Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia

ObjectiveAccumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolic waste from the brain, whereas the underlying mechanism on the interplay between impairments in glymphatic clearance and PPA is poorly understood. Therefore, the aim of this study is to investigate the role that dysregulated macroscopic cerebrospinal fluid (CSF) movement plays in the pathology of PPA. Methods56 PPA patients and 94 healthy controls (HCs) participated this work. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow within the subarachnoid space and ventricular system was calculated by using Pearson correlation and made comparison between the two groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were also quantified. ResultsThe PPA group exhibited decreased global BOLD and CSF coupling as compared to that of HCs, indicating impaired glymphatic functions of the patients (p = 0.006). More importantly, it was discovered that BOLD-CSF coupling of PPA group rather than that of the HCs demonstrated significant correlations with the CDR scores (p = 0.04), hippocampal volume (p = 0.005), and entorhinal cortex thickness (p = 0.04). InterpretationThe measured decoupling between global brain activation (hemodynamic response) and CSF flow and its association with symptomology and brain structural changes in PPA revealed the glymphatic dysregulation in PPA. Herein, this evidence supports the potential role of BOLD-CSF coupling as a noninvasive biomarker for the detection and prediction of PPA.