Abstract
Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.
Highlights
This review explores the role of neuroimaging in characterizing frontotemporal pathology in motor neuron diseases (MNDs)
Primary Lateral Sclerosis is an upper motor neuron disorder that typically presents with insidious spino-bulbar spasticity in adulthood [27, 90]
Extra-motor manifestations are increasingly recognized in primary lateral sclerosis (PLS) [83, 91], occurring in a similar behavioral and cognitive profile to amyotrophic lateral sclerosis (ALS) [83], and rarely fulfilling the diagnostic criteria for FTD [83, 91]
Summary
This review explores the role of neuroimaging in characterizing frontotemporal pathology in motor neuron diseases (MNDs). While frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) (Table 1), it is relatively under evaluated in other MND phenotypes, such as primary lateral. There are synergistic efforts to evaluate frontotemporal disease burden using computational imaging in combination with clinical instruments. In parallel, these advances help to advance our understanding of disease pathology, propagation patterns, and the dynamics of anatomical spread. The objective of this review is to collate evidence from robust neuroimaging studies, distill emerging research trends, identify pertinent gaps in the literature, highlight clinical implications, and postulate research priorities in the evaluation of frontotemporal pathology across the spectrum of MND phenotypes
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