Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment

Abstract

Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (A␤42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and A␤42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization.

Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

“…Specifically, these areas displayed a hybrid pattern of Tau and Aβ deposits. There are regions in the brain that appear to be in the middle of both functional extreme profiles, and, congruently, previous reports have shown, for instance, reduced and increased functional connectivity in DMN regions associated to abnormal levels of CSF p- Tau and CSF Aβ [37]. Consequently, it is arguable that the hypo- and hyper-functional changes (and their respective partners of Tau and Aβ accumulation) may be integrated in a common and strongly interdependent process.…”

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

“…Interestingly, p-tau-related DMN alpha connectivity deficits were found to be associated with structural connectivity abnormalities, particularly with impaired axonal integrity of the hippocampal cingulum. Overall connectivity abnormalities predicted cognitive impairment [57]. These findings demonstrate that DMN functional and structural connectivity deficits are at the center of neurocognitive aging and neurodegeneration, and underlie AD pathology.…”

“…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].…”

“…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.…”

“…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.…”