Association of Glymphatic Function With Clinical Characteristics in Patients With Clinical and Asymptomatic Creutzfeldt-Jakob Disease

Abstract

Background and ObjectivesAbnormal glymphatic system–related proteins have been identified in a small-scale pathologic study of patients with Creutzfeldt-Jakob disease (CJD). However, it remains unclear whether glymphatic dysfunction occurs in vivo in patients with CJD and whether this decline begins during the preclinical stage. This study aimed to investigate the relationship between glymphatic dysfunction and clinical characteristics in patients with CJD, as well as potential glymphatic impairment in preclinical CJD.MethodsThis prospective cohort study recruited patients with CJD and healthy controls (HCs) from the Department of Neurology at Xuanwu Hospital, Capital Medical University, Beijing, China, from 2018 to 2022. In addition, a family with preclinical genetic CJD carrying the G114V pathogenic variant was followed over 6 years with 3 evaluations. All participants underwent diffusion tensor imaging along the perivascular space (DTI-ALPS) to measure glymphatic function in vivo and 18F-fludeoxyglucose-PET to identify CJD-related metabolic patterns. Associations between the DTI-ALPS index and Medical Research Council Prion Disease Rating Scale (MRC-PDRS) score were evaluated using multiple linear regression.ResultsWe enrolled 35 patients with CJD (mean age 59.6 ± 10.7 years, 40% female, with the time from onset to glymphatic dysfunction assessment averaging 39% of the total disease course), 28 age-matched and sex-matched HCs, and a family with preclinical genetic CJD consisting of 7 carriers and 7 noncarriers. Patients with CJD exhibited lower DTI-ALPS values compared with HCs (p < 0.001). Partial correlation analyses revealed significant correlations between the DTI-ALPS index and MRC-PDRS score (r = 0.346, p = 0.049) and disease progression (r = −0.468, p = 0.006), but not with disease duration or cognitive severity after adjusting for age and sex. Multivariate linear analysis demonstrated that poorer MRC-PDRS scores (β = 0.702, p = 0.014) were associated with a lower DTI-ALPS index. The DTI-ALPS index of asymptomatic G114V carriers showed no significant difference compared with noncarriers. However, a preclinical CJD case exhibited an 8.2% decrease in the DTI-ALPS index 3.3 years before onset. No significant correlation was found between regional metabolic standardized uptake value ratios and DTI-ALPS index.DiscussionOur study indicates that glymphatic dysfunction is associated with CJD severity and disease progression. Glymphatic dysfunction may occur in the preclinical stage, but these findings should be interpreted with caution because they are based on individual findings.