A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity

Abstract

Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimer's type (DAT). The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI) at the group level, but there are very few Magnetoencephalography (MEG) studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links) that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT.

Epileptic activity in Alzheimer's disease: causes and clinical relevance

“…85 Additionally, resting-state MEG has shown network hypersynchronisation across multiple frequency bands in frontoparietal and interhemispheric networks in patients with amnestic mild cognitive impairment. 86 …”

Healthy and Pathological Brain Aging: From the Perspective of Oscillations, Functional Connectivity, and Signal Complexity

“…Pathological aging is characterized by early synaptic disruption and synaptic loss that lead to white-matter abnormalities, anatomofunctional connectivity deficits and progressive cognitive decline [29, 57-60]. This is known to be related to the magnitude and spatial distribution of intracellular aggregates of tau protein filaments (neurofibrillary tangles) and the extracellular deposition of Aβ peptides (amyloid plaques) [29, 57].…”

“…Thus, recent studies have looked at neuronal network organization in cognitively normal elderly subjects and in patients with AD, and its association with disease biomarkers. In addition to abnormalities in alpha source oscillatory activity, disruption in functional connectivity in the alpha band is reported in biomarker-positive elderly subjects who progress to AD and in patients who have developed the disease [57, 60-62]. Rossini et al [61] reported the changes of cortical connectivity and LORETA sources of EEG rhythms between the baseline (i.e., at the time of MCI diagnosis) and follow-up (approx.…”

“…A hypersynchronization pattern in MCI patients was also found in a recent blinded, multicenter MEG study. This functional connectivity abnormality was interpreted as an early sign of synaptic disruption, and a possible preclinical biomarker for early stage AD before a global cortical disconnection emerged with the progression of the disease [60]. Others have reported a decreased alpha functional connectivity within DMN regions in patients with MCI.…”

Dynamic Causal Modeling of Preclinical Autosomal-Dominant Alzheimer’s Disease

“…of the disease [4,5]. For example, in individuals with mild cognitive impairment (MCI), reductions in sensor-space N400 (see below) or P600 word repetition effects are associated with greater likelihood of subsequent transition to AD dementia [6].…”