Group-level progressive alterations in brain connectivity patterns revealed by diffusion-tensor brain networks across severity stages in Alzheimer’s disease

Abstract

Abstract. Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusiontensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G 1 ( N 1 =36 , healthy control subjects, Control), G 2 ( N 2 =36 , early mild cognitive impairment, EMCI), G 3 ( N 3 =36 , late mild cognitive impairment, LMCI) and G 4 ( N 4 =36 , AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs EMCI), stage II (Control vs LMCI) and stage III (Control vs AD). The group comparisonwas performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were three-fold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process.Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario. Progressive brain disconnection in AD 1.IntroductionAlzheimer's disease (AD), the most common form of dementia, is a chronically progressive neurodegenerative disease highly correlated to aging; indeed, although the prevalence of clinically manifested AD is about 2% at the age of 65 years, it increases to 30% at the age of 85 years (Wimo et al. 1997).AD is characterized by an accumulation of beta-amyloid plaques and neurofibrillary tangles composed of tau amyloid fibrils (Hardy 2006) associated with synapse loss and neurodegeneration leading to long-term memory impairment and other cognitive problems. To date, there is no treatment known to slow down the progression of this disorder.The initial AD pathology develops many years before the cognitive and functional impairments are evident. Different terms have been used to describe this disease-starting condition, including predementia a...

Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative

“…Early pathogenic crosstalk between CSF Ab42 and tau may induce intracellular NFT deposition causing neuronal death, atrophy, and cognitive changes [38]. Network analyses suggest a specific and progressive disconnection of functional and anatomical networks over the course of the disease [103][104][105][106]. Interestingly, some evidence suggests that subtle cognitive impairment occurs before detectable atrophy [164], and this is an area yet to be fully explored.…”

“…The view of AD as a disconnection syndrome in which brain regions become successively disconnected both structurally and functionally during the course of AD disease progression is now well established with considerable evidence to support it [7]. Progressive alterations in brain functional networks were reported in a study, which used diffusion tensor imaging of 20 modules shown to have the best correspondence between structural and functional network modules [103]. Compared to CN participants, early MCI participants showed no significant differences in functional connectivity, but late MCI participants differed in the con-nectivity of a memory function subnetwork (module 18), and AD participants had widespread disconnection affecting the same memory subnetwork in addition to the DMN, medial visual network, sensorimotor network, subcortical networks, and others (Fig.…”

“…Compared to CN participants, early MCI participants showed no significant differences in functional connectivity, but late MCI participants differed in the con-nectivity of a memory function subnetwork (module 18), and AD participants had widespread disconnection affecting the same memory subnetwork in addition to the DMN, medial visual network, sensorimotor network, subcortical networks, and others (Fig. 22) [103]. Increasing disconnection throughout AD disease progression was also observed using another measure of whole-brain functional network organization, eigenvector centrality, which was decreased in important nodes of the hippocampal network in progressive compared to stable MCI participants [104].…”

“…Abbreviations: AD, Alzheimer's disease; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment. Reproduced with permission from Rasero et al [103].…”

The Long-Term Effects of Acupuncture on Hippocampal Functional Connectivity in aMCI with Hippocampal Atrophy: A Randomized Longitudinal fMRI Study

“…An fMRI study also demonstrated significant alteration of connectivity patterns in a memory-related subnetwork, including part of the HP, amygdala, fusiform gyrus, ITG, and MTG at the late stage of MCI and the deficits propagated to the rest of the brain as disease progressed. [23] Granger causality analysis revealed that directed FC between the HP and the temporal lobe, frontal lobe, and cingulate cortex were significantly changed in MCI [24]. On the other hand, increased spontaneous brain activities and FC have also been revealed in the frontal and temporal cortex in aMCI patients [25,26].…”