Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers

Abstract

Mutations in progranulin ( GRN ) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN , in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN -associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 “presymptomatic” clinically normal and three “prodromal” with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

Striatal connectivity in pre‐manifest Huntington’s disease is differentially affected by disease burden

“…[26] reported a significant increase of neuronal activity in the dorsomedial striatum of pre‐HD mice, which disappeared as soon as the motor symptoms became manifest. Similar compensatory mechanisms have been described in pre‐clinical progranulin mutation carriers [9]. However, no significant associations between caudate nucleus FC and cognitive functioning were reported, indirectly supporting the idea that compensation is likely to be effective at the behavioral level.…”

“…These mechanisms have also been reported in several neurodegenerative diseases, such as Alzheimer's disease and frontotemporal dementia. Specifically, compensatory responses have been linked to increased brain connectivity in pre-clinical/ mild stages, when brain functional organization might be relatively resilient to the incoming structural damage [7][8][9]. By contrast, progressive degeneration in the Alzheimer's disease/frontotemporal dementia continuum is associated with an early breakdown of functional connections, related to disease severity [10,11].…”

Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice

“…For the clinician this might be curious as neurodegeneration in the frontal, temporal, and parietal lobes is widely recognized as driving clinical symptoms across FTLD syndromes. However, a recent study in preclinical GRN carriers found prominent hyperconnectivity between the thalamus and cortical hub regions in several intrinsic connectivity networks, assessed by functional magnetic resonance imaging [25]. The implications of these findings are not fully clear, but abnormal thalamic physiology, which is robustly demonstrated in FTD-GRN mouse models either through histology or electrophysiology, may have important implications for the earliest changes in human FTD-GRN.…”

Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

“…38 Additionally, including functional neuroimaging, measures in future studies possibly provide new insights into the temporal biomarker sequence and underlying disease mechanism as well. Recent papers have addressed functional changes in FTD-GRN, showing thalamic-cortical hyperconnectivity in early preclinical stages 39 and presymptomatic abnormalities in neurophysiology. 40 A minor limitation in our study is the difference in mean age between the non-carrier, presymptomatic and symptomatic mutation carrier groups.…”