Whole-brain DTI parameters associated with tau protein and hippocampal volume in Alzheimer's disease.

The causes of the neurodegenerative processes in Alzheimer's disease (AD) are not completely known. Recent studies have shown that white matter (WM) damage could be more severe and widespread than whole-brain cortical atrophy and that such damage may appear even before the damage to the gray matter (GM). In AD, Amyloid-beta (Aß42 ) and tau proteins could directly affect WM, spreading across brain networks. Since hippocampal atrophy is common in the early phase of disease, it is reasonable to expect that hippocampal volume (HV) might be also related to WM integrity. Our study aimed to evaluate the integrity of the whole-brain WM, through diffusion tensor imaging (DTI) parameters, in mild AD and amnestic mild cognitive impairment (aMCI) due to AD (with Aß42 alteration in cerebrospinal fluid [CSF]) in relation to controls; and possible correlations between those measures and the CSF levels of Aß42 , phosphorylated tau protein (p-Tau) and total tau (t-Tau). We found a widespread WM alteration in the groups, and we also observed correlations between p-Tau and t-Tau with tracts directly linked to mesial temporal lobe (MTL) structures (fornix and hippocampal cingulum). However, linear regressions showed that the HV better explained the variation found in the DTI measures (with weak to moderate effect sizes, explaining from 9% to 31%) than did CSF proteins. In conclusion, we found widespread alterations in WM integrity, particularly in regions commonly affected by the disease in our group of early-stage disease and patients with Alzheimer's disease. Nonetheless, in the statistical models, the HV better predicted the integrity of the MTL tracts than the biomarkers in CSF.

Differences in structural and functional default mode network connectivity in amyloid positive mild cognitive impairment: a longitudinal study.

PURPOSE: Default mode network (DMN) has emerged as a potential biomarker of Alzheimer's disease (AD); however, it is not clear whether it can differentiate amnestic mild cognitive impairment with altered amyloid (aMCI-Aß +) who will evolve to AD. We evaluated if structural and functional connectivity (FC), hippocampal volumes (HV), and cerebrospinal fluid biomarkers (CSF-Aß42, p-Tau, and t-Tau) can differentiate aMCI-Aß + converters from non-converters. METHODS: Forty-eight individuals (18 normal controls and 30 aMCI subjects in the AD continuum - with altered Aß42 in the CSF) were followed up for an average of 13 months. We used MultiAtlas, UF2C, and Freesurfer software to evaluate diffusion tensor imaging, FC, and HV, respectively, INNOTEST® kits to measure CSF proteins, and neuropsychological tests. Besides, we performed different MANOVAs with further univariate analyses to differentiate groups. RESULTS: During follow-up, 8/30 aMCI-Aß + converted (26.6%) to AD dementia. There were no differences in multivariate analysis between groups in CSF biomarkers (p = 0.092) or at DMN functional connectivity (p = 0.814). aMCI-Aß + converters had smaller right HV than controls (p = 0.013), and greater right cingulum parahippocampal bundle radial diffusivity than controls (p < 0.001) and non-converters (p = 0.036). CONCLUSION: In this exploratory study, structural, but not functional, DMN connectivity alterations may differentiate aMCI-Aß + subjects who converted to AD dementia.

Cognitive and structural cerebral changes in amnestic mild cognitive impairment due to Alzheimer's disease after multicomponent training.

Introduction: Information about how physical exercise affects patients with amnestic mild cognitive impairment (aMCI) due to Alzheimer's disease (AD) is still missing. This study evaluated the impact of multicomponent exercise training on cognition and brain structure in aMCI subjects with cerebral spinal fluid positive AD biomarkers. Methods: Forty aMCI subjects were divided in training (multicomponent exercise thrice a week for 6 months) and nontraining groups. Assessments included cardiorespiratory fitness, neurocognitive tests, and a structural magnetic resonance imaging using 3.0 T scanner. FreeSurfer software analyzed hippocampal volume and cortical thickness. Results: The training group showed increased volume in both hippocampi and better performance in episodic memory test after 6 months. In contrast, the nontraining group declined in functional activities, recognition, and cardiorespiratory fitness for the same period. Discussion: Multicomponent exercise seems to improve hippocampal volume and episodic memory, and maintains VO2max in aMCI due to AD.

Cognitive Reserve Relates to Functional Network Efficiency in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, with no means of cure or prevention. The presence of abnormal disease-related proteins in the population is, in turn, much more common than the incidence of dementia. In this context, the cognitive reserve (CR) hypothesis has been proposed to explain the discontinuity between pathophysiological and clinical expression of AD, suggesting that CR mitigates the effects of pathology on clinical expression and cognition. fMRI studies of the human connectome have recently reported that AD patients present diminished functional efficiency in resting-state networks, leading to a loss in information flow and cognitive processing. No study has investigated, however, whether CR modifies the effects of the pathology in functional network efficiency in AD patients. We analyzed the relationship between CR, pathophysiology and network efficiency, and whether CR modifies the relationship between them. Fourteen mild AD, 28 amnestic mild cognitive impairment (aMCI) due to AD, and 28 controls were enrolled. We used education to measure CR, cerebrospinal fluid (CSF) biomarkers to evaluate pathophysiology, and graph metrics to measure network efficiency. We found no relationship between CR and CSF biomarkers; CR was related to higher network efficiency in all groups; and abnormal levels of CSF protein biomarkers were related to more efficient networks in the AD group. Education modified the effects of tau-related pathology in the aMCI and mild AD groups. Although higher CR might not protect individuals from developing AD pathophysiology, AD patients with higher CR are better able to cope with the effects of pathology-presenting more efficient networks despite pathology burden. The present study highlights that interventions focusing on cognitive stimulation might be useful to slow age-related cognitive decline or dementia and lengthen healthy aging.

Intranetwork and internetwork connectivity in patients with Alzheimer disease and the association with cerebrospinal fluid biomarker levels.

BACKGROUND: In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF). METHODS: We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks' functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease. RESULTS: Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anticorrelation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas. LIMITATIONS: The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used. CONCLUSION: We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease.