Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Abstract

Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or "resting-state" analysis, may help to clarify this issue. Using such approaches, alterations in the default-mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting-state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default-mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy.

Keywords: Alzheimer's disease; default mode network; functional connectivity; neuropsychiatric symptoms; salience network.

Figure 1

Box and whiskers plot showing the distribution of NPI syndromes scores: hyperactivity (mean ± SD: 4.05 ± 6.18), apathy (4.25 ± 3.22), affective syndrome (2.50 ± 4.28), and psychosis (1.45 ± 2.41). The box extends from the 25th percentile to the 75th percentile, with a horizontal line at the median. Whiskers extend down to the smallest value and up to the largest.

Figure 2

(A) Dorsal DMN areas of decreased functional connectivity in AD patients (atrophy corrected): right precuneus (MNI coordinates: 6, −66, 24) and left precuneus (−2, −64, 54); P < 0.01, corrected for multiple comparisons. (B) Anterior SN areas of increased connectivity in AD patients (atrophy corrected): right cingulate gyrus (18, 20, 38) and left medial frontal gyrus (−8, 32, 38); P < 0.01, corrected.

Figure 3

Areas of positive correlations between anterior SN and hyperactivity syndrome (atrophy corrected): right ACC (MNI: 8, 28, 18) and right insula (44, 10, −6); P < 0.01, corrected for multiple comparisons.