Altered Neurofluid Dynamics Markers in Middle-Aged and Older Women With Insomnia: A Multiparametric MR Neuroimaging...

Despite known brain alterations in insomnia-particularly prevalent in older females-how it affects sleep-dependent glymphatic clearance remains understudied due to in vivo human measurement challenges.

To investigate altered neurofluid dynamics in women with insomnia using indirect neuroimaging markers.

Prospective.

46 healthy controls (HC; 56.3 ± 5.5 years) and 28 females with insomnia disorder (ID; 58.2 ± 4.9 years).

3.0 T, 3D T1-weighted magnetization-prepared rapid acquisition gradient echo, resting-state fMRI using gradient-echo echo-planar imaging, and multi-shell diffusion MRI using spin-echo-planar sequence.

(1) Blood oxygen level dependent cerebral spinal fluid (BOLD-CSF) coupling measuring temporal coordination between neurovascular and CSF oscillations, (2) diffusion tensor image analysis along the perivascular space (DTI-ALPS) quantifying directional diffusivity in periventricular white matter, (3) choroid plexus (ChP) volume reflecting morphology of primary CSF-producing structures, and (4) nucleus basalis of Meynert (NBM) volume evaluating cholinergic system integrity potentially relevant to vascular regulation; (5) all participants completed self-reported sleep measures, including the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Fatigue Severity Scale (FSS), and also underwent cognitive function testing.

Analysis of covariance evaluated between-group differences controlling for demographic and clinical covariates. Relationships with cognitive and sleep scores were assessed using partial correlations, stratified by group only when significant interaction effects were detected. Multiple comparisons were false discovery rate corrected (p < 0.05). Classification model performance was evaluated using the area under the receiver operating characteristic curve (AUC). Model comparisons were performed using DeLong's tests (ΔAUC) and stepwise likelihood ratio tests (LRT) to assess classification gain and the independent incremental contribution of each biomarker; all tests were two-sided with α = 0.05.

Compared to controls, insomnia patients showed significantly reduced BOLD-CSF coupling (-0.18 ± 0.20 vs. -0.32 ± 0.17), indicating altered temporal coordination between neurovascular and CSF dynamics. ChP volume was significantly enlarged in the insomnia group (1.72% ± 0.42% vs. 1.55% ± 0.39% of total intracranial volume), potentially reflecting compensatory CSF production upregulation, inflammatory changes, or vascular remodeling. NBM volume was significantly reduced in insomnia patients (201.75 ± 17.66 vs. 217.47 ± 21.04 mm³), suggesting cholinergic system alterations. In contrast, the DTI-ALPS index did not differ between groups (p = 0.85). BOLD-CSF coupling positively correlated with PSQI (r = 0.34), ISI (r = 0.41), and FSS (r = 0.40); ChP volume positively correlated with ISI (r = 0.32) and FSS (r = 0.35) (all FDR-corrected). A dataset consists of 74 participants (46 HC and 28 ID) were included, the four-marker classification model achieved moderate performance (AUC = 0.785, accuracy = 71.9%).

Multiple indirect neuroimaging markers potentially related to neurofluid dynamics were altered in middle-aged and older women with chronic insomnia, except for DTI-ALPS. These findings include altered neurovascular-CSF coordination, ChP enlargement, and cholinergic system volume reduction.

2.

Stage 2.