Imaging gradual neurodegeneration in a basal ganglia model disease

Abstract

ObjectiveX‐linked dystonia‐parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present.MethodsWe used multimodal structural magnetic resonance imaging (voxel‐based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age‐matched male controls.ResultsVoxel‐based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (−55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (−20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = −0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = −0.649, p = 0.004).InterpretationThis multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome‐rich striatal areas in XDP. ANN NEUROL 2019;86:517–526

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

“…We show for the first time evidence of abnormally high levels of NfL in XDP plasma, reflecting a neurodegenerative process occurring in the brains of patients with XDP, but not in males with presymptomatic XDP or asymptomatic female carriers. Our results are consistent with the knowledge that XDP is a disease of basal ganglia neurodegeneration 1‐4,9 . This adds XDP to the list of atypical parkinsonian syndromes with increased plasma NfL 24,29,30 …”

“…Our results are consistent with the knowledge that XDP is a disease of basal ganglia neurodegeneration. [1][2][3][4]9 This adds XDP to the list of atypical parkinsonian syndromes with increased plasma NfL. 24,29,30 Although NfL may be a nonspecific biomarker of neurodegeneration in XDP, it may still be useful in monitoring disease onset and progression in presymptomatic and symptomatic patients under therapeutic treatment.…”

“…X‐linked dystonia‐parkinsonism (XDP) is a rare neurological disease found predominantly in men with maternal ancestry linked to the island of Panay, Philippines. Dystonic symptoms typically appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum 1‐9 . In the most recent study in 2010, 505 patients with XDP were registered in the Philippines, 312 of which were survivors.…”

“…Dystonic symptoms typically appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. [1][2][3][4][5][6][7][8][9] In the most recent study in 2010, 505 patients with XDP were registered in the Philippines, 312 of which were survivors. The reported prevalence rate in the country overall was 0.31 per 100,000, and for Panay Island, 5.74 per 1,000,000.…”

Dystonia updates: definition, nomenclature, clinical classification, and etiology

“…Several studies suggest that there is no apparent macroscopic degeneration or irregularity in the brain in isolated dystonia (Rostasy et al 2003;Paudel et al 2012Paudel et al , 2016. This is different in forms of dystonia with a neurodegenerative pattern, such as DYT/PARK-TAF1 (Hanssen et al 2019). Neuroimaging studies, on the other hand, have identified more subtle alterations, with respect to cortical thickness and gray matter volume differences in cortical regions, basal ganglia, thalamus, hippocampus, and amygdala in focal dystonia (Tomić et al 2020), as well as for the subthalamic area of the brain stem in myoclonus-dystonia (van der Meer et al 2012).…”