Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status

Abstract

IntroductionChoroid plexus (CP)-related mechanisms have been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease. In this pilot study, we aimed to elucidate the association between longitudinal changes in CP volume, sex and cognitive impairment.MethodsWe assessed longitudinal changes in CP volume in a cohort of n = 613 subjects across n = 2,334 datapoints from ADNI 2 and ADNI-GO, belonging to cognitively unimpaired (CN), stable mild cognitive impairment (MCI), clinically diagnosed Alzheimer’s disease dementia (AD) or convertor (to either AD or MCI) subgroups. CP volume was automatically segmented and used as a response variable in linear mixed effect models with random intercept clustered by patient identity. Temporal effects of select variables were assessed by interactions and subgroup analyses.ResultsWe found an overall significant increase of CP volume in time (14.92 mm3 per year, 95% confidence interval, CI (11.05, 18.77), p < 0.001). Sex-disaggregated results showed an annual rate of increase 9.48 mm3 in males [95% CI (4.08, 14.87), p < 0.001], and 20.43 mm3 in females [95% CI (14.91, 25.93), p < 0.001], indicating more than double the rate of increase in females, which appeared independent of other temporal variables. The only diagnostic group with a significant CP increase as compared to CN was the convertors group, with an increase of 24.88 mm3/year [95% CI (14, 35.82), p < 0.001]. ApoE exhibited a significant temporal effect, with the E4 homozygote group’s CP increasing at more than triple the rate of non-carrier or heterozygote groups [40.72, 95% CI (25.97, 55.46), p < 0.001 vs. 12.52, 95% CI (8.02, 17.02), p < 0.001 for ApoE E4 homozygotes and E4 non-carriers, respectively], and may have modified the diagnostic group relationship.ConclusionOur results contribute to potential mechanisms for sex differences in cognitive impairment with a novel finding of twice the annual choroid plexus enlargement in females and provide putative support for CP-related mechanisms of cognitive deterioration and its relationship to ApoE E4.

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

“…Our results correspond with previous research on the association of APOE ε4 with the middle temporal lobe, more specifically the entorhinal cortex, amygdala and hippocampus (26, 52). APOE ε4 has also been linked to enlargement of the choroid plexus, a hallmark of LOAD (53). Mediation analysis has been applied previously to study the determinants of LOAD.…”

“…Accumulation of amyloid-β is one of the hallmarks of LOAD and plays a central role in the post-mortem diagnosis of LOAD and in many running theories regarding LOAD pathology (7). The choroid plexus has an important role in the production and removal of amyloid-β, and an enlargement of the choroid plexus has been associated with LOAD and was shown to be modified by APOE ε4 status (53). Possible explanations for the enlargement of the choroid plexus in LOAD were accumulation of amyloid-β and neuroinflammation, though it is not clear whether a larger choroid plexus is cause or consequence (53).…”

“…The choroid plexus has an important role in the production and removal of amyloid-β, and an enlargement of the choroid plexus has been associated with LOAD and was shown to be modified by APOE ε4 status (53). Possible explanations for the enlargement of the choroid plexus in LOAD were accumulation of amyloid-β and neuroinflammation, though it is not clear whether a larger choroid plexus is cause or consequence (53). Enlargement of the choroid plexus is also related to larger inferior ventricles.…”

The Time Trajectory of Choroid Plexus Enlargement in Multiple Sclerosis

“…It is important to note that plexus alterations do not seem to be specific to MS. CP enlargement has also been reported in disease states linked with inflammation such as meningitis, depression, psychosis, schizophrenia, complex regional pain syndrome, epilepsy, ischemic stroke, hypoxia, obesity, as well as in primary neurodegenerative disorders, such as Alzheimer's, frontotemporal dementia, Huntington's disease, and Parkinson disease, as well as normal aging [7,[46][47][48]51,56,[62][63][64][65][66][67][68][69][70][71][72][73][74]. As such, CPV increase does not fulfill the established criteria of either a diagnostic or prognostic marker in MS [75], and up to now, there is no indication that it could replace the current clinical and radiological assessment of disease activity in any form of MS.…”

How Early Is Early Multiple Sclerosis?

“…Therefore, large-scale studies need to be conducted in order to properly assess the prognostic value of choroid plexus enlargement in multiple sclerosis patients. Moreover, choroid plexus enlargement has also been observed in individuals with other disorders, including Alzheimer’s disease, depression, and schizophrenia [ 121 , 122 , 123 ]. Table 1 summarizes all potential predictive biomarkers that could be used for the recognition of RIS progression to definite MS found either via laboratory or neuroimaging techniques, and the currently available research results.…”