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BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD. ispartof: ALZHEIMERS & DEMENTIA vol:19 issue:3 pages:807-820 ispartof: location:United States status: published

Language dysfunction is common in Alzheimer’s disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer’s disease. Here we examined in 35 cognitively intact older adults (age range 52–78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a 5–6-year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex. In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuo-perceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxel-wise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in functional MRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer’s disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer’s disease., Using fMRI and amyloid PET in a longitudinal multimodal study, Reinartz et al. reveal functional changes in the language network occurring with increasing amyloid accumulation in an early asymptomatic phase of Alzheimer's disease.

Background We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course. Methods One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52–80 years, 81 women) belonging to the Flemish Prevent Alzheimer’s Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and 18F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change. Results A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline. Conclusion In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.

Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition. This research was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013), and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007, and #15005). R.V. is a senior clinical investigator of the Flemish Research Foundation (FWO). J.S. is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The authors acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIBCMN is funded in part by the University of Antwerp Research Fund. F.B. is supported by the NIHR biomedical research centre at UCLH. L.S. is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215).

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD. ispartof: ALZHEIMERS & DEMENTIA vol:17 issue:10 pages:1628-1640 ispartof: location:United States status: published

The bridging integrator 1(TheForty-four percent of F-PACK participants wereWe could not confirm the association between

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, ageing populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e. case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n=931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

BACKGROUNDPhysiological differences between males and females could contribute to the development of AD. Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODSWe explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, CSF biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites’ discriminatory performance in AD.RESULTSIn females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (AUC = 0.83, SE = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONSMetabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, associated to females, paving the way to personalised treatment.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case–control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case–control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

BackgroundBlood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.MethodsIn this prospective cross-sectional study, we quantified plasma Aβ1–42/Aβ1–40ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ1–42/Aβ1–40to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer’s disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.ResultsELISA and SIMOA plasma Aβ1–42/Aβ1–40detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72–0.84; SIMOA: AUC 0.79, 95% CI 0.73–0.85), and both increased the performance of a basic demographic model including only age andAPOE-ε4genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ1–42/Aβ1–40correlated similarly with amyloid-PET for both platforms (Spearmanρ = − 0.32,p 1–42/t-tau were stronger for ELISA (ρ = 0.41,p = 0.002) than for SIMOA (ρ = 0.29,p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ1–42and Aβ1–40measured by SIMOA consistently underestimating those measured by ELISA.ConclusionsELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ1–42/Aβ1–40, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.Trial registrationEudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014,https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE).

© 2020 – IOS Press and the authors., [Background]: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. [Objective]: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. [Methods]: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). [Results]: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. [Conclusions]: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo., This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). The Lausanne cohort study was supported by a grant from the Swiss National Research Foundation to JP (SNF 320030_141179). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). JS is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. FB is supported by the NIHR biomedical research centre at UCLH. RD is supported by Health Data Research UK, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King’s College London and the NIHR University College London Hospitals Biomedical Research Centre. LS is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). Also support was received from the NIHR Biomedical Research Centre at Oxford Health NHS Foundation Trust.

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimer’s disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome.MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates.FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1.InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:74 issue:1 pages:213-225 ispartof: location:Netherlands status: published

Background With the shift of research focus towards the pre-dementia stage of Alzheimer’s disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. Conclusions Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

Objective: In some patients with apraxia of speech (AOS), we observed impaired perceptual timing abilities, which lead us to propose a shared mechanism of impaired perceptual timing underlying impaired rhythm discrimination (perceptual processing) and AOS (motor speech output). Given that considerable white matter damage is often observed in these patients, we here investigate whether white matter changes are related to impaired rhythm processing as one possible mechanism underlying AOS. Methods: We applied deformation-based morphometry (DBM) and diffusion tensor imaging (DTI) in 12 patients with the nonfluent variant (NFV) of Primary Progressive Aphasia (PPA) with AOS, as well as 11 patients with the semantic variant and 24 controls. Results: Seventy-five percent of the patients with NFV displayed impaired rhythm processing and the severity of their impairment correlated with their degree of AOS. Moreover, left frontal white matter volume loss adjacent to the supplementary motor area (SMA) correlated with impaired rhythm processing. In addition, we obtained tract-based metrics of the left Aslant tract, which is typically damaged in NFV. The structural integrity of the left Aslant tract also correlated with rhythmic discrimination abilities in NFV. Conclusions: Our data suggest that a shared white matter substrate adjacent to the SMA contributes to impaired rhythm perception and motor speech impairments. This indicates that impaired perceptual timing may be one of the neurocomputational mechanisms underlying AOS. Our observation that regional variations in left frontal lobe atrophy are linked to the phenotypical heterogeneity in NFV may lead the way for earlier diagnosis.

Purpose To assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. Methods The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction. Results Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results. Conclusion [18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment. ispartof: European journal of nuclear medicine and molecular imaging vol:45 issue:13 pages:2342-2357 ispartof: location:Germany status: published

Altres ajuts: Fundació Bancària Obra Social La Caixa, Fundació Catalana Síndrome de Down, Fundació La Marató de TV3, Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica, Fundación BBVA i Fundació Víctor Grífols i Lucas Background: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. Results: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). Conclusions: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.Results: Eight metabolites were associated with amyloid b and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.Discussion: PFAMs have been found increased and associated with amyloid b burden in CSF and clinical measures. Crown Copyright (C) 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

INTRODUCTIONMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer’s Disease (AD). Here we set out to test the performance of metabolites in blood to categorise AD when compared to CSF biomarkers.METHODSThis study analysed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n=883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).RESULTSOn the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.DISCUSSIONThis study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders

Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers. This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders. The present study was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01. 41142.001.H). Kristel Sleegers is supported by the Research Fund of the University of Antwerp. Daniel Stamate is supported by the Alzheimer’s Research UK (ARUK-PRRF2017-012).

Purpose To assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. Methods The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction. Results Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results. Conclusion [18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment. Electronic supplementary material The online version of this article (10.1007/s00259-018-4075-3) contains supplementary material, which is available to authorized users.

Background A subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a ‘mixed variant’ phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype. Methods A consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [18F]-THK5351 and amyloid-tracer [11C]-Pittsburgh Compound B. Results Seven out of 12 subjects who had been classified a priori with nonfluent variant PPA showed deficits on conventional single-word comprehension tasks along with speech apraxia and agrammatism, corresponding to a mixed variant phenotype. These mixed variant cases included three females and four males, with a mean age at onset of 65 years (range 44–77 years). Object knowledge and object recognition were additionally affected, although less severely compared with the semantic variant. The mixed variant was characterized by a distributed atrophy pattern in frontal and temporoparietal regions. A more focal pattern of elevated [18F]-THK5351 binding was present in the supplementary motor area, the left premotor cortex, midbrain, and basal ganglia. This pattern was closely similar to that seen in pure nonfluent variant PPA. At the individual patient level, elevated [18F]-THK5351 binding in the supplementary motor area and premotor cortex was present in six out of seven mixed variant cases and in five and four of these cases, respectively, in the thalamus and midbrain. Amyloid biomarker positivity was present in two out of seven mixed variant cases, compared with none of the five pure nonfluent cases. Conclusions A substantial proportion of PPA patients with speech apraxia and agrammatism also have single-word comprehension deficits. At the neurobiological level, the mixed variant shows a high degree of similarity with the pure nonfluent variant of PPA. Trial registration EudraCT, 2014–002976-10. Registered on 13-01-2015. Electronic supplementary material The online version of this article (10.1186/s13195-018-0393-8) contains supplementary material, which is available to authorized users.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia. ispartof: FRONTIERS IN AGING NEUROSCIENCE vol:10 ispartof: location:Switzerland status: published

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.

It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility.