Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a ‘European <scp>ADNI</scp> study’

Galluzzi, Samantha; Marizzoni, Moira; Babiloni, Claudio; Albani, Diego; Antelmi, Luigi; Bagnoli, Cristina; Bartrés‐Faz, David; Cordone, Susanna; Didic, Mira; Farotti, Lucia; Fiedler, Ute; Forloni, Gianluigi; Girtler, Nicola; Hensch, Tilman; Jovicich, Jorge; Leeuwis, Anna E.; Marra, Camillo; Molinuevo, José Luís; Nobili, Flavio; Pariente, Jérémie; Parnetti, Lucilla; Payoux, Pierre; Percio, Claudio Del; Ranjeva, Jean Philippe; Rolandi, E; Rossini, Paolo Maria; Schönknecht, Peter; Soricelli, Andrea; Tsolaki, Magda; Visser, Pieter Jelle; Wiltfang, Jens; Richardson, Jill C.; Bordet, Régis; Blin, Olivier; Frisoni, Giovanni B.

doi:10.1111/joim.12482

Cited by 64 publications

(60 citation statements)

References 82 publications

(94 reference statements)

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“…The data used in this study was acquired as part of the PharmaCog project, a large European project aimed at profiling biomarkers sensitive to prodromal Alzheimer’s disease in elderly subjects with amnestic mild cognitive impairment in the age range of 50–80 (Galluzzi et al, 2016). The raw MRI data of the healthy subjects is public, its demographics, study design and data preparation steps have been described in a preliminary calibration study showing that test-retest reproducibility errors of diffusion metrics derived from the standard single tensor model were consistent across sites and consistent with previous reports of single site studies (Jovicich et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Free water elimination improves test–retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects

Albi

Pasternak

Minati

et al. 2016

Human Brain Mapping

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Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55–80 years old) scanned in two sessions at least one week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects.

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Section: Methodsmentioning

confidence: 99%

Free water elimination improves test–retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects

Albi

Pasternak

Minati

et al. 2016

Human Brain Mapping

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“…679 (78%) of the Cardiff sample set were also included in the Oxford sample set. Participants were included in these 'Oxford' and 'Cardiff' sample sets from across three multi-center studies: DESCRIPA [18], EDAR [19], and Pharma-Cog [20], and eight single center studies: Amsterdam [21], Antwerp [22], San Sebastian GAP [23], Gothenburg [24], Barcelona IDIBAPS [25], Lausanne [26], Leuven [27], and Barcelona St Pau [28]. Sample number differences between the 'Oxford' and 'Cardiff' sample sets were necessary due to plasma sample availability.…”

Section: Subjects: Emif-ad Multimodal Biomarker Discovery Study (Emifmentioning

confidence: 99%

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer’s Disease Multimodal Biomarker Discovery Cohort

Westwood

Baird

Anand

et al. 2020

JAD

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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 4 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.

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“…Several initiatives have defined a panel of diagnostic and prognostic imaging as well as cerebrospinal fluid (CSF) and blood biomarkers that identify people at the earliest stages of the disease, with most fluid biomarker studies focusing detecting changes in CSF Aβ peptide and tau protein levels at varying AD stages [119]. The National Institute on Aging-Alzheimer's Association (NIA-AA) developed criteria for using biomarkers to determine the likelihood of AD pathology and for classifying patients accordingly [119, 120] which included CSF Aβ 42 , positron emission tomography (PET) amyloid, CSF total tau, pT181 phospho-tau, MTL atrophy on Magnetic Resonance Imaging (MRI), tempoparietal/precuneus hypometabolism or hypoperfusion on PET or single-photon emission computed tomography (SPECT) [119]. Findings indicate that loss of hippocampal volume and the ratio of CSF Aβ 42 to total tau or phospho-tau are predictive of longitudinal changes in cognitive measures [121-124].…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular pathophysiology of preclinical Alzheimer’s disease

Mufson

Ikonomović

Counts

et al. 2016

Behavioural Brain Research

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Although the two pathological hallmarks of Alzheimer's disease (AD), senile plaques composed of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that Aβ plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state), and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than Aβ plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including Aβ and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuron plasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.

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Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a ‘European ADNI study’

Abstract: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Cited by 64 publications

References 82 publications

Free water elimination improves test–retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects

Free water elimination improves test–retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer’s Disease Multimodal Biomarker Discovery Cohort

Molecular and cellular pathophysiology of preclinical Alzheimer’s disease

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