Publications by authors named "José L Molinuevo"

82 Publications

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Department of Psychiatry, University of Oxford, Oxford, UK.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
March 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 Mar 18. Epub 2021 Mar 18.

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
March 2021

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.

J Alzheimers Dis 2020 ;77(3):1353-1368

Department of Psychiatry, University of Oxford, UK.

Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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http://dx.doi.org/10.3233/JAD-200208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683080PMC
January 2020

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia.

Alzheimers Dement 2020 07 5;16(7):1078-1094. Epub 2020 Jul 5.

Division of Medical and Scientific Relations, Alzheimer's Association, Chicago, Illinois, USA.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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http://dx.doi.org/10.1002/alz.12123DOI Listing
July 2020

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

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

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

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

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

J Alzheimers Dis 2020 ;74(1):213-225

Department of Psychiatry, University of Oxford, UK.

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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http://dx.doi.org/10.3233/JAD-190434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175945PMC
January 2020

A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort.

Alzheimers Dement (N Y) 2019 18;5:933-938. Epub 2019 Dec 18.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Introduction: Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.

Methods: This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).

Results: On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.

Discussion: This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.trci.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928349PMC
December 2019

Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers.

Alzheimers Res Ther 2019 11 28;11(1):94. Epub 2019 Nov 28.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Background: Results from recent clinical studies suggest that cerebrospinal fluid (CSF) biomarkers that are indicative of Alzheimer's disease (AD) can be replicated in blood, e.g. amyloid-beta peptides (Aβ and Aβ) and neurofilament light chain (NFL). Such data proposes that blood is a rich source of potential biomarkers reflecting central nervous system pathophysiology and should be fully explored for biomarkers that show promise in CSF. Recently, soluble fragments of the triggering receptor expressed on myeloid cells 2 (sTREM2) protein in CSF have been reported to be increased in prodromal AD and also in individuals with TREM2 rare genetic variants that increase the likelihood of developing dementia.

Methods: In this study, we measured the levels of plasma sTREM2 and plasma NFL using the MesoScale Discovery and single molecule array platforms, respectively, in 48 confirmed TREM2 rare variant carriers and 49 non-carriers.

Results: Our results indicate that there are no changes in plasma sTREM2 and NFL concentrations between TREM2 rare variant carriers and non-carriers. Furthermore, plasma sTREM2 is not different between healthy controls, mild cognitive impairment (MCI) or AD.

Conclusion: Concentrations of plasma sTREM2 do not mimic the recent changes found in CSF sTREM2.
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http://dx.doi.org/10.1186/s13195-019-0545-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883551PMC
November 2019

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

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

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

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

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias.

Alzheimers Dement 2020 02 6;16(2):262-272. Epub 2020 Jan 6.

Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Fundació Clínic per a la Recerca Biomèdica, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.

Introduction: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD).

Methods: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins.

Results: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used.

Discussion: Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.
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http://dx.doi.org/10.1016/j.jalz.2019.09.001DOI Listing
February 2020

Early detection of subtle motor dysfunction in cognitively normal subjects with amyloid-β positivity.

Cortex 2019 12 30;121:117-124. Epub 2019 Aug 30.

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Electronic address:

Since the current neuropsychological assessments are not sensitive to subtle deficits that may be present in cognitively normal subjects with amyloid-β positivity, more accurate and efficient measures are needed. Our aim was to investigate the presence of subtle motor deficits in this population and its relationship with cerebrospinal fluid (CSF) amyloid-β levels. We adapted the Finger Tapping Task to measure tapping speed and intrasubject variability. Seventy-two right-handed participants completed the study. Subjects were divided into three groups according to their CSF biomarker profile: 37 control participants (negative CSF AD biomarkers, CTR), 20 cognitively normal subjects with amyloid-β positivity (abnormal levels of CSF Aβ, Aβ+) and 15 AD patients. All subjects underwent lumbar puncture for the CSF analysis, apolipoprotein E genotyping and completed the Finger Tapping Task, a neuropsychological battery and cardiovascular risk factor and physical activity assessments. An overall difference between groups was found both in tapping speed [F(2,66) = 19.37, p < .01] and in intrasubject variability [F(2,66) = 11.40, p < .01]. More specifically, the Aβ+ group showed lower speed [F(1,52) = 5.33, p < .05] and greater intrasubject variability [F(1,52) = 8.48, p < .01] than the CTR group, and higher speed than the AD group [F(1,30) = 13.61, p < .01]. Speed (β = .263, p < .05) and intrasubject variability (β = -.558, p < .01) were significantly associated with CSF amyloid-β levels. The present findings suggest that subtle motor difficulties can be detected in cognitively healthy subjects with amyloid-β positivity and be related to CSF Aβ levels. An accurate assessment of motor functions could help on identifying individuals at the earliest stage of the Alzheimer's continuum.
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http://dx.doi.org/10.1016/j.cortex.2019.07.021DOI Listing
December 2019

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

Alzheimers Dement 2019 11 5;15(11):1478-1488. Epub 2019 Sep 5.

Department of Psychiatry, University of Oxford, Oxford, UK.

Introduction: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.

Methods: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.

Results: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.

Discussion: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880298PMC
November 2019

Multipurpose Virtual Reality Environment for Biomedical and Health Applications.

IEEE Trans Neural Syst Rehabil Eng 2019 08 4;27(8):1511-1520. Epub 2019 Jul 4.

Virtual reality is a trending, widely accessible, and contemporary technology of increasing utility to biomedical and health applications. However, most implementations of virtual reality environments are tailored to specific applications. We describe the complete development of a novel, open-source virtual reality environment that is suitable for multipurpose biomedical and healthcare applications. This environment can be interfaced with different hardware and data sources, ranging from gyroscopes to fMRI scanners. The developed environment simulates an immersive (first-person perspective) run in the countryside, in a virtual landscape with various salient features. The utility of the developed VR environment has been validated via two test applications: an application in the context of motor rehabilitation following injury of the lower limbs and an application in the context of real-time functional magnetic resonance imaging neurofeedback, to regulate brain function in specific brain regions of interest. Both applications were tested by pilot subjects that unanimously provided very positive feedback, suggesting that appropriately designed VR environments can indeed be robustly and efficiently used for multiple biomedical purposes. We attribute the versatility of our approach on three principles implicit in the design: selectivity, immersiveness, and adaptability. The software, including both applications, is publicly available free of charge, via a GitHub repository, in support of the Open Science Initiative. Although using this software requires specialized hardware and engineering know-how, we anticipate our contribution to catalyze further progress, interdisciplinary collaborations and replicability, with regards to the usage of virtual reality in biomedical and health applications.
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http://dx.doi.org/10.1109/TNSRE.2019.2926786DOI Listing
August 2019

Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.

J Alzheimers Dis 2019 ;70(1):211-225

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

Background: We investigated a sample of cognitively healthy subjects with normal Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes.

Objective: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline.

Methods: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau < 228.64 pg/ml; n = 16) and CBN-Tau↑ (tau > 228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance.

Results: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = -0.17, p < 0.05; r = -0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes.

Conclusions: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.
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http://dx.doi.org/10.3233/JAD-190046DOI Listing
September 2020

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

Alzheimers Dement 2019 06 8;15(6):817-827. Epub 2019 May 8.

Institute of Pharmaceutical Science, King's College London, London, UK; Steno Diabetes Center Copenhagen, Gentofte, Denmark. Electronic address:

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.

Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.

Results: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.

Discussion: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
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http://dx.doi.org/10.1016/j.jalz.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849698PMC
June 2019

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid.

Mol Cell Proteomics 2019 Mar 22;18(3):546-560. Epub 2020 Sep 22.

§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;; ¶Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025Barcelona, Spain.

A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.
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http://dx.doi.org/10.1074/mcp.RA118.001290DOI Listing
March 2019

Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid.

Mol Cell Proteomics 2019 03 3;18(3):546-560. Epub 2019 Jan 3.

§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;

A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsynytenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages ( = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold ( < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, = 0.04) in an independent cohort ( = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, < 0.04), a finding that was replicated (0.7 to 0.8-fold, < 0.05) for 6 proteins in a third cohort ( = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold ( < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.
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http://dx.doi.org/10.1074/mcp.RA118.001290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398205PMC
March 2019

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Nat Rev Neurol 2018 11;14(11):639-652

Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.
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http://dx.doi.org/10.1038/s41582-018-0079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211654PMC
November 2018

Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.

Front Aging Neurosci 2018 25;10:193. Epub 2018 Jun 25.

Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.
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http://dx.doi.org/10.3389/fnagi.2018.00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027060PMC
June 2018

CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration.

Neurology 2017 Jul 7;89(2):178-188. Epub 2017 Jun 7.

From the Department of Neurology (D.A., E.V., M.S.-C., I.I.-G., R.B., J.C., J.F., A. Lleó), Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona; Alzheimer's Disease and Other Cognitive Disorders Unit (A. Lladó, R.S.-V., J.L.M.), Department of Neurology, Hospital Clínic, Institut d'Investigació Biomèdica August Pi I Sunyer, Barcelona; Servicio de Neurología (G.G.-R.), Hospital Universitario Ramón y Cajal, Madrid; Parkinson's Disease and Movement Disorders Unit (Y.C., M.J.M.), Neurology Service, Institute of Clinical Neurosciences, Hospital Clínic/IDIBAPS and University of Barcelona; Unitat de Trastorns Cognitius (G.P.-R.), Hospital Santa Maria, Lleida; Unidad de Neurología Cognitiva (G.A.-F., A.N., A.G.-M.), Servicio de Neurología, Hospital Universitari Son Espases, Palma de Mallorca; and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (D.A., E.V., M.S.-C., I.I.-G., R.B., J.C., Y.C., M.J.M., J.F., A. Lleó), Madrid, Spain.

Objective: To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD).

Methods: We analyzed 3 CSF biomarkers (YKL-40, soluble β fragment of amyloid precursor protein [sAPPβ], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (β-amyloid, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility.

Results: Patients with FTLD-related syndromes had lower levels of sAPPβ than CN and patients with AD. The levels of sAPPβ showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPβ/YKL-40 and NfL/sAPPβ ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD.

Conclusions: The combination of sAPPβ with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice.

Classification Of Evidence: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.
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http://dx.doi.org/10.1212/WNL.0000000000004088DOI Listing
July 2017

Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer's Disease Stage 1.

J Alzheimers Dis 2017 ;58(3):855-870

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

We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer's Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n = 31; PreAD-1, n = 14; PreAD-2, n = 4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p = 0.08). In the whole sample, significant correlations between CSF Aβ42/tau ratio and the AFE-T were found, both in the total learning score (r = 0.52; p < 0.001) and in the three-month cued forgetting rate (r = -0.38; p < 0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer's disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.
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http://dx.doi.org/10.3233/JAD-161173DOI Listing
March 2018

Higher prevalence of cerebral white matter hyperintensities in homozygous APOE-ɛ4 allele carriers aged 45-75: Results from the ALFA study.

J Cereb Blood Flow Metab 2018 02 11;38(2):250-261. Epub 2017 May 11.

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

Cerebral white matter hyperintensities are believed the consequence of small vessel disease and are associated with risk and progression of Alzheimer's disease. The ɛ4 allele of the APOE gene is the major factor accountable for Alzheimer's disease heritability. However, the relationship between white matter hyperintensities and APOE genotype in healthy subjects remains controversial. We investigated the association between APOE-ɛ4 and vascular risk factors with white matter hyperintensities, and explored their interactions, in a cohort of cognitively healthy adults (45-75 years). White matter hyperintensities were assessed with the Fazekas Scale from magnetic resonance images (575 participants: 74 APOE-ɛ4 homozygotes, 220 heterozygotes and 281 noncarriers) and classified into normal (Fazekas < 2) and pathological (≥2). Stepwise logistic regression was used to study the association between pathological Fazekas and APOE genotype after correcting for cardiovascular and sociodemographic factors. APOE-ɛ4 homozygotes, but not heterozygotes, bear a significantly higher risk (OR 3.432; 95% CI [1.297-9.082]; p = 0.013) of displaying pathological white matter hyperintensities. As expected, aging, hypertension and cardiovascular and dementia risk scales were also positively associated to pathological white matter hyperintensities, but these did not modulate the effect of APOE-ɛ4/ɛ4. In subjects at genetic risk of developing Alzheimer's disease, the control of modifiable risk factors of white matter hyperintensities is of particular relevance to reduce or delay dementia's onset.
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http://dx.doi.org/10.1177/0271678X17707397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951016PMC
February 2018

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk.

J Alzheimers Dis 2017 ;56(3):1065-1074

Dermatology Department, Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain.

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.
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http://dx.doi.org/10.3233/JAD-161113DOI Listing
February 2018

Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes.

J Alzheimers Dis 2017 ;56(2):543-555

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.
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http://dx.doi.org/10.3233/JAD-160668DOI Listing
February 2018

Implementation of subjective cognitive decline criteria in research studies.

Alzheimers Dement 2017 Mar 5;13(3):296-311. Epub 2016 Nov 5.

German Center for Neurodegenerative Disorders (DZNE), Bonn-Cologne, Germany; Department of Psychiatry, University Hospital Cologne, Medical Faculty, Cologne, Germany.

Introduction: Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed.

Methods: Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly.

Results: Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors.

Discussion: Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.
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http://dx.doi.org/10.1016/j.jalz.2016.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344703PMC
March 2017

The roles of inflammation and immune mechanisms in Alzheimer's disease.

Alzheimers Dement (N Y) 2016 Jun 30;2(2):99-109. Epub 2016 May 30.

Pfizer, Inc. Neuroscience Research Unit, Cambridge, MA, USA.

The Alzheimer's Association's Research roundtable met in April 2015 to explore the role of neuroinflammatory mechanisms in the progression of Alzheimer's disease (AD). The ability of innate immune cells, particularly microglia and astrocytes, to mediate neuroinflammation in AD has been implicated as a significant contributor to disease pathogenesis. Adaptive immunity, which plays an important role in responding to injury and some diseases of the central nervous system, may contribute to neuroinflammation in AD as well. Communication between the central and peripheral immune systems may also be important in AD. An increased understanding of the physiology of the innate immune system may aid the identification of new therapeutic targets or mechanisms. The development of predictive animal models and translatable neuroinflammation biomarkers for AD would also facilitate the advancement of novel treatments for innate immunity. Important challenges impeding the advancement of new therapeutic agents and strategies to overcome them were discussed.
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http://dx.doi.org/10.1016/j.trci.2016.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644267PMC
June 2016

The Memory Binding Test: Development of Two Alternate Forms into Spanish and Catalan.

J Alzheimers Dis 2016 03;52(1):283-93

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

Background: The Memory Binding Test (MBT) is emerging as a promising tool for the detection of subtle memory impairment suggestive of Alzheimer's disease (AD). For such a test to be widely accessed and used, the availability of both alternate forms and language adaptations is required.

Objectives: To develop a thorough methodology for obtaining alternate forms (A and B) of the MBT in Spanish and Catalan and to assess their equivalence.

Method: According to the original development of the test, frequency was taken as the lexical variable of reference for the Spanish and Catalan adaptations. A crossed design protocol by form and language was used to compare the MBT results in a sample of 290 cognitively normal middle-aged participants. Pairwise Intraclass Correlation Coefficients (ICCs) were calculated among the six possible combinations.

Results: The Spanish and Catalan lists of words for the MBT A and B resulting from the adaptation process as well as the original lists in English are presented. ICC indices for the comparisons between forms and languages ranged from 0.56 to 0.82.

Conclusion: The MBT A and B in Spanish and Catalan showed similar outcomes and can be considered equivalent. Moreover, the thorough methodology presented here for the transcultural adaptation and equivalence study, could serve as a model for future adaptations of the MBT and other verbal tests.
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http://dx.doi.org/10.3233/JAD-151175DOI Listing
March 2016

Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

Alzheimers Dement 2016 05 15;12(5):614-22. Epub 2016 Mar 15.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.
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http://dx.doi.org/10.1016/j.jalz.2016.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861656PMC
May 2016

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers.

EMBO Mol Med 2016 05 2;8(5):466-76. Epub 2016 May 2.

BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.
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http://dx.doi.org/10.15252/emmm.201506123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120370PMC
May 2016

Psychometric Properties of the Memory Binding Test: Test-Retest Reliability and Convergent Validity.

J Alzheimers Dis 2016 ;50(4):999-1010

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

Background: Episodic memory testing is fundamental for the diagnosis of Alzheimer's disease (AD). Although the Free and Cued Selective Reminding Test (FCSRT) is widely used for this purpose, it may not be sensitive enough for early detection of subtle decline in preclinical AD. The Memory Binding Test (MBT) intends to overcome this limitation.

Objectives: To analyze the test-retest reliability of the MBT and its convergent validity with the FCRST.

Methods: 36 cognitively healthy participants of the ALFA Study, aged 45 to 65, were included for the test-retest study and 69 for the convergent analysis. They were visited twice in a period of 6 ± 2 weeks. Test-retest reliability was determined by the calculation of the intra-class correlation coefficient (ICC). Score differences were studied by computing the mean percentage of score variation between visits and visualized by Bland-Altman plots. Convergent validity was determined by Pearson's correlations.

Results: ICC values in the test-retest reliability analysis of the MBT direct scores ranged from 0.64 to 0.76. Subjects showed consistent practice effects, with mean amounts of score increasing between 10% and 26%. Pearson correlation between MBT and FCSRT direct scores showed r values between 0.40 and 0.53. The FCSRT displayed ceiling effects not observed in the MBT.

Conclusions: The MBT shows adequate test-retest reliability and overall moderate convergent validity with the FCSRT. Unlike the FCSRT, the MBT does not have ceiling effects and it may therefore be especially useful in longitudinal studies, facilitating the measurement of subtle memory performance decline and the detection of very early AD.
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http://dx.doi.org/10.3233/JAD-150776DOI Listing
December 2016