ORCID Profile
0000-0002-5714-9282
Current Organisation
Barcelona Supercomputing Center
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Publisher: Wiley
Date: 29-06-2022
DOI: 10.1002/JNR.25100
Abstract: The most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the hexanucleotide repeat expansion in C9orf72 . An important neuropathological hallmark associated with this mutation is the accumulation of the phosphorylated form of TAR (trans‐activation response element) DNA‐binding protein 43 (pTDP‐43). Glia plays a crucial role in the neurodegeneration observed in C9orf72 ‐associated disorders. However, less is known about the role of oligodendrocytes (OLs). Here, we applied digital neuropathological methods to compare the expression pattern of glial cells in the frontal cortex (FrCx) of human post‐mortem s les from patients with C9‐FTLD and C9‐FTLD/ALS, sporadic FTLD (sFTLD), and healthy controls (HCs). We also compared MBP levels in CSF from an independent clinical FTD cohort. We observed an increase in GFAP, and Iba1 immunoreactivity in C9 and sFTLD compared to controls in the gray matter (GM) of the FrCx. We observed a decrease in MBP immunoreactivity in the GM and white matter (WM) of the FrCx of C9, compared to HC and sFTLD. There was a negative correlation between MBP and pTDP‐43 in C9 in the WM of the FrCx. We observed an increase in CSF MBP concentrations in C9 and sFTLD compared to HC. In conclusion, the C9 expansion is associated with myelin loss in the frontal cortex. This loss of MBP may be a result of oligodendroglial dysfunction due to the expansion or the presence of pTDP‐43 in OLs. Understanding these biological processes will help to identify specific pathways associated with the C9orf72 expansion.
Publisher: Frontiers Media SA
Date: 18-01-2022
DOI: 10.3389/FNEUR.2021.750543
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.
Publisher: Wiley
Date: 16-11-2020
DOI: 10.1002/ALZ.12224
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 10-12-2021
DOI: 10.1186/S40035-021-00275-W
Abstract: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and their clinical utility in predicting disease progression. pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile. Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78 pGFAP 0.7 pNfL 0.61, all P 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P 0.005) and in AD (1.20 points annually, HR 2.26, P 0.005). pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2021
DOI: 10.1038/S41467-021-24319-X
Abstract: 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 in iduals 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 in iduals 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.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2022
DOI: 10.1186/S13195-022-00974-0
Abstract: Cortical mean diffusivity is a novel imaging metric sensitive to early changes in neurodegenerative syndromes. Higher cortical mean diffusivity values reflect microstructural disorganization and have been proposed as a sensitive biomarker that might antedate macroscopic cortical changes. We aimed to test the hypothesis that cortical mean diffusivity is more sensitive than cortical thickness to detect cortical changes in primary progressive aphasia (PPA). In this multicenter, case-control study, we recruited 120 patients with PPA (52 non-fluent, 31 semantic, and 32 logopenic variants and 5 GRN -related PPA) as well as 89 controls from three centers. The 3-Tesla MRI protocol included structural and diffusion-weighted sequences. Disease severity was assessed with the Clinical Dementia Rating scale. Cortical thickness and cortical mean diffusivity were computed using a surface-based approach. The comparison between each PPA variant and controls revealed cortical mean diffusivity increases and cortical thinning in overlapping regions, reflecting the canonical loci of neurodegeneration of each variant. Importantly, cortical mean diffusivity increases also expanded to other PPA-related areas and correlated with disease severity in all PPA groups. Cortical mean diffusivity was also increased in patients with very mild PPA when only minimal cortical thinning was observed and showed a good correlation with measures of disease severity. Cortical mean diffusivity shows promise as a sensitive biomarker for the study of the neurodegeneration-related microstructural changes in PPA.
Publisher: American Medical Association (AMA)
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
DOI: 10.1186/S13024-020-00398-0
Abstract: 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). 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 1–42 , CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([ 18 F]-fluorodeoxyglucose positron emission tomography). 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 2 = 0.2, p = 0.003), adults with DS ( r 2 = 0.4, p 0.0001) and sporadic AD ( r 2 = 0.4, p 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ 1–42 ( r 2 0.3, p 0.006), low CSF t-tau ( r 2 0.3, p 0.001), increased cortical atrophy ( p 0.05) and reduced glucose metabolism ( p 0.05). 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.
Publisher: Impact Journals, LLC
Date: 31-10-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-07-2020
DOI: 10.1212/NXI.0000000000000829
Abstract: To identify transcriptomic changes, neuropathologic correlates, and cellular subpopulations in the motor cortex of sporadic amyotrophic lateral sclerosis (ALS). 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. 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. 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.
Publisher: Oxford University Press (OUP)
Date: 02-03-2023
DOI: 10.1093/BRAINCOMMS/FCAD074
Abstract: The study of sex differences in Alzheimer’s disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer’s disease (& % in the 7th decade). Yet, sex differences in Alzheimer’s disease manifestations have not been fully investigated in these in iduals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6 50.7) years], we compared Alzheimer’s disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience s le recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippoc al volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer’s disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.
Location: Spain
No related grants have been discovered for Victor Montal.