Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3

Abstract

BackgroundIn spinocerebellar ataxia type 3 (SCA3), volume loss has been reported in the basal ganglia, an iron-rich brain region, but iron content has not been examined. Recent studies have reported that patients with SCA6 have markedly decreased iron content in the cerebellar dentate, coupled with severe volume loss. Changing brain iron levels can disrupt cognitive and motor functions, yet this has not been examined in the SCAs, a disease in which iron-rich regions are affected.MethodsIn the present study, we used quantitative susceptibility mapping (QSM) to measure tissue magnetic susceptibility (indicating iron concentration), structural volume, and normalized susceptibility mass (indicating iron content) in the cerebellar dentate and basal ganglia in people with SCA3 (n = 10) and SCA6 (n = 6) and healthy controls (n = 9). Data were acquired using a 7T Philips MRI scanner. Supplemental measures assessed motor, cognitive, and mood domains.ResultsPutamen volume was lower in both SCA groups relative to controls, replicating prior findings. Dentate susceptibility mass and volume in SCA6 was lower than in SCA3 or controls, also replicating prior findings. The novel finding was that higher basal ganglia susceptibility mass in SCA6 correlated with lower cognitive performance and greater motor impairment, an association that was not observed in SCA3. Cerebellar dentate susceptibility mass, however, had the opposite relationship with cognition and motor function in SCA6, suggesting that, as dentate iron is depleted, it relocated to the basal ganglia, which contributed to cognitive and motor decline. By contrast, basal ganglia volume loss, rather than iron content, appeared to drive changes in motor function in SCA3.ConclusionThe associations of higher basal ganglia iron with lower motor and cognitive function in SCA6 but not in SCA3 suggest the potential for using brain iron deposition profiles beyond the cerebellar dentate to assess disease states within the cerebellar ataxias. Moreover, the role of the basal ganglia deserves greater attention as a contributor to pathologic and phenotypic changes associated with SCA.

MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers

“…The excellent depiction of deep grey matter on susceptibility maps also allows for quantification of atrophy of these structures. For instance, atrophy of dentate nuclei has been demonstrated in patients with different ataxias, including SCA6 and FRDA [ 56 , 58 , 59 ]. Consequently, integrating a high spatial isotropic resolution (≤ 1 mm) multi-echo GRE scan into the MRI protocol allows for voxel-based statistics of volumes, susceptibilities, and R2*, opening the door to identifying disease-related patterns.…”

Parkinson's disease and Parkinsonism syndromes: Evaluating iron deposition in the putamen using magnetic susceptibility MRI techniques - A systematic review and literature analysis

“…However, there is a notable absence of comprehensive review articles addressing the specific topic of iron accumulation and deposition in PUT within these disorders. Given that PUT plays a pivotal role in the basal ganglia circuitry, impacting both motor and cognitive functions, it is particularly susceptible to irregular iron regulation and associated neurodegenerative processes [ 3 , 70 , 71 ]. Keeping a close watch on iron levels and neurodegenerative alterations in PUT holds significant importance for gaining insights into the underlying pathophysiology and progression of these conditions [ 72 , 73 ].…”