Abstract
Ventriculomegaly (expansion of the brain’s fluid-filled ventricles), a condition commonly found in the aging brain, results in areas of gliosis where the ependymal cells are replaced with dense astrocytic patches. Loss of ependymal cells would compromise trans-ependymal bulk flow mechanisms required for clearance of proteins and metabolites from the brain parenchyma. However, little is known about the interplay between age-related ventricle expansion, the decline in ependymal integrity, altered periventricular fluid homeostasis, abnormal protein accumulation and cognitive impairment. In collaboration with the Baltimore Longitudinal Study of Aging (BLSA) and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we analyzed longitudinal structural magnetic resonance imaging (MRI) and subject-matched fluid-attenuated inversion recovery (FLAIR) MRI and periventricular biospecimens to map spatiotemporally the progression of ventricle expansion and associated periventricular edema and loss of transependymal exchange functions in healthy aging individuals and those with varying degrees of cognitive impairment. We found that the trajectory of ventricle expansion and periventricular edema progression correlated with degree of cognitive impairment in both speed and severity, and confirmed that areas of expansion showed ventricle surface gliosis accompanied by edema and periventricular accumulation of protein aggregates, suggesting impaired clearance mechanisms in these regions. These findings reveal pathophysiological outcomes associated with normal brain aging and cognitive impairment, and indicate that a multifactorial analysis is best suited to predict and monitor cognitive decline.
Highlights
The human brain’s ventricular system is essential for the movement of nutrient-rich cerebrospinal fluid (CSF) throughout the central nervous system, providing trophic support of brain function via a wide array of vitamins, growth factors, peptides and nucleosides (Johanson et al, 2008)
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Baltimore Longitudinal Study of Aging (BLSA), we investigated the relationships among the following variables: ventricle expansion, Periventricular hyperintensities (PVH), periventricular white matter tract integrity and degree of cognitive impairment
The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)
Summary
The human brain’s ventricular system is essential for the movement of nutrient-rich cerebrospinal fluid (CSF) throughout the central nervous system, providing trophic support of brain function via a wide array of vitamins, growth factors, peptides and nucleosides (Johanson et al, 2008). Ventricular Anomalies: Aging and Dementia ependymal cells allows for the movement of CSF nutrients into the brain parenchyma as well as clearance of proteins and metabolites from the interstitial fluid (ISF; Johanson et al, 2008, 2011; Del Bigio, 2010). Ventricle expansion rates correlate strongly with declining cognitive performance (Carmichael et al, 2007; Nestor et al, 2008; Grimm et al, 2012; Madsen et al, 2015) and the rate of ventricle volume increase has been linked to an increase in Alzheimer’s disease (AD)-related amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (Silbert et al, 2003), as well as alterations in CSF biomarker composition Together, these point towards defective CSF-ISF exchange and impaired clearance mechanisms that are characteristic of AD (Ott et al, 2010; van Waalwijk van Doorn et al, 2017). Due to the rarity of longitudinal MRI data sets and associated subject-matched periventricular tissue biospecimens, this has never been directly demonstrated
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