title: Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis.
abstract: There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-beta peptide (Abeta) from the interstitial-fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimer's disease (AD) or as normal-pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Abeta in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Abeta. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH-AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA. geralds@leland.stanford.edu
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Silverberg
authors.forename: Martha
authors.initials: M
authors.lastname: Mayo
authors.forename: Thomas
authors.initials: T
authors.lastname: Saul
authors.forename: Edward
authors.initials: E
authors.lastname: Rubenstein
authors.forename: Dawn
authors.initials: D
authors.lastname: McGuire
mesh_terms: D000375:Aging / Q000134:cerebrospinal fluid*; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid* / Q000503:physiopathology / Q000628:therapy