Abstract
ObjectiveImpaired glymphatic waste clearance function during brain aging leads to the accumulation of metabolic waste and neurotoxic proteins (e.g., amyloid-β, tau) which contribute to neurological disorders. However, how the age-related glymphatic dysfunction exerts its effects on different cerebral regions and affects brain waste clearance remain unclear.MethodsWe investigated alterations of glymphatic transport in the aged rat brain using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and advanced kinetic modeling. Healthy young (3–4 months) and aged (18–20 months) male rats (n = 12/group) underwent the identical MRI protocol, including T2-weighted imaging and 3D T1-weighted imaging with intracisternal administration of contrast agent (Gd-DTPA). Model-derived parameters of infusion rate and clearance rate, characterizing the kinetics of cerebrospinal fluid (CSF) tracer transport via the glymphatic system, were evaluated in multiple representative brain regions. Changes in the CSF-filled cerebral ventricles were measured using contrast-induced time signal curves (TSCs) in conjunction with structural imaging.ResultsCompared to the young brain, an overall impairment of glymphatic transport function was detected in the aged brain, evidenced by the decrease in both infusion and clearance rates throughout the brain. Enlarged ventricles in parallel with reduced efficiency in CSF transport through the ventricular regions were present in the aged brain. While the age-related glymphatic dysfunction was widespread, our kinetic quantification demonstrated that its impact differed considerably among cerebral regions with the most severe effect found in olfactory bulb, indicating the heterogeneous and regional preferential alterations of glymphatic function.ConclusionThe robust suppression of glymphatic activity in the olfactory bulb, which serves as one of major efflux routes for brain waste clearance, may underlie, in part, age-related neurodegenerative diseases associated with neurotoxic substance accumulation. Our data provide new insight into the cerebral regional vulnerability to brain functional change with aging.
Highlights
Changes of Glymphatic Transport in the Aged Brain Visualized by Dynamic Contrast-Enhanced Magnetic Resonance Imaging
Our dynamic imaging and kinetic quantification demonstrated a widespread impairment of glymphatic transport in the aged brain, characterized by an overall reduction of both glymphatic influx and efflux compared to the young brain
While the effects of age on the glymphatic function were evident throughout the brain, a distinctive and dramatic decline in both glymphatic infusion rate and clearance rate was detected in olfactory bulb as compared with other cerebral regions, indicating the heterogeneous and regional preferential alterations of glymphatic function with aging
Summary
Aging is accompanied by a wide array of progressive and deteriorating changes in the brain (Peters, 2006; Kirkwood, 2010; Harada et al, 2013) These broad-spectrum and complex changes occur at all levels (e.g., from molecules to morphology), profoundly impacting the structure and function of the brain and cognition. Studies of the glymphatic system show that a large proportion of subarachnoid CSF reenters the brain parenchyma along periarterial spaces, exchanges with the interstitial fluid (ISF) and exits the brain along peri-venous spaces (Iliff et al, 2012, 2013) This process, supported by astrocytic aquaporin-4 (AQP4) water channels, facilitates removal of metabolic waste products (Jessen et al, 2015; Mestre et al, 2018). How the age-related glymphatic dysfunction exerts its effects on different cerebral regions and affects brain waste clearance remain unclear
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