ERP generator anomalies in presymptomatic carriers of the Alzheimer's disease E280A PS‐1 mutation

Abstract

Although subtle anatomical anomalies long precede the onset of clinical symptoms in Alzheimer's disease, their impact on the reorganization of brain networks underlying cognitive functions has not been fully explored. A unique window into this reorganization is provided by presymptomatic cases of familial Alzheimer's disease (FAD). Here we studied neural circuitry related to semantic processing in presymptomatic FAD cases by estimating the intracranial sources of the N400 event-related potential (ERP). ERPs were obtained during a semantic-matching task from 24 presymptomatic carriers and 25 symptomatic carriers of the E280A presenilin-1 (PS-1) mutation, as well as 27 noncarriers (from the same families). As expected, the symptomatic-carrier group performed worse in the matching task and had lower N400 amplitudes than both asymptomatic groups, which did not differ from each other on these variables. However, N400 topography differed in mutation carrier groups with respect to the noncarriers. Intracranial source analysis evinced that the presymptomatic-carriers presented a decrease of N400 generator strength in right inferior-temporal and medial cingulate areas and increased generator strength in the left hippocampus and parahippocampus compared to the controls. This represents alterations in neural function without translation into behavioral impairments. Compared to controls, the symptomatic-carriers presented a similar anatomical shift in the distribution of N400 generators to that found in presymptomatic-carriers, albeit with a larger reduction in generator strength. The redistribution of N400 generators in presymptomatic-carriers indicates that early focal degeneration associated with the mutation induces neural reorganization, possibly contributing to a functional compensation that enables normal performance in the semantic task.

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

“…Ochoa et al [8] have found increases in effective connectivity, assessed using information theoretic measures, in the same PreC group during encoding of scene information. This same Colombian kindred has been studied [9] with high-density EEG while performing a picture matching task, in which a first picture provided context and a second picture either matched or did not match that context. This paradigm elicited a characteristic change in the EEG signal-between matching and non-matching trials-400 ms after the presentation of the second picture, the so-called "N400".…”

“…They found smaller N400 s in right inferotemporal cortex and increased N400 s in left hippocampus and parahippocampus. This paper uses dynamic causal modeling (DCM) [10] to identify the changes in brain connectivity that cause the ERP effects observed in the Bobes et al [9] study. One of the motivations for revisiting this data is that it was acquired in 1999 and since then, follow-up cognitive assessments have periodically been made of subjects with the PSEN1 mutation.…”

“…Subjects with a history of neurological or psychiatric illness were excluded from the study. See [9] for a complete description of study inclusion and exclusion criteria. Each participant gave their informed consent according to a protocol approved by the Human Subjects Committee of the University of Antioquia.…”

“…Additionally, we only use subjects referred to in Bobes et al [9] who had data recorded using a 120-electrode EEG system (see below). This was thought necessary to obtain accurate estimates of brain connectivity parameters.…”

“…This was thought necessary to obtain accurate estimates of brain connectivity parameters. In the original study [9], there were 16 NonC and 17 PreC. Unfortunately, original epoched EEG data from 5 subjects were stored on DVDs which were corrupted since the original data acquisition.…”