title: Blood-cerebrospinal fluid barrier dysfunction for high molecular weight proteins in Alzheimer disease and major depression: indication for disease subsets.
abstract: There is a diversity of opinions concerning the function of the blood-brain barrier and the blood-cerebrospinal fluid barrier (BCB) in Alzheimer disease and other neuropsychiatric disorders. In this paper we investigate and review the evidence for BCB dysfunction in Alzheimer disease and major depression. The hypothetical roles of immunologically mediated mechanisms in the central nervous system (CNS) are discussed. Special consideration is given to methodological factors influencing BCB function and analysis. Serum and cerebrospinal fluid (CSF) of 29 patients with major depression (MD) and 51 patients with "probable Alzheimer disease" (AD) were investigated. The AD patients were subdivided in two groups of 21 early-onset (EO) and 30 late-onset (LO) cases and assayed for concentrations of albumin and IgG. The results were compared with those for 11 age-matched healthy controls. The severity of dementia was assessed with the Mini-Mental State Examination (MMSE). AD and MD patients showed significantly lower serum albumin [AD: p < 0.05 (LO: p < 0.038); MD p < 0.01] and IgG (AD: p < 0.01; MD: p < 0.013) concentrations compared with controls. MD (p < 0.001) and LO-AD (p < 0.07) patients displayed significantly lower absolute serum albumin levels than did EO-AD patients. The CSF/serum ratio for albumin and IgG was used to evaluate BCB function. There were no significant group differences; however, subsets of MD (29%) and AD (16%) patients showed a higher frequency of a pathological albumin ratio than did control subjects. Furthermore, a subset of 24% of MD and18% of AD patients and none of the controls showed an elevated IgG ratio. Different mechanisms of alteration of IgG distribution are presented. The degree of cognitive impairment in AD did not correlate positively with protein and ratio parameters. The BCB is critical to the maintenance of homeostasis within nervous system tissue. We suggest that the altered function can result from immune-mediated events such as altered levels of circulating inflammatory mediators. Furthermore, we assume that in the AD and MD subgroups, the BCB dysfunction for high molecular weight proteins permits access of components of the immune system to the CNS, which may contribute to disease pathology.
authors.affiliation: Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hampel
authors.forename: H U
authors.initials: HU
authors.lastname: Kötter
authors.forename: H J
authors.initials: HJ
authors.lastname: Möller
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000503:physiopathology*; D001812:Blood-Brain Barrier; D002555:Cerebrospinal Fluid / Q000502:physiology*; D003866:Depressive Disorder / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight