Mathematical modeling reveals the correlates of cognitive impairment across the FTLD spectrum

Abstract Background Amyotrophic lateral sclerosis (ALS), and behavioral variant frontotemporal dementia (bvFTD) lie on a continuum. The study aim was to apply mathematical modeling to unravel MRI connectomic signatures of cognitive/behavioral impairment in ALS. Method Eighty‐three ALS, 35 bvFTD and 61 controls underwent clinical/cognitive evaluations and MRI scan. Neuropsychological testing identified 54 ALS with only motor deficits (ALS‐motor), 21 ALS with cognitive/behavioral impairment (ALS‐ci/bi) and 8 ALS with bvFTD (ALS‐FTD). Structural and functional connectivity values were considered and normalized relative to controls. Statistical distribution analysis was performed between patient groups. Result Compared to ALS‐motor, bvFTD showed greater structural disruption within and between frontal, temporal and parietal lobes. Conversely, ALS‐motor showed a greater damage within sensorimotor–basal ganglia connections relative to bvFTD. ALS‐ci/bi and ALS‐FTD showed an ALS‐like pattern within motor areas, whereas a bvFTD‐like pattern was found only within the parietotemporal connections in ALS‐ci/bi and within frontal and frontal‐sensorimotor connections in ALS‐FTD. Functionally, bvFTD showed decreased functional connectivity in frontotemporal and sensorimotor‐parietal connections compared to ALS‐motor. ALS‐ci/bi showed enhanced functional connectivity relative to bvFTD in the frontal‐sensorimotor, parietotemporal connections and within sensorimotor areas, while ALS‐FTD showed reduced functional connectivity in temporal‐sensorimotor connections compared to ALS subgroups. Conclusion Two characteristic patterns were identified: alterations of the frontotemporal and parietal networks as bvFTD‐like, and a more focal damage within sensorimotor‐basal ganglia areas as ALS‐like, bringing to light features that ALS‐ci/bi and ALS‐FTD shared with the two ends of ALS‐bvFTD spectrum. The Italian Ministry of Health (GR‐2011‐02351217; GR‐2013‐02357415; RF‐2011‐02351193), AriSLA (ConnectALS), European Research Council (StG‐2016_714388_NeuroTRACK).