SLC9A6 -Linked Parkinson Syndrome in Female Heterozygotes Is Associated with PET-Detectable Tau Pathology

Background and ObjectivesA previous postmortem study of men with Christianson syndrome, a disorder caused by loss-of-function mutations in the gene SLC9A6, reported a mechanistic link between pathologic tau accumulation and progressive symptoms such as cerebellar atrophy and cognitive decline. This study aimed to characterize the relationships between neuropathologic manifestations and tau accumulation in heterozygous women with SLC9A6 mutation.MethodsWe conducted a multimodal neuroimaging and plasma biomarker study on 3 middle-aged heterozygous women with SLC9A6 mutations (proband 1: mid-50s; proband 2: early 50s; proband 3: mid-40s) presenting with progressive extrapyramidal symptoms. Examinations included 11C-PiB PET; 18F-florzolotau PET; structural MRI; and plasma measures of neurofilament light chain (NfL) polypeptide, glial fibrillary acidic protein, phosphorylated (p)Tau181, Aβ40, and Aβ42. Neuroimaging results of all 3 patients were compared with those of 12 healthy age-matched women (49.8 ± 4.7 years) while plasma biomarker levels of probands 1 and 2 were compared with those of 14 age-matched healthy women (54.1 ± 9.0 years).ResultsProband 1 was diagnosed with Parkinson disease while probands 2 and 3 were diagnosed with atypical parkinsonism. 11C-PiB PET results were negative in all patients. 18F-florzolotau PET revealed focal tau accumulations in all 3 patients, predominantly in the striatum contralateral to motor symptoms. Moreover, greater extrapyramidal symptom severity was associated with higher standardized uptake value ratios (SUVRs) for 18F-florzolotau in the striatum. Multiple comparisons showed significantly higher 18F-florzolotau SUVR values in both the caudate and putamen of proband 1, who exhibited the most severe extrapyramidal signs, while no significant increases in 18F-florzolotau SUVR values were detected in any brain region of probands 2 and 3. Structural MRI revealed slightly lower regional subcortical and gray matter volumes in all patients but not significant after multiple comparisons. Finally, plasma NfL concentration was significantly higher in probands 1 and 2 compared with healthy controls.DiscussionOur 18F-florzolotau PET analysis revealed greater tau accumulation in the striatum of heterozygous women with SLC9A6 mutation associated with worsening extrapyramidal symptom severity. The heterozygosity of loss-of-function SLC9A6 mutations further suggests that tauopathy may be a primary contributor to extrapyramidal signs.