Connectomic imaging reveals Huntington‐related pathological and pharmaceutical effects in a mouse model

Abstract

Recent studies suggest that neurodegenerative diseases could affect brain structure and function in disease‐specific network patterns; however, how spontaneous activity affects structural covariance network (SC) is not clear. We hypothesized that hyper‐excitability in Huntington disease (HD) disrupts the coordinated structural and functional connectivity, and treatment with memantine helps to reduce excitotoxicity and normalize the connectivity. MRI was conducted to measure somatosensory activation, resting‐state functional‐connectivity (rsFC), SC, amplitude of low frequency fluctuation (ALFF) and ALFF covariance (ALFFC) in the YAC128 mouse model of HD. We found somatosensory activation was unchanged but the subcortical ALFF was increased in HD mice, indicating subcortical but not cortical hyperactivity. The reduced sensorimotor rsFC but spared hippocampal and default mode networks in the HD mice was consistent with the more pronounced impairment in motor function compared with cognitive performance. The disease suppressed SC globally and reduced ALFFC in the basal ganglia network as well as its anti‐correlation with the default mode network. By comparing these connectivity measures, we found that the originally coupled rsFC‐SC relationship was impaired whereas SC‐ALFFC correlation was increased by HD, suggesting disease facilitated covariation of brain volume and activity amplitude but not neural synchrony. The comparison with mono‐synaptic axonal projection supports the hypothesis that rsFC, but not SC or ALFFC, is highly dependent on structural connectivity under healthy conditions. Treatment with memantine had a strong effect on normalizing the SC and reducing ALFF while slightly increasing other connectivity measures and restoring the rsFC‐SC coupling, which is consistent with its effect on alleviating hyper‐excitability and improving the coordinated neural growth. These results indicate that HD affects the cerebral structure–function relationship which could be partially reverted by NMDA antagonism. These connectivity measures provide unique insights into pathological and pharmaceutical effects in brain circuitry, and could be translatable biomarkers for evaluating drug effect and refining its efficacy.

Animal Functional Magnetic Resonance Imaging: Trends and Path Toward Standardization

“…ALFF and fALFF are low-level parameters. In rodents, they are most commonly used to compare across experimental groups (Yao et al, 2012;Chang et al, 2018;Wen et al, 2018).…”

Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

“…For example, the use of volumetric MRI to assess striatal atrophy is one of the most sensitive imaging biomarkers in HD and, while detected in premanifest HDGCs, may rely on neuronal loss, which therapeutic intervention would precede ideally. DTI, functional MRI, and magnetic resonance spectroscopy may detect pathology at earlier stages than volumetric MRI, and NODDI affords sensitivity and better definition of the underlying neurobiological basis of pathology [19,39,92,93,[131][132][133][134][135]. Thus, using these MRI metrics together could provide interrelated information and may reduce noise inherent to each measure.…”

Multimodal treatment strategies in Huntington’s disease

“…Memantine as a NMDA antagonist can reduce the excitotoxicity and normalize the brain connectivity [94]. Chidambaram, et al reported simultaneous blockade of NMDAR and suppression of PARP activity is necessary to ameliorate immune-excitotoxicity and improve bioenergetics in 3-NP induced neurodegeneration.…”