Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With GRN Frontotemporal Dementia

Abstract

Background and objectives: Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD-GRN) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD-GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease.

Methods: Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD-GRN. Depending on the side of the asymmetry, we classified symptomatic GRN patients as right-GRN or left-GRN and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain.

Results: A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, p < 0.001) and presymptomatic carriers (1.0, p < 0.001), making it possible to classify most of them as right-GRN (n = 21) or left-GRN (n = 36). Patients with right-GRN showed more disease severity at baseline (β = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year (β = -1.5, 95% CI -2.7 to -0.31, p = 0.015) than patients with left-GRN. Brain asymmetry could be found in GRN carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68).

Discussion: FTD-GRN affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in GRN carriers.

Figure 1. Flowchart Detailing the Participants, Visits, and Procedures of the Study

Figure 2. Asymmetry Index Distribution by Genetic Status

Histograms showing the distribution of asymmetry in noncarriers (upper), presymptomatic carriers (middle), and symptomatic carriers (bottom). Values around 0 reflect no volumetric differences between hemispheres while positive values mean asymmetry due to right atrophy and negative values asymmetry due to left atrophy. The vertical dashed lines indicate the best cutoff values of asymmetry to differentiate symptomatic carriers from controls. Symptomatic carriers below the negative cutoff were classified as left-GRN while those above the positive cutoff were classified as right-GRN. Note that scales differ in the y-axis for the different subplots.

Figure 3. Disease Progression in Patients With Left-GRN and Right-GRN

Evolution of the CDR plus NACC FTLD sum of boxes scores by disease duration in left-GRN (purple) and right-GRN (green) in (A) all symptomatic patients and (B) presymptomatic carriers who converted to left-GRN or right-GRN syndromes during the follow-up. CDR plus NACC FTLD = the Clinical Dementia Rating Scale plus National Alzheimer's Coordinating Center for Frontotemporal Lobar Degeneration.

Figure 4. Asymmetry Index Trajectories

(A) Trajectories of the absolute asymmetry index by the estimated years to onset in GRN pathogenic variant carriers (red) and noncarriers (blue). (B) Distribution of the asymmetry index in presymptomatic carriers who converted during the follow-up.

Figure 5. Models of the Asymmetry Index and Other Onset Biomarkers

Standardized difference between all pathogenic variant carriers and noncarriers in cortical gray matter volumetric imaging measures vs estimated years to expected symptom onset. Individual data points were not plotted to prevent the disclosure of genetic status. The time at which the upper 95% CI for each curve crosses 0 on the y-axis (the point at which a significant difference exists between pathogenic variant carriers and noncarriers) is shown on the x-axis. Individual curves with 95% CIs are presented in eFigures 5 and 6.