Alzheimer’s Disease Projection From Normal to Mild Dementia Reflected in Functional Network Connectivity: A Longitudinal Study

Spontaneous fluctuations are a hallmark of recordings of neural signals, emergent over time scales spanning milliseconds and tens of minutes. However, investigations of intrinsic brain organization based on resting-state functional magnetic resonance imaging have largely not taken into account the presence and potential of temporal variability, as most current approaches to examine functional connectivity (FC) implicitly assume that relationships are constant throughout the length of the recording. In this work, we describe an approach to assess whole-brain FC dynamics based on spatial independent component analysis, sliding time window correlation, and k-means clustering of windowed correlation matrices. The method is applied to resting-state data from a large sample (n = 405) of young adults. Our analysis of FC variability highlights particularly flexible connections between regions in lateral parietal and cingulate cortex, and argues against a labeling scheme where such regions are treated as separate and antagonistic entities. Additionally, clustering analysis reveals unanticipated FC states that in part diverge strongly from stationary connectivity patterns and challenge current descriptions of interactions between large-scale networks. Temporal trends in the occurrence of different FC states motivate theories regarding their functional roles and relationships with vigilance/arousal. Overall, we suggest that the study of time-varying aspects of FC can unveil flexibility in the functional coordination between different neural systems, and that the exploitation of these dynamics in further investigations may improve our understanding of behavioral shifts and adaptive processes.

Alzheimer's disease is a chronic illness with long preclinical and prodromal phases (20 years) and an average clinical duration of 8-10 years. The disease has an estimated prevalence of 10-30% in the population >65 years of age with an incidence of 1-3%. Most patients with Alzheimer's disease (>95%) have the sporadic form, which is characterized by a late onset (80-90 years of age), and is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. A large number of genetic risk factors for sporadic disease have been identified. A small proportion of patients (<1%) have inherited mutations in genes that affect processing of Aβ and develop the disease at a much younger age (mean age of ∼45 years). Detection of the accumulation of Aβ is now possible in preclinical and prodromal phases using cerebrospinal fluid biomarkers and PET. Several approved drugs ameliorate some of the symptoms of Alzheimer's disease, but no current interventions can modify the underlying disease mechanisms. Management is focused on the support of the social networks surrounding the patient and the treatment of any co-morbid illnesses, such as cerebrovascular disease.