Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

Abstract

Centres of Excellence in Neurodegeneration.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…These regions are highly anatomically congruent with atrophy patterns found in C9orf72 ‐associated frontotemporal dementia 45, 47, 48, 49, 50. Notably, several studies confirmed that the medial thalamus is a region affected across C9orf72 expansion carriers,50 even during the presymptomatic phase 23, 36, 46. Interestingly, our subgroup analysis of presymptomatic carriers showed that higher NfL levels were associated with smaller bilateral frontoparietal and caudate volumes, which may indicate that these regions are among the earliest regions of neurodegeneration, but longitudinal presymptomatic studies are needed to test this hypothesis.…”

“…In parallel with the ROI analysis, the voxel‐wise analysis showed that certain sparse regions of lower grey matter volumes tended to associate with higher poly(GP), which included regions in the bilateral dorsolateral prefrontal, medial frontal, and lateral temporal cortices. Although higher poly(GP) levels showed a relatively weak association with lower grey matter volumes in our analyses, the regions identified include those atrophied in C9orf72‐ associated FTD patients,45, 47, 48, 49 and show reduced volume in presymptomatic C9orf72 expansion carriers 23, 36…”

“…Similarly, previous studies show no correlation between poly(GP) and NfL,14 nor neurofilament heavy chain (a different neurofilament subunit) in C9orf72 ‐associated ALS 20. Because previous studies have shown lower grey matter volumes in both presymptomatic and symptomatic carriers compared to controls,23, 36, 45, 46 we had hypothesized that higher levels of poly(GP) might be associated with lower grey matter volumes in C9orf72 ‐targeted regions. We found a trend toward higher poly(GP) with lower frontal and cingulate volume in our ROI analysis.…”

“…MRI images were analyzed using two methods: region of interest (ROI) analysis and voxel‐based morphometry (VBM). For ROI analysis, scans were parcellated into brain regions as previously described,23 using an atlas propagation and label fusion strategy,24 combining bilateral ROIs to calculate grey matter cortical (frontal, temporal, parietal, occipital, cingulate, insular), subcortical (hippocampus, amygdala, caudate, putamen, thalamus), and cerebellar volumes 25, 26. Whole brain volumes were calculated by combining all grey and white matter regions extracted from the automated brain segmentation method.…”

Cardiac responses to viewing facial emotion differentiate frontotemporal dementias

“…Larger patient cohorts representing a wider range of neurodegenerative pathologies and with additional psychophysiological markers would increase power to detect physiological disease signatures; ultimately, this will require histopathological and molecular correlation. There are successful precedents for large, multi‐center studies of FTD syndromes informed by proof‐of‐principle work in intensively phenotyped patient cohorts 45. Experiments to parse the roles played by sympathetic and parasympathetic nervous systems, and the relative contribution of more basic indices of psychophysiological reactivity (such as startle and orienting responses) would further elucidate the neurobiological basis for deficits in FTD.…”