Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation.

INTRODUCTION Degraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brain's intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. METHODS Resting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. RESULTS Across multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. CONCLUSIONS The present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may represent a compensatory response to the absence of affective feedback during the planning and execution of behavior. Increased reliance upon prefrontal processes in isolation from subcortical structures appears to be maladaptive and may drive behavioral withdrawal that is commonly observed in later phases of neurodegeneration.