Lymphatic drainage of the brain and the pathophysiology of neurological disease.

There are no conventional lymphatics in the brain but physiological studies have revealed a substantial and immunologically significant lymphatic drainage from brain to cervical lymph nodes. Cerebrospinal fluid drains via the cribriform plate and nasal mucosa to cervical lymph nodes in rats and sheep and to a lesser extent in humans. More significant for a range of human neurological disorders is the lymphatic drainage of interstitial fluid (ISF) and solutes from brain parenchyma along capillary and artery walls. Tracers injected into grey matter, drain out of the brain along basement membranes in the walls of capillaries and cerebral arteries. Lymphatic drainage of antigens from the brain by this route may play a significant role in the immune response in virus infections, experimental autoimmune encephalomyelitis and multiple sclerosis. Neither antigen-presenting cells nor lymphocytes drain to lymph nodes by the perivascular route and this may be a factor in immunological privilege of the brain. Vessel pulsations appear to be the driving force for the lymphatic drainage along artery walls, and as vessels stiffen with age, amyloid peptides deposit in the drainage pathways as cerebral amyloid angiopathy (CAA). Blockage of lymphatic drainage of ISF and solutes from the brain by CAA may result in loss of homeostasis of the neuronal environment that may contribute to neuronal malfunction and dementia. Facilitating perivascular lymphatic drainage of amyloid-beta (Abeta) in the elderly may prevent the accumulation of Abeta in the brain, maintain homeostasis and provide a therapeutic strategy to help avert cognitive decline in Alzheimer's disease.

Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Abeta from the aging human brain. Sections from 100 aged and AD brains were stained for Abeta by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Abeta in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Abeta, there was an inverse relationship between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Abeta plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Abeta along capillary walls and changes the distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase elimination of Abeta in AD need to consider the effects of CVD on the elimination of Abeta from the aging human brain.