Publications by authors named "Rafael Blesa"

142 Publications

Metabolite Signature of Alzheimer's Disease in Adults with Down Syndrome.

Ann Neurol 2021 Sep 6;90(3):407-416. Epub 2021 Aug 6.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: The purpose of this study was to examine the Alzheimer's disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's disease biomarkers and cortical thickness.

Methods: We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo-inositol (a marker of neuroinflammation) and N-acetyl-aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's disease, and Alzheimer's disease dementia stages). We assessed the relationship between these metabolites and Aβ /Aβ ratio, phosphorylated tau-181, neurofilament light (NfL), and YKL-40 cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer.

Results: Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo-inositol, but equal levels of N-acetyl-aspartate compared to euploid healthy controls. With disease progression, myo-inositol levels increased, whereas N-acetyl-aspartate levels decreased in symptomatic stages of the disease. Myo-inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N-acetyl-aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants.

Interpretation: Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease-stage biomarker in Down syndrome. ANN NEUROL 2021;90:407-416.
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http://dx.doi.org/10.1002/ana.26178DOI Listing
September 2021

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.

Lancet Neurol 2021 08;20(8):605-614

Sant Pau Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain; Horizon 21 Consortium, Paris, France. Electronic address:

Background: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.

Methods: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.

Findings: Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1).

Interpretation: Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.

Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.
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http://dx.doi.org/10.1016/S1474-4422(21)00129-0DOI Listing
August 2021

Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer's disease in adults with Down syndrome.

Nat Commun 2021 07 14;12(1):4304. Epub 2021 Jul 14.

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.
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http://dx.doi.org/10.1038/s41467-021-24319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280160PMC
July 2021

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome.

JAMA Neurol 2021 Aug;78(8):937-947

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce.

Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS.

Design, Setting, And Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers.

Main Outcomes And Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume.

Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers.

Conclusions And Relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.
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http://dx.doi.org/10.1001/jamaneurol.2021.1893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261691PMC
August 2021

VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome.

Alzheimers Res Ther 2021 06 28;13(1):119. Epub 2021 Jun 28.

Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, c/Sant Quintí, 77-79, 08025, Barcelona, Spain.

Background: There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.

Methods: We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ ratio, CSF Aβ, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing.

Results: In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002).

Conclusion: These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
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http://dx.doi.org/10.1186/s13195-021-00861-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240298PMC
June 2021

Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias.

J Neurol Neurosurg Psychiatry 2021 Nov 8;92(11):1206-1214. Epub 2021 Jun 8.

Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalunya, Spain.

Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach.

Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination.

Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001).

Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.
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http://dx.doi.org/10.1136/jnnp-2021-326603DOI Listing
November 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

AMYQ: An index to standardize quantitative amyloid load across PET tracers.

Alzheimers Dement 2021 09 2;17(9):1499-1508. Epub 2021 Apr 2.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: Positron emission tomography (PET) amyloid quantification methods require magnetic resonance imaging (MRI) for spatial registration and a priori reference region to scale the images. Furthermore, different tracers have distinct thresholds for positivity. We propose the AMYQ index, a new measure of amyloid burden, to overcome these limitations.

Methods: We selected 18F-amyloid scans from ADNI and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) with the corresponding T1-MRI. A subset also had neuropathological data. PET images were normalized, and the AMYQ was calculated based on an adaptive template. We compared AMYQ with the Centiloid scale on clinical and neuropathological diagnostic performance.

Results: AMYQ was related with amyloid neuropathological burden and had excellent diagnostic performance to discriminate controls from patients with Alzheimer's disease (AD) (area under the curve [AUC] = 0.86). AMYQ had a high agreement with the Centiloid scale (intraclass correlation coefficient [ICC] = 0.88) and AUC between 0.94 and 0.99 to discriminate PET positivity when using different Centiloid cutoffs.

Discussion: AMYQ is a new MRI-independent index for standardizing and quantifying amyloid load across tracers.
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http://dx.doi.org/10.1002/alz.12317DOI Listing
September 2021

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration.

JAMA Netw Open 2021 03 1;4(3):e211290. Epub 2021 Mar 1.

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

Importance: The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking.

Objective: To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI).

Design, Setting, And Participants: In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020.

Main Outcomes And Measures: The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration.

Results: Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001).

Conclusions And Relevance: Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953307PMC
March 2021

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

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

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

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

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

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

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

Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study.

Alzheimers Dement 2021 04 23;17(4):605-617. Epub 2020 Nov 23.

Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

Background: The discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology.

Methods: We examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD-symptomatic (DSAD) and AD-asymptomatic (aDS) individuals with DS, as well as controls (HC).

Results: ProNGF and MMP-3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP-3, and MMP-9. ProNGF and MMP-9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex.

Discussion: Brain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS.
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http://dx.doi.org/10.1002/alz.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043977PMC
April 2021

Biphasic cortical macro- and microstructural changes in autosomal dominant Alzheimer's disease.

Alzheimers Dement 2021 04 16;17(4):618-628. Epub 2020 Nov 16.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Introduction: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials.

Methods: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network.

Results: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations.

Discussion: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.
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http://dx.doi.org/10.1002/alz.12224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043974PMC
April 2021

Cortical microstructure in the amyotrophic lateral sclerosis-frontotemporal dementia continuum.

Neurology 2020 11 10;95(18):e2565-e2576. Epub 2020 Sep 10.

From the Sant Pau Memory Unit (I.I.-G., V.M., J.P., E.V., D.A., O.D.-I., L.M.-R., M.B.S.-S., A.S., L.V., I.S., I.B., S.V., R.B., J.C., A.L., J.F.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona; Neuromuscular Diseases Unit (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Valencia; Barcelona Down Medical Center (I.I.G., L.V., J.F.), Fundació Catalana de Síndrome de Down, Barcelona; and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (I.I.-G., V.M., J.P., E.V., D.A., O.D.-I., I.B., R.B., J.C., A.L., J.F.), CIBERNED, Madrid, Spain.

Objective: To characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) continuum.

Methods: We prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences: 31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into ALS without cognitive or behavioral impairment (ALSno-cbi; n = 12) and ALS with cognitive or behavioral impairment (ALScbi; n = 19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral ALS Screen.

Results: The ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness.

Conclusions: Cortical mean diffusivity might be a useful biomarker for the study of extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum.

Classification Of Evidence: This study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.
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http://dx.doi.org/10.1212/WNL.0000000000010727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682829PMC
November 2020

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer's disease-related inhibitory circuit dysfunction in adults with Down syndrome.

Mol Neurodegener 2020 08 17;15(1):46. Epub 2020 Aug 17.

Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain.

Background: Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging).

Methods: This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([F]-fluorodeoxyglucose positron emission tomography).

Results: Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r = 0.2, p = 0.003), adults with DS (r = 0.4, p < 0.0001) and sporadic AD (r = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ (r > 0.3, p < 0.006), low CSF t-tau (r > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05).

Conclusions: Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.
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http://dx.doi.org/10.1186/s13024-020-00398-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433053PMC
August 2020

Evaluation of biochemical and hematological parameters in adults with Down syndrome.

Sci Rep 2020 08 13;10(1):13755. Epub 2020 Aug 13.

Department of Biochemistry, Hospital de La Santa Creu i Sant Pau, Biomedical Research Institute (IIB) Sant Pau, C/Sant Quintí 89, 08041, Barcelona, Spain.

Down syndrome (DS) is the most common worldwide cause of intellectual disability of genetic origin and the most common chromosomal disorder affecting live-born infants. In addition to intellectual disability, individuals with DS have other comorbidities and complex medical conditions. The increase in the life expectancy of patients with DS requires expanding the knowledge about their clinical characteristics and related laboratory parameters. Several studies exploring laboratory tests in DS patients exist, but their focus is limited to specific areas of metabolism. Therefore, our main goal was to describe the biochemical and hematological findings in a DS cohort and to compare the values to those of a control population. A total of 248 DS individuals and 84 control subjects were enrolled. DS individuals had a higher frequency of several clinical conditions compared to control individuals and presented with significant differences with respect to the controls in both biochemical and hematological parameters. We found age- and sex-related differences in several of the parameters. A good understanding of the differences in our cohort might be of aid in the clinical follow-up of adults with DS, especially considering that the lifespan of DS individuals may reach 60 years of age in developed countries.
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http://dx.doi.org/10.1038/s41598-020-70719-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426851PMC
August 2020

Obesity impacts brain metabolism and structure independently of amyloid and tau pathology in healthy elderly.

Alzheimers Dement (Amst) 2020 28;12(1):e12052. Epub 2020 Jul 28.

Obesity Unit, Endocrinology and Diabetes Department Hospital Clinic Universitari de Barcelona Barcelona Spain.

Aims/hypothesis: Midlife obesity is a risk factor for dementia. We investigated the impact of obesity on brain structure, metabolism, and cerebrospinal fluid (CSF) core Alzheimer's disease (AD) biomarkers in healthy elderly.

Methods: We selected controls from ADNI2 with CSF AD biomarkers and/or fluorodeoxyglucose positron emission tomography (FDG-PET) and 3T-MRI. We measured cortical thickness, FDG uptake, and CSF amyloid beta (Aβ)1-42, p-tau, and t-tau levels. We performed regression analyses between these biomarkers and body mass index (BMI).

Results: We included 201 individuals (mean age 73.5 years, mean BMI 27.4 kg/m). Higher BMI was related to less cortical thickness and higher metabolism in brain areas typically not involved in AD (family-wise error [FWE] <0.05), but not to AD CSF biomarkers. It is notable that the impact of obesity on brain metabolism and structure was also found in amyloid negative individuals.

Conclusions/interpretation: In the cognitively unimpaired elderly, obesity has differential effects on brain metabolism and structure independent of an underlying AD pathophysiology.
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http://dx.doi.org/10.1002/dad2.12052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385480PMC
July 2020

Motor cortex transcriptome reveals microglial key events in amyotrophic lateral sclerosis.

Neurol Neuroimmunol Neuroinflamm 2020 09 15;7(5). Epub 2020 Jul 15.

From the Memory Unit (O.D.-I., V.M., S.S., G.L.-P., L.C.-C., M.Q.-V., L.M., O.B., D.A., J.P., R.B., A.L., J.F., J.C.), Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (O.D.-I., V.M., S.S., G.L.-P., L.C.-C., M.Q.-V., L.M., O.B., D.A., J.P., R.B., A.L., J.F., J.C.), Madrid; Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS (L.M.-P.), Barcelona; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department (L.M.-P.), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; Network Center for Biomedical Research in Rare Diseases (CIBERER) (J.T.-S., R.R.-G.), Madrid; and Neuromuscular Disorders Unit (J.T.-S., R.R.-G.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.

Objective: To identify transcriptomic changes, neuropathologic correlates, and cellular subpopulations in the motor cortex of sporadic amyotrophic lateral sclerosis (ALS).

Methods: We performed massive RNA sequencing of the motor cortex of patients with ALS (n = 11) and healthy controls (HCs; n = 8) and analyzed gene expression alterations, differential isoform usage, and gene coexpression networks. Furthermore, we used cell type deconvolution algorithms with human single-nucleus RNA sequencing data as reference to identify perturbations in cell type composition associated with ALS. We performed immunohistochemical techniques to evaluate neuropathologic changes in this brain region.

Results: We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synaptic-related pathways. The assembly of gene coexpression modules confirmed the involvement of these 2 major transcriptomic changes, which also showed opposite directions related to the disease. Cell type deconvolution revealed an overrepresentation of microglial cells in ALS compared with HC. Notably, microgliosis was driven by a subcellular population presenting a gene expression signature overlapping with the recently described disease-associated microglia (DAM). Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that the density of pTDP43 aggregates negatively correlates with the proportion of microglial cells.

Conclusions: DAM has a central role in microglia-related neuroinflammatory changes in the motor cortex of patients with ALS, and these alterations are coupled with a reduced expression of postsynaptic transcripts.
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http://dx.doi.org/10.1212/NXI.0000000000000829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371375PMC
September 2020

Diagnosis of prodromal and Alzheimer's disease dementia in adults with Down syndrome using neuropsychological tests.

Alzheimers Dement (Amst) 2020 28;12(1):e12047. Epub 2020 Jun 28.

Barcelona Down Medical Center Fundació Catalana Síndrome de Down Barcelona Spain.

Introduction: We aimed to define prodromal Alzheimer's disease (AD) and AD dementia using normative neuropsychological data in a large population-based cohort of adults with Down syndrome (DS).

Methods: Cross-sectional study. DS participants were classified into asymptomatic, prodromal AD and AD dementia, based on neurologist's judgment blinded to neuropsychological data (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG-DS] and modified Cued Recall Test [mCRT]). We compared the cutoffs derived from the normative data in young adults with DS to those from receiver-operating characteristic curve (ROC) analysis.

Results: Diagnostic performance of the CAMCOG-DS and modified Cued Recall Test (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, both for diagnosing prodromal AD and AD dementia (area under the curve [AUC] 0.73-0.83 and 0.90-1, respectively). The cutoffs derived from the normative data were similar to those derived from the ROC analyses.

Discussion: Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy.
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http://dx.doi.org/10.1002/dad2.12047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322242PMC
June 2020

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

Lancet 2020 06;395(10242):1988-1997

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.

Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.

Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life.

Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.

Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(20)30689-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322523PMC
June 2020

The Added Value of Tau-PET in the Assessment of Progressive Supranuclear Palsy.

Clin Nucl Med 2020 May;45(5):e239-e240

From the Department of Nuclear Medicine.

Progressive supranuclear palsy (PSP) is rare neurodegenerative disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells. This disorder is underdiagnosed due to the overlap of the clinical syndrome with other related conditions. The clinical manifestations include cognitive impairment associated with behavioral changes, akinetic rigid syndrome, and prominent oculomotor dysfunction. We present the F-FDG and F-THK5351 PET images of a 71-year-old man diagnosed of probable PSP. This image highlights the hopeful results of the new tau-PET ligands radiotracers, because it allows to assess the distribution of tau-protein over time, closely associated with neurodegeneration in PSP.
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http://dx.doi.org/10.1097/RLU.0000000000002977DOI Listing
May 2020

Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer's Disease.

Cereb Cortex 2020 04;30(4):2083-2098

CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, 28031 Madrid, Spain.

Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer's disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1-Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.
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http://dx.doi.org/10.1093/cercor/bhz224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493660PMC
April 2020

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

Ann Clin Transl Neurol 2019 12 2;6(12):2518-2530. Epub 2019 Dec 2.

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls.

Methods: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1-42, Aβ1-40, Aβ1-38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis.

Results: The CSF levels of Aβ1-40, Aβ1-38, and sAPPβ were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function.

Interpretation: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aβ1-42 levels are considered an indirect biomarker of cerebral amyloidosis.
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http://dx.doi.org/10.1002/acn3.50948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917306PMC
December 2019

The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: A data set for biomarker discovery and validation in neurodegenerative disorders.

Alzheimers Dement (N Y) 2019 14;5:597-609. Epub 2019 Oct 14.

Department of Neurology, Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - IIB Sant Pau, Barcelona, Spain.

Introduction: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach.

Methods: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged.

Results: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases.

Discussion: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches.
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http://dx.doi.org/10.1016/j.trci.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804606PMC
October 2019

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.

Nat Commun 2019 10 18;10(1):4766. Epub 2019 Oct 18.

Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
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http://dx.doi.org/10.1038/s41467-019-12739-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800452PMC
October 2019

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse.

Ann Clin Transl Neurol 2019 09 28;6(9):1815-1824. Epub 2019 Aug 28.

Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain.

Objective: To determine the cutoffs that optimized the agreement between F-Florbetapir positron emission tomography (PET) and Aβ1-42, Aβ1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available F-Florbetapir imaging.

Methods: Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of Aβ1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with F-Florbetapir PET and evaluated concordance between markers of the amyloid category.

Results: Aβ1-42, tTau and pTau (but not Aβ1-40) and the ratios with Aβ1-42 had good diagnostic agreement with F-Florbetapir PET. As a marker of amyloid pathology, the Aβ1-42/Aβ1-40 ratio had higher agreement and better correlation with amyloid PET than Aβ1-42 alone.

Interpretation: CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of Aβ1-42 with Aβ1-40 increases the agreement between markers of amyloid pathology.
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http://dx.doi.org/10.1002/acn3.50873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764494PMC
September 2019

Different pattern of CSF glial markers between dementia with Lewy bodies and Alzheimer's disease.

Sci Rep 2019 05 24;9(1):7803. Epub 2019 May 24.

Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer's disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aβ, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aβ (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T-. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.
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http://dx.doi.org/10.1038/s41598-019-44173-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534578PMC
May 2019

Cortical microstructure in the behavioural variant of frontotemporal dementia: looking beyond atrophy.

Brain 2019 04;142(4):1121-1133

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Cortical mean diffusivity has been proposed as a novel biomarker for the study of the cortical microstructure in Alzheimer's disease. In this multicentre study, we aimed to assess the cortical microstructural changes in the behavioural variant of frontotemporal dementia (bvFTD); and to correlate cortical mean diffusivity with clinical measures of disease severity and CSF biomarkers (neurofilament light and the soluble fraction beta of the amyloid precursor protein). We included 148 participants with a 3 T MRI and appropriate structural and diffusion weighted imaging sequences: 70 patients with bvFTD and 78 age-matched cognitively healthy controls. The modified frontotemporal lobar degeneration clinical dementia rating was obtained as a measure of disease severity. A subset of patients also underwent a lumbar puncture for CSF biomarker analysis. Two independent raters blind to the clinical data determined the presence of significant frontotemporal atrophy to dichotomize the participants into possible or probable bvFTD. Cortical thickness and cortical mean diffusivity were computed using a surface-based approach. We compared cortical thickness and cortical mean diffusivity between bvFTD (both using the whole sample and probable and possible bvFTD subgroups) and controls. Then we computed the Cohen's d effect size for both cortical thickness and cortical mean diffusivity. We also performed correlation analyses with the modified frontotemporal lobar degeneration clinical dementia rating score and CSF neuronal biomarkers. The cortical mean diffusivity maps, in the whole cohort and in the probable bvFTD subgroup, showed widespread areas with increased cortical mean diffusivity that partially overlapped with cortical thickness, but further expanded to other bvFTD-related regions. In the possible bvFTD subgroup, we found increased cortical mean diffusivity in frontotemporal regions, but only minimal loss of cortical thickness. The effect sizes of cortical mean diffusivity were notably higher than the effect sizes of cortical thickness in the areas that are typically involved in bvFTD. In the whole bvFTD group, both cortical mean diffusivity and cortical thickness correlated with measures of disease severity and CSF biomarkers. However, the areas of correlation with cortical mean diffusivity were more extensive. In the possible bvFTD subgroup, only cortical mean diffusivity correlated with the modified frontotemporal lobar degeneration clinical dementia rating. Our data suggest that cortical mean diffusivity could be a sensitive biomarker for the study of the neurodegeneration-related microstructural changes in bvFTD. Further longitudinal studies should determine the diagnostic and prognostic utility of this novel neuroimaging biomarker.
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http://dx.doi.org/10.1093/brain/awz031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439330PMC
April 2019

Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment).

J Alzheimers Dis 2019 ;67(2):685-705

Department of Psychiatry, New York University Langone Health, New York, NY, USA.

Background: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2.

Objective: Two-year interval behavioral markers were investigated herein.

Methods: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years.

Results: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01).

Conclusion: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.
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http://dx.doi.org/10.3233/JAD-180341DOI Listing
March 2020

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
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