Longitudinal multimodal MRI as prognostic and diagnostic biomarker in presymptomatic familial frontotemporal dementia

Abstract

Developing and validating sensitive biomarkers for the presymptomatic stage of familial frontotemporal dementia is an important step in early diagnosis and for the design of future therapeutic trials. In the longitudinal Frontotemporal Dementia Risk Cohort, presymptomatic mutation carriers and non-carriers from families with familial frontotemporal dementia due to microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations underwent a clinical assessment and multimodal MRI at baseline, 2-, and 4-year follow-up. Of the cohort of 73 participants, eight mutation carriers (three GRN, five MAPT) developed clinical features of frontotemporal dementia ('converters'). Longitudinal whole-brain measures of white matter integrity (fractional anisotropy) and grey matter volume in these converters (n = 8) were compared with healthy mutation carriers ('non-converters'; n = 35) and non-carriers (n = 30) from the same families. We also assessed the prognostic performance of decline within white matter and grey matter regions of interest by means of receiver operating characteristic analyses followed by stepwise logistic regression. Longitudinal whole-brain analyses demonstrated lower fractional anisotropy values in extensive white matter regions (genu corpus callosum, forceps minor, uncinate fasciculus, and superior longitudinal fasciculus) and smaller grey matter volumes (prefrontal, temporal, cingulate, and insular cortex) over time in converters, present from 2 years before symptom onset. White matter integrity loss of the right uncinate fasciculus and genu corpus callosum provided significant classifiers between converters, non-converters, and non-carriers. Converters' within-individual disease trajectories showed a relatively gradual onset of clinical features in MAPT, whereas GRN mutations had more rapid changes around symptom onset. MAPT converters showed more decline in the uncinate fasciculus than GRN converters, and more decline in the genu corpus callosum in GRN than MAPT converters. Our study confirms the presence of spreading predominant frontotemporal pathology towards symptom onset and highlights the value of multimodal MRI as a prognostic biomarker in familial frontotemporal dementia.

Figure 1

Study design. A schematic timeline of the 4-year follow-up of presymptomatic mutation carriers, converters and non-carriers within FTD-RisC. Eight mutation carriers converted to clinical FTD within the study window; two between baseline and follow-up after 2 years, and six between follow-up after 2 and 4 years. For the data analysis, the data were restructured into three new time points: 4 years before symptom onset, 2 years before symptom onset, and symptom onset.

Figure 2

Cross-sectional whole brain grey matter volume and white matter integrity differences between converters, non-converters and non-carriers. Maps illustrate significant differences in white matter integrity (fractional anisotropy; left) and grey matter volume (right) between (A) converters and non-converters, and (B) between converters and non-carriers at (i) 4 years before onset; (ii) 2 years before onset; and (iii) at symptom onset. Fractional anisotropy thresholded (P < 0.05) statistical images were thickened using tbss_fill in FSL for better visibility. Colour bars represent P-values.

Figure 3

Longitudinal whole brain grey matter volume and white matter integrity differences between converters, non-converters and non-carriers. Maps illustrate significant differences in white matter integrity (left) and grey matter volume (right) between (A) converters and non-converters and (B) between converters and non-carriers. Fractional anisotropy thresholded (P < 0.05) statistical images were thickened using tbss_fill in FSL for better visibility. Colour bars represent P-values.

Figure 4

Longitudinal trajectories and classification accuracy of white matter integrity decline from the presymptomatic to symptomatic phase. (A) Longitudinal trajectories of white matter integrity (fractional anisotropy, FA) loss (z-score) in the right uncinate fasciculus (UF; top row) and genu of the corpus callosum (gCC; bottom row) in converters, non-converters and non-carriers. Open circles represent GRN converters; filled circles represent MAPT converters. Note that data points for two converters (one MAPT, one GRN) are missing at 4 years before symptom onset, as they converted between baseline and first follow-up, and therefore do not have the 4 years before symptom onset scan available. DTI data were of unsatisfactory quality for one (MAPT) converter 4 years before symptom onset (only uncinate fasciculus), and another (MAPT) converter 2 years before symptom onset (both uncinate fasciculus and genu of the corpus callosum) and were therefore excluded. Data were unavailable at symptom onset for one converter (MAPT) as the scan session was terminated prematurely. (B) Classification between converters, non-converters and non-carriers using the z-score delta fractional anisotropy of the right uncinate fasciculus (top) and the genu of the corpus callosum (bottom). The dashed line represents the optimal cut-off to separate converters and non-converters (uncinate fasciculus: delta fractional anisotropy = −0.51; sensitivity = 100%, specificity = 62.5%; genu of the corpus callosum: delta fractional anisotropy = −0.85; sensitivity = 100%, specificity = 81.3%). The optimal cut-off between converters and non-carriers (not shown) is −0.39 (sensitivity = 100%, specificity = 69.6%) and −0.87 (sensitivity = 100%, specificity = 91.3%) for the uncinate fasciculus and genu of the corpus callosum, respectively. Open circles represent GRN converters; filled circles represent MAPT converters. Note that deltas for two converters (one MAPT, one GRN) are missing, as they converted between baseline and first follow-up, and therefore do not have the 4 years before symptom onset scan available. DTI data of the uncinate fasciculus for one (MAPT) converter were excluded due to unsatisfactory quality.

Figure 5

Within-individual trajectories of clinical and neuroimaging changes in converters. Raw data for each marker were first converted to z-scores by standardization to the baseline data of non-carriers. Each subplot (labelled with the converters number) presents the longitudinal global cognitive, neuropsychological and grey matter neuroimaging values (z-scores, y-axis) from 4 years to symptom onset to symptom onset (x-axis). The grey matter volumes of the most affected hemisphere are displayed (i.e. right side in converters with bvFTD, left side in all converters with nfvPPA). Coloured asterisks denote significant longitudinal decline (≥1 SD) over time. FAB = Frontal Assessment Battery; MMSE = Mini-Mental State Examination.