Evidence supporting a causal relationship between CP morphological parameters and dementia risk that is partly mediated by specific brain phenotypes is provided, and it is suggested that the CP parameters may be valuable biomarkers for structural brain aging and dementia.
Abstract
The choroid plexus (CP) plays a crucial role in cerebrospinal fluid secretion and the maintenance of brain homeostasis. Its structure and function have been implicated in the pathogenesis of dementia; however, the longitudinal associations of CP with dementia and structural brain biomarkers remain unclear. This prospective cohort study utilized data from the UK Biobank, including 45,306 participants (mean age, 64 years; 47.2% men) who underwent 3.0 T multiparametric brain MRI scans. CP volume and signal intensity were quantified by FreeSurfer software. Measures of grey or white matter macrostructures or microstructures were derived from structural or diffusion MRI. Dementia outcomes were identified using linkage of hospital admission records or death register. Tests for global and domain-specific cognitive functions were administrated at baseline and follow up. Data were analyzed using Cox proportional hazards, Mendelian randomization, linear mixed-effects models, and mediation models. Advancing age was correlated with increased CP volume (R = 0.49, P < 0.001) and decreased CP signal intensity (R = -0.44, P < 0.001). Meanwhile, greater CP volume was associated with an increased risk of all-cause dementia (hazard ratio, 1.61; 95% confidence interval, 1.32-1.97), while higher CP intensity was correlated with a reduced dementia risk (0.44; 0.36-0.55). Reduced volumes of the hippocampus, amygdala, and nucleus accumbens, increased white matter hyperintensity volume, mean diffusivity, and isotropic compartment volume fraction, and decreased intracellular volume fraction significantly mediated up to 42.9% of these associations. This study provides evidence supporting a causal relationship between CP morphological parameters and dementia risk that is partly mediated by specific brain phenotypes, and further suggests that the CP parameters may be valuable biomarkers for structural brain aging and dementia.
Background Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood. Methods We investigated the relationship between CP volume, glymphatic diffusion, and cognitive performance in 100 memory clinic patients. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used as an imaging proxy of glymphatic diffusion, and CP volume and WMH volume were derived from structural MRI using FastSurfer segmentation. Multivariable linear regression models examined associations between CP volume, ALPS index, and global cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Models were adjusted for age, sex, education, APOE ε4 status, WMH burden and plasma phosphorylated tau (pTau217). Interaction terms tested whether CP structure and glymphatic diffusion jointly influenced cognition. Results Larger CP volume was associated with lower ALPS index after adjustment for demographic and molecular covariates (β = −282.19, p = 0.015). CP volume and ALPS index were not independently associated with MoCA scores; however, a significant interaction between CP volume and ALPS index was observed (β = −13,299.09, p = 0.036). The association between CP volume and cognitive performance depended on DTI-ALPS, such that larger CP volumes were associated with poorer MoCA scores at higher ALPS values, whereas CP volume showed little association with cognition at lower ALPS values. This interaction improved model fit compared with main-effects models (R2 = 0.31). The findings remained significant after adjusting for CSF volume and were replicated using MMSE as the outcome. Plasma pTau217 levels were strongly associated with worse cognition but did not significantly modify the CP-ALPS interaction. Conclusion CP enlargement is associated with glymphatic diffusion, and its relationship with cognitive performance varies across DTI-ALPS index values. These findings suggest that interactions between CSF regulatory systems may correlate with cognitive performance in a state-dependent manner. Notably, higher ALPS values in individuals with enlarged CP may reflect compensatory or altered perivascular fluid dynamics rather than preserved glymphatic function, highlighting the complexity of interpreting diffusion-based markers of brain clearance.
N. Tan, T. Welton, Yi Jayne Tan et al.· Frontiers in Aging Neuroscie...· 0 citations
Standardized acquisition and segmentation, harmonized cognitive assessment, and adequately powered longitudinal studies are needed to establish their independent and predictive value for choroid plexus volume, as the evidence remains limited and methodologically heterogeneous.
Weronika Galus, Patrycja Romaniszyn-Kania, Aleksandra Urantówka et al.· Brain Science· 0 citations
Introduction The choroid plexus (CP) increases in volume across the Alzheimer’s disease (AD) continuum, suggesting its potential as a clearance-related biomarker. However, few studies have examined ante-mortem CP volume in relation to post-mortem AD pathology, the gold standard for diagnosis. Methods Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of ≤ 5 years between imaging and death, were examined. Normalized CP volume (NCPV) was semi-automatically segmented from the lateral ventricles and analyzed using Bayesian linear regression to estimate associations with cognitive impairment (CI), AD pathology, and relevant clinical/demographic data. Results Intermediate and high levels of AD pathology and CI were associated with larger NCPV, whereas female sex was associated with lower NCPV. Subgroup analyses showed larger NCPV in individuals with greater CI despite comparable levels of AD pathology. Discussion These findings link CP enlargement to neuropathologically confirmed AD burden and CI, supporting further investigation of CP structure and function in AD.
Francis A Fernandes, Avyarthana Dey, Andy Ma et al.· The journal of prevention of...· 0 citations
Purpose Vascular dementia (VAD) is the second most common type of dementia worldwide. Therefore, early detection and diagnosis, along with a clear understanding of its pathogenesis are critical for mitigating disease progression. In the present study, we aimed to elucidate the associations of brain volume and iron deposition with VAD based on structural brain and iron content analyses. Methods Fifty-three patients with VAD and 43 control participants were recruited for this study. All participants underwent the Mini-Mental State Examination (MMSE) and brain MRI scans. This study primarily focused on the volume of specific brain regions (assessed using FreeSurfer) and iron deposition (evaluated using quantitative susceptibility mapping [QSM]). Linear regression analysis was also performed. Results Patients with VAD exhibited significant reductions in brain volume in the left putamen (β = −0.342, 95% CI: −0.581 to −0.104), left pallidum (β = −0.099, 95% CI: −0.187 to −0.001), left hippocampus (β = −0.138, 95% CI: −0.271 to −0.004), and right hippocampus (β = −0.235, 95% CI: −0.420 to −0.051). Additionally, significant increases in iron levels were identified in the left (β = 0.006, 95% CI: 0.002 to 0.010) and right (β = 0.005, 95% CI: 0.001 to 0.009) hippocampus. Conclusions These findings indicate that brain volume reduction and increased iron levels in specific regions may be associated with cognitive deficits in patients with VAD.
Jun Yang, Cuiping Bao, Xuehuan Liu et al.· Frontiers in Neuroscience· 0 citations
Background In Alzheimer’s disease (AD), neurovascular unit and blood–brain barrier (BBB) abnormalities are assessed using biologically distinct readouts, often across separate cohorts, complicating interpretation across clinical stages and biomarker domains. Methods We searched major databases (inception to February 7, 2026) for human observational studies quantifying cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor-β (sPDGFRβ), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) Ktrans, or the CSF/serum albumin quotient (QAlb) in cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia groups. Primary contrasts were MCI versus CN, AD dementia versus CN, and AD dementia versus MCI. Outcomes were analyzed separately using standardized mean differences (SMDs) in random-effects models with restricted maximum-likelihood estimation and Hartung–Knapp adjustment. Sensitivity analyses incorporated amyloid/AT (N)-informed biologic anchoring and evidence-tier restrictions where possible. Results We included 24 cross-sectional studies (3,644 participants). Compared to CN, MCI showed higher CSF sPDGFRβ (SMD 0.38, 95% CI 0.03–0.73) and DCE-MRI Ktrans (SMD 0.91, 95% CI 0.09–1.73; highly heterogeneous and based on five studies), whereas the difference for QAlb was smaller (SMD 0.19, 95% CI 0.01–0.37). Stricter etiologic restriction weakened the robustness of MCI-stage estimates, particularly for early AD-specific inferences in cohorts without consistent biomarker confirmation. Tier 1-only pooling was not feasible because biomarker-confirmed MCI-stage evidence was sparse. AD dementia versus CN comparisons showed higher values across all readouts: CSF sPDGFRβ (SMD 0.43, 95% CI 0.12–0.73), Ktrans (SMD 0.90, 95% CI 0.56–1.25; based on four studies), and QAlb (SMD 0.28, 95% CI 0.10–0.45). AD dementia versus MCI comparisons showed no significant pooled differences for CSF sPDGFRβ or QAlb; Ktrans pooling was precluded by insufficient data. Conclusion Pericyte- and BBB-related readouts showed readout-specific, cross-sectional detectability patterns across the AD clinical continuum. Ktrans findings should be considered preliminary because of the small evidence base, and MCI-stage estimates remain limited by etiologic uncertainty. Overall, CSF sPDGFRβ, DCE-MRI Ktrans, and QAlb appear related but non-interchangeable, and the present cross-sectional evidence should not be interpreted as demonstrating temporal priority, within-person progression, or head-to-head biomarker superiority. Systematic review registration PROSPERO, CRD420251142518.
Wenchuan Wang, Hanying Xu, Tong Wu et al.· Frontiers in Aging Neuroscie...· 0 citations
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.
Martina Valletta, D. L. Vetrano, E. Laukka et al.· Annals of Neurology· 0 citations