Brain network connectivity differs in early-onset neurodegenerative dementia

Abstract

Objective: To investigate functional brain network architecture in early-onset Alzheimer disease (EOAD) and behavioral variant frontotemporal dementia (bvFTD).

Methods: Thirty-eight patients with bvFTD, 37 patients with EOAD, and 32 age-matched healthy controls underwent 3D T1-weighted and resting-state fMRI. Graph analysis and connectomics assessed global and local functional topologic network properties, regional functional connectivity, and intrahemispheric and interhemispheric between-lobe connectivity.

Results: Despite similarly extensive cognitive impairment relative to controls, patients with EOAD showed severe global functional network alterations (lower mean nodal strength, local efficiency, clustering coefficient, and longer path length), while patients with bvFTD showed relatively preserved global functional brain architecture. Patients with bvFTD demonstrated reduced nodal strength in the frontoinsular lobe and a relatively focal altered functional connectivity of frontoinsular and temporal regions. Functional connectivity breakdown in the posterior brain nodes, particularly in the parietal lobe, differentiated patients with EOAD from those with bvFTD. While EOAD was associated with widespread loss of both intrahemispheric and interhemispheric functional correlations, bvFTD showed a preferential disruption of the intrahemispheric connectivity.

Conclusions: Disease-specific patterns of functional network topology and connectivity alterations were observed in patients with EOAD and bvFTD. Graph analysis and connectomics may aid clinical diagnosis and help elucidate pathophysiologic differences between neurodegenerative dementias.

Figure 1. Graph analysis properties of brain lobar networks in healthy controls (HC), patients with behavioral variant of frontotemporal dementia (bvFTD), and patients with early-onset Alzheimer disease (EOAD)

Mean values of nodal strength (A), path length (B), local efficiency (C), and clustering coefficient (D) of each brain lobe for HC, patients with EOAD, and patients with bvFTD. Error bars are shown. *p < 0.05 in patients with EOAD vs HC; °p < 0.05 in patients with bvFTD vs HC; †p < 0.05 in patients with EOAD vs patients with bvFTD (see table e-3 for further details). The direct comparison between patients with EOAD and patients with bvFTD was adjusted for Mini-Mental State Examination scores.

Figure 2. Intralobar and interlobar connectivity weights (LCW) in healthy controls (HC), patients with behavioral variant of frontotemporal dementia (bvFTD), and patients with early-onset Alzheimer disease (EOAD)

The figure shows the lobar regions arranged as a ring (the size of the regions being proportional to the number of brain nodes included; see table e-1 for further details). Red lines indicate decreased LCW in patients with EOAD relative to HC, patients with bvFTD relative to HC, and patients with EOAD relative to patients with bvFTD. Black lines indicate increased LCW in patients with bvFTD compared with HC. The direct comparison between patients with EOAD and patients with bvFTD was adjusted for Mini-Mental State Examination scores. Front-ins = frontoinsular; OCC = occipital; PAR = parietal; Sensmot = sensorimotor; TEMP = temporal.

Figure 3. Affected functional connections in patients with early-onset Alzheimer disease (EOAD) and patients with behavioral variant of frontotemporal dementia (bvFTD) relative to healthy controls (HC) and each other (network-based statistic)

Subnetworks show reduced functional connectivity in (A) patients with EOAD relative to HC, (B) patients with bvFTD relative to HC, and (C) patients with EOAD relative to patients with bvFTD. The direct comparison between patients with EOAD and patients with bvFTD was adjusted for Mini-Mental State Examination scores. The principal connected component is represented in red; the other affected connections not included in the principal connected component are shown in green. Table e-1 reports the names of each brain node with the corresponding number. A = anterior; P = posterior.