Jordi Pegueroles

Cerebrospinal fluid β‐amyloid and phospho‐tau biomarker interactions affecting brain structure in preclinical Alzheimer disease

To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).

Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer's disease

Cerebrospinal fluid YKL-40 has been described as a marker of glial inflammation. We aimed to study the relationship between YKL-40 and brain structure and its interactions with core Alzheimers disease (AD) biomarkers. We measured cortical thickness (CTh) and cerebrospinal fluid biomarkers (amyloid-β 1-42 [Aβ42], total tau, p-tau, and YKL-40) of 80 cognitively normal controls and 27 patients with amnestic mild cognitive impairment. Subjects were classified as Aβ42+ (<550 pg/mL) or Aβ42- (>550 pg/mL). CTh difference maps were derived from the interaction and correlation analyses in the whole sample and within clinical groups. There was a strong correlation between YKL-40 and markers of neurodegeneration (total tau and p-tau). In the whole sample, we found a negative correlation between YKL-40 and CTh in AD vulnerable areas in Aβ42+ subjects but not in Aβ42 participants. Our results suggest that YKL-40 could track the inflammatory processes associated to tau-related neurodegeneration in the presence of the AD pathophysiological process.

APOE -by-sex interactions on brain structure and metabolism in healthy elderly controls

Background The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC). Methods Cross-sectional study. HC from the Alzheimer’s Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β1–42 (Aβ1–42), total-tau (t-tau) and phospho-tau (p-tau181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses. Results APOE4 carriers had lower CSF Aβ1–42 and higher CSF p-tau181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers. Conclusions The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.

Longitudinal brain structural changes in preclinical Alzheimer's disease.

Brain structural changes in preclinical Alzheimers disease (AD) are poorly understood.

YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer’s disease and other tauopathies

BackgroundThe innate immune system is known to be involved early in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders. The inflammatory response in the central nervous system can be measured postmortem or through a series of inflammatory mediator surrogates. YKL-40 (also named Chitinase-3-like I) has been frequently investigated in body fluids as a surrogate marker of neuroinflammation in AD and other neurological disorders. However, the expression pattern of YKL-40 in the human brain with neurodegenerative pathology remains poorly investigated. Our aim was to study the cellular expression pattern of YKL-40 in the brain of patients with clinical and neuropathological criteria for AD (n = 11); three non-AD tauopathies: Pick’s disease (PiD; n = 8), corticobasal degeneration (CBD; n = 8) and progressive supranuclear palsy (PSP; n = 9) and a group of neurologically healthy controls (n = 6).MethodsSemiquantitative neuropathological evaluation and quantitative confocal triple immunofluorescence studies were performed. An in-house algorithm was used to detect and quantify pathology burden of random regions of interest on a full tissue-section scan. Kruskal-Wallis and Dunn’s multiple comparison tests were performed for colocalization and quantification analyses.ResultsWe found that brain YKL-40 immunoreactivity was observed in a subset of astrocytes in all four diseases and in controls. There was a strong colocalization between YKL-40 and the astroglial marker GFAP but not with neuronal nor microglial markers. Intriguingly, YKL-40-positive astrocytes were tau-negative in PSP, CBD and PiD. The number of YKL-40-positive astrocytes was increased in tauopathies compared with that in controls. A positive correlation was found between YKL-40 and tau immunoreactivities.ConclusionsThis study confirms that YKL-40 is expressed by a subset of astrocytes in AD and other tauopathies. YKL-40 expression is elevated in several neurodegenerative conditions and correlates with tau pathology.

Cortical microstructural changes along the Alzheimer's disease continuum

Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimers disease (AD).

Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

BACKGROUND Diagnosis of Alzheimers disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population. METHODS We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimers disease, or Alzheimers disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ)1-40, Aβ1-42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimers disease and between asymptomatic participants and those with Alzheimers disease dementia. FINDINGS Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimers disease, 49 Alzheimers disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimers disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimers disease dementia group. In CSF, except for Aβ1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimers disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ1-42, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimers disease dementia comparison (AUC ≥0·90 for all except Aβ1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001). INTERPRETATION Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimers disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimers disease in Down syndrome in clinical practice and clinical trials. FUNDING Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.

Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer’s disease

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer´s Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD.

The pitfalls of biomarker-based classification schemes

We read with great interest the elegant work by Pascoal et al. [1] describing a synergistic effect between florbetapir uptake values and cerebrospinal fluid (CSF) p-tau levels on the 2-year risk of progression to Alzheimer’s disease (AD) dementia in patients with amnestic mild cognitive impairment (aMCI) from the Alzheimer Disease Neuroimaging Initiative (ADNI). This synergistic toxic effect between amyloid (A) and tau (T) has strong biological evidence and has been shown to accelerate cognitive decline and brain atrophy in healthy elderly [2,3]. The authors used two different biomarker modalities for subject classification. The use of CSF biomarker levels alone would have obvious practical advantages, but might influence the results. Classification schemes using AD biomarkers are highly dependent on the standardization and reproducibility of biomarker measures [4]. A and T can be measured through different biomarkers with similar accuracy [5]. These different biomarkers often correlate with each other, but when classifying a subject into normal or abnormal for a given modality, they sometimes have poor agreement [6]. This has been described as a limitation of classification schemes [4]. To address the effect of the classification method on clinical outcomes in the study of Pascoal et al., we compared the use of CSFAb1–42 levels instead of florbetapir uptake values and the use of CSF t-tau instead of CSF p-tau values in the same group of aMCI subjects from ADNI. We first assessed the correlation between those biomarkers and their agreement for A and T classification. We then compared the prevalence for each category (A2T2, A1T2, A2T1, and A1T1) and their respective risk of progression to AD dementia in the same group of aMCI. We used the florbetapir uptake values and CSF biomarker levels provided by the

Obesity and Alzheimer’s disease, does the obesity paradox really exist? A magnetic resonance imaging study

Mid-life obesity is an established risk factor for Alzheimers disease (AD) dementia, whereas late-life obesity has been proposed as a protective state. Weight loss, which predates cognitive decline, might explain this obesity paradox on AD risk. We aimed to assess the impact of late life obesity on brain structure taking into account weight loss as a potential confounder. We included 162 elderly controls of the Alzheimers Disease Neuroimaging Initiative (ADNI) with available 3T MRI scan. Significant weight loss was defined as relative weight loss ≥5% between the baseline and last follow-up visit. To be able to capture weight loss, only subjects with a minimum clinical and anthropometrical follow-up of 12 months were included. Individuals were categorized into three groups according to body mass index (BMI) at baseline: normal-weight (BMI<25 Kg/m2), overweight (BMI 25-30 Kg/m2) and obese (BMI>30 Kg/m2). We performed both an interaction analysis between obesity and weight loss, and stratified group analyses in the weight-stable and weigh-loss groups. We found a significant interaction between BMI and weight loss affecting brain structure in widespread cortical areas. The stratified analyses showed atrophy in occipital, inferior temporal, precuneus and frontal regions in the weight stable group, but increased cortical thickness in the weight-loss group. In conclusion, our data support that weight loss negatively confounds the association between late-life obesity and brain atrophy. The obesity paradox on AD risk might be explained by reverse causation.