Abstract
ObjectiveNovel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD).MethodsTwenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ∼1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated.ResultsIn the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: −6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: −7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: −6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: −6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change.InterpretationSerial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials.
Highlights
Demographics, Neuropsychological Performance, and Changes in Whole Brain Volume Demographic and volumetric imaging characteristics of study participants are shown in Table 1; of the 23 behavioral variant frontotemporal dementia (bvFTD) patients, 9 had apparently sporadic bvFTD, having no family history of bvFTD and a negative test for relevant genetic mutations; 8 patients had mutations in microtubule-associated protein tau (MAPT) (5 exon 10 116 mutations, 2 R407W mutations, and 1 P301L mutation); 4 patients had a chromosome 9 open-reading frame 72 (C9ORF72) mutation
The greatest change observed in the bvFTD group was a 30.4% decline in score on the graded naming test compared with a 2% increase in cognitively normal participants (p < 0.001)
Compared with cognitively normal participants, the largest reductions in fractional anisotropy (FA) were within bilateral uncinate fasciculus in MAPT mutation carriers; bilateral paracallosal cingulum bundle in those with sporadic bvFTD, and in right paracallosal cingulum bundle (6.8%/yr, 95% CI 5 211.3 to 2.2%, p 5 0.004) in C9ORF72 mutation carriers
Summary
Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials. Longitudinal magnetic resonance imaging (MRI) has been shown to be a useful biomarker in neurodegenerative diseases, given its wide availability, ease of interpretation, and sensitivity in detecting change (most typically in brain volume) over time. Previous longitudinal imaging studies of bvFTD have used structural MRI to measure rates of whole brain and ventricular change.[3,4,5,6] A limitation of some of these studies has been the tendency to measure rates of whole brain atrophy, rather than regionally based measures This is significant, as whole brain techniques may be insensitive to the focal. Volumetric MRI may miss microstructural damage and may not provide sufficient sensitivity to detect meaningful change in individuals with slowly progressive forms of bvFTD, or in presymptomatic individuals with little macroscopic brain atrophy.[2,7]. We investigate the utility of DTI as a potential biomarker for clinical trials by comparing DTI measures of change with established MRI and neuropsychological measures and estimate sample size requirements for potential future clinical trials
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