The Emerging Relationship Between Interstitial Fluid–Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep

Erin L. Boespflug, Jeffrey J. Iliff
2018 Biological Psychiatry  
Amyloid β (Aβ) plaques are a key histopathological hallmark of Alzheimer's disease (AD) and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrates that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although
more » ... clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences has shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid (CSF) along a brain-wide network of perivascular pathways recently termed the 'glymphatic' system. Glymphatic function is primarily a feature of the sleeping, rather than the waking brain, and is slowed in the aging and post-traumatic brain. These changes may underlie the diurnal fluctuations in interstitial and CSF Aβ levels observed in both the rodent and human. These and other emerging studies suggest that age-related sleep disruption may be one key factor rendering the aging brain vulnerable to Aβ deposition and the development of AD. If true, sleep may represent a key modifiable risk factor or therapeutic target in the pre-clinical phases of AD. Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid β (Aβ)containing plaques, intracellular neurofibrillary tangles comprised of hyper-phosphorylated tau, and associated progressive cognitive impairment. The determinants of progressive pathology in AD remain incompletely understood, and the failure of recent clinical trials aimed at reducing production or aggregation of Aβ (see(1) for review) has raised doubts about the sufficiency of the "amyloid cascade hypothesis", which postulates that Aβ deposition is the key event initiating the pathogenic processes in AD. Notwithstanding, Aβ deposition measured via the cerebrospinal fluid (CSF) or by Aβ positron-emission tomography (PET) is among the earliest events in the neuropathological cascade characterizing sporadic AD and is considered a key driver of the disease. Alzheimer's-related changes, including regional hypometabolism, cortical and hippocampal atrophy, neuroinflammation, and Aβ and tau aggregation develop over decades prior to the onset of clinical dementia. Accordingly, a "preclinical" phase of AD has been proposed characterized by the presence of Aβ and tau aggregates detectible by CSF-or PET-based measurement prior to onset of clinical symptoms(2, 3), offering a potential window of opportunity for therapeutic intervention. Increasing sleep disruption, slowing clearance of Aβ, and increasing Aβ deposition are each present in the preclinical stage. While each is strongly linked to cognitive decline and AD diagnosis, emerging research suggests that they may be linked biologically ( Figure 1A -B). The glymphatic system is a brain-wide perivascular network that supports the exchange interstitial fluid (ISF) and CSF, facilitating the clearance of interstitial solutes, including Aβ and tau from the brain parenchyma (4-6). Experimental studies demonstrate that glymphatic function is primarily active during sleep (7) , and is impaired in the aging and post-traumatic brain(8-10). In this review we provide a framework for understanding the relationship between Aβ dynamics, sleep, and ISF flow in the context of AD and discuss the potential role that age-related impairment of glymphatic function may play in linking these features in the preclinical phase of AD. Boespflug and Iliff
doi:10.1016/j.biopsych.2017.11.031 pmid:29279202 pmcid:PMC5767516 fatcat:42s7wp2g7jc2flstyxawckh2pm