Altered functional connectivity in asymptomatic MAPT subjects

Abstract

Objective: To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). Methods:In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. Results:The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Conclusions:Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease. Neurology ® 2011;77:866-874 GLOSSARY AD ϭ Alzheimer disease; BOLD ϭ blood oxygenation level-dependent; bvFTD ϭ behavioral variant frontotemporal dementia; DMN ϭ default mode network; FOV ϭ field of view; FTD ϭ frontotemporal dementia; FWE ϭ familywise error; ICA ϭ independent component analysis; MPRAGE ϭ magnetization-prepared rapid acquisition gradient echo; PPND ϭ pallido-ponto-nigral degeneration; ROI ϭ region of interest; TE ϭ echo time; TIV ϭ total intracranial volume; TR ϭ repetition time.Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder characterized by behavioral and language deficits.1,2 A large proportion of subjects with FTD have an autosomal dominant pattern of inheritance, 3,4 with many showing mutations in the microtubule associated protein tau (MAPT) gene.5 Subjects with mutations in MAPT typically present with behavioral variant FTD (bvFTD), with poor semantic abilities, 6 -8 and show predominant temporal atrophy, with less severe involvement of frontal and parietal lobes.9,10 Families characterized by the presence of mutations in MAPT provide the ideal construct to identify preclinical disease changes. Case studies assessing imaging in asymptomatic MAPT carriers show

Functional MRI in Patients with the C9ORF72 Expansion associate Frontotemporal Dementia

“…However, previous findings associated with the salience network have been somewhat controversial, while both increase and decrease of connectivity have been detected [12,[14][15][16][17][18]20]. The controversial findings in functional connectivity between different mutation carriers may be explained by neuroanatomical and neuropathological differences between the genetically driven disease groups, severity of the disease and small sample size in all genetic studies.…”

“…Until now, only one rfMRI study of genetically determined and clinically affected FTLD patients with mutations in the PGRN has been published and decreased salience network connectivity and increased DMN connectivity was found [15]. The other studies of genetically determined bvFTD have been conducted on presymptomatic patients and the results are contradictory (Table 4) [16,20].…”

“…However, decreased functional connectivity in the salience network has been the most frequent finding in bvFTD. In some studies increased connectivity in the DMN has been observed, but there has been a lot of variation concerning the DMN related findings in bvFTD [12,14,[15][16][17][18].…”

“…Imaging genomics is an emerging field investigating the role of genes in brain function [19]. There are only a few reports available of resting state brain networks using rfMRI in genetically determined FTLD patients or asymptomatic mutation carriers [15,16,20]. These studies have shown that functional changes are present in the brain already before atrophy can be detected on structural MRI and even before symptom onset [15,16,20].…”

“…There are only a few reports available of resting state brain networks using rfMRI in genetically determined FTLD patients or asymptomatic mutation carriers [15,16,20]. These studies have shown that functional changes are present in the brain already before atrophy can be detected on structural MRI and even before symptom onset [15,16,20]. In a small study of clinically affected bvFTD patients with PGRN-mutation a decrease in the salience network connectivity and an increase in the DMN connectivity was detected [15].…”