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Alzheimer’s disease (AD) is characterized by hallmarks pathological changes in the brain, in particular intracellular aggregates of tau protein filaments (neurofibrillary tangles) and extracellular deposition of beta amyloid peptides (amyloid plaques). Synaptic dysfunction is at the center of cognitive abnormalities in AD, and may precede hallmark pathological abnormalities. Soluble Aβ oligomers and tau fibrilar lesions impair synaptic plasticity and cause synaptic loss leading to a collapse of neural networks relevant for cognition. There is evidence that genetic alterations, including the apolipoprotein E epsilon 4 (APOE-4) mutation, disrupt interneuronal communication and represent important risk factors for developing the disease. All of this supports the notion that AD is best characterized as a disruption of functional and structural integration of neural systems (“disconnection syndrome”) rather than as regionally localized abnormalities.
Purpose: In a previous work using EEG, we identified APOE4-related functional network abnormalities in patients with AD. In this study, we used MEG to determine whether functional connectivity patterns, as an index of synaptic dysfunction, associate with cerebrospinal fluid (CSF) biomarkers (i.e., phospho-tau and amyloid beta -Aβ42- levels) in patients with Mild Cognitive Impairment due to Alzheimer’s disease or prodromal AD. We also assessed correlations of aberrant functional connections with structural connectivity abnormalities and with cognitive deficits.
Methods: Resting-state MEG was recorded in patients with Mild Cognitive Impairment. Neuropyschological tests, including the MMSE and the Recall test were evaluated. Phase-locking value was used to analyze functional connectivity, and diffusion tensor imaging for structural connectivity.
Results: One third of the patients converted to Alzheimer’s disease during a follow-up of 2.5 years. Patients with abnormal CSF phospho-tau and Aβ42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, or medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by phospho-tau associated with impaired axonal integrity of the hippocampal cingulum. Phospho-tau and Aβ42–related connectivity abnormalities correlated with cognitive scores.
Conclusions: 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 fronto-temporal circuits. MEG may represent a potential “non-invasive” tool to detect early synaptic dysfunction associated with AD brain pathology.