased by 0.8 on placebo (p=0.02). Brain ketone uptake increased in the kMCT arm only and directly as the increase in plasma ketones (r = 0.87, p<0.01). Average drop‐out rate on both arms was 31% and, in completers, protocol adherence was 89% over six months.ConclusionsIn MCI, a kMCT supplement had a clinically meaningful effect on some cognitive outcomes directly related to risk of progression toward Alzheimer’s disease, and significantly improved brain energy supply. It is feasible for an MCI population to consume a kMCT supplement daily for six months. Acknowledgements: Financial support was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science.
Bridging the gap: Engaging people with lived experience and health care providers on research review panels
Authors: Sivananthan Saskia 
Published: December 2020

AbstractBackgroundThe Alzheimer Society of Canada’s prevailing theme is “nothing for us, without us”. This value is embedded in all aspects of their work. Since 2015, people with lived experience of dementia have been engaged in the organization’s annual grant competition, sharing their perspectives of grant applications on peer review panels. In 2019, the Alzheimer Society of Canada introduced a relevancy review panel to supplement the peer review process. This interdisciplinary panel included organizational staff with direct contact with people with lived experience as well as citizen reviewers. Collectively, they reviewed and scored research proposals for clarity and relevance to their experience, contributing to recommendations about which proposals should receive funding.MethodIn 2019, the Alzheimer Society of Canada recruited seven people with lived experience of dementia and five staff from across the country to become more deeply engaged in decision‐making for the society’s annual grant‐awarding competition. Participants attended an inaugural training workshop to learn more about the organization’s research program and its funding priorities while helping to co‐develop the training to address further need. The workshop was evaluated and feedback used to inform the planning and delivery of future engagement sessions. Participants were subsequently allocated to either the Peer Review Panel or Relevancy Review Panel. Their involvement on these panels will be evaluated in Spring 2020 and results used to inform future panel participation.ResultAll the participants agreed that the training workshop achieved its objectives. The workshop provided an opportunity for people with lived experience and staff to engage directly with each other while co‐designing the scoring criteria and guidelines of the panel. It also created a new opportunity to meaningfully engage people with lived experience in the research process while balancing the expertise required to assess proposals. Participants’ involvement on the research panels will be evaluated in Spring 2020.ConclusionPeople with lived experience of dementia are important partners in the research process. Their practical involvement in scoring research proposals for importance and relevance will ensure that research more closely meets their needs while developing a new role for their meaningful engagement.