Publications by authors named "Carles Falcon"

111 Publications

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

Neurology 2021 Sep 23. Epub 2021 Sep 23.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Objective: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer's and associated with Alzheimer's disease (AD) risk factors, primary pathology, and neurodegeneration markers.

Methods: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker NfL were also measured. Participants underwent structural MRI, and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.

Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values) and, importantly, the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism, but lower cortical thickness in AD-related brain regions.

Conclusion: CSF synaptic biomarkers increase in early preclinical stages of the Alzheimer's even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, ε4 and markers of neurodegeneration.
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http://dx.doi.org/10.1212/WNL.0000000000012853DOI Listing
September 2021

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum.

Alzheimers Res Ther 2021 08 5;13(1):135. Epub 2021 Aug 5.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.

Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.

Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).

Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.

Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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http://dx.doi.org/10.1186/s13195-021-00878-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340485PMC
August 2021

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

Brain correlates of urban environmental exposures in cognitively unimpaired individuals at increased risk for Alzheimer's disease: A study on Barcelona's population.

Alzheimers Dement (Amst) 2021 5;13(1):e12205. Epub 2021 Jul 5.

Barcelonaβeta Brain Research Center (BBRC) Pasqual Maragall Foundation Barcelona Spain.

Introduction: Urban environmental exposures might contribute to the incidence of Alzheimer's disease (AD). Our aim was to identify structural brain imaging correlates of urban environmental exposures in cognitively unimpaired individuals at increased risk of AD.

Methods: Two hundred twelve participants with brain scans and residing in Barcelona, Spain, were included. Land use regression models were used to estimate residential exposure to air pollutants. The daily average noise level was obtained from noise maps. Residential green exposure indicators were also generated. A cerebral 3D-T1 was acquired to obtain information on brain morphology. Voxel-based morphometry statistical analyses were conducted to determine the areas of the brain in which regional gray matter (GM) and white matter (WM) volumes were associated with environmental exposures.

Results: Exposure to nitrogen dioxide was associated with lower GM volume in the precuneus and greater WM volume in the splenium of the corpus callosum and inferior longitudinal fasciculus. In contrast, exposure to fine particulate matter was associated with greater GM in cerebellum and WM in the splenium of corpus callosum, the superior longitudinal fasciculus, and cingulum cingulate gyrus. Noise was positively associated with WM volume in the body of the corpus callosum. Exposure to greenness was associated with greater GM volume in the middle frontal, precentral, and the temporal pole.

Discussion: In cognitively unimpaired adults with increased risk of AD, exposure to air pollution, noise, and green areas are associated with GM and WM volumes of specific brain areas known to be affected in AD, thus potentially conferring a higher vulnerability to the disease.
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http://dx.doi.org/10.1002/dad2.12205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256622PMC
July 2021

Genetic Predisposition to Alzheimer's Disease Is Associated with Enlargement of Perivascular Spaces in Centrum Semiovale Region.

Genes (Basel) 2021 05 27;12(6). Epub 2021 May 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain.

This study investigated whether genetic factors involved in Alzheimer's disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with -rs744373, as well as genotypes. We found a significant association of the -rs744373 polymorphism in the CS subscale ( value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by - status (carriers vs. non-carriers), these results remained significant only for ε4 carriers ( value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.
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http://dx.doi.org/10.3390/genes12060825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226614PMC
May 2021

Management and Quality Control of Large Neuroimaging Datasets: Developments From the Barcelonaβeta Brain Research Center.

Front Neurosci 2021 15;15:633438. Epub 2021 Apr 15.

Barcelonabeta Brain Research Center, Barcelona, Spain.

Recent decades have witnessed an increasing number of large to very large imaging studies, prominently in the field of neurodegenerative diseases. The datasets collected during these studies form essential resources for the research aiming at new biomarkers. Collecting, hosting, managing, processing, or reviewing those datasets is typically achieved through a local neuroinformatics infrastructure. In particular for organizations with their own imaging equipment, setting up such a system is still a hard task, and relying on cloud-based solutions, albeit promising, is not always possible. This paper proposes a practical model guided by core principles including user involvement, lightweight footprint, modularity, reusability, and facilitated data sharing. This model is based on the experience from an 8-year-old research center managing cohort research programs on Alzheimer's disease. Such a model gave rise to an ecosystem of tools aiming at improved quality control through seamless automatic processes combined with a variety of code libraries, command line tools, graphical user interfaces, and instant messaging applets. The present ecosystem was shaped around XNAT and is composed of independently reusable modules that are freely available on GitLab/GitHub. This paradigm is scalable to the general community of researchers working with large neuroimaging datasets.
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http://dx.doi.org/10.3389/fnins.2021.633438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081968PMC
April 2021

DHA intake relates to better cerebrovascular and neurodegeneration neuroimaging phenotypes in middle-aged adults at increased genetic risk of Alzheimer disease.

Am J Clin Nutr 2021 06;113(6):1627-1635

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI.

Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status.

Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4.

Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors.

Conclusions: In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage.This trial was registered at clinicaltrials.gov as NCT01835717.
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http://dx.doi.org/10.1093/ajcn/nqab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168359PMC
June 2021

Subclinical Atherosclerosis and Brain Metabolism in Middle-Aged Individuals: The PESA Study.

J Am Coll Cardiol 2021 02;77(7):888-898

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Background: Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored.

Objectives: This study sought to determine the association between brain metabolism, subclinical atherosclerosis, and CVRFs in middle-aged asymptomatic individuals.

Methods: This study included 547 asymptomatic middle-aged participants (50 ± 4 years, 82% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study with evidence of subclinical atherosclerosis. Participants underwent F-fluorodeoxyglucose (FDG)-positron emission tomography. Global brain FDG uptake and voxel-wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3-dimensional vascular ultrasound.

Results: Global FDG uptake showed an inverse correlation with 30-year Framingham Risk Score (FRS) (β = -0.15, p < 0.001). This association was mainly driven by the presence of hypertension (d = 0.36, p < 0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β = -0.16, p < 0.001), even after adjusting for 30-year FRS. Voxel-wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30-year FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus.

Conclusions: In asymptomatic middle-aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include those known to be affected in dementia. These data reinforce the need to control CVRFs early in life in order to potentially reduce the brain's midlife vulnerability to future cognitive dysfunction.
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http://dx.doi.org/10.1016/j.jacc.2020.12.027DOI Listing
February 2021

Functional connectivity alterations associated with literacy difficulties in early readers.

Brain Imaging Behav 2021 Aug 13;15(4):2109-2120. Epub 2020 Oct 13.

Department of Clinical Psychology and Psychobiology, University of Barcelona, Pg. Vall d'Hebron 171, 08035, Barcelona, Catalonia, Spain.

The link between literacy difficulties and brain alterations has been described in depth. Resting-state fMRI (rs-fMRI) has been successfully applied to the study of intrinsic functional connectivity (iFc) both in dyslexia and typically developing children. Most related studies have focused on the stages from late childhood into adulthood using a seed to voxel approach. Our study analyzes iFc in an early childhood sample using the multivariate pattern analysis. This facilitates a hypothesis-free analysis and the possible identification of abnormal functional connectivity patterns at a whole brain level. Thirty-four children with literacy difficulties (LD) (7.1 ± 0.69 yr.) and 30 typically developing children (TD) (7.43 ± 0.52 yr.) were selected. Functional brain connectivity was measured using an rs-fMRI acquisition. The LD group showed a higher iFc between the right middle frontal gyrus (rMFG) and the default mode network (DMN) regions, and a lower iFc between the rMFG and both the bilateral insular cortex and the supramarginal gyrus. These results are interpreted as a DMN on/off routine malfunction in the LD group, which suggests an alteration of the task control network regulating DMN activity. In the LD group, the posterior cingulate cortex also showed a lower iFc with both the middle temporal poles and the fusiform gyrus. This could be interpreted as a failure in the integration of information between brain regions that facilitate reading. Our results show that children with literacy difficulties have an altered functional connectivity in their reading and attentional networks at the beginning of the literacy acquisition. Future studies should evaluate whether or not these alterations could indicate a risk of developing dyslexia.
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http://dx.doi.org/10.1007/s11682-020-00406-3DOI Listing
August 2021

Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals.

Hum Brain Mapp 2021 01 5;42(1):47-64. Epub 2020 Oct 5.

BCN MedTech, Departament de Tecnologies de la Informació i les Comunicacions, Universitat Pompeu Fabra, Barcelona, Spain.

The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4-enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi-atlas-based approach, obtaining high-dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way.
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http://dx.doi.org/10.1002/hbm.25202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721244PMC
January 2021

Effect of BDNF Val66Met on hippocampal subfields volumes and compensatory interaction with APOE-ε4 in middle-age cognitively unimpaired individuals from the ALFA study.

Brain Struct Funct 2020 Nov 17;225(8):2331-2345. Epub 2020 Aug 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Current evidence supports the involvement of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and the ε4 allele of APOE gene in hippocampal-dependent functions. Previous studies on the association of Val66Met with whole hippocampal volume included patients of a variety of disorders. However, it remains to be elucidated whether there is an impact of BDNF Val66Met polymorphism on the volumes of the hippocampal subfield volumes (HSv) in cognitively unimpaired (CU) individuals, and the interactive effect with the APOE-ε4 status.

Methods: BDNF Val66Met and APOE genotypes were determined in a sample of 430 CU late/middle-aged participants from the ALFA study (ALzheimer and FAmilies). Participants underwent a brain 3D-T1-weighted MRI scan, and volumes of the HSv were determined using Freesurfer (v6.0). The effects of the BDNF Val66Met genotype on the HSv were assessed using general linear models corrected by age, gender, education, number of APOE-ε4 alleles and total intracranial volume. We also investigated whether the association between APOE-ε4 allele and HSv were modified by BDNF Val66Met genotypes.

Results: BDNF Val66Met carriers showed larger bilateral volumes of the subiculum subfield. In addition, HSv reductions associated with APOE-ε4 allele were significantly moderated by BDNF Val66Met status. BDNF Met carriers who were also APOE-ε4 homozygous showed patterns of higher HSv than BDNF Val carriers.

Conclusion: To our knowledge, the present study is the first to show that carrying the BDNF Val66Met polymorphisms partially compensates the decreased on HSv associated with APOE-ε4 in middle-age cognitively unimpaired individuals.
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http://dx.doi.org/10.1007/s00429-020-02125-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544723PMC
November 2020

The relation between APOE genotype and cerebral microbleeds in cognitively unimpaired middle- and old-aged individuals.

Neurobiol Aging 2020 11 29;95:104-114. Epub 2020 Jun 29.

Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands; Institutes of Neurology and Healthcare Engineering, UCL, London, UK.

Positive associations between cerebral microbleeds (CMBs) and APOE-ε4 (apolipoprotein E) genotype have been reported in Alzheimer's disease, but show conflicting results. We investigated the effect of APOE genotype on CMBs in a cohort of cognitively unimpaired middle- and old-aged individuals enriched for APOE-ε4 genotype. Participants from ALFA (Alzheimer and Families) cohort were included and their magnetic resonance scans assessed (n = 564, 50% APOE-ε4 carriers). Quantitative magnetic resonance analyses included visual ratings, atrophy measures, and white matter hyperintensity (WMH) segmentations. The prevalence of CMBs was 17%, increased with age (p < 0.05), and followed an increasing trend paralleling APOE-ε4 dose. The number of CMBs was significantly higher in APOE-ε4 homozygotes compared to heterozygotes and non-carriers (p < 0.05). This association was driven by lobar CMBs (p < 0.05). CMBs co-localized with WMH (p < 0.05). No associations between CMBs and APOE-ε2, gray matter volumes, and cognitive performance were found. Our results suggest that cerebral vessels of APOE-ε4 homozygous are more fragile, especially in lobar locations. Co-occurrence of CMBs and WMH suggests that such changes localize in areas with increased vascular vulnerability.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.015DOI Listing
November 2020

Association of years to parent's sporadic onset and risk factors with neural integrity and Alzheimer biomarkers.

Neurology 2020 10 31;95(15):e2065-e2074. Epub 2020 Jul 31.

From the Barcelonaβeta Brain Research Center (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., M.S.-C., J.L.M.), Madrid, Spain; Department of Epidemiology (M.C.-B.), Harvard TH Chan School of Public Health, Boston, MA; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar, Barcelona; Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (C.F., J.D.G.), Madrid, Spain; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Universitat Pompeu Fabra (J.D.G., J.L.M.), Barcelona, Spain.

Objective: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors.

Methods: This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, ε4, education, and vascular and mental health.

Results: Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.

Conclusion: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.

Clinicaltrialsgov Identifier: NCT02485730.

Classification Of Evidence: This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.
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http://dx.doi.org/10.1212/WNL.0000000000010527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774330PMC
October 2020

Sex Differences of Longitudinal Brain Changes in Cognitively Unimpaired Adults.

J Alzheimers Dis 2020 ;76(4):1413-1422

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.

Background: There is increasing evidence that AD progression differs by sex.

Objective: The aim of this work was to determine sex differences in the association of baseline levels of cerebrospinal fluid (CSF) biomarkers (Aβ42, p-tau, YKL-40, sTREM2) with longitudinal brain changes in cognitively unimpaired (CU) older adults.

Methods: This pilot study included 36 CU subjects (age 66.5±5.5, 12 male) scanned twice, two years apart. Using a voxel-wise analysis, we determined the sex differences in the association maps between CSF biomarkers and atrophy rates.

Results: We did not find differences related to Aβ42. We found a greater impact of the rest of CSF biomarkers in areas of the Papez circuit in women versus men. Men showed greater involvement in lateral parietal and paracentral areas.

Discussion: Results suggest an early differential progression of brain atrophy between sexes. Further research will elucidate whether the mechanisms responsible for sex-specific atrophy patterns are biological and/or environmental.
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http://dx.doi.org/10.3233/JAD-200293DOI Listing
June 2021

NeAT: a Nonlinear Analysis Toolbox for Neuroimaging.

Neuroinformatics 2020 10;18(4):517-530

BarcelonaBeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

NeAT is a modular, flexible and user-friendly neuroimaging analysis toolbox for modeling linear and nonlinear effects overcoming the limitations of the standard neuroimaging methods which are solely based on linear models. NeAT provides a wide range of statistical and machine learning non-linear methods for model estimation, several metrics based on curve fitting and complexity for model inference and a graphical user interface (GUI) for visualization of results. We illustrate its usefulness on two study cases where non-linear effects have been previously established. Firstly, we study the nonlinear effects of Alzheimer's disease on brain morphology (volume and cortical thickness). Secondly, we analyze the effect of the apolipoprotein APOE-ε4 genotype on brain aging and its interaction with age. NeAT is fully documented and publicly distributed at https://imatge-upc.github.io/neat-tool/ .
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http://dx.doi.org/10.1007/s12021-020-09456-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498484PMC
October 2020

APOE-ε4 Shapes the Cerebral Organization in Cognitively Intact Individuals as Reflected by Structural Gray Matter Networks.

Cereb Cortex 2020 06;30(7):4110-4120

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain.

Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer's disease (AD). Apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition.
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http://dx.doi.org/10.1093/cercor/bhaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264689PMC
June 2020

Impact of urban environmental exposures on cognitive performance and brain structure of healthy individuals at risk for Alzheimer's dementia.

Environ Int 2020 05 6;138:105546. Epub 2020 Mar 6.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain. Electronic address:

Background: Air quality might contribute to incidence of dementia-related disorders, including Alzheimer's dementia (AD). The aim of our study is to evaluate the effect of urban environmental exposures (including exposure to air pollution, noise and green space) on cognitive performance and brain structure of cognitively unimpaired individuals at risk for AD.

Participants And Methods: The ALFA (ALzheimer and FAmilies) study is a prospective cohort of middle-age, cognitively unimpaired subjects, many of them offspring of AD patients. Cognitive performance was measured by the administration of episodic memory and executive function tests (N = 958). Structural brain imaging was performed in a subsample of participants to obtain morphological information of brain areas, specially focused on cortical thickness, known to be affected by AD (N = 228). Land Use Regression models were used to estimate residential exposure to air pollutants. The daily average noise level at the street nearest to each participant's residential address was obtained from noise maps. For each participant residential green exposure indicators, such as surrounding greenness or amount of green, were generated. General linear models were conducted to assess the association between environmental exposures, cognitive performance and brain structure in a cross-sectional analysis.

Results: No significant associations were observed between urban environmental exposures and the cognitive composite (p > 0.1). Higher exposure to air pollutants, but not noise, was associated with lower cortical thickness in brain regions known to be affected by AD, especially NO (β = -16.4; p = 0.05) and PM (β = -5.34; p = 0.05). On the other hand, increasing greenness indicators was associated with greater thickness in these same areas (β = 0.08; p = 0.03).

Conclusion: In cognitively unimpaired adults with increased risk for AD, increased exposure to air pollution was suggested to be associated with greater global atrophy and reduced volume and thickness in specific brain areas known to be affected in AD, thus suggesting a potential link between environmental exposures and cerebral vulnerability to AD. Although more research in the field is needed, air pollution reduction is crucial for decreasing the burden of age-related disorders.
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http://dx.doi.org/10.1016/j.envint.2020.105546DOI Listing
May 2020

Earliest amyloid and tau deposition modulate the influence of limbic networks during closed-loop hippocampal downregulation.

Brain 2020 03;143(3):976-992

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-β peptide 42 (amyloid-β42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-β peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-β42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-β42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.
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http://dx.doi.org/10.1093/brain/awaa011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089658PMC
March 2020

Association between insomnia and cognitive performance, gray matter volume, and white matter microstructure in cognitively unimpaired adults.

Alzheimers Res Ther 2020 01 7;12(1). Epub 2020 Jan 7.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08003, Barcelona, Spain.

Background: Mounting evidence links poor sleep quality with a higher risk of late-life dementia. However, the structural and cognitive correlates of insomnia are still not well understood. The study aims were to characterize the cognitive performance and brain structural pattern of cognitively unimpaired adults at increased risk for Alzheimer's disease (AD) with insomnia.

Methods: This cross-sectional study included 1683 cognitively unimpaired middle/late-middle-aged adults from the ALFA (ALzheimer and FAmilies) study who underwent neuropsychological assessment, T1-weighted structural imaging (n = 366), and diffusion-weighted imaging (n = 334). The World Health Organization's World Mental Health Survey Initiative version of the Composite International Diagnostic Interview was used to define the presence or absence of insomnia. Multivariable regression models were used to evaluate differences in cognitive performance between individuals with and without insomnia, as well as potential interactions between insomnia and the APOE genotype. Voxel-based morphometry and tract-based spatial statistics were used to assess between-group differences and potential interactions between insomnia and the APOE genotype in gray matter volume and white matter diffusion metrics.

Results: Insomnia was reported by 615 out of 1683 participants (36.5%), including 137 out of 366 (37.4%) with T1-weighted structural imaging available and 119 out of 334 (35.6%) with diffusion-weighted imaging. Individuals with insomnia (n = 615) performed worse in executive function tests than non-insomniacs and displayed lower gray matter volume in left orbitofrontal and right middle temporal cortex, bilateral precuneus, posterior cingulate cortex and thalamus, higher gray matter volume in the left caudate nucleus, and widespread reduction of mean and axial diffusivity in right hemisphere white matter tracts. Insomnia interacted with the APOE genotype, with APOE-ε4 carriers displaying lower gray matter volumes when insomnia was present, but higher volumes when insomnia was not present, in several gray matter regions, including the left angular gyrus, the bilateral superior frontal gyri, the thalami, and the right hippocampus.

Conclusions: Insomnia in cognitively unimpaired adults at increased risk for AD is associated to poorer performance in some executive functions and volume changes in cortical and subcortical gray matter, including key areas involved in Alzheimer's disease, as well as decreased white matter diffusivity.
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http://dx.doi.org/10.1186/s13195-019-0547-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945611PMC
January 2020

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants.

Hum Brain Mapp 2020 04 28;41(5):1309-1322. Epub 2019 Nov 28.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle-aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS-IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion-weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel-wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)-ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle-aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.
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http://dx.doi.org/10.1002/hbm.24877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267988PMC
April 2020

Associations Between the Subjective Cognitive Decline-Questionnaire's Scores, Gray Matter Volume, and Amyloid-β Levels.

J Alzheimers Dis 2019 ;72(4):1287-1302

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clinic, Barcelona, Spain.

Background: Exploring the relationship between Alzheimer's disease (AD) biomarkers and subjective cognitive decline (SCD) is needed for better defining its clinical meaning in preclinical AD (preAD).

Objective: To assess the association between the Subjective Cognitive Decline Questionnaire (SCD-Q), gray matter (GM), and cerebrospinal fluid amyloid-β (Aβ).

Methods: 56 cognitively healthy older adults and their informants answered the SCD-Q. Correlations between GM and SCD-Q scores were explored using structural voxel-based morphometry models including Aβ levels. SCD-Q*Aβ vectors were calculated with higher scores reflecting higher SCD and cerebral amyloid, simultaneously. Subjects were classified according to their perception of cognitive worsening in the last two years, exploring for GM differences between-groups.

Results: Higher self-reported SCD-Q scores correlated with reduced GM in the right frontal lobe and increased volumes in the occipital lobe, calcarine sulcus, fusiform gyrus, and cerebellum, while higher informant's scores correlated with increased GM in the right middle temporal gyrus. Correlations were more significant for SCD-Q language items, self-complaints, and more positive than negative correlations were found. The SCD-Q*Aβ vectors were negatively associated with GM both in self and informant's reports. Finally, lower Aβ levels related to lower GM in subjects who noticed cognitive worsening, but related to higher GM in subjects who have not noticed this decline.

Conclusions: Our results suggest that SCD-Q scores relate with incipient brain changes that may be due to preAD. Independent studies are needed to confirm our observations.
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http://dx.doi.org/10.3233/JAD-190624DOI Listing
December 2020

Interactive effect of age and APOE-ε4 allele load on white matter myelin content in cognitively normal middle-aged subjects.

Neuroimage Clin 2019 16;24:101983. Epub 2019 Aug 16.

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. Electronic address:

The apolipoprotein E gene (APOE) ε4 allele has a strong and manifold impact on cognition and neuroimaging phenotypes in cognitively normal subjects, including alterations in the white matter (WM) microstructure. Such alterations have often been regarded as a reflection of potential thinning of the myelin sheath along axons, rather than pure axonal degeneration. Considering the main role of APOE in brain lipid transport, characterizing the impact of APOE on the myelin coating is therefore of crucial interest, especially in healthy APOE-ε4 homozygous individuals, who are exposed to a twelve-fold higher risk of developing Alzheimer's disease (AD), compared to the rest of the population. We examined T1w/T2w ratio maps in 515 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 197 heterozygotes, and 250 non-carriers). Using tract-based spatial statistics, we assessed the impact of age and APOE genotype on this ratio taken as an indirect descriptor of myelin content. Healthy APOE-ε4 carriers display decreased T1w/T2w ratios in extensive regions in a dose-dependent manner. These differences were found to interact with age, suggesting faster changes in individuals with more ε4 alleles. These results obtained with T1w/T2w ratios, confirm the increased vulnerability of WM tracts in APOE-ε4 healthy carriers. Early alterations of myelin content could be the result of the impaired function of the ε4 isoform of the APOE protein in cholesterol transport. These findings help to clarify the possible interactions between the APOE-dependent non-pathological burden and age-related changes potentially at the source of the AD pathological cascade.
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http://dx.doi.org/10.1016/j.nicl.2019.101983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742967PMC
September 2020

Prediction of amyloid pathology in cognitively unimpaired individuals using voxel-wise analysis of longitudinal structural brain MRI.

Alzheimers Res Ther 2019 08 17;11(1):72. Epub 2019 Aug 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, C/ Wellington 30, 08005, Barcelona, Spain.

Background: Magnetic resonance imaging (MRI) has unveiled specific alterations at different stages of Alzheimer's disease (AD) pathophysiologic continuum constituting what has been established as "AD signature". To what extent MRI can detect amyloid-related cerebral changes from structural MRI in cognitively unimpaired individuals is still an area open for exploration.

Method: Longitudinal 3D-T1 MRI scans were acquired from a subset of the ADNI cohort comprising 403 subjects: 79 controls (Ctrls), 50 preclinical AD (PreAD), and 274 MCI and dementia due to AD (MCI/AD). Amyloid CSF was used as gold-standard measure with established cutoffs (< 192 pg/mL) to establish diagnostic categories. Cognitively unimpaired individuals were defined as Ctrls if were amyloid negative and PreAD otherwise. The MCI/AD group was amyloid positive. Only subjects with the same diagnostic category at baseline and follow-up visits were considered for the study. Longitudinal morphometric analysis was performed using SPM12 to calculate Jacobian determinant maps. Statistical analysis was carried out on these Jacobian maps to identify structural changes that were significantly different between diagnostic categories. A machine learning classifier was applied on Jacobian determinant maps to predict the presence of abnormal amyloid levels in cognitively unimpaired individuals. The performance of this classifier was evaluated using receiver operating characteristic curve analysis and as a function of the follow-up time between MRI scans. We applied a cost function to assess the benefit of using this classifier in the triaging of individuals in a clinical trial-recruitment setting.

Results: The optimal follow-up time for classification of Ctrls vs PreAD was Δt > 2.5 years, and hence, only subjects within this temporal span are used for evaluation (15 Ctrls, 10 PreAD). The longitudinal voxel-based classifier achieved an AUC = 0.87 (95%CI 0.72-0.97). The brain regions that showed the highest discriminative power to detect amyloid abnormalities were the medial, inferior, and lateral temporal lobes; precuneus; caudate heads; basal forebrain; and lateral ventricles.

Conclusions: Our work supports that machine learning applied to longitudinal brain volumetric changes can be used to predict, with high precision, the presence of amyloid abnormalities in cognitively unimpaired subjects. Used as a triaging method to identify a fixed number of amyloid-positive individuals, this longitudinal voxel-wise classifier is expected to avoid 55% of unnecessary CSF and/or PET scans and reduce economic cost by 40%.
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http://dx.doi.org/10.1186/s13195-019-0526-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698344PMC
August 2019

Patterns of white matter hyperintensities associated with cognition in middle-aged cognitively healthy individuals.

Brain Imaging Behav 2020 Oct;14(5):2012-2023

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Wellington 30, 08003, Barcelona, Spain.

White matter hyperintensities (WMH) are commonly detected in the brain of elderly individuals and have been associated with a negative impact on multiple cognitive domains. We aim to investigate the impact of global and regional distribution of WMH on episodic memory and executive function in middle-aged cognitively unimpaired participants [N = 561 (45-75 years)] enriched for Alzheimer's disease risk factors. WMH were automatically segmented from FLAIR, T1 and FSE MR images. WMH load was calculated both globally and regionally. At each cerebral lobe, regional WMH load was measured at four equidistant layers extending from the lateral ventricles to juxtacortical areas. Cognition was measured by The Memory Binding Test (MBT) and WAIS-IV subtests. Global composite z-scores were calculated for the two cognitive domains. Association between global and regional WMH measurements were sought against cognitive measures, both in global composite scores and in individual subtests. We adjusted cognition and WMH burden for the main sociodemographic (age, sex and education) and genetic factors (APOE-ε4). Memory and executive function were significantly associated with global WMH load. Regionally, lower executive performance was mainly associated with higher deep WMH load in frontal areas and, to a lower degree, in occipital, parietal and temporal regions. Lower episodic memory performance was correlated with higher WMH burden in deep frontal and occipital areas. Our novel methodological approach of regional analysis allowed us to reveal the association between cognition and WMH in strategic brain locations. Our results suggest that, even a small WMH load can impact cognition in cognitively unimpaired middle-aged subjects.
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http://dx.doi.org/10.1007/s11682-019-00151-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572336PMC
October 2020

APOE-ε4 risk variant for Alzheimer's disease modifies the association between cognitive performance and cerebral morphology in healthy middle-aged individuals.

Neuroimage Clin 2019 8;23:101818. Epub 2019 Apr 8.

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:

The APOE-ε4 genotype is the highest genetic risk factor for Alzheimer's disease (AD). In cognitively unimpaired individuals, it has been related to altered brain morphology, function and earlier amyloid beta accumulation. However, its impact on cognitive performance is less evident. Here, we examine the impact of APOE-ε4 allele load in modulating the association between cognitive functioning and brain morphology in middle-aged healthy individuals. A high-resolution structural MRI scan was acquired and episodic memory (EM) as well as executive functions (EFs) were assessed in a sample of 527 middle-aged unimpaired individuals hosting a substantial representation of ε4-homozygous (N = 64). We adopted a voxel-wise unbiased method to assess whether the number of APOE-ε4 alleles significantly modified the associations between gray matter volumes (GMv) and performance in both cognitive domains. Even though the APOE-ε4 allele load did not exert a direct impact on any cognitive measures, it reversed the relationships between GMv and cognitive performance in a highly symmetrical topological pattern. For EM, interactions mapped onto the inferior temporal gyrus and the dorsal anterior cingulate cortex. Regarding EFs, significant interactions were observed for processing speed, working memory, and visuospatial attention in distinct brain regions. These results suggest that APOE-ε4 carriers display a structure-function association corresponding to an older age than their chronological one. Our findings additionally indicate that APOE-ε4 carriers may rely on the integrity of multiple compensatory brain systems in order to preserve their cognitive abilities, possibly due to an incipient neurodegeneration. Overall this study provides novel insights on the mechanisms through which APOE-ε4 posits an increased AD risk.
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http://dx.doi.org/10.1016/j.nicl.2019.101818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463204PMC
April 2020

CSF glial biomarkers YKL40 and sTREM2 are associated with longitudinal volume and diffusivity changes in cognitively unimpaired individuals.

Neuroimage Clin 2019 1;23:101801. Epub 2019 Apr 1.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Neurology Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain; Universitat Pompeu Fabra, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. Electronic address:

Cerebrospinal fluid (CSF) YKL40 and sTREM2 are astroglial and microglial activity biomarkers, respectively. We assessed whether CSF YKL40 and sTREM2 baseline levels are associated with longitudinal brain volume and diffusivity changes in cognitively unimpaired adults. Two brain MRI scans of 36 participants (57 to 78-years old, 12 male) were acquired in a 2-year interval. Aβ, p-tau, YKL40 and sTREM2 concentrations in CSF were determined at baseline. We calculated gray and white matter volume changes per year maps (ΔGM and ΔWM, respectively) by means of longitudinal pairwise registration, and mean diffusivity variation per year (ΔMD) by subtraction. We checked voxel-wise for associations between ΔGM, ΔWM and ΔMD and baseline CSF level of YKL40 and sTREM2 and verified to what extent these associations were modulated by age (YKL40xAGE and sTREM2xAGE interactions). We found a positive association between ΔGM and YKL40 in the left inferior parietal region and no association between sTREM2 and ΔGM. Negative associations were also observed between ΔGM and YKL40xAGE (bilateral frontal areas, left precuneus and left postcentral and supramarginal gyri) and sTREM2xAGE (bilateral temporal and frontal cortex, putamen and left middle cingulate gyrus). We found negative associations between ΔWM and YKL40xAGE (bilateral superior longitudinal fasciculus) and sTREM2xAGE (bilateral superior longitudinal fasciculus, left superior corona radiata, retrolenticular external capsule and forceps minor, among other regions) but none between ΔWM and neither YKL40 nor sTREM2. ΔMD was positively correlated with YKL40 in right orbital region and negatively with sTREM2 in left lingual gyrus and precuneus. In addition, significant associations were found between ΔMD and YKL40xAGE (tail of left hippocampus and surrounding areas and right anterior cingulate gyrus) and sTREM2xAGE (right superior temporal gyrus). Areas showing statistically significant differences were disjoint in analyses involving YKL40 and sTREM2. These results suggest that glial biomarkers exert a relevant and distinct influence in longitudinal brain macro- and microstructural changes in cognitively unimpaired adults, which appears to be modulated by age. In younger subjects increased glial markers (both YKL40 and sTREM2) predict a better outcome, as indicated by a decrease in ΔGM and ΔWM and an increase in ΔMD, whereas in older subjects this association is inverted and higher levels of glial markers are associated with a poorer neuroimaging outcome.
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http://dx.doi.org/10.1016/j.nicl.2019.101801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458453PMC
April 2020

Mechanisms of functional compensation, delineated by eigenvector centrality mapping, across the pathophysiological continuum of Alzheimer's disease.

Neuroimage Clin 2019 12;22:101777. Epub 2019 Mar 12.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address:

Background: Mechanisms of functional compensation throughout the progression of Alzheimer's disease (AD) remain largely underspecified. By investigating functional connectomics in relation to cerebrospinal fluid (CSF) biomarkers across the pathophysiological continuum of AD, we identify disease-stage-specific patterns of functional degradation and functional compensation.

Methods: Data from a sample of 96 participants, comprised of 49 controls, 11 preclinical AD subjects, 21 patients with mild cognitive impairment (MCI) due to AD and 15 patients with mild dementia due to AD, were analyzed. CSF ratio of phosphorylated tau protein over amyloid beta peptide 42 (p-tau/Aβ42) was computed and used as a marker of progression along the AD continuum. Whole-brain, voxel-wise eigenvector centrality mapping (ECM) was computed from resting-state fMRI and regression against p-tau/Aβ42 was performed. Surviving clusters were used as data-derived seeds in functional connectivity analyses and investigated in relation to memory performance scores (delayed free recall and memory alteration) via complementary regression models. To investigate disease-stage-specific effects, the whole-brain connectivity maps of each cluster were compared between progressive groups.

Results: Centrality in BA39-BA19 is negatively correlated with the p-tau/Aβ42 ratio and associated to memory function impairment across the AD continuum. The thalamus, anterior cingulate (ACC), midcingulate (MCC) and posterior cingulate cortex (PCC) show the opposite effect. The MCC shows the highest increase in centrality as memory performance decays. In the asymptomatic preclinical group, MCC shows reduced functional connectivity (FC) with the left hippocampus and stronger FC with the precuneus (PCu). Additionally, BA39-BA19 show reduced FC with the cerebellum, compensated by stronger FC between cerebellum and PCC. In the MCI group, PCC shows reduced FC with PCu, compensated by stronger FC with the left pars orbitalis, insula and temporal pole, as well as by stronger FC of MCC with its anterior and ventral neighboring areas and the cerebellum. In the mild dementia group, extensive functional decoupling occurs across the entire autobiographical memory network and functional resilience ensues in posterior regions and the cerebellum.

Conclusions: Functional decoupling in preclinical AD occurs predominantly in AD-vulnerable regions (e.g. hippocampus, cerebellar lobule VI / Crus I, visual cortex, frontal pole) and coupling between MCC and PCu, as well as between PCC and cerebellum, emerge as intrinsic mechanisms of functional compensation. At the MCI stage, the PCu can no longer compensate for hippocampal decoupling, but the compensatory role of the MCC and PCC ensue into the stage of dementia. These findings shed light on the neural mechanisms of functional compensation across the pathophysiological continuum of AD, highlighting the compensatory roles of several key brain areas.
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http://dx.doi.org/10.1016/j.nicl.2019.101777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434094PMC
January 2020

Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers.

Alzheimers Res Ther 2019 03 21;11(1):27. Epub 2019 Mar 21.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.

Methods: A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([F]flutemetamol and [F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.

Results: All Centiloid cut-offs fell within the range of 25-35, except for CSF Aβ that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ ratios was higher than that of CSF Aβ. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.

Conclusions: A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.

Trial Registration: ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969.
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http://dx.doi.org/10.1186/s13195-019-0478-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429814PMC
March 2019

Spatial patterns of white matter hyperintensities associated with Alzheimer's disease risk factors in a cognitively healthy middle-aged cohort.

Alzheimers Res Ther 2019 01 24;11(1):12. Epub 2019 Jan 24.

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: White matter hyperintensities (WMH) of presumed vascular origin have been associated with an increased risk of Alzheimer's disease (AD). This study aims to describe the patterns of WMH associated with dementia risk estimates and individual risk factors in a cohort of middle-aged/late middle-aged individuals (mean 58 (interquartile range 51-64) years old).

Methods: Magnetic resonance imaging and AD risk factors were collected from 575 cognitively unimpaired participants. WMH load was automatically calculated in each brain lobe and in four equidistant layers from the ventricular surface to the cortical interface. Global volumes and regional patterns of WMH load were analyzed as a function of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, as well as family history of AD and Apolipoprotein E (APOE) genotype. Additional analyses were performed after correcting for the effect of age and hypertension.

Results: The studied cohort showed very low WMH burden (median 1.94 cm) and 20-year dementia risk estimates (median 1.47 %). Even so, higher CAIDE scores were significantly associated with increased global WMH load. The main drivers of this association were age and hypertension, with hypercholesterolemia and body mass index also displaying a minor, albeit significant, influence. Regionally, CAIDE scores were positively associated with WMH in anterior areas, mostly in the frontal lobe. Age and hypertension showed significant association with WMH in almost all regions analyzed. The APOE-ε2 allele showed a protective effect over global WMH with a pattern that comprised juxtacortical temporo-occipital and fronto-parietal deep white matter regions. Participants with maternal family history of AD had higher WMH load than those without, especially in temporal and occipital lobes.

Conclusions: WMH load is associated with AD risk factors even in cognitively unimpaired subjects with very low WMH burden and dementia risk estimates. Our results suggest that tight control of modifiable risk factors in middle-age/late middle-age could have a significant impact on late-life dementia.
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http://dx.doi.org/10.1186/s13195-018-0460-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346579PMC
January 2019

Brain and cognitive correlates of subjective cognitive decline-plus features in a population-based cohort.

Alzheimers Res Ther 2018 12 20;10(1):123. Epub 2018 Dec 20.

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington 30, 08005, Barcelona, Spain.

Background: Subjective cognitive decline (SCD) consists of self-perceived decline in cognition over time. The occurrence of specific additional features in SCD (so-called SCDplus) confers a higher risk of future cognitive decline. However, it is not known whether SCDplus patients have a distinct cognitive and neuroimaging profile. Therefore, we aimed to study the associations between SCDplus features and cognitive and neuroimaging profiles in a population-based cohort.

Methods: A total of 2670 individuals from the ALFA cohort underwent clinical, cognitive, and MRI (n = 532) explorations. Subjects were classified as self-reporting cognitive decline (SCD) or not self-reporting cognitive decline (non-SCD). Within the SCD group, participants were also classified according to the number of SCDplus features they met (SCD+, > 3; SCD-, ≤ 3).

Results: The prevalence of SCD in the cohort was 21.4% (55.8% SCD-, 44.2% SCD+). SCD+ subjects performed worse than non-SCD and SCD- subjects in memory and executive function. Among the SCDplus features, confirmation of decline by an informant was the best predictor of worse cognitive performance and lower gray matter volumes.

Conclusions: Our findings show that individuals with SCDplus features have a distinct cognitive and brain volumetric profile similar to that found in Alzheimer's disease and therefore support the use of the SCDplus concept as an enrichment criterion in population-based cohorts.
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http://dx.doi.org/10.1186/s13195-018-0449-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302483PMC
December 2018
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