Cristina Solé-Padullés

Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance

White matter (WM) damage has been reported in Alzheimers 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.

Cognitive reserve modulates task-induced activations and deactivations in healthy elders, amnestic mild cognitive impairment and mild Alzheimer's disease

INTRODUCTION Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology in order to minimize clinical manifestations. Previous studies showed that CR modulates the patterns of brain activity in both healthy and clinical populations. In the present study we sought to determine whether reorganizations of functional brain resources linked to CR could already be observed in amnestic mild cognitive impairment (a-MCI) and mild Alzheimers disease (AD) patients when performing a task corresponding to an unaffected cognitive domain. We further investigated if activity in regions showing task-induced deactivations, usually identified as pertaining to the default-mode network (DMN), was also influenced by CR. METHODS Fifteen healthy elders, 15 a-MCI and 15 AD patients underwent functional magnetic resonance imaging (fMRI) during a speech comprehension task. Differences in the regression of slopes between CR proxies and blood-oxygen-level dependent (BOLD) signals across clinical groups were investigated for activation and deactivation areas. Correlations between significant fMRI results and a language comprehension test were also computed. RESULTS Among a-MCI and AD we observed positive correlations between CR measures and BOLD signals in task-induced activation areas directly processing speech, as well as greater deactivations in regions of the DMN. These relationships were inverted in healthy elders. We found no evidence that these results were mediated by gray matter volumes. Increased activity in left frontal areas and decreased activity in the anterior cingulate were related to better language comprehension in clinical evaluations. CONCLUSIONS The present findings provide evidence that the neurofunctional reorganizations related to CR among a-MCI and AD patients can be seen even when considering a preserved cognitive domain, being independent of gray matter atrophy. Areas showing both task-induced activations and deactivations are modulated by CR in an opposite manner when considering healthy elders versus patients. Brain reorganizations facilitated by CR may reflect behavioral compensatory mechanisms.

Interactions of cognitive reserve with regional brain anatomy and brain function during a working memory task in healthy elders.

Cognitive reserve (CR) defines the capacity of the adult brain to cope with pathology in order to minimize symptomatology. Relevant lifetime social, cognitive and leisure activities represent measurable proxies of cognitive CR but its underlying structural and functional brain mechanisms remain poorly understood. We investigated the relationship between CR and regional gray matter volumes and brain activity (fMRI) during a working memory task in a sample of healthy elders. Participants with higher CR had larger gray matter volumes in frontal and parietal regions. Conversely, a negative correlation was observed between CR and fMRI signal in the right inferior frontal cortex, suggesting increased neural efficiency for higher CR individuals. This latter association however disappeared after adjusting for gray matter images in a voxel-based manner. Altogether, present results may reflect both general and specific anatomofunctional correlates of CR in the healthy elders. Thus, whereas heteromodal anterior and posterior gray matter regions correspond to passive (i.e. morphological) correlates of CR unrelated to functional brain activation during this particular cognitive task, the right inferior frontal area reveals interactions between active and passive components of CR related to the cognitive functions tested in the fMRI study.

Cognitively Preserved Subjects with Transitional Cerebrospinal Fluid ß-Amyloid 1-42 Values Have Thicker Cortex in Alzheimer's Disease Vulnerable Areas

BACKGROUND 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 Alzheimers 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Cerebrospinal fluid biomarkers and memory present distinct associations along the continuum from healthy subjects to AD patients.

The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), t-tau, and p-tau and cognitive performance along the Alzheimers disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ(1-42), t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ(1-42) levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = -0.483; p < 0.005) and p-tau levels (r = -0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = -0.420; p < 0.005) and p-tau levels (r = -0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ(1-42) levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ(1-42) levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage.

Apolipoproteins E and C1 and brain morphology in memory impaired elders

Previous research has shown that polymorphisms of the apolipoproteins E (APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies.

Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of prodromal AD

We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosed using the new research criteria in a clinical setting. In order to further characterize these patients, we also study the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging (MRI) findings.

Effect of CPAP on Cognition, Brain Function, and Structure Among Elderly Patients With OSA: A Randomized Pilot Study

BACKGROUND Despite the increasing aging population and the high prevalence of OSA in elderly adults, little is known about cognitive effects of OSA and the effectiveness of CPAP treatment. Therefore, this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment. METHODS This randomized, evaluator-blinded, parallel-group, single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome. Thirty-three patients were assigned to receive either conservative care (CC) or CPAP plus CC for 3 months. At baseline and 3 months after treatment, patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network (DMN) and of cortical thickness. RESULTS Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline. By contrast, after CPAP treatment, patients showed a significant improvement in episodic (between-group difference in change, 7.60; 95% CI, 1.66-13.55; P = .014) and short-term memory (between-group difference in change, 1.06; 95% CI, 0.10-2.01; P = .032) and in executive function (speed of mental processing, 5.74; 95% CI, 1.69-9.79; P = .007; mental flexibility, -47.64; 95% CI, -81.83 to -13.45; P = .008), whereas no changes were observed in the CC group. Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group. No association was seen between cognition and brain functional connectivity changes within the DMN. CONCLUSIONS Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment. Moreover, CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01826032; URL: www.clinicaltrials.gov.

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.

Donepezil treatment stabilizes functional connectivity during resting state and brain activity during memory encoding in Alzheimer's disease.

Abstract Previous studies with functional magnetic resonance imaging (fMRI) demonstrated a differential brain activity and connectivity after treatment with donepezil in Alzheimer’s disease (AD) when compared to healthy elders. Importantly however, there are no available studies where the placebo or control group included comparable AD patients relative to the treated groups. Fifteen patients recently diagnosed of AD were randomized to treatment (n = 8) or to control group (n = 7); the former receiving daily treatment of donepezil during 3 months. At baseline and follow-up, both groups underwent resting-state as well as task-fMRI examinations, this latter assessing encoding of visual scenes. The treated group showed higher connectivity in areas of the default mode network, namely the right parahippocampal gyrus at follow-up resting-fMRI as compared to the control group. On the other hand, for the task-fMRI, the untreated AD group presented progressive increased activation in the left middle temporal gyrus and bilateral precuneus at the 3-month examination compared to baseline, whereas the treated group exhibited stable patterns of brain activity. Donepezil treatment is associated with stabilization of connectivity of medial temporal regions during resting state and of brain efficiency during a cognitive demand, on the whole reducing progressive dysfunctional reorganizations observed during the natural course of the disease.