bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of domain‐specific cognitive functions with regional pattern of atrophy and functional connectivity across the Alzheimer’s disease spectrum: An analysis from the DELCODE cohort
Authors: Amaefule Chimezie O. , Dyrba Martin , Wolfsgruber Steffen , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Bürger Katharina , Laske Christoph , Fliessbach Klaus , Spottke Annika , Düzel Emrah , Metzger Coraline D. , Wagner Michael , Jessen Frank , Teipel Stefan J. ,   The DELCODE Study Group
Published: December 2020

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) has been found associated with regional structural atrophy and functional disruption of neural networks, such as the default mode (DMN), visual (VN) and executive networks (EN) in structural and functional imaging (fMRI) studies, mostly using single test scores of cognitive performance among monocentric cohorts. In contrast to single test scores, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Using a multicentric resting state fMRI (rs‐fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD with a focus on visuo‐spatial deficits, which manifest in the early stages of the disease.MethodWe analyzed MRI, rs‐fMRI and cognitive domain score data of 490 participants from the N700 cohort of the multicenter DELCODE study, including 54 people with Alzheimer’s Dementia (AD), 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) (Table 1). Resulting cognitive domain composite scores (executive, visuo‐spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE‐NP), were derived using confirmatory factor analysis. Statistical analysis examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network‐specific functional connectivity.ResultCognitive performance significantly differed between diagnostic groups in AD‐spectrum (Table 2). Regional gray matter atrophy was associated with visuospatial and other cognitive impairments in AD‐spectrum (Figure 1). Patterns of network‐specific resting‐state functional connectivity (except VN) was associated with distinct cognitive impairments in AD‐spectrum (Figure 2).ConclusionRobust associations between cognitive domain scores and both regional atrophy and network‐specific functional connectivity (except for VN), suggest the utility of the multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in AD‐spectrum.
Subtype and stage inference identifies distinct atrophy patterns in genetic frontotemporal dementia that MAP onto specific MAPT mutations
Authors: Young Alexandra L. , Bocchetta Martina , Cash David M , Convery Rhian S , Moore Katrina M , Neason Mollie R , Thomas David L , van Swieten John C. , Borroni Barbara , Sanchez‐Valle Raquel , Moreno Fermin , Laforce Robert , Graff Caroline , Synofzik Matthis , Galimberti Daniela , Rowe James B , Masellis Mario , Tartaglia Carmela , Finger Elizabeth , Vandenberghe Rik , Mendonca Alexandre , Tagliavini Fabrizio , Santana Isabel , Ducharme Simon , Butler Christopher , Gerhard Alexander , Levin Johannes , Danek Adrian , Otto Markus , Frisoni Giovanni B , Ghidoni Roberta , Sorbi Sandro , Williams Steven CR , Alexander Daniel C. , Rohrer Jonathan D ,   Genetic FTD Initiative (GENFI)
Published: December 2020

AbstractBackgroundMutations in the MAPT gene are known to cause frontotemporal dementia (FTD), but there is heterogeneity in FTD phenotype across individuals. Here we used an unsupervised learning algorithm – Subtype and Stage Inference (SuStaIn) – to relate phenotypic heterogeneity to specific mutations in the MAPT gene.MethodSuStaIn evaluates the optimal grouping of individuals into disease subtypes, where each subtype consists of a sequence (set of stages) in which biomarkers transition between different z‐scores. We applied SuStaIn to cross‐sectional regional brain volumes extracted from T1‐weighted MRI data from MAPT carriers in the GENFI study to find the best stratification of the data into subtypes, and the temporal progression of each subtype. We used data from 82 MAPT carriers (57 presymptomatic and 25 symptomatic) to identify subtypes and data from a control group of 300 non‐carriers to derive z‐scores. We subtyped and staged individuals at up to five annual follow‐up visits to assess the consistency of the subtypes longitudinally. We compared the specific mutations and clinical and neuropsychological test scores of individuals assigned to each subtype.ResultSuStaIn identified two groups of MAPT carriers with distinct atrophy patterns (Figure 1), which we termed a ‘temporal’ subtype and a ‘frontotemporal’ subtype. The subtype assignments were consistent at follow‐up visits (Table 1): there were no individuals that changed from the temporal to the frontotemporal subtype or vice‐versa. Subtype assignment was strongly associated with IVS10+16, R406W and P301L mutations (Table 2): there was a one‐to‐one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one‐to‐one mapping between P301L mutations and the frontotemporal subtype. The temporal subtype was associated with memory problems, whereas the frontotemporal subtype was associated with worse performance on tests of attention and visuospatial skills (Table 3).ConclusionOur results demonstrate the utility of SuStaIn for identifying disease subgroups and associating imaging patterns with genetics and cognition. We show that different MAPT mutations give rise to distinct atrophy patterns and clinical syndromes, providing insights into the underlying disease biology, and potential utility for patient stratification.
The power of genetic knowledge of a population: A lesson from the Generation study 2
Authors: Snædal Jón , Thordardottir Steinunn , Eyjolfsdottir Helga , Gislason Thorstein 
Published: December 2020

AbstractBackgroundAlzheimer´s Prevention Initiative Generation Program enrolled ApoE4 carriers to focus on individuals with highest likelihood for the disease. The greatest risk for sporadic AD is among ApoE4 carriers, primarily homozygotes (HM) but to some extent for heterozygotes (HT). Frequency of HM is 2‐3% in Caucasians and HT in about 24%, making it difficult to identify suitable participants. DeCode Genetics has collected samples from 160.000 individuals (Iceland pop. 360.000). More than 50.000 have been analysed by whole genome sequencing, allowing targeted invitation to participate in the Generation Study 2. Our site was selected for enrolment of 200 participants (10% of total planned in the study).MethodFrom the genetic database of DeCode, individuals were selected after un‐coding by an independent data committee. Of those 1000 (45%) were HM for ApoE4, 1000 (45%) were HT. 200 (10%) non‐carriers were also selected to maintain study site blinded to the genetic status. Individuals meeting eligibility criteria were contacted by phone. Written information was sent if interested, followed by invitation for the screening visit at the site.ResultOver the selected 2.200 individuals, 315 cases (15.0%) met an exclusion criteria based on their medical records. Of 1749 individuals approached by telephone, 883 (51,5%) declined to receive further information. Letters were sent to 866 individuals out of which 516 (60%) consented to participate in the study. Screening started with confirmation of the ApoE4 genotype and disclosure to the participant. Amyloid status was tested by lumbar puncture or PET scan when it became available. In July 2019, treatment with umibecestat in the Generation program was terminated. At that point, ApoE4 status had been disclosed to 432 participants (HM 38%, HT 54%, NC 8%). A total of 129 participants had been randomized of which 98 were HM and 31 HT with elevated amyloid. 150 participants were still in the screening phase.ConclusionExtensive knowledge of the genetic information in a population gives great advantages for prevention studies in diseases with an identified genetic risk factor. Leveraging the unique genetic knowledge among Icelandic individuals has enabled this significant single‐site contribution to recruitment in the Generation Program.
Catecholamine activity in delirium with and without pre‐existing dementia
Authors: Henjum Kristi , Godang Kristin , Quist‐Paulsen Else , Hassel Bjørnar , Neerland Bjørn Erik , Sandvig Heidi , Jens Bollerslev , Watne Leiv Otto 
Published: December 2020

AbstractBackgroundDelirium “acute confusion” is an unpleasant but common complication of acute illness in the aged population associated with prolonged hospitalization. Dementia is a substantial risk factor for delirium that may be apparent already in preclinical Alzheimer’s disease, but a delirium is also a risk factor for dementia. Effective agents for preventing and treating delirium are therefore searched. This include administration of antipsychotics targeting anticipated excessive dopaminergic activity in delirium and alpha‐2‐receptor (α2) agonists reducing noradrenergic activity. Data of noradrenergic and dopaminergic activity in delirium is however limited. We therefore aimed to characterize the cerebrospinal fluid (CSF) levels of dopamine and noradrenaline (norepinephrine) in delirium, with or without pre‐existing dementia.MethodCSF levels of dopamine and noradrenaline were determined by high‐performance‐liquid‐chromatography (HPLC) in: 1) cognitively healthy (controls; n=122) 2) Hip fracture patients (n=118) with and without delirium and pre‐fracture dementia 3) Patients with delirium precipitated by another medical condition (n=26). Non‐parametric statistical analyzes were applied.ResultPatients with delirium following a hip fracture and another medical condition had lower CSF dopamine levels relative to hip fracture patients without delirium and controls respectively. Stratified analyzes of hip fracture patients according to dementia status and separating patients with delirium before and after surgery showed differences in the two stratas. Interestingly there was a trend for higher levels of noradrenaline in incident delirium among those without pre‐fracture dementia, but there were few patients in this group (n=7).ConclusionThe lower levels of dopamine in CSF in delirium align with recent meta‐analyzes not recommending use of antipsychotics. Further evaluation of α2‐agonists for delirium prevention, in particular in those without pre‐existing dementia is supported, although the data should be reproduced in larger studies.
White matter integrity disruption in early amyloid accumulators
Authors: Collij Lyduine , Top Herwin , Stickney Kristine , Ingala Silvia , Tomassen Jori , Alves Isadora Lopes , Yaqub Maqsood , Wink Alle Meije , van 't Ent Dennis , Scheltens Philip , Van Berckel Bart N.M. , Visser Pieter Jelle , Barkhof Frederik , den Braber Anouk 
Published: December 2020

AbstractBackgroundAmyloid‐β (Aβ) accumulation is the pathological hallmark of Alzheimer’s disease (AD), suggested to be closely followed by white matter (WM) integrity alterations in preclinical subjects. However, reports on the relationship between the two measures have been conflicting. This study aimed to investigate the relationship between amyloid burden and WM integrity in preclinical AD on a regional level.Methods179 subjects from the EMIF‐AD preclinAD study who underwent Diffusion Weighted MRI (DWI) and dynamic [18F]flutemetamol PET imaging (Philips Ingenuity PET‐MR) were included (Table 1). Global and tract‐level Fractional anisotropy (FA) and mean diffusivity (MD) were determined using the JHU WM atlas. Amyloid burden was determined by the non‐displaceable binding potential (BPND+1) with cerebellar grey matter as the reference region. The relationship between amyloid burden and WM integrity was tested using Generalized estimating equations, correcting for family relatedness (Figure 1). Linear and quadratic fits were tested using QIC. Analyses were corrected for age, sex, and white matter hyperintensity load. The strongest associations are shown (significance set at p<0.05, Bonferroni‐corrected).ResultsLow amyloid burden was associated with increased FA and decreased MD, followed by decreased FA and increased MD upon higher amyloid burden. This relationship was most robustly observed in the body of the corpus callosum (body CC), for which a quadratic fit was preferred according to QIC, and was mainly driven by amyloid accumulation in the precuneus (FA: β
linear=0.352, β
quadratic=‐0.103, ΔQIC=6.7; MD: β
linear=‐0.434, β
quadratic=0.128, ΔQIC=8.0, Figure 2), PCC (MD: β
linear=‐0.393, β
quadratic=0.101, ΔQIC=4.0), and to a lesser extent by the insula (MD: β
linear=‐0.256, β
quadratic=0.063, ΔQIC=2.0).ConclusionEarly amyloid deposition is associated with WM changes, particularly evident in the body CC. Importantly, a quadratic fit was preferred by QIC, and this pattern might reflect multiple stages of axonal damage, with initial oligodendrocyte proliferation and axonal swelling upon lower amyloid burden, and actual axonal degeneration only becoming apparent at a higher amyloid burden. Thus, WM integrity specifically in the body CC could be considered as an indicator of early AD pathology in addition to amyloid burden in preclinical subjects.
White matter microstructure and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged cognitively unimpaired participants (the ALFA study)
Authors: Operto Greg , Milà‐Alomà Marta , Suárez‐Calvet Marc , Falcon Carles , Kollmorgen Gwen , Eichenlaub Udo , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Gispert Juan Domingo ,   ALFA Study
Published: December 2020

AbstractBackgroundPrevious studies comparing white matter (WM) integrity and biomarkers of Alzheimer’s disease (AD) at early stages have yielded inconsistent results and findings have remained inconclusive. In this work, we used diffusion‐weighted imaging (DWI) and cerebrospinal fluid (CSF) biomarkers to study the relationship between neuropathological burden and neural injury in the WM in a middle‐aged cognitively unimpaired population: the ALFA+ study.MethodsN=318 cognitively unimpaired individuals from the ALFA+ study, aged from 45 to 74 (mean: 60.79∓4.66) underwent DWI and lumbar puncture. Biomarkers were measured with Elecsys® and NeuroToolKit robust prototype assays (Roche Diagnostics). Using tract‐based spatial statistics, we assessed their association with DWI metrics using individuals models including CSF markers of core AD pathology (A𝛃42, A𝛃42/40 ratio, p‐tau), neuronal injury (neurofilament light [NfL], t‐tau), synaptic dysfunction (neurogranin [NGR], 𝛂Synuclein), and inflammation (sTREM2, YKL40, GFAP, IL6, S100b). Age, sex and APOE e4 carriership were included as covariates. Supplementary analyses were performed including levels of AD core biomarkers as additional covariates and stratifying the sample into A/T groups.ResultsDWI metrics showed significant associations with A𝛃42, YKL40, IL6, NFL, NGR, pTau, tTau, S100, 𝛂Synuclein; none with GFAP, sTREM2, nor A𝛃42/40 ratio (Figures 1 and 2). Positive associations in fractional anisotropy (FA) (and negative with diffusivity) were found with A𝛃42, YKL40, NFL, NGR, S100, p‐tau and t‐tau. Negative association in FA (positive in diffusivity) was found for IL6 only. p‐tau showed the only association to be significant in both directions with FA, positive in cingular/callosal and negative in corticospinal tracts. Post‐hoc analyses on p‐tau showed significant interaction with A/T stage (Figure 3) with positive association with FA in A‐T‐ and negative in A+T+ subjects (inversely with diffusivity).ConclusionWM microstructural properties correlate in extensive regions with CSF AD core biomarkers, inflammation and axonal degeneration markers. Such associations illustrate the interplay of multiple pathways in early stages of Alzheimer’s continuum such as deleterious effects of amyloid deposition or the involvement of glial activation/inflammatory processes, resulting in observed reduced diffusivity. Furthermore, interaction with A/T stage suggest the presence of non‐monotonic dynamics occurring along the Alzheimer’s continuum.
Ultra long‐acting oral therapies for Alzheimer's: Proof of principle
Authors: Scranton Richard E. , Avery William , Kruger Cecilia , Bellinger Andrew , Silverman Bernard 
Published: December 2020

AbstractBackgroundPoor compliance [1] and high rates of discontinuation [2] with daily oral therapy, such as memantine hydrochloride (HCl) and donepezil HCl, in Alzheimer’s patients compromises the effectiveness of medications that may slow progression of disease severity. Lyndra Therapeutics is developing extended release (ER) capsules for long‐acting oral therapies in several therapeutic areas, including Alzheimer’s disease. Weekly administered oral therapies may improve adherence, provide more consistent plasma drug levels, and facilitate observed administration.MethodThe Lyndra ER capsule has modular features serving specific functions for extended delivery to the stomach. The features include a star‐shaped drug‐releasing formulation (stellate) with up to six drug‐loaded polymer arms formulated to achieve controlled drug release while maintaining gastric residence. Polymer‐coated arms yield a steady rate of drug release into the stomach. The formulation is designed to lose its structural integrity after a period of residence and to pass safely through the GI tract. To test the feasibility of this approach, 8 healthy volunteers received a single dose of LYN‐157 containing 40 mg of memantine HCl and 38mg of donepezil HCl while under observation in a Phase 1 unit for 7 days.ResultsPlasma drug concentrations peaked within 48‐72 hours. LYN‐157 achieved consistent and linear release of both memantine and donepezil, with concentrations maintained over 7 days. No serious adverse events were observed. The most common adverse events were headache, abdominal pain and nausea, generally beginning near time of administration and resolving within 2 days.ConclusionLyndra's novel drug delivery technology achieved controlled release of memantine and donepezil resulting in consistent pharmacokinetics (PK) exposure over 7 days. The ability to deliver one or more oral drugs over one week with a single oral capsule has the potential to improve compliance, quality of life, and care of people with Alzheimer's disease. References: 1. Austrom MG, Boustani M, LaMantia MA. Ongoing Medical Management to Maximize Health and Well‐being for Persons Living With Dementia. Gerontologist. 582018. p. S48‐57. 2. Haider B, Schmidt R, Schweiger C, Forstner T, Labek A, Lampl C. Medication adherence in patients with dementia: an Austrian cohort study. Alzheimer Dis Assoc Disord. 2014;28(2):128‐33.
Development of a primary calibrator and candidate reference method for metrological traceability of tau protein results
Authors: Giangrande Chiara , Vaneeckhoutte Hélène , Boeuf Amandine , Lalere Béatrice , Reimann Sophie Vaslin , Hirtz Christophe , Lehmann Sylvain , Quaglia Milena , Delatour Vincent 
Published: December 2020

AbstractBackgroundEarly and accurate diagnosis of Alzheimer’s disease relies on different techniques, including cognitive tests, imaging and biomarkers measurement. Here we describe the potential of the use of a well characterized primary calibrator (traceable to the SI) and the development of a candidate reference method by LC‐IDMS for worldwide standardization of t‐tau measurements in CSF.MethodA recombinant form of tau‐441 has been produced: the impurity profile has been carried out by high resolution mass spectrometry coupled to liquid chromatography and amino acid analysis. The primary calibrator has then been used to calibrate a candidate reference method for absolute quantification of t‐tau in CSF samples. Calibration blends and CSF samples are subjected to the same experimental workflow including the spiking with a 15N‐labelled standard, the protein precipitation followed by solid phase extraction (SPE), the trypsin digestion and the analysis by LC‐MS exploiting the potential of PRM (Parallel Reaction Monitoring) in the measure of the ratio between the unlabeled and the labeled form of the tryptic peptide GAAPPGQK finally used as quantifier.ResultA SI‐traceable primary calibrator has been developed and an LC‐IDMS candidate reference method for t‐tau quantification in CSF samples is under validation. A time‐course experiment to evaluate the completeness of the digestion has allowed choosing the best digestion time. The use of a protein primary calibrator and of a labeled protein internal standard has reduced the effect of digestion time on ratio GAA/GAA*. Three different CSF pools, corresponding to three different concentration ranges (low, medium, high) have been successfully quantified and the uncertainty has been determined by considering different parameters: the weighing of the CSF samples, the internal standard and the primary calibrator, alongside its concentration, the calibration curve and the intermediate precision, calculated as the standard deviation of the individual results.ConclusionIn collaboration with reference laboratories taking part in IFCC working group on CSF proteins the candidate reference method will be used to certify t‐tau concentration in international standards with which all t‐tau immuno‐assays will be recalibrated. This enables optimal uptake of mass spectrometry methods directly in routine clinical practice or for standardization purposes.
Augmented reality detects gait deterioration over time and predicts AD risk in Asian older adults
Authors: Tseng Benjamin 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) and AD related dementia (ADRD) are under‐recognized and under‐treated in individuals with Asian cultural heritages due to the social stigma. Asians account for more than 60% of the world population. With the rapidly aging society, it is imperative to effectively detect and prevent AD & ADRD prior to its onset in order to alleviate social healthcare burden in the next decades to come.MethodWe conducted a 1‐year observational study in 42 non‐AD adults of Asian races (age=55±9, m=13, f=29) to monitor changes in gait profile using augmented reality (AR) technology via RADAR (i.e. Report for Alzheimer’s Disease Accumulated Risks), an in‐house smart device app developed by the PI. Gait profile (i.e. velocity (m/s), stride length (cm), deviation (%)) was recorded and calculated at baseline, 6 months, and 12 months with and without dual‐task conditions (i.e. delayed recall+sorting). Cognitive performance was evaluated using previously described methods. To the best of our knowledge, this was the first attempt to use a novel behavioral marker (i.e. gait deteriorations under dual‐task conditions) to predict early stages of cognitive decline in Asian adults.ResultUsing multiple linear regression modeling, we found that gait velocity decline (i.e. >10%Δ compared to baseline under dual‐task conditions or >20%Δ compared to non‐dual‐task condition) independently predicts AD risks (adjusted R2=.38, p=.01) in Asian adults.ConclusionWe have demonstrated a cost‐effective alternative instrument that is shown to be sensitive in detecting early dementia. Current consensus emphasizes the prominence in early AD diagnosis. Although existing diagnostic tools such as positron emission tomography (PET) is effective in detecting beta‐amyloid protein, the hallmark of AD, PET scan is costly and not readily accessible for most patients. Emerging literature suggests that gait deteriorations at middle age are predictive of AD. Further more, AD prevalence and care in Asian people is under‐recognized; this novel tool that can be implemented in those cultures that might be reluctant to seek professional consultation due to cultural bias.