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Roser Sala-Llonch,
Juan Fortea,
David Bartrés-Faz,
Beatriz Bosch,
Albert Lladó,
Cleofé Peña-Gómez,
Anna Antonell,
Fernando Castellanos-Pinedo,
Nuria Bargalló,
José Luis Molinuevo,
Raquel Sánchez-Valle
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ABSTRACT: PSEN1 mutations are the most frequent cause of familial Alzheimer's disease and show nearly full penetrance. Here we studied alterations in brain function in a cohort of 19 PSEN1 mutation carriers: 8 symptomatic (SMC) and 11 asymptomatic (AMC). Asymptomatic carriers were, on average, 12 years younger than the predicted age of disease onset. Thirteen healthy subjects were used as a control group (CTR). Subjects underwent a 10-min resting-state functional magnetic resonance imaging (fMRI) scan and also performed a visual encoding task. The analysis of resting-state fMRI data revealed alterations in the default mode network, with increased frontal connectivity and reduced posterior connectivity in AMC and decreased frontal and increased posterior connectivity in SMC. During task-related fMRI, SMC showed reduced activity in regions of the left occipital and left prefrontal cortices, while both AMC and SMC showed increased activity in a region within the precuneus/posterior cingulate, all as compared to CTR. Our findings suggest that fMRI can detect evolving changes in brain mechanisms in PSEN1 mutation carriers and support the use of this technique as a biomarker in Alzheimer's disease, even before the appearance of clinical symptoms.
Journal of Alzheimer's disease: JAD 04/2013; · 3.74 Impact Factor
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Eider M Arenaza-Urquijo,
José-Luis Molinuevo, Roser Sala-Llonch,
Cristina Solé-Padullés,
Mircea Balasa,
Beatriz Bosch,
Jaume Olives,
Anna Antonell,
Albert Lladó,
Raquel Sánchez-Valle,
Lorena Rami,
David Bartrés-Faz
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ABSTRACT: Cognitive reserve capacity may increase tolerance of neurodegenerative processes. However, its role regarding amyloid-β (Aβ42) deposition in cognitively normal subjects is not well understood. We aimed to investigate the association between areas showing Aβ42-related structural changes and cognitive reserve proxies in cognitively intact subjects showing normal or abnormal Aβ42 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 Aβ42 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 normal Aβ42 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 Aβ42 CSF levels. Thus, subjects with abnormal Aβ42 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.
Journal of Alzheimer's disease: JAD 03/2013; · 3.74 Impact Factor
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Lorena Rami, Roser Sala-Llonch,
Cristina Solé-Padullés,
Juan Fortea,
Jaume Olives,
Albert Lladó,
Cleofe Peña-Gómez,
Mircea Balasa,
Bea Bosch,
Anna Antonell,
Raquel Sanchez-Valle,
David Bartrés-Faz,
Jose L Molinuevo
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ABSTRACT: 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.
Journal of Alzheimer's disease: JAD 05/2012; 31(3):517-26. · 3.74 Impact Factor
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ABSTRACT: In recent years, several theories have been proposed in attempts to identify the neural mechanisms underlying successful cognitive aging. Old subjects show increased neural activity during the performance of tasks, mainly in prefrontal areas, which is interpreted as a compensatory mechanism linked to functional brain efficiency. Moreover, resting-state studies have concluded that elders show disconnection or disruption of large-scale functional networks. We used functional MRI during resting-state and a verbal n-back task with different levels of memory load in a cohort of young and old healthy adults to identify patterns of networks associated with working memory and brain default mode. We found that the disruption of resting-state networks in the elderly coexists with task-related overactivations of certain brain areas and with reorganizations within these functional networks. Moreover, elders who were able to activate additional areas and to recruit a more bilateral frontal pattern within the task-related network achieved successful performance on the task. We concluded that the balanced and plastic reorganization of brain networks underlies successful cognitive aging. This observation allows the integration of several theories that have been proposed to date regarding the aging brain.
Frontiers in Human Neuroscience 01/2012; 6:152. · 2.34 Impact Factor
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ABSTRACT: Brain regions simultaneously activated during any cognitive process are functionally connected, forming large-scale networks. These functional networks can be examined during active conditions [i.e., task-functional magnetic resonance imaging (fMRI)] and also in passive states (resting-fMRI), where the default mode network (DMN) is the most widely investigated system. The role of the DMN remains unclear, although it is known to be responsible for the shift between resting and focused attention processing. There is also some evidence for its malleability in relation to previous experience. Here we investigated brain connectivity patterns in 16 healthy young subjects by using an n-back task with increasing levels of memory load within the fMRI context. Prior to this working memory (WM) task, participants were trained outside fMRI with a shortened test version. Immediately after, they underwent a resting-state fMRI acquisition followed by the full fMRI n-back test. We observed that the degree of intrinsic correlation within DMN and WM networks was maximal during the most demanding n-back condition (3-back). Furthermore, individuals showing a stronger negative correlation between the two networks under both conditions exhibited better behavioural performance. Interestingly, and despite the fact that we considered eight different resting-state fMRI networks previously identified in humans, only the connectivity within the posteromedial parts of the DMN (precuneus) prior to the fMRI n-back task predicted WM execution. Our results using a data-driven probabilistic approach for fMRI analysis provide the first evidence of a direct relationship between behavioural performance and the degree of negative correlation between the DMN and WM networks. They further suggest that in the context of expectancy for an imminent cognitive challenge, higher resting-state activity in the posteromedial parietal cortex may be related to increased attentional preparatory resources.
Cortex 08/2011; 48(9):1187-96. · 6.08 Impact Factor
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Juan Fortea, Roser Sala-Llonch,
David Bartrés-Faz,
Albert Lladó,
Cristina Solé-Padullés,
Beatriz Bosch,
Anna Antonell,
Jaume Olives,
Raquel Sanchez-Valle,
Jose L Molinuevo,
Lorena Rami
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ABSTRACT: Establishing the relationship between cerebrospinal fluid (CSF) ß-amyloid 1-42 (Aß) and cortical thickness (CTh) would represent a major step forward in the understanding of the Alzheimer's disease (AD) process. We studied this relationship in a group of healthy control subjects and subjects with subjective memory complaints with preserved cognitive function at neuropsychological testing.
In this cross-sectional study, 33 individuals (17 healthy control subjects and 16 subjects with subjective memory complaints) underwent structural 3-Tesla magnetic resonance image scanning and a spinal tap. Cerebrospinal fluid Aß was measured by enzyme-linked immunosorbent assay. The relationship between CSF Aß values and CTh in several regions of interest, both susceptible and unrelated to AD pathology, was analyzed with a curve fit analysis and CTh difference maps were derived from group comparisons.
Dichotomizing the whole sample according to Aß values (cutoff 500 pg/mL), we found the expected cortical thinning in Aß positive subjects in temporoparietal areas (p < .05 corrected). When analyzing the relationship between CSF Aß and CTh in AD-susceptible regions, we found a significant inverted U-shaped relationship (quadratic). Therefore, the sample was further divided into tertiles (according to CSF Aß values) to perform subsequent subgroup comparisons. Increased CTh in temporoparietal areas and precuneus (p < .05 corrected) was found in the middle Aß tertile (CSF Aß between 416 and 597 pg/mL) when compared with the high Aß tertile (616-881 pg/mL).
The relationship between Aß and CTh in preclinical stages may not be linear. Cortical thickness in temporoparietal and precuneus regions is greater in subjects with transitional CSF Aß values.
Biological psychiatry 04/2011; 70(2):183-90. · 8.93 Impact Factor
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ABSTRACT: to investigate the associations between white matter (WM) integrity and cognitive reserve (CR) in healthy elders (HE), amnestic mild cognitive impairment (a-MCI), and Alzheimer's disease (AD). The authors studied correlations between CR and WM integrity in regions showing WM age-related effects or pathologic changes and tested the differences of slopes between groups.
diffusion tensor images (DTIs) were obtained from 18 young individuals, 15 HE, 16 a-MCI cases, and 15 AD cases. Tract-based spatial statistics was used to process DTI data. Areas showing age-related fractional anisotropy (FA) shrinkages (HE < young) and pathology-related FA network "(AD < HE)" were defined. Correlations between CR and WM integrity were adjusted for age, gender, memory performance and brain volumes.
he presented more negative correlations between CR and WM integrity than patients with a-MCI and AD in age-related areas, such as the genum of the corpus callosum. However, these results were mediated by normal variability in memory function and brain volumes. For patients with a-MCI, negative associations between CR and FA were found in several major tracts, being more robust than in AD group. Although longitudinal results need to be interpreted with caution because of the reduced sample of patients with MCI, after 2 years of follow-up, all patients who progressed to AD had high-CR scores, suggesting a putative link between reduced WM integrity (maximal in patients with high CR) and risk of progression to AD.
CR correlates are implemented in different anatomic WM areas in HE and patients with a-MCI. Healthy elders with high CR may present better tolerance of typical age-related effects on WM integrity; in patients with a-MCI, the association may reflect increased capacity to cope with incipient cerebral damage.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 01/2011; 19(1):33-42. · 3.35 Impact Factor
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ABSTRACT: White matter (WM) damage has been reported in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in diffusion tensor imaging (DTI) studies. It is, however, unknown how the investigation of multiple tensor indexes in the same patients, can differentiate them from normal aging or relate to patients cognition. Forty-six individuals (15 healthy, 16 a-MCI and 15 AD) were included. Voxel-based tract based spatial-statistics (TBSS) was used to obtain whole-brain maps of main WM bundles for fractional anisotropy (FA), radial diffusivity (DR), axial diffusivity (DA) and mean diffusivity (MD). FA reductions were evidenced among AD patients with posterior predominance. A-MCI patients displayed reduced mean FA in these critical regions, compared to healthy elders. MD increases were widespread in both groups of patients. Interestingly, a-MCI patients exhibited DR increases in overlapping areas of FA shrinkages in AD, whereas DA increases were only observed in AD. Gray matter atrophy explained most DTI differences, except those regarding MD in both groups as well as DR increases in posterior associative pathways among a-MCI cases. FA values were the only DTI measure significantly related to memory performance among patients. Present findings suggest that most DTI-derived changes in AD and a-MCI are largely secondary to gray matter atrophy. Notably however, specific DR signal increases in posterior parts of the inferior fronto-occipital and longitudinal fasciculi may reflect early WM compromise in preclinical dementia, which is independent of atrophy. Finally, global measures of integrity, particularly orientation coherence (FA) of diffusion, appear to be more closely related to the cognitive profile of our patients than indexes reflecting water movement parallel (DA) and perpendicular (DR) to the primary diffusion direction.
Neurobiology of aging 04/2010; 33(1):61-74. · 5.94 Impact Factor
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ABSTRACT: Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n=6) or symptomatic (n=5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-β1-42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p<0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p<0.01), increased caudate volumes (p<0.01), and decreased MD (p<0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC.
Journal of Alzheimer's disease: JAD 01/2010; 22(3):909-22. · 3.74 Impact Factor
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ABSTRACT: We conducted an integrated multi-modal magnetic resonance imaging (MRI) study based on functional MRI (fMRI) data during a complex but cognitively preserved visual task in 15 amnestic mild cognitive impairment (a-MCI) patients and 15 Healthy Elders (HE). Independent Component Analysis of fMRI data identified a functional network containing an Activation Task Related Pattern (ATRP), including regions of the dorsal and ventral visual stream, and a Deactivation Task Related Pattern network (DTRP), with high spatial correspondence with the default-mode network (DMN). Gray matter (GM) volumes of the underlying ATRP and DTRP cortical areas were measured, and probabilistic tractography (based on diffusion MRI) identified fiber pathways within each functional network. For the ATRP network, a-MCI patients exhibited increased fMRI responses in inferior-ventral visual areas, possibly reflecting compensatory activations for more compromised dorsal regions. However, no significant GM or white matter group differences were observed within the ATRP network. For the DTRP/DMN, a-MCI showed deactivation deficits and reduced GM volumes in the posterior cingulate/precuneus, excessive deactivations in the inferior parietal lobe, and less fiber tract integrity in the cingulate bundles. Task performance correlated with DTRP-functionality in the HE group. Besides allowing the identification of functional reorganizations in the cortical network directly processing the task-stimuli, these findings highlight the importance of conducting integrated multi-modal MRI studies in MCI based on spared cognitive domains in order to identify functional abnormalities in critical areas of the DMN and their precise anatomical substrates. These latter findings may reflect early neuroimaging biomarkers in dementia.
Journal of Alzheimer's disease: JAD 01/2010; 22(2):523-39. · 3.74 Impact Factor
