Publications by authors named "Eider M Arenaza-Urquijo"

50 Publications

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

The Effect of Mindfulness-based Programs on Cognitive Function in Adults: A Systematic Review and Meta-analysis.

Neuropsychol Rev 2021 Aug 4. Epub 2021 Aug 4.

Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.

Mindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904].
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http://dx.doi.org/10.1007/s11065-021-09519-yDOI Listing
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

Amyloid-β positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to lower hippocampal volume.

Neurobiol Aging 2021 08 6;104:24-31. Epub 2021 Mar 6.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Present address: H. Lundbeck A/S, Denmark. Electronic address:

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.026DOI Listing
August 2021

Effects of a Mindfulness-Based Intervention versus Health Self-Management on Subclinical Anxiety in Older Adults with Subjective Cognitive Decline: The SCD-Well Randomized Superiority Trial.

Psychother Psychosom 2021 19;90(5):341-350. Epub 2021 Apr 19.

Swiss Center for Affective Sciences, Department of Medicine and Department of Psychology, Department of Political Science and International Relations, University of Geneva, Geneva, Switzerland.

Introduction: Older adults experiencing subjective cognitive decline (SCD) have a heightened risk of developing dementia and frequently experience subclinical anxiety, which is itself associated with dementia risk.

Objective: To understand whether subclinical anxiety symptoms in SCD can be reduced through behavioral interventions.

Methods: SCD-Well is a randomized controlled trial designed to determine whether an 8-week mindfulness-based intervention (caring mindfulness-based approach for seniors; CMBAS) is superior to a structurally matched health self-management program (HSMP) in reducing subclinical anxiety. Participants were recruited from memory clinics at 4 European sites. The primary outcome was change in anxiety symptoms (trait subscale of the State-Trait Anxiety Inventory; trait-STAI) from pre- to postintervention. Secondary outcomes included a change in state anxiety and depression symptoms postintervention and 6 months postrandomization (follow-up).

Results: One hundred forty-seven participants (mean [SD] age: 72.7 [6.9] years; 64.6% women; CMBAS, n = 73; HSMP, n = 74) were included in the intention-to-treat analysis. There was no difference in trait-STAI between groups postintervention (adjusted change difference: -1.25 points; 95% CI -4.76 to 2.25) or at follow-up (adjusted change difference: -0.43 points; 95% CI -2.92 to 2.07). Trait-STAI decreased postintervention in both groups (CMBAS: -3.43 points; 95% CI -5.27 to -1.59; HSMP: -2.29 points; 95% CI -4.14 to -0.44) and reductions were maintained at follow-up. No between-group differences were observed for change in state anxiety or depression symptoms.

Conclusions: A time-limited mindfulness intervention is not superior to health self-management in reducing subclinical anxiety symptoms in SCD. The sustained reduction observed across both groups suggests that subclinical anxiety symptoms in SCD are modifiable. ClinicalTrials.gov identifier: NCT03005652.
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http://dx.doi.org/10.1159/000515669DOI Listing
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

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):46. Epub 2021 Feb 17.

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

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.

Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.

Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.

Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.

Trial Registration: NCT01835717 , NCT02485730 , NCT02685969 .
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http://dx.doi.org/10.1186/s13195-021-00781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890889PMC
February 2021

Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve.

Alzheimers Dement 2021 08 16;17(8):1329-1341. Epub 2021 Feb 16.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.

Introduction: Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity in Alzheimer's disease, but its role in the behavioral variant of frontotemporal dementia (bvFTD) is unknown.

Methods: We included 216 patients with bvFTD and 235 controls with magnetic resonance imaging (MRI) from a large multicenter cohort. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We followed the residuals approach to study behavioral and cognitive reserve.

Results: At diagnosis, women with bvFTD showed greater atrophy burden in the frontotemporal regions compared to men despite similar clinical characteristics. For a similar amount of atrophy, women demonstrated better-than-expected scores on executive function and fewer changes in apathy, sleep, and appetite than men.

Discussion: Our findings suggest that women might have greater behavioral and executive reserve than men, and neurodegeneration must be more severe in women to produce symptoms similar in severity to those in men.
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http://dx.doi.org/10.1002/alz.12299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364861PMC
August 2021

Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults.

Neuroimage 2021 05 5;231:117819. Epub 2021 Feb 5.

Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France. Electronic address:

Background: As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults.

Methods: One hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations.

Results: Only physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively.

Conclusions: Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117819DOI Listing
May 2021

Quantitative informant- and self-reports of subjective cognitive decline predict amyloid beta PET outcomes in cognitively unimpaired individuals independently of age and .

Alzheimers Dement (Amst) 2020 11;12(1):e12127. Epub 2020 Nov 11.

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

Introduction: Amyloid beta (Aβ) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict Aβ positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals.

Methods: A total of 261 participants from the ALFA+ study underwent [F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict Aβ PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to Aβ status.

Results: Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted Aβ PET outcome. Longitudinal increase of self-reported executive decline was predictive of Aβ in women ( = .003).

Discussion: Subjective reports of cognitive decline are useful to predict Aβ and may improve recruitment strategies.
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http://dx.doi.org/10.1002/dad2.12127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656171PMC
November 2020

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected.

EMBO Mol Med 2020 12 10;12(12):e12921. Epub 2020 Nov 10.

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

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays.
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http://dx.doi.org/10.15252/emmm.202012921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721364PMC
December 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

Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.

Alzheimers Dement 2020 10 23;16(10):1358-1371. Epub 2020 Jun 23.

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

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.

Methods: We used NeuroToolKit and Elecsys immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.

Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.

Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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http://dx.doi.org/10.1002/alz.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586814PMC
October 2020

Repetitive negative thinking is associated with amyloid, tau, and cognitive decline.

Alzheimers Dement 2020 07 7;16(7):1054-1064. Epub 2020 Jun 7.

Studies on Prevention of Alzheimer's Disease (StOP-AD) Centre, Douglas Mental Health University Institute, Montreal, Quebec, Canada.

Introduction: The Cognitive Debt hypothesis proposes that repetitive negative thinking (RNT), a modifiable process common to many psychological risk factors for Alzheimer's disease (AD) may itself increase risk. We sought to empirically examine relationships between RNT and markers of AD, compared with anxiety and depression symptoms.

Methods: Two hundred and ninety-two older adults with longitudinal cognitive assessments, including 113 with amyloid-positron emission tomography (PET) and tau-PET scans, from the PREVENT-AD cohort and 68 adults with amyloid-PET scans from the IMAP+ cohort were included. All participants completed RNT, anxiety, and depression questionnaires.

Results: RNT was associated with decline in global cognition (P = .02); immediate (P = .03) and delayed memory (P = .04); and global amyloid (PREVENT-AD: P = .01; IMAP+: P = .03) and entorhinal tau (P = .02) deposition. Relationships remained after adjusting for potential confounders.

Discussion: RNT was associated with decline in cognitive domains affected early in AD and with neuroimaging AD biomarkers. Future research could investigate whether modifying RNT reduces AD risk.
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http://dx.doi.org/10.1002/alz.12116DOI Listing
July 2020

Improving the resistance and resilience framework for aging and dementia studies.

Alzheimers Res Ther 2020 04 14;12(1):41. Epub 2020 Apr 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Background: The "resistance vs resilience" to Alzheimer's disease (AD) framework (coping vs avoiding) has gained interest in the field in the last year. In this viewpoint, our effort is (i) to provide clarity to the usage of the framework in the context of the ATN (amyloid/tau/neurodegeneration) system as well as in lifespan and cognitive aging studies and (ii) to discuss the challenges of matching these concepts to specific biological mechanisms.

Main Body: In the context of the ATN system, the main goal of the resistance vs resilience framework is to make a fundamental distinction between risk factors that may help halt the development of AD pathologies (AT) ("resistance") vs delay processes downstream to AT, i.e., neurodegeneration (N) and the clinical expression of the disease ("resilience"). The process of resilience in dementia and aging research should be envisioned as a process that is developed over the lifespan. Greater neurobiological capital to start with (initial brain reserve), maintaining brain structure and function (brain maintenance), or greater adaptability of cognitive strategies to perform a task (cognitive reserve) could all contribute to higher resilience to pathologies later in life. Simply put, resilience is not only a response to pathological processes (i.e. increased brain function to compensate for increasing AD pathology) but also reflects individual differences in brain structure and function that can be built over the lifespan (e.g., through education, lifetime cognitive, and physical activities). Further, the resistance vs resilience terminology can be extended to study other pathological processes such as cerebrovascular lesions, Lewy body disease, or TDP-43. However, some challenges do exist: (i) when studying multiple neuropathologies, the study design and framework will drive the usage of terminology; (ii) it is unavoidable that the measurements of resilience (brain structure and function) will reflect both the effect of pathologies and the impact of several risk and protective factors throughout the lifespan. Therefore, identifying resilience brain markers across lifespan, aging, and dementia studies, notably with longitudinal study designs, will be an important step towards understanding mechanisms of action.

Conclusions: While the field advances towards consensus definitions of existing concepts, the resistance vs resilience terminology may provide clarity in the communication of results in aging and dementia studies as well as provide a framework for the development of both hypotheses and study designs.
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http://dx.doi.org/10.1186/s13195-020-00609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158381PMC
April 2020

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Neurol 2020 06;77(6):716-724

Normandie Université, Université de Caen, Paris Sciences & Lettres Université, École Pratique des Hautes Études, Institut National de la Santé et de la Recherche Médicale, Unité 1077 "Neuropsychologie et Imagerie de la Mémoire Humaine," Centre Hospitalier Universitaire de Caen, GIP Cyceron, Caen, France.

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.

Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism.

Design, Setting, And Participants: This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses.

Main Outcomes And Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes.

Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms.

Conclusions And Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.
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http://dx.doi.org/10.1001/jamaneurol.2020.0311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091393PMC
June 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

Better stress coping associated with lower tau in amyloid-positive cognitively unimpaired older adults.

Neurology 2020 04 21;94(15):e1571-e1579. Epub 2020 Jan 21.

From the Departments of Radiology (E.M.A.-U., V.J.L., A.L.R., C.R.J., P.V.), Health Sciences Research (S.A.P., M.M.M.), Psychiatry and Psychology (M.M. Machulda), and Neurology (D.S.K., M.M. Mielke, R.C.P.), Mayo Clinic, Rochester, MN; and Department of Neurology (Y.E.G.), Mayo Clinic, Scottsdale, AZ.

Objective: Research in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A-) in cognitively unimpaired (CU) older adults.

Methods: We included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B-PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.

Results: Higher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A- but weaker in A- CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.

Conclusions: A faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.
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http://dx.doi.org/10.1212/WNL.0000000000008979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251516PMC
April 2020

Dynamic change of cognitive reserve: associations with changes in brain, cognition, and diagnosis.

Neurobiol Aging 2019 11 21;83:95-104. Epub 2019 Aug 21.

Department of Neurology, UC Davis School of Medicine, Sacramento, CA, USA.

Cognitive reserve is inherently a dynamic construct; however, traditional methods of estimating reserve have focused on static proxy variables. A recently proposed psychometric approach entails modeling reserve as residual cognition not explained by demographic and brain variables. In this study, we extended this approach to longitudinal measurement and examined how change in reserve relates to clinical outcomes in late life and influences the effect of brain atrophy on cognitive decline. Results indicated that cognitive reserve changes were associated with progression of clinical diagnosis. More rapid depletion of cognitive reserve was associated with faster decline in nonmemory cognitive functions, even after accounting for longitudinal brain atrophy. The effect of longitudinal brain atrophy on cognitive decline differed based on the extent to which an individual's reserve changed. Whereas depletion of reserve appeared to unmask the effects of brain atrophy on cognitive decline, maintenance of reserve buffered against the negative effects of brain atrophy. Study results highlight that changes in reserve may have important implications for individual differences in cognitive aging trajectories.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977973PMC
November 2019

White matter hyperintensities: relationship to amyloid and tau burden.

Brain 2019 08;142(8):2483-2491

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer's disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer's disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer's biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen's d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.
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http://dx.doi.org/10.1093/brain/awz162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658846PMC
August 2019

The metabolic brain signature of cognitive resilience in the 80+: beyond Alzheimer pathologies.

Brain 2019 04;142(4):1134-1147

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Research into cognitive resilience imaging markers may help determine the clinical significance of Alzheimer's disease pathology among older adults over 80 years (80+). In this study, we aimed to identify a fluorodeoxyglucose (FDG)-PET based imaging marker of cognitive resilience. We identified 457 participants ≥ 80 years old (357 cognitively unimpaired, 118 cognitively impaired at baseline, mean age of 83.5 ± 3.2 years) from the population-based Mayo Clinic Study of Aging (MCSA) with baseline MRI, Pittsburgh compound B-PET and FDG-PET scans and neuropsychological evaluation. We identified a subset of 'resilient' participants (cognitively stable 80+, n = 192) who maintained normal cognition for an average of 5 years (2-10 years). Global PIB ratio, FDG-PET ratio and cortical thickness from Alzheimer's disease signature regions were used as Alzheimer's disease imaging biomarker outcomes and global cognitive z-score was used as a cognitive outcome. First, using voxel-wise multiple regression analysis, we identified the metabolic areas underlying cognitive resilience in cognitively stable 80+ participants, which we call the 'resilience signature'. Second, using multivariate linear regression models, we evaluated the association of risk and protective factors with the resilience signature and its added value for predicting global cognition beyond established Alzheimer's disease imaging biomarkers in the full 80+ sample. Third, we evaluated the utility of the resilience signature in conjunction with amyloidosis in predicting longitudinal cognition using linear mixed effect models. Lastly, we assessed the utility of the resilience signature in an independent cohort using ADNI (n = 358, baseline mean age of 80 ± 3.8). Our main findings were: (i) FDG-PET uptake in the bilateral anterior cingulate cortex and anterior temporal pole was associated with baseline global cognition in cognitively stable 80+ (the resilience signature); (ii) established Alzheimer's disease imaging biomarkers did not predict baseline global cognition in this subset of participants; (iii) in the full MCSA 80+ and ADNI cohorts, amyloid burden and FDG-PET in the resilience signature were the stronger predictors of baseline global cognition; (iv) sex and systemic vascular health predicted FDG-PET in the resilience signature, suggesting vascular health maintenance as a potential pathway to preserve the metabolism of these areas; and (v) the resilience signature provided significant information about global longitudinal cognitive change even when considering amyloid status in both the MCSA and ADNI cohorts. The FDG-PET resilience signature may be able to provide important information in conjunction with other Alzheimer's disease biomarkers for the determination of clinical prognosis. It may also facilitate identification of disease targeting modifiable risk factors such as vascular health maintenance.
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http://dx.doi.org/10.1093/brain/awz037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439329PMC
April 2019

Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance.

Alzheimers Dement 2020 09 6;16(9):1305-1311. Epub 2020 Jan 6.

Institute for Molecular Medicine Finland, University of Helsinki, Finland.

Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.
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http://dx.doi.org/10.1016/j.jalz.2018.07.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417987PMC
September 2020

Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies.

Neurology 2018 04 28;90(15):695-703. Epub 2018 Mar 28.

From INSERM UMR-S U1237 (E.M.A.-U.), Université de Caen-Normandie, Caen, Normandy, France; and Department of Radiology (P.V.), Mayo Clinic, Rochester, MN.

Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000005303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894932PMC
April 2018

Regional patterns of gray matter volume, hypometabolism, and beta-amyloid in groups at risk of Alzheimer's disease.

Neurobiol Aging 2018 03 7;63:140-151. Epub 2017 Nov 7.

Inserm, Inserm UMR-S U1237, Université de Caen-Normandie, GIP Cyceron, Boulevard H. Becquerel, Caen, France; Normandie Université, UNICAEN, PSL Research University, EPHE, Inserm, U1077, CHU de Caen, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen, France. Electronic address:

Alzheimer's disease (AD) is characterized by the presence of β-amyloid (Aβ) deposition and neurodegeneration. To seek for signs of such pathologies, we compared regional biomarker degrees and patterns of Aβ deposition, glucose hypometabolism, and gray matter volume (GMV) reduction in 3 groups at risk of AD. In elderly carriers of the apolipoprotein E ε4 (APOE4, n = 17), patients with subjective cognitive decline (n = 16), and patients with mild cognitive impairment (n = 30), head-to-head intermodality comparisons were performed on cross-sectional structural magnetic resonance images as well as 18F-fluorodeoxyglucose and 18F-florbetapir positron emission tomography scans. In mild cognitive impairment patients, 3 distinct biomarker patterns were recovered, similarly seen in AD patients: (1) in medial temporal regions, local GMV reduction exceeded hypometabolism, (2) in temporoparietal regions, hypometabolism predominated over GMV reduction, and (3) in frontal regions, Aβ deposition exceeded GMV reduction and hypometabolism. In subjective cognitive decline patients, only pattern 1 was detected, while APOE4 carriers demonstrated only pattern 3. Our findings highlight that regional AD-like biomarker patterns may vary across different at-risk populations, potentially reflecting differential mediators of these risks.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.10.023DOI Listing
March 2018

Increased florbetapir binding in the temporal neocortex from age 20 to 60 years.

Neurology 2017 Dec 17;89(24):2438-2446. Epub 2017 Nov 17.

From Neuropsychologie et Imagerie de la Mémoire Humaine, PSL Research University, EPHE, INSERM U1077, CHU de Caen (J.G., E.M.A.-U., F.M., B.L., M.G., A.B., R.d.F., M.W., C.T., G.P., A.A., B.D., G.C.), and INSERM UMR-S U1237, GIP Cyceron (J.G., E.M.A.-U., F.M., B.L., A.B., R.d.F., C.T., G.P., G.C.), UNICAEN, Normandie University, Caen, France.

Objective: To improve our understanding of early β-amyloid (Aβ) accumulation processes using florbetapir-PET scan in 20- to 60-year-old individuals.

Methods: Seventy-six cognitively normal individuals aged 20 to 60 years, 57 cognitively normal older individuals (61-84 years old), and 70 patients with mild cognitive impairment or probable Alzheimer disease (AD) underwent a florbetapir-PET scan. Images were spatially normalized and scaled using the whole cerebellum. The relationship with age was assessed on the mean neocortical standardized uptake value ratio (SUVR) and voxelwise in the younger group to assess early Aβ accumulation processes. To compare the topography of early-age-related vs AD-related changes, Aβ increase in patients vs cognitively normal older adults was also assessed.

Results: A linear increase of Aβ deposition from 20 to 60 years old was found on the mean neocortical SUVR, and more specifically on the temporal neocortex. By contrast, increase in patients predominated in frontal and medial parietal areas. The temporal increase in healthy participants was still significant when including only the 20- to 50-year-old individuals and controlling for several possible methodologic confounds.

Conclusions: Florbetapir binding increases linearly from 20 to 60 years old in the temporal lobe. Pending replication, including with other PET tracers, this study suggests that the well-described medial frontal and parietal accumulation in late adulthood and AD might superimpose to a physiologic accumulation of Aβ, starting from young adulthood, in temporal lobes.
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http://dx.doi.org/10.1212/WNL.0000000000004733DOI Listing
December 2017

Association between educational attainment and amyloid deposition across the spectrum from normal cognition to dementia: neuroimaging evidence for protection and compensation.

Neurobiol Aging 2017 11 24;59:72-79. Epub 2017 Jun 24.

INSERM, U1077, Caen, France; Université de Caen-Normandie, UMR-S1077, Caen, France; Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France; CHU de Caen, U1077, Caen, France.

The brain mechanisms underlying the effect of intellectual enrichment may evolve along the normal aging Alzheimer's disease (AD) cognitive spectrum and may include both protective and compensatory mechanisms. We assessed the association between early intellectual enrichment (education, years) and average cortical florbetapir standardized uptake value ratio as well as performed voxel-wise analyses in a total of 140 participants, including cognitively normal older adults, mild cognitive impairment (MCI), and AD patients. Higher education was associated with lower cortical florbetapir positron emission tomography (florbetapir-PET) uptake, notably in the frontal lobe in normal older adults, but with higher uptake in frontal, temporal, and parietal regions in MCI after controlling for global cognitive status. No association was found in AD. In MCI, we observed an increased fluorodeoxyglucose positron emission tomography (FDG-PET) uptake with education within the regions of higher florbetapir-PET uptake, suggesting a compensatory increase. Early intellectual enrichment may be associated with protection and compensation for amyloid beta (Aβ) deposition later in life, before the onset of dementia. Previous investigations have been controversial as regard to the effects of intellectual enrichment variables on Aβ deposition; the present findings call for approaches aiming to evaluate mechanisms of resilience across disease stages.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.06.016DOI Listing
November 2017
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