Abstract Background Anxiety and depression are more prevalent in women and caregivers and are associated with increased Alzheimer’s disease (AD) risk. We investigated multimodal predictors of increased anxiety/depression during the Covid19‐related confinement in cognitively unimpaired (CU) older adults with an increased risk for AD with a special focus on sex/gender. Method We included 921 CU participants from the ALFA study (Table 1). Anxiety and depression (Hospital Depression and Anxiety Scale, HADS), perceived stress (Perceived Stress Scale, PSS) and stress resilience (Brief Resilience Scale, BRS) were measured during Covid19‐related confinement. A subgroup completed the HADS (n=767) and underwent [ 18 F]flutemetamol‐PET imaging and sMRI (n=254) 2.4±0.8 years before confinement. Cross‐sectional anxiety/depression measurements and change in anxiety/depression (delta score) from baseline to confinement were our primary outcomes of interest. We considered amyloid status (+/‐) and cortical thickness (Cth) from the AD signature regions as imaging biomarkers. First, we investigated sex differences in the variables assessed during confinement. Second, we ran regression models to predict (i) cross‐sectional anxiety/depression scores during confinement and (ii) change in anxiety/depression from baseline to confinement. Age, sex, education, APOE ‐ε4 status, caregiver status, stress related‐variables and imaging biomarkers were considered as predictors. Result Fifteen percent of the participants were caregivers, 69% of which were women. Women showed increased stress perception relative to men (p=<0.001) – notably, when they were caregivers (p=0.01). There were no sex‐differences in stress resilience (p=0.5). In cross‐sectional models, sex (women) and higher stress perception were independent predictors of greater anxiety/depression during confinement (Table 2a). Being a caregiver additionally predicted increase in anxiety/depressive symptomatology from baseline (Table 3a). Finally, in the subsample with biomarkers, amyloid positivity ‐ but not Cth in the AD signature ‐ contributed to predict anxiety/depression both cross‐sectionally (Table 2b) and longitudinally (Table 3b) along with sex (women), caregiver status and stress perception. Conclusion Our results showed sex differences in caregiver status and stress perception during the Covid19‐related confinement. Further, women, caregivers and those with higher self‐perceived stress showed an increase in anxiety/depressive symptomatology. Amyloid pathology prior to confinement was associated with greater levels of anxiety/depression suggesting a role of amyloid pathology in anxiety/depressive symptomatology.

Depression

Perceived Stress Scale

10.1002/alz.053907

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P3-370: GENDER DIFFERENCES IN THE ASSOCIATION BETWEEN LONGITUDINAL BRAIN CHANGES AND BASELINE LEVELS OF CSF ALZHEIMER'S DISEASE AND GLIAL BIOMARKERS IN HEALTHY ELDERS

Alzheimer s & Dementia (2019)

Carles Falcón Oriol Grau‐Rivera Marc Suárez‐Calvet Raquel Sánchez‐Valle Lorena Rami

The incidence of Alzheimer's disease (AD) doubles in women. Being age the major risk factor for AD, this difference was thought to be due to women's longer lifespan. However, recent studies suggest that sexual hormones could have an impact on disease progression. The aim of this study is to assess whether there are gender differences in the association between baseline levels of CSF biomarkers for AD (Aβ42, ptau) and for glial activity (YKL40 and sTREM2) and longitudinal brain volume changes in cognitively unimpaired adults. Two brain MRI scans of 36 participants (57 to 78-year-old, 12 male, figure 1) were acquired in a 2-year interval. CSF biomarkers concentration were determined at baseline. sTREM2 was log-transformed to become normally distributed. For each subject, we calculated GM and WM volume change-per-year maps (ΔGM and ΔWM, respectively) by means of longitudinal pairwise registration of SPM12. We voxel-wise determined where the associations between ΔGM, ΔWM and baseline levels of CSF biomarkers depended on gender, correcting for age, gender, TIV, ΔTIV (to deal with potential scanner miscalibrations between scans) and the rest of CSF biomarkers. Statistical threshold was set at p<0.001 uncorrected with a minimum extend of 100 voxels per cluster. Figures 2, 3 and 4 displays gender differences in the association between ΔGM or ΔWM and baseline levels of CSF biomarkers. Figure 5 plots ΔGM or ΔWM values against biomarkers in some of the peaks of areas reported in Figure 2. In some AD regions, the sign of the association between ΔGM or ΔWM and baseline CSF levels of p-tau, YKL40 and sTREM2 differed between genders. It is significant the greater atrophy of medial temporal areas related to high values of CSF-ptau in women than in men No gender differences were observed with respect to Aβ42 associated ΔGM or ΔWM.

Longitudinal Study

10.1016/j.jalz.2019.06.3403

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Association of body mass index with brain structure and biomarkers of inflammation in cognitively unimpaired middle‐aged adults with and without evidence of β‐amyloid pathology

Alzheimer s & Dementia (2021)

Oriol Grau‐Rivera Aleix Sala‐Vila Greg Operto Marina Garcia Eider M. Arenaza‐Urquijo

Abstract Background Obesity has been linked to brain atrophy and peripheral inflammation. However, the association between body mass index (BMI) and brain structure can be confounded by Alzheimer’s disease (AD) pathology‐related weight loss, and its association with neuroinflammation remains unknown. We explored associations of BMI with brain structure and biomarkers of peripheral and central nervous system inflammation in cognitively unimpaired middle‐aged adults with and without evidence of β‐amyloid (Aβ) pathology. Method We analyzed data from 385 ALFA+ study participants. We measured plasma C‐reactive protein (CRP), CSF p‐tau and t‐tau with the Elecsys® immunoassays and CSF Aβ42, Aβ40 and neuroinflammation biomarkers (sTREM2, GFAP, YKL40, S100 and IL6) with the exploratory Roche NeuroToolKit robust prototype assays. We used separated linear regression models to analyze associations of BMI with plasma CRP, CSF AD and neuroinflammation biomarkers, and mean cortical thickness (CTh) in a composite AD signature region. We explored voxelwise associations (p<0.001, k=100) between BMI and gray matter volume (GMv) with SPM12. We stratified all analyses by Aβ status (defining positivity as Aβ42/40<0.071) and adjusted by age, sex, systolic blood pressure, triglyceride, glycated hemoglobin and physical exercise levels. Result BMI was positively associated with CRP levels in Aβ‐ and Aβ+ groups (p<0.001). We found no significant associations between BMI and CSF AD or neuroinflammation biomarkers. BMI was negatively associated with mean CTh in the AD signature region in the Aβ‐ (p<0.001), but not in the Aβ+ group (p=0.543). Voxel‐based morphometry analyses showed widespread negative associations between BMI and GMv in Aβ‐ participants involving bilateral prefrontal, medial temporal, parietal, occipital, thalamic and cerebellar regions (Figure 1), without positive associations. Among Aβ+ participants, we found positive associations with BMI in small clusters in the cerebellum, middle frontal and anterior cingulate gyri (Figure 2), without negative associations. Conclusion In the absence of Aβ pathology, higher BMI is associated with brain atrophy involving AD‐related areas, suggesting that midlife obesity may increase dementia risk by mechanisms unrelated to AD pathology. Conversely, among individuals on the AD continuum , higher BMI appears to be associated with more preserved brain structure. We found no evidence of an association between higher BMI and neuroinflammation.

Glycated hemoglobin

10.1002/alz.053531

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Use of plasma p‐tau217 as a pre‐screening method for detecting amyloid‐PET positivity in cognitively unimpaired participants: A multicenter study

Alzheimer s & Dementia (2024)

Gemma Salvadó Shorena Janelidze Joseph Therriault Wagner S. Brum Alexa Pichet Binette

Abstract Background Recent results from clinical trials in Alzheimer’s disease (AD) emphasize the importance of treating early‐stage disease. However, recruitment of preclinical AD participants is difficult due to the lack of symptoms, and the costs and/or invasiveness of established CSF and PET tests. We aimed to investigate whether plasma p‐tau217 could be used to pre‐screen cognitively unimpaired (CU) potential participants for amyloid‐β (Aβ) pathology to improve the efficiency of clinical trial recruitment. Method We included 1,471 CU participants from eight cohorts (Table 1) with available plasma p‐tau217, Aβ CSF biomarkers and Aβ‐PET status (served as standard‐of‐truth). Plasma p‐tau217 concentrations were z‐scored based on Aβ‐negative participants and harmonized across cohorts using neuroCombat. Cut‐offs for plasma p‐tau217 were derived in the BioFINDER‐1 cohort (n=104) based on different specificity levels (90%, 95% and 97.5%) to maximize positive predictive values (PPV). These cut‐offs were used in the other cohorts to assess the accuracy of plasma p‐tau217 for detecting Aβ‐PET positivity. Next, within plasma positive participants only, we evaluated the value of dichotomized Aβ CSF (based on established clinical thresholds) on assessing Aβ‐PET positivity. All models included age and APOE‐ε4 carriership as covariates. Result 334 (24.4%) of participants were Aβ‐PET positive. Using the a priori defined cutoffs, plasma p‐tau217 categorization resulted in high PPVs (72.9%‐81.2%), negative predictive values (NPVs, 82.5%‐86.2%), and accuracy (82.4%‐83.8%), with an overall rate of positivity between 10.9%‐18.1% (Figure 1). When applying CSF biomarkers to the plasma positive participants in a second step, the PPVs increased up to 90.8%‐95.3%, with NPVs ranging between 82.8%‐86.7% and accuracies between 84.0%‐87.3%, with a slight decrease in the proportion of overall positive cases (9.3%‐14.3% from the original sample) given that the CSF positivity in the plasma positive participants ranged between 79.4%‐85.2% (Figure 2). Conclusion Plasma p‐tau217 can identify Aβ‐PET positive CU individuals with PPVs reaching 81%, which can be further improved to PPVs of up to 95% with a subsequent CSF measurement. Plasma p‐tau217 could be used, either as stand‐alone biomarker, or as an initial step before CSF biomarkers (reducing their need by ∼80‐90%), for pre‐screening in clinical trials of preclinical AD depending on the certainty needed for Aβ‐PET positivity.

Concordance

10.1002/alz.085773

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Cross‐sectional associations between sleep quality reports and core Alzheimer’s disease biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)

Alzheimer s & Dementia (2021)

Laura Stankeviciute Oriol Grau‐Rivera Jonathan Blackman Eider M. Arenaza‐Urquijo Marc Suárez‐Calvet

Abstract Background Sleep disturbances are prevalent in Alzheimer’s disease (AD), with sleep quality having been reported to be already impaired at the preclinical stage of the disease. However, most results originate from studies with rather limited sample sizes. This research aimed to evaluate the association of subjective sleep measures with cerebrospinal fluid (CSF) AD biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD‐LCS). Method This cross‐sectional study included 1257 cognitively unimpaired adults [CDR(clinical dementia rating scale)=0] aged over 50 years who underwent CSF sampling and filled out the Pittsburgh sleep quality index (PSQI) questionnaire. The PSQI includes 7 components (scored 0‐3), which summed yield a total score ranging from 0 to 21. We used multivariate linear regressions to analyse associations between CSF biomarkers (i.e. Aβ42, p‐tau and t‐tau) and the following PSQI measures: total score, binarized score (poor sleep categorized as PSQI>5), sleep latency, duration, efficiency and disturbance. For sleep duration and disturbance, the two highest categories were collapsed into one due to an insufficient number of responses. We used separated models, with each biomarker as the dependent variable and each sleep measure as the predictor, and adjusted them by known potential confounders. Result Poor sleep quality (PSQI total>5) was associated with higher CSF levels of p‐tau (std. β=0.060, p=0.040) and t‐tau (std. β=0.066, p=0.019). Shorter sleep duration (6‐7 hours vs >7 hours) was associated with higher CSF levels of p‐tau (std. β=0.063, p=0.017) and t‐tau (std. β=0.054, p=0.037). A higher degree of sleep disturbance (1‐9 vs 0 and >9 vs 0) was associated with lower CSF levels of Aβ42 (std. β=‐0.106, p=0.016; std. β=‐0.091, p=0.046). Conclusion Our results show that self‐reported sleep quality is associated with AD biomarkers in people without cognitive impairment. Specifically, overall poor sleep quality and shorter sleep duration are related to higher p‐tau and t‐tau levels, whilst more profound sleep disturbances are associated with lower Aβ42 levels. These results potentially support sleep impairment before cognitive symptom onset in AD. Future longitudinal studies using objective sleep quantification will more precisely illuminate the role of sleep in the early stages of the AD continuum .

Clinical Dementia Rating

Sleep

10.1002/alz.057495

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Impact of CSF pTau/Aβ42 ratio on brain structure and metabolism in middle‐aged cognitively unimpaired individuals

Alzheimer s & Dementia (2022)

Raffaele Cacciaglia Marta Milà‐Alomà Mahnaz Shekari Grégory Operto Carles Falcón

Abstract Background The cerebrospinal fluid (CSF) pTau/Aβ42 ratio has emerged as a promising biomarker to monitor the pathological progression of Alzheimer’s disease (AD), even at preclinical stages. To date, no studies have assessed the impact of this continuous biomarker on the brain structure and metabolism in cognitively unimpaired (CU) individuals. Method We included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI) and 18 F‐Fluorodeoxyglucose (FDG) positron emission tomography (PET). CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). After image preprocessing, we applied a voxel‐wise linear regression to test the impact of CSF pTau/Aβ42 ratio, as well as its interaction with age, sex and APOE ‐ε4, on both gray matter volume (GMv) and brain metabolism. The statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels. Result There were no main effects of pTau/Aβ42 on either GMv or brain metabolism. However, a significant interaction with age indicated that for older individuals, a higher pTau/Aβ42 was associated with reduced GMv in the middle cingulum, the middle and superior frontal gyrus, and the angular gyrus (Fig. 1a). An interaction with sex indicated that for females, a higher pTau/Aβ42 was associated with reduced GMv in the precuneus, superior frontal and fusiform gyrus (Fig. 1b). For FDG, we found a significant interaction with sex indicating that females exhibited a metabolism reduction with increasing levels of pTau/Aβ42, in the hippocampus and anterior cingulum (Fig. 1c). Finally, an interaction with APOE ‐ε4 indicated that ε4‐carriers showed lower metabolism in the bilateral striatum, as a function of increasing pTau/Aβ42 ratio (Fig.1 d). Conclusion In CU individuals, the impact of the progression of AD pathophysiology as indicated by a higher CSF pTau/Aβ42 ratio, on both brain structure and metabolism is modulated by AD risk factors. These data suggest that each of these risk factors confers a higher vulnerability to the progression of AD pathology in asymptomatic individuals, as manifested by an early impact on brain structure and metabolism in brain areas which are known to be affected in clinical AD stages.

Statistical parametric mapping

Superior frontal gyrus

Middle frontal gyrus

Parahippocampal gyrus

10.1002/alz.064111

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Pachymeningitis, Painful Ophthalmoplegia, and Multiple Cranial Neuropathy of Presumed Tuberculous Origin

Neuro-Ophthalmology (2011)

Marc Suárez‐Calvet Ricardo Rojas‐García Joaquín López‐Contreras Beatriz Gómez‐Ansón Carles Roig-Arnall

The authors describe a patient with persistent headache initially diagnosed as idiopathic hypertrophic pachymeningitis after a comprehensive study that included meningeal biopsy. Despite early response to corticosteroids, the headache relapsed 3 years later and he further developed painful ophthalmoplegia and multiple cranial neuropathies (V1, VI, VIII, and X). A cervical lymph node biopsy revealed caseating granulomas and antituberculous therapy was started. Symptoms had resolved at 3-month follow-up. The authors discuss tuberculosis as a possible cause of pachymeningitis, painful ophthalmoplegia, and multiple cranial neuropathy syndromes, and describe the common features of these clinical conditions.

External ophthalmoplegia

Lymph node biopsy

10.3109/01658107.2011.620215

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Soluble TREM2 mediates earliest amyloid-associated p-tau increases and cerebral glucose hypermetabolism in Alzheimer’s disease

medRxiv (Cold Spring Harbor Laboratory) (2022)

Davina Biel Marc Suárez‐Calvet Paul Hager Anna Rubinski Anna Dewenter

Abstract Background Microglial activation occurs early in Alzheimer’s disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Therefore, it is critical to investigate at which AD stages microglial activation could be protective or detrimental to evaluate microglia as a treatment target. To address this, we used CSF sTREM2 (i.e. Triggering receptor expressed on myeloid cells 2) to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD biomarker progression. Methods We included 402 cognitively normal and mild cognitively impaired patients with CSF sTREM2 assessments. To assess AD severity, we included measures of earliest beta-amyloid (i.e. Aβ) in CSF (i.e. Aβ 1-42 ) and late-stage fibrillary Aβ pathology (i.e. amyloid-PET centiloid), as well as p-tau 181 and FDG-PET for assessing downstream changes in tau and cerebral glucose metabolism. To determine disease stage, we stratified participants according to earliest Aβ abnormalities (i.e. Aβ CSF+/PET−; early Aβ-accumulators, n=70) or fully developed fibrillary Aβ pathology (i.e. Aβ CSF+/PET+; late Aβ-accumulators, n=201) plus 131 healthy controls (i.e. Aβ CSF−/PET−). Results In early Aβ-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau increases, suggesting reactive microglial and p-tau increases in response to earliest Aβ fibrillization. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau increases and higher sTREM2 was associated with FDG-PET hypermetabolism in line with previous findings of increased glucose consumption of activated microglia. In late Aβ-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau and glucose hypometabolism, suggesting that sTREM2 parallels tau and neurodegeneration rather than Aβ once fully developed Aβ pathology is present. Conclusions Our findings suggest that sTREM2-related microglial activation occurs in response to earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau increases in earliest AD, while previous reports of protective sTREM2 effects may occur in later AD stages.

Hypermetabolism

TREM2

Amyloid beta

Tau protein

Amyloid (mycology)

10.1101/2022.08.26.22279269

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The CORCOBIA study: Cut-off points of Alzheimer’s disease CSF biomarkers in a clinical cohort

Neurología (English Edition) (2022)

Albert Puig‐Pijoan Greta García‐Escobar Aída Fernández-Lebrero Rosa María Manero-Borràs G. Sánchez-Benavides

The analysis of the core biomarkers of Alzheimer's Disease (AD) in the cerebrospinal fluid (CSF) is recommended in the clinical units where it is available. Because of the absence of universal validated values, the determination of specific cut-off points for each center and its population is recommended. The main objective of the CORCOBIA study was to determine the cut-off points of core AD CSF biomarkers for several centers (Parc de Salut Mar, Barcelona and Hospital General de Granollers), which work with the same reference laboratory (Laboratori de Referència de Catalunya).

Youden's J statistic

10.1016/j.nrleng.2022.05.002

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Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer’scontinuum

medRxiv (Cold Spring Harbor Laboratory) (2023)

Natàlia Vilor‐Tejedor Patricia Genius Blanca Rodríguez‐Fernández Carolina Minguillón Iman Sadeghi

Abstract In 2013, the ALFA (ALzheimer and FAmilies) project was established to investigate pathophysiological changes in preclinical Alzheimer’s disease (AD), and to foster research on early detection and preventive interventions. Since then, it has prospectively followed cognitively unimpaired late/middle-aged participants, most of whom are adult children of AD patients. Risk stratification of cognitively unimpaired individuals, including genetic factors is key for implementing AD prevention strategies. Here, we report the genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers, emphasizing amyloid/tau status and gender differences. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic risk of AD. It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum . Highlights Prevalence of ε4 carriers in ALFA is higher than in the general European population. The ALFA study is highly enriched in AD genetic risk factors beyond APOE . AD genetic profiles in ALFA are similar to clinical groups along the continuum . ALFA has succeeded in establishing a cohort of CU individuals at high genetic AD risk. ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Endophenotype

10.1101/2023.04.26.23289138

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