Glymphatic failure as a final common pathway to dementia

Abstract

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.

Fig. 1.. The brain glymphatic system is a highly organized fluid transport system

(A) The vascular endfeet of astrocytes create the perivascular spaces through which CSF enters the brain and pervades its interstitium. CSF enters these perivascular spaces from the subarachnoid space, and is propelled by arterial pulsatility deep into the brain, from where CSF enters the neuropil, facilitated by the dense astrocytic expression of the water channel AQP4, which is arrayed in nanoclusters within the endfeet. CSF mixes with fluid in the extracellular space and leaves the brain via the perivenous spaces, as well as along cranial and spinal nerves. Interstitial solutes, including protein waste, are then carried through the glymphatic system and exported from the central nervous system via meningeal and cervical lymphatic vessels. (B) Amyloid-ß plaque formation is associated with an inflammatory response, including reactive micro- and astrogliosis with dispersal of AQP4 nanoclusters. An age-related decline in CSF production, the decrease in perivascular AQP4 polarization, gliosis and plaque formation all impede directional glymphatic flow, and thereby impair waste clearance. Of note, vascular amyloidosis might be initiated by several mechanisms. Amyloid-ß might be taken up from the CSF by vascular smooth muscle cells expressing the low-density lipoprotein receptor-related protein 1 (LRP1) (111). Alternatively, amyloid deposition might be initiated by the backflow of extracellular fluid containing amyloid-ß into the periarterial space from the neuropil – rather than proceeding on to the perivenous spaces - due to an increase in hydrostatic pressure on the venous side, or because of an inflammation-associated loss of AQP4 localization to astrocytic endfeet.

Fig. 2.. Sleep architecture in young and old subjects

Hypnograms are constructed from EEG recordings and display the cyclic transitions between sleep stages. The two schematic hypnograms illustrate the sleep architecture of a young and an old subject that transitions spontaneously between awake, REM and NREM (stage 1–3) sleep. Stages 1 NREM sleep is light sleep whereas stage 3 NREM sleep is the deepest sleep stage and characterized by slow wave EEG activity. Deep stage 3 NREM sleep dominates in the early phases of sleep, whereas REM sleep is more frequent in the later phases of sleep in young subjects. Sleep spindles are most frequent in stage 2 NREM sleep. In subjects older than 60 years, sleep is often interrupted by short awake episodes, and older subjects do not typically enter stage 3 NREM sleep; total sleep time decreases by 10 min for each decade of life (79). Blue coloring indicates the proposed efficacy of glymphatic clearance based on data collected in rodents (35, 36). The lack of stage 3 NREM sleep, the frequent interruptions of stage 1–2 NREM sleep, and the shorter total sleep time, all serve to decrease glymphatic activity in aging. Critically, a number of disorders and conditions can suppress glymphatic function during NREM sleep (Fig. 3B), further exacerbating the effects of glymphatic dysfunction in neurodegenerative disease.

Fig. 3.. Prion-like spread of protein aggregates and proposed role of glymphatic transport

(A) Seeding and prion-like spread of protein aggregates (amyloid-ß and tau) in Alzheimer disease, and α-synuclein in Parkinson disease, relative to the distribution of glymphatic influx of a CSF tracer after intrathecal delivery (67). Prion-like spread of protein aggregates includes an extracellular component and thereby the possibility that the seeds are transported by the glymphatic system. (B) In this model, the glymphatic system resides at the intersection of a broad scope of disorders, which share an association with diminished brain fluid clearance. In addition, normal aging is also linked to a sharp decrease in the quality of sleep and in glymphatic flow. In turn, the stagnation of glymphatic flow, and hence that of extracellular proteins, contribute to protein aggregation, with misfolding and seeding, leading in turn to local inflammation, neuronal loss, and ultimately dementia.

Fig. 4.. Arterial pulsatility propels fluid flow in the brain

The brain receives 20–25% of cardiac output, yet comprises ~2% of total body weight. The large caliber arteries of the circle of Willis are positioned in the CSF-containing basal cisterns below the ventral surface of the brain. Arterial pulsatility provides the motive force for CSF transit into the perivascular spaces surrounding the major arteries, while respiration and slow vasomotion contribute to sustaining its flow (112). The anterior (ACA), middle (MCA), and posterior (PCA) arteries transport CSF to the penetrating arteries (insert), from which CSF is then driven into the neuropil via the still-contiguous perivascular spaces. Cardiovascular diseases associated with reduced cardiac output, such as left heart failure and atrial arrhythmias, reduce arterial wall pulsatility, resulting in less CSF flow. In addition, thickening of the arterial wall in small vessel disease, hypertension and diabetes all reduce arterial wall compliance and hence pulsatility. Each of these fundamentally cardiovascular disorders serves to attenuate glymphatic flow, providing a potential causal link between these vascular etiologies and Alzheimer disease (113).