Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus?

Abstract

Objectives: In animal models and in vitro studies leptomeninges have been shown to be the origin of neurotrophic substances that support the survival and growth of neuronal cells. Because dementia is associated with neuronal loss, we investigated whether leptomeningeal dysfunction may be involved in the pathogenesis of dementia disorders. Methods: We analysed the cerebrospinal fluid (CSF) concentrations of the leptomeningeal derived b trace protein, b2 microglobulin, and cystatin C.Results: There was a statistically significant difference of the CSF b trace protein levels among different groups. Patients with idiopathic normal pressure hydrocephalus (NPH) (17.5 (SD 4.3) mg/l) showed significantly lower CSF b trace protein levels than patients with Alzheimer's disease (23.8 (6.2) mg/l), depression (24.2 (7.3) mg/l), and normal controls (25.3 (4.9) mg/l). To patients with vascular dementia (20.1 (5.6) mg/l) and frontotemporal dementia (21.9 (7.0) mg/l), the difference was not significant. There was no significant difference regarding the CSF and serum concentrations of b2 microglobulin or cystatin C among the different groups. Conclusions:We conclude that leptomeningeal dysfunction may be involved in certain types of dementia such as NPH and that reduced CSF b trace protein levels in patients with NPH may aid in differentiating this difficult to diagnose disorder from other syndromes such as Alzheimer's disease. T he leptomeninges have been shown to support the survival and growth of neuronal cells and to produce neurotrophic factors. [1][2][3][4] Because dementia is associated with neuronal loss, leptomeningeal dysfunction may be a possible pathomechanism in dementia syndromes. In Alzheimer's disease, the leptomeninges have been shown to be a major site of b amyloid deposition. 5 In idiopathic normal pressure hydocepalus (NPH), several studies showed a leptomeningeal fibrosis of unknown origin.6 7 To assess meningeal function in vivo, we measured cerebrospinal fluid (CSF) proteins produced by the leptomeninges. b Trace protein has been shown to be mainly synthesised in the spinal leptomeninges and pachymeninx.8 9 It seems to have a function related to prostaglandin metabolism 10 and to act as a carrier protein for retinoids.11 b2 microglobulin is a cell membrane associated peptide expressed on the surface of most nucleated cells that may be involved in immunological reactions.12 Cystatin C is an important extracellular inhibitor of cysteine proteinases. 13The aim of this study was to investigate concentrations of CSF proteins with a known leptomeningeal origin in various subtypes of dementia to determine whether signs of meningeal dysfunction are present. METHODSPaired lumbar CSF and serum samples were obtained from 96 patients from the department of neurology, University Hospital of Ulm, with different subtypes of dementia.We examined 30 patients (18 female, 12 male) fulfilling the diagnostic criteria of Alzheimer's disease as described by McKhann et al.14 Furthermore, we investigated 13 patients (6 female, 7 ma...

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review

“…Additionally, lipocalin-type prostaglandin D synthase (PGDS), also known as b-trace protein, considered to be mainly produced in the leptomeninges playing a role in prostaglandin metabolism and in retinoids’ transfer, has been found to have significantly lower concentration in CSF of NPH patients than in patients with other causes of dementia, such as AD, patients with depression and healthy individuals [ 67 , 68 ].…”

Multiplexed Immunoassay Panel Identifies Novel CSF Biomarkers for Alzheimer's Disease Diagnosis and Prognosis

“…It is important to note that while the models used in our study suggest diagnostic value of the novel biomarkers, other combinations of these markers may be optimal; it will be of interest in future studies to validate the results of this discovery study in additional cohorts and to determine whether alternative combinations of these markers may demonstrate improved performance. The levels of at least 7 of the novel biomarkers have been evaluated in AD subjects in other studies: no change was observed in plasma PAI-1 levels [44] ; in agreement with our findings, two studies have reported increased CSF MIF in AD and MCI subjects [45] , [46] ; also consistent with our findings, increased fibrinogen levels have been observed in AD and MCI CSF [47] and in AD plasma [48] , and increased plasma levels have been associated with an increased risk of future dementia [49] ; results have been mixed regarding CSF FAS levels in AD [50] , [51] ; AD plasma/serum VEGF levels have been reported to be unchanged [52] , [53] , decreased [54] , and increased [55] , while CSF levels have been reported to be unchanged [56] or increased [57] ; no change in CSF or serum levels of TNF RII in AD has been reported [58] ; cystatin C findings have been inconsistent, with reports of serum/plasma levels unchanged [59] , increased in AD [60] or in those who later develop AD [61] , and decreased [62] or decreased levels associated with increased risk of future AD [63] , while CSF levels have been reported to be unchanged [59] , [64] , decreased [65] , or increased [21] . These inconsistent results may be due in part to the existence of a truncated form of cystatin C, which was found to be increased in AD CSF, while the full length protein was decreased [20] , [21] .…”

Association of lipocalin-type prostaglandin D synthase with disproportionately enlarged subarachnoid-space in idiopathic normal pressure hydrocephalus

“…In regards to L-PGDS, its decrease has been attributed to arachnoidopathy (i.e., loss of arachnoid cells producing L-PGDS) particularly in secondary NPH after subarachnoid hemorrhage [ 13 , 26 ]. In our study, decreased L-PGDS was correlated with a narrow callosal angle, which is a feature of an uneven CSF distribution in DESH-type iNPH.…”