Hypometabolic and hypermetabolic brain regions in patients with ALS-FTD show distinct patterns of grey and white matter degeneration: A pilot multimodal neuroimaging study

Background: Up to 50% of amyotrophic lateral sclerosis (ALS) patients develop some degree of cognitive dysfunction and a small proportion of these develop frontotemporal dementia (FTD). Non-invasive techniques of magnetic resonance imaging (MRI) and [¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography (PET) have demonstrated structural and metabolic abnormalities, respectively, in the brains of such patients with ALS-FTD. Although initial ¹⁸F-FDG PET studies in ALS patients showed only hypometabolism of motor and extramotor brain regions, subsequent studies have demonstrated hypermetabolic changes as well. Such contrasting findings prompted us to hypothesize that hypo- and hypermetabolic brain regions in ALS-FTD patients are associated with divergent degeneration of structural grey matter (GM) and white matter (WM). Methods: Cerebral glucose metabolic rate (CMR_glc), cortical thickness (CT), fractal dimension (FD), and graph theory WM network analyses were performed on clinical MRI and ¹⁸F-FDG PET images from 8 ALS-FTD patients and 14 neurologic controls to explore the relationship between GM-WM degeneration and hypo- and hypermetabolic brain regions. Results: CMR_glc revealed significant hypometabolism in frontal and precentral gyrus brain regions, with hypermetabolism in temporal, occipital and cerebellar regions. Cortical thinning was noted in both hypo- and hypermetabolic brain areas. Unlike CT, FD did not reveal widespread GM degeneration in hypo- and hypermetabolic brain regions of ALS-FTD patients. Graph theory analysis showed severe WM degeneration in hypometabolic but not hypermetabolic areas, especially in the right hemisphere. Conclusion: Our multimodal MRI-PET study provides insights into potentially differential pathophysiological mechanisms between hypo- and hypermetabolic brain regions of ALS-FTD patients.