The hippocampal longitudinal axis – relevance for underlying tau and TDP-43 pathology?

Recent studies suggest that hippocampus has different cortical connectivity and functionality along its longitudinal axis. We sought to elucidate the possible different pattern of atrophy in longitudinal axis of hippocampus between Amyloid/Tau pathology and TDP-43-pathies. Seventy-three presenile subjects were included: Amyloid/Tau group (33 Alzheimer’s disease (AD) with confirmed CSF biomarkers), probable TDP-43 group (7 semantic variant progressive primary aphasia, 5 GRN and 2 C9orf72 mutation carriers) and 26 healthy controls. We conducted a region-of-interest voxel-based morphometry analysis on the hippocampal longitudinal axis, by contrasting the groups, covarying with CSF biomarkers (Aβ42, total tau, p-tau) and covarying with episodic memory scores. Amyloid/Tau pathology affected mainly posterior hippocampus while anterior left hippocampus was more atrophied in probable TDP-43pathies. We also observed a significant correlation of posterior hippocampal atrophy with AD CSF biomarkers and visual memory scores. Taken together, these data suggest that there is a potential differentiation along the hippocampal longitudinal axis based on the underlying pathology, which could be used as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases

Subtle visuomotor difficulties in preclinical Alzheimer's disease

Background: Individuals with preclinical Alzheimer's disease (Pre-AD) present nonimpaired cognition, as measured by standard neuropsychological tests. However, detecting subtle difficulties in cognitive functions may be necessary for an early diagnosis and intervention. Objectives: A new computer-based visuomotor coordination task (VMC) was developed to investigate the possible presence of early visuomotor difficulties in Pre-AD individuals. Associations between VMC task performance and AD biomarkers were studied. The influence of ApoE status on participants' performance was addressed, as well as the relationship between performance and subjective cognitive decline (SCD). Methods: Sixty-six cognitively normal (CN) elders (19 Pre-AD and 47 control participants [CTR]) and 15 patients with AD performed the VMC task, which consisted in executing visually guided goal-directed movements that required the coordination of the visual and motor systems. All participants underwent ApoE analysis and lumbar puncture. CN participants also completed an extensive standard neuropsychological battery. Results: Despite presenting normal cognition in standard tests, Pre-AD participants exhibited higher response times (RTs) to complete the VMC task than CTR (p < .01). Besides, patients with AD showed higher RTs than CTR (p < .001) and Pre-AD (p < .05), and more errors than CTR (p < .005). RTs in ApoE4 carriers were higher than that observed in ApoE4 noncarriers (p < .01). In CN individuals, RTs were related to amyloid β-protein 42 (AB42) biomarker (p < .01) and informant-rated SCD (p < .01). Conclusions: The VMC task is able to discriminate Pre-AD from CTR individuals. Moreover, VMC results are associated with AB42 levels in CN individuals, suggesting that visuomotor dysfunction may be a sensitive marker of Pre-AD

Cognitive Reserve Proxies Relate to Gray Matter Loss in Cognitively Healthy Elderly with Abnormal Cerebrospinal Fluid Amyloid-β Levels

Cognitive reserve capacity may increase tolerance of neurodegenerative processes. However, its role regarding amyloid-B (AB 42) deposition in cognitively normal subjects is not well understood. We aimed to investigate the association between areas showing A 42-related structural changes and cognitive reserve proxies in cognitively intact subjects showing normal or abnormal AB 42 cerebrospinal fluid (CSF) concentrations. Thirty-three subjects (aged 55-85) underwent lumbar puncture and high resolution anatomical magnetic resonance imaging analyzed by voxel-based morphometry and cortical thickness procedures. Subjects with abnormal A 42 CSF levels showed significant left hippocampal atrophy and greater cortical thinning in parietal, temporal, and frontal regions (including the supramarginal and the anterior cingulate gyrus) compared to subjects with normalA 42 CSF levels. Using a multivariate general linear model, we investigated the relationship between these areas and cognitive reserve proxies. We found a significant relationship between decreased volume of the left hippocampus or decreased cortical thickness of the right supramarginal gyrus and higher cognitive reserve proxies only in the group with abnormal A 42 CSF levels. Thus, subjects with abnormal A 42 CSF levels (which may be at a higher risk of developing Alzheimer's disease) and with high scores on cognitive reserve proxies may be tolerating a more advanced neurodegenerative process in critical cortical and subcortical regions. The present results emphasize the relevance of evaluating cognitive reserve proxies, as well as the importance of using neuroimaging techniques for early diagnosis in individuals with higher reserve

Distinct functional activity of the precuneus and posterior cingulate cortex during encoding in the preclinical stage of Alzheimer's Disease

In this study functional magnetic resonance imaging (fMRI) is used to investigate the functional brain activation pattern in the preclinical stage of AD (pre-AD) subjects during a visual encoding memory task. Thirty subjects, eleven in the pre-AD stage, with decreased cerebrospinal fluid levels of Aβ42 (<500 pg/ml), and 19 controls with normal Aβ42 levels (CTR) were included. fMRI was acquired during a visual encoding task. Data were analyzed through an Independent Component Analysis (ICA) and region-of-interest-based univariate analysis of task-related BOLD signal change. From the ICA decomposition, we identified the main task-related component, which included the activation of visual associative areas and prefrontal executive regions, and the deactivation of the default-mode network. The activation was positively correlated with task performance in the CTR group (p < 0.0054). Within this pattern, subjects in the pre-AD stage had significantly greater activation of the precuneus and posterior cingulate cortex during encoding. Subjects in the pre-AD stage present distinct functional neural activity before the appearance of clinical symptomatology. These findings may represent that subtle changes in functional brain activity precede clinical and cognitive symptoms in the AD continuum. Present findings provide evidence suggesting that fMRI may be a suitable biomarker of preclinical AD

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

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). 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

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD

Longitudinal brain atrophy and CSF biomarkers in early-onset Alzheimer&#039;s disease

There is evidence longitudinal atrophy in posterior brain areas in early-onset Alzheimer&#039;s disease (EOAD; aged &lt; 65 years), but no studies have been conducted in an EOAD cohort with fluid biomarkers characterization. We used 3T-MRI and Freesurfer 6.0 to investigate cortical and subcortical gray matter loss at two years in 12 EOAD patients (A + T + N + ) compared to 19 controls (A-T-N-) from the Hospital Clínic Barcelona cohort. We explored group differences in atrophy patterns and we correlated atrophy and baseline CSF-biomarkers levels in EOAD. We replicated the correlation analyses in 14 EOAD (A + T + N + ) and 55 late-onset AD (LOAD; aged ? 75 years; A + T + N + ) participants from the Alzheimer&#039;s disease Neuroimaging Initiative. We found that EOAD longitudinal atrophy spread with a posterior-to-anterior gradient and beyond hippocampus/amygdala. In EOAD, higher initial CSF NfL levels correlated with higher ventricular volumes at baseline. On the other hand, higher initial CSF A?42 levels (within pathological range) predicted higher rates of cortical loss in EOAD. In EOAD and LOAD subjects, higher CSF t-tau values at baseline predicted higher rates of subcortical atrophy. CSF p-tau did not show any significant correlation. In conclusion, posterior cortices, hippocampus and amygdala capture EOAD atrophy from early stages. CSF A?42 might predict cortical thinning and t-tau/NfL subcortical atrophy.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved

Aula d'Ecologia : cicles de conferències 1999 i 2000

Descripció del recurs: 13 juny 2007Conté: Rafael Argullol, Natura i ciutat en el canvi de mil·lenni ; Antoni Lloret, Energies per al segle XXI ; Jorge Wagensberg, Investigació científica i sostenibilitat: l'experiència amazònica ; Manuel Ludevid, El paper de les empreses en la societat sostenible ; Rafael Grasa, El paper de les ONG en la societat sostenible ; Luis Ángel Fernández Hermana, La comunicació en la transició cap a una societat sostenible ; Frederic Ximeno, Estratègies i eines de planificació territorial cap a una ciutat sostenible ; José Luis Porcuna, Estratègies agroecològiques cap a una agricultura sostenible ; Josep Germain, Estratègia catalana per a la biodiversitat ; Carles Gràcia, Els boscos i el funcionament sostenible del planeta ; Manuel Herce, El territori de la ciutat: criteris de sostenibilitat, ordenació i urbanització ; Josep Enric Llebot, Ciència i política del canvi climàtic ; Àlex Aguilar, L'extinció de les espècies: entre la ignorància i la tolerància ; Josep Olives, La ciutat com a idea d'equilibri ; Anna Cabré, Demografia i migracions al segle XXI: què és raonable preveure? ; Manolis Kogevinas, Càncer i exposicions mediambientals ; Ramon Arandes, L'aprofitament de les aigües del subsòl de Barcelona ; Rafael Simó, L'oceà i l'atmosfera, inseparables davant el canvi climàtic global ; Joan Caylà, Sobre el possible impacte mundial de la sida en la dècada 2000-2010 ; Jordi Serra Raventós, Ocupació del litoral i implicacions sobre el territori ; Joan Manuel Vilaplana, Catàstrofes i societat ; Montserrat Vilà, Causes i conseqüències de les invasions biològiques ; Josep Egozcue, Clonatge humà: tècnica i ètica ; Millán M. Millán, Contaminación fotoquímica en la cuenca mediterránea: revisión de los resultados de proyectos de investigación europeos ; Jaume Terradas i José Ángel Burriel, Mapa ecològic de Barcelona

Modelling the cascade of biomarker changes in progranulin‐related frontotemporal dementia

AbstractBackgroundProgranulin related frontotemporal dementia (FTD‐GRN) is a fast progressive disorder, in which pathophysiological changes precede overt clinical symptoms in only a short time period. Modelling the cascade of multimodal biomarker changes aids in understanding the etiology of this disease, enables monitoring of individual mutation carriers, and would give input for disease‐modifying treatments. In this cross‐sectional study, we estimated the temporal cascade of biomarker changes for FTD‐GRN, in a data‐driven way.MethodWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non‐carriers. Of the symptomatic subjects, 17 had behavioural variant FTD (bvFTD), 16 presented as non‐fluent variant primary progressive aphasia (nfvPPA). The selected biomarkers for establishing the cascade of changes were neurofilament light chain, regional grey matter volumes, fractional anisotropy of white matter tracts, and cognitive domains. We used a data‐driven analysis called discriminative event‐based modelling (Venkatraghavan, NeuroImage, 2019) with a novel modification to its Gaussian Mixture Model (GMM) called Siamese GMM, to estimate the cascade of biomarker changes for FTD‐GRN. Using cross‐validation, we estimated disease severities of individual mutation carriers in the test set based on their progression along the biomarker cascade established on the training set.ResultNeurofilament light chain and white matter tracts were the earliest biomarkers to become abnormal in FTD‐GRN mutation carriers. Attention and executive functioning were also affected early on in the disease process. Based on the estimated individual disease severities, presymptomatic mutation carriers could be distinguished from symptomatic mutation carriers with a sensitivity of 95% and specificity of 100% in the cross‐validation experiment. There was a high correlation (r=0.94, p<0.001) between estimated disease severity and years since symptom onset in nfvPPA, but not in bvFTD (r=0.33, p=0.46).ConclusionIn this study, we unravelled the temporal cascade of multimodal biomarker changes for FTD‐GRN. Our results suggest that axonal degeneration is one of the first disease events in FTD‐GRN, which calls for designing disease modifying treatments that strengthens the axons. We also demonstrated a good delineation between symptomatic and presymptomatic carriers using the estimated disease severities, which suggest that our model could enable monitoring of individual mutation carriers

Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia

© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions. Measures of topological efficiency of the brain's functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. We propose that maintaining the efficient organization of the brain's functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.This work was funded by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant [grant number CoEN015]. JBR was supported by the Wellcome Trust [grant number 103838]. JBR, RB, TR, and SJ were supported by the NIHR Cambridge Biomedical Research Centre and Medical Research Council [grant number G1100464]. The Dementia Research Centre at UCL is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation, NIHR Queen Square Dementia Biomedical Research Unit, NIHR UCL/H Biomedical Research Centre and Dementia Platforms UK. JDR is supported by an MRC Clinician Scientist Fellowship [grant number MR/M008525/1] and has received funding from the NIHR Rare Disease Translational Research Collaboration [grant number BRC149/NS/MH]. MM is supported by the Canadian Institutes of Health Research, Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, and the Sunnybrook Research Institute. RL is supported by Réseau de médecine génétique appliquée, Fonds de recherche du Québec—Santé [grant number FRQS]. FT is supported by the Italian Ministry of Health. DG is supported by the Fondazione Monzino and Italian Ministry of Health, Ricerca Corrente. SS is supported by Cassa di Risparmio di Firenze [grant number CRF 2013/0199] and the Ministry of Health [grant number RF-2010-2319722]. JvS is supported by The Netherlands Organisation for Health Research and Development Memorable grant [grant number 733050103] and Netherlands Alzheimer Foundation Memorable grant [grant number 733050103].info:eu-repo/semantics/publishedVersio