Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Immunoreactivities of amyloid beta peptide((1-42)) and total tau protein in lumbar cerebrospinal fluid of patients with normal pressure hydrocephalus.

Immunoreactivities of amyloid beta peptide((1-42)) (Abeta42-IR) and total tau protein (TTIR) were measured in lumbar cerebrospinal fluid of 48 patients (12 patients in each group) with normal pressure hydrocephalus (NPH), vascular dementia (VD), Alzheimer's disease (AD), Parkinson's disease without dementia (PD) and 24 controls (CON) using sensitive and specific enzyme immunoassays. TTIR in NPH was not significantly changed compared with VD, PD and CON, while NPH-Abeta42-IR was significantly decreased compared with PD and CON. In AD, significant increases of TTIR and significant decreases of Abeta42-IR were found. Using a TTIR by Abeta42 plot, all NPH, PD, and CON samples were within the non-AD plot region. 92% of AD and VD samples were within the AD and non-AD area, respectively. We conclude that combined measurement of Abeta42-IR and TTIR contributes to the differential diagnosis of NPH vs. AD and of AD vs. VD, respectively.

Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients.

Immunoreactivities of total apolipoprotein E (ApoE-IR), amyloid beta peptide(1-42) (Abeta42-IR), interleukin-6 (IL-6-IR), substance P (SPIR) and total tau protein (TTIR) were measured in lumbar cerebrospinal fluid samples of patients with Alzheimer's disease (AD), non-Alzheimer's dementias (NAD), neurological disorders without cognitive impairment (OND) and controls without central nervous system disease using sensitive and specific enzyme immunoassay methods. TTIR was highly significantly increased (P < 0,001) and Abeta42-IR was significantly decreased (P < 0,001 vs. OND/CO, P < 0,03 vs. NAD) in the AD cohort compared with the other diagnostic groups. Significant increases in AD were also found for ApoE-IR (P < 0,001) and IL-6 (P < 0,03), but there was a considerable overlap between groups. In the total AD cohort, SPIR was not significantly changed, but AD patients with late disease onset (>65 years) showed significantly higher values than both early onset patients (<65 years) and controls (P < 0,05). Discriminant function analysis showed that Abeta42-IR (cut-off value 375pg/ml) and TTIR (cut-off value 440 pg/ml) levels contributed most to the group classification of patients. At 85% sensitivity for AD and 100% specificity for controls, the combined evaluation of Abeta42-IR and TTIR in this cross-sectional study resulted in a graph separating AD from non-AD patients with increased specificity of 91% and 75% for AD versus OND and NAD, respectively.

Intra vitam lumbar and post mortem ventricular cerebrospinal fluid immunoreactive interleukin-6 in Alzheimer's disease patients.

OBJECTIVES: In view of contradictory findings in previous studies, to examine the diagnostic value of interleukin-6 measurements in cerebrospinal fluid (CSF) of Alzheimer's disease patients. MATERIAL AND METHODS: Interleukin-6-immunoreactivity (IL-6-IR) was measured in 169 intra vitam lumbar and 21 post mortem ventricular CSF samples of patients with probable and neuropathologically confirmed Alzheimer's disease (AD), non-AD dementias (NAD), neurological disorders without cognitive impairment (OND) and controls (CON) using a specific sandwich enzyme immunoassay. RESULTS: Intra vitam lumbar samples had significantly elevated (P < 0.03) IL-6-IR not only in the AD, but also in the NAD and OND group compared with controls. AD patients with late onset (> 65 years) had slightly (P > 0.05) higher values than patients with early onset (< 65 years). In post mortem ventricular fluid, differences among groups did not reach significance (P > 0.05). CONCLUSION: We conclude that elevations of CSF IL-6-IR can not serve as a diagnostic marker of the disease, but, hypothetically, could reflect presence or activity of IL-6 mediated immunological phenomena in single AD patients.

Ex vivo lumbar and post mortem ventricular cerebrospinal fluid substance P-immunoreactivity in Alzheimer's disease patients.

The concentration of substance P-immunoreactivity (SPIR) in ex vivo lumbar cerebrospinal fluid (CSF) of patients with probable Alzheimer's disease (AD), non-Alzheimer dementias, neurological patients without dementia and control subjects was determined using a sensitive and specific competitive enzyme-immunoassay. There were no significant differences between AD patients and the other groups, but patients with late onset AD (>65 years) showed significantly higher levels of SPIR than patients with early onset (<65 years) and controls. In post mortem ventricular fluid, SPIR levels of all groups were lower compared with the lumbar compartment, but without significant group differences. It is concluded that CSF SPIR may not serve as a diagnostic marker for AD, but possibly could reflect immunological or neuroprotective processes modulated by substance P in late onset AD patients.

Biological markers for the diagnosis of Alzheimer's disease.

A diagnostic test for Alzheimer's disease (AD) based on biochemical markers in the cerebrospinal fluid can help improve diagnostic accuracy, which currently is approximately 90%, leaving every tenth AD patient undiagnosed or falsely diagnosed as having the disease. From all biochemical abnormalities described in AD patients, those related to the hallmark neuropathologic lesions, deposition of amyloid and formation of paired helical filaments mainly consisting of abnormally phosphorylated tau protein, are the most promising and the best documented, even though other markers bear some potential and remain to be further studied. Determining an increase of tau and a reduction of A beta 42 bears satisfactory, even though not absolute specificity for AD and represents a true aid for clinicians in diagnosing AD during the patients lifetime. It remains open if these markers will be helpful for the most challenging goal, diagnosing AD in the preclinical phase, when, according to morphological data, high amounts of these pathological proteins are already deposited in the brain tissue.

Intra vitam lumbar cerebrospinal fluid and serum and postmortem ventricular immunoreactive apolipoprotein E in patients with Alzheimer's disease.

Using a specific enzyme linked immunosorbent assay (ELISA) method, total apolipoprotein E immunoreactivity (tApoE-IR) was measured in premortem lumbar CSF and serum of patients with "probable" Alzheimer's disease and in postmortem ventricular CSF of patients with Alzheimer's disease confirmed by necropsy. Concentrations were compared with those from patients with other neurological diseases and controls. The mean serum:lumbar CSF ratio of ApoE-IR was 15.9 suggesting that the main portion of lumbar ApoE-IR is synthesised intrathecally. No significant differences in ApoE-IR between patients with Alzheimer's disease and the other groups were detected in either CSF compartment. In lumbar CSF, there was no correlation between ApoE-IR of patients with Alzheimer's disease and their mini mental state scores. These results suggest that the diagnostic value of ApoE-IR measurements in CSF of patients with Alzheimer's disease as a single determination is less than that of other markers, in particular tau protein. On the other hand, ApoE determinations could be useful as part of a neurochemical profile of Alzheimer's disease.

Tau protein and apolipoprotein E in CSF diagnostics of Alzheimer's disease: impact on non Alzheimer's dementia?

Tau protein and apolipoprotein E are suggested to be biochemically related to neurofibrillary tangles and senile plaques in Alzheimer's disease (AD) brains. They can be detected as immunoreactive material (total tau immunoreactivity [TTIR] and apolipoprotein E-immunoreactivity [ApoEIR]) in the cerebrospinal fluid (CSF). TTIR and ApoE-IR have been measured in ex vivo lumbar and post mortem ventricular CSF in AD, other neurological diseases without cognitive impairment, elderly depressive patients, and young and elderly controls. In lumbar CSF, there was a highly significant increase of TTIR and a minor, insignificant decrease of ApoE-IR in CSF of AD patients. The latter result was also found in ventricular CSF, whereas TTIR showed no significant difference between groups in the rostral CSF compartment. As depressive periods in the elderly may mimick a dementing process, these findings contribute to the differential diagnosis of these disorders by showing a different neurobiochemical CSF profile. Work in progress will include a variety of non-Alzheimer's dementias and possibly will further increase the value of CSF investigation in neurodegenerative disorders.

Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type.

"Oxidative stress" may be of significance in the etiopathogenesis of dementia of Alzheimer type (DAT). Therefore, we measured activities of the enzymes superoxide dismutase (SOD) and catalase (CAT), which detoxicate reactive oxygen species. Enzyme activities were measured postmortem in basal ganglia, cortical, and limbic brain regions of patients with DAT and age-matched controls. SOD activity increased with age in basal nucleus of Meynert. However, there was no significant difference in SOD activity between DAT and controls. CAT activity was independent of age and postmortem time. There were significant reductions in CAT activity in parietotemporal cortex, basal ganglia, and amygdala in DAT compared with controls (p < 0.05 to 0.01). Our findings are in line with the assumption that reactive oxygen species could contribute to the pathogenesis of DAT. Absence of these changes in basal nucleus of Meynert might reflect retrograde degeneration of cholinergic fibers.

How to run a brain bank. A report from the Austro-German brain bank.

The sophisticated analysis of and growing information on the human brain requires that acquisition, dissection, storage and distribution of rare material are managed in a professional way. In this publication we present the concept and practice of our brain bank. Both brain tissue and information are handled by standardized procedures and flow in parallel from pathology to neuropathology and neurochemistry. Data concerning brain material are updated with clinical information gained by standardized procedures.

Preliminary brain autopsy findings in progredient Rett syndrome.

Postmortem human brain analyses have been performed to further evaluate pathogenetic aspects of the Rett syndrome. While there are no significant abnormalities with respect to amino acid concentrations in putamen, caudate nucleus, red nucleus and thalamus, the concentration of kynurenine is increased in putamen, caudate nucleus, gl. pallidus, raphe and amygdaloid n. In contrast, serotonin and its metabolite 5-hydroxyindole acetic acid are below normal levels. D2-receptor number is decreased and there is a significant drop in the concentration of the iron-binding protein ferritin. It can be concluded, that reduction of D2-receptors is due to loss of cholinergic and GABA-ergic cell bodies in the striatum or may be a response to iron deficiency. Low serotonergic and high kynurenergic activity may be of pathogenetic importance in the frequently observed cerebral seizures in Rett syndrome.