How well does the CSF inform upon pathology in the brain in Creutzfeldt-Jakob and Alzheimer's diseases?

Analysis of lumbar cerebrospinal fluid (CSF) plays a major role in the inve stigation of central nervous system disease, but how well do the changes in the CSF reflect pathology within the brain and spinal cord parenchyma? Bot h Creutzfeldt-Jakob (CJD) and Alzheimer's disease (AD) are characterized by the deposition of insoluble beta -pleated sheet peptides [prion protein (P rP) and beta -amyloid (A beta), respectively] in the extracellular spaces o f grey matter in the brain, but there is discordance in both diseases betwe en the peptide le, els in the brain and in the CSF, Experimental studies us ing tracers have shown that interstitial fluid (ISF) drains through very na rrow intercellular spaces within grey matter into bulk flow perivascular ch annels that surround penetrating arteries. ISF then flows to the surface of the brain and joins CSF to drain to cervical lymph nodes. Such drainage of ISF and CSF to regional lymph nodes in the rat plays a significant role in B-cell and T-cell immune reactions within the brain. In man, the pia mater separates the periarterial ISF drainage pathways from the CSF in the subar achnoid space. The almost complete lack of insoluble protease-resistant PrP entering the CSF from the brain in patients with CJD, reported by Wong et al. in this issue of the Journal of Pathology, illustrates the limitations of ISF drainage pathways for the elimination of insoluble peptides from bra in tissue. Insoluble A beta accumulates in the extracellular spaces as plaq ues in AD and in periarterial ISF drainage pathways as cerebral amyloid ang iopathy. Soluble A beta appears to become entrapped by the insoluble All in the ISF drainage pathways; thus, as the level of soluble A beta in the bra in rises in AD, the level in the CSF falls. Thus, the changes in the CSF do not accurately reflect the accumulation of the abnormal peptides in the br ain parenchyma in either CJD or AD, In both diseases, facilitation of ISF d rainage and elimination of PrP and A beta peptides from the extracellular s paces of the brain may lead to practical therapeutic strategies for these d evastating disorders. Copyright (C) 2001 John Wiley & Sons, Ltd.