Protein tyrosine phosphatase receptor type Q in cerebrospinal fluid reflects ependymal cell dysfunction and is a potential biomarker for adult chronic hydrocephalus.

BACKGROUND AND PURPOSE: Protein tyrosine phosphatase receptor type Q (PTPRQ) was extracted from the cerebrospinal fluid (CSF) of patients with probable idiopathic normal-pressure hydrocephalus (iNPH) by proteome analysis. We aimed to assess the feasibility of using CSF PTPRQ concentrations for the additional diagnostic criterion of iNPH in Japanese and Finnish populations. METHODS: We compared PTPRQ concentrations among patients with probable iNPH and neurologically healthy individuals (normal control [NC] group), patients with normal-pressure hydrocephalus (NPH) of acquired and congenital/developmental aetiologies, patients with Alzheimer's disease and patients with Parkinson's disease in a Japanese analysis cohort. A corresponding iNPH group and NC group in a Finnish cohort was used for validation. Patients in the Finnish cohort who underwent biopsy were classified into two groups based on amyloid and/or tau deposition. We measured PTPRQ expression levels in autopsied brain specimens of iNPH patients and the NC group. RESULTS: Cerebrospinal fluid PTPRQ concentrations in the patients with NPH of idiopathic, acquired and congenital/developmental aetiologies were significantly higher than those in the NC group and those with Parkinson's disease, but iNPH showed no significant differences when compared with those in the Alzheimer's disease group. For the patients with iNPH, the area under the receiver-operating characteristic curve was 0.860 in the Japanese iNPH and 0.849 in the Finnish iNPH cohorts. Immunostaining and in situ hybridization revealed PTPRQ expression in the ependymal cells and choroid plexus. It is highly possible that the elevated PTPRQ levels in the CSF are related to ependymal dysfunction from ventricular expansion. CONCLUSIONS: Cerebrospinal fluid PTPRQ levels indicated the validity of this assay for auxiliary diagnosis of adult chronic hydrocephalus.

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings.

OBJECTIVE: To assess the relationship between Alzheimer disease (AD)-related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. METHODS: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Aß plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Aß42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. RESULTS: The patients with Aß plaques in the cortical biopsy had lower (p = 0.009) CSF Aß42 levels than those with no Aß plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Aß42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Aß42 and highest tau and p-tau 181 levels in CSF. The Aß42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Aß was independently predicted by the APOE ε4 carrier status and age but not by CSF Aß42 or tau levels. CONCLUSIONS: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aß42 and high CSF tau and p-tau levels, respectively.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Metabolome in progression to Alzheimer's disease.

Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.

Plasma Abeta42 and Abeta40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study.

BACKGROUND: Single measurements of plasma Aß are not useful in the diagnostics of Alzheimer's disease (AD). However, changes in plasma Aß levels during repeated testing may be helpful in the prediction and evaluation of progression of the incipient AD or mild cognitive impairment. OBJECTIVE: To examine the relation of baseline and serial plasma Aß levels to cognitive change in follow-up. METHODS: 269 subjects (52 cognitively impaired and 217 controls) from a population-based cohort were clinically followed up from 3 to 6 years. Serial plasma samples were available from 70 subjects who were followed up for 3 years and 43 subjects followed for 6 years. The plasma Aß levels were measured using ELISA. RESULTS: Subjects who declined cognitively during the follow-up had lower levels of plasma Aß42 at the baseline. Plasma Aß42 and the Aß42/Aß40 ratio decreased (-2.4 pg/ml for Aß42 in 6 years) in those who declined in follow-up, whereas Aß42 and the Aß42/Aß40 ratio increased in the subjects who remained cognitively stable or improved in follow-up. Subjects using acetylsalicylic acid, dipyridamole, antidiabetic or anticoagulant drugs as well as subjects with coronary heart disease had higher levels of Aß40. CONCLUSIONS: Low or decreasing plasma Aß42 during the follow-up is associated with cognitive decline. Serial measurement of plasma Aß42 may be useful in the detection of the subjects who are at risk for cognitive decline.

PET amyloid ligand [11C]PIB uptake and cerebrospinal fluid beta-amyloid in mild cognitive impairment.

BACKGROUND: In mild cognitive impairment (MCI), Alzheimer's disease (AD)-type cerebrospinal fluid (CSF) biomarker profiles predict rapid progression and conversion to AD. An increased brain amyloid burden in AD and MCI has been demonstrated with PET using [(11)C]PIB (Pittsburgh compound B). Little is known about the relationship between these biomarkers in MCI. METHODS: We studied 15 patients with amnestic MCI and 22 controls with PET using [(11)C]PIB. In MCI patients, CSF levels of Abeta42, pTAU, totalTAU and the Abeta42/pTAU ratio were measured. RESULTS: In MCI patients, CSF Abeta42 was abnormal in 53% of patients, totalTAU in 67%, pTAU in 64% and the Abeta42/pTAU ratio in 64%. A composite neocortical [(11)C]PIB uptake score was increased in 87% of the MCI patients. Only 54% of [(11)C]PIB-positive subjects showed AD-type Abeta42 values. During a 2-year follow-up, 6 MCI patients converted to AD, all of them had increased neocortical PIB scores at the MCI stage. Abnormal CSF Abeta42 was found in 3 patients, pTAU in 3 patients and Abeta42/pTAU ratio in 4 patients. CONCLUSION: Follow-up studies are needed to confirm whether [(11)C]PIB uptake might be more sensitive than CSF Abeta42 concentration in detecting increased amyloid burden in MCI, as suggested by the results of this study.

Genetic study evaluating LDLR polymorphisms and Alzheimer's disease.

We genotyped SNPs rs11668477, rs12983082, rs11669576, rs2738444, rs5925 and rs1433099 in 405 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison and estimated the haplotype frequencies between cases and controls and evaluated the level of biomarkers in haplotype carriers. We observed that T allele of rs2738444 was overrepresented in AD women with p=0.014 (Bonferroni corrected p=0.252). A specific haplotype block consisting of SNPs rs11669576, rs2738444 and rs5925 was identified and in women the haplotype GTT was overrepresented in AD cases when compared to controls with p=0.008. We measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of cases and controls and found that some genotypes were associated with increased levels of tau and ptau or a decreased Abeta(42) level in women. The specific risk haplotype GTT was associated with an increased level of tau and ptau in both men and women. Our findings suggest that LDLR gene may be associated with AD risk and its CSF biomarkers, especially in women.

Study on the association between SOAT1 polymorphisms, Alzheimer's disease risk and the level of CSF biomarkers.

BACKGROUND: In Alzheimer's disease (AD) the beta-amyloid precursor protein is excessively cleaved into Abeta(42), causing the abundant amyloid plaque loads in affected brain areas. Sterol O-acyltransferase 1 (SOAT1) has been found to regulate the production of beta-amyloid precursor protein. METHODS: We genotyped 4 SOAT1 single nucleotide polymorphism (SNP) sites (rs2247071, rs2862616, rs3753526 and rs1044925) in 410 Finnish AD cases and 455 controls and conducted a single allele and genotypic distribution comparison as well as estimating the haplotype frequencies between cases and controls and the level of biomarkers in genotype and haplotype carriers. RESULTS: The CC genotype of rs2247071 was overrepresented in the AD cases (OR = 1.38, 95% CI = 1.01-1.89, p = 0.043, Bonferroni corrected p = 0.172 with 4 tests) independent of gender, age and APOE epsilon4 allele carrier status. We did not find any significant differences between Abeta(42), tau or ptau levels in different allele, genotype or haplotype carrier cases. CONCLUSION: Our findings suggest that SOAT1 gene may possibly be only a minor risk factor in AD.

The association study between DHCR24 polymorphisms and Alzheimer's disease.

DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased. To examine genetic association of the DHCR24 with AD, we genotyped four single nucleotide polymorphism (SNP) sites (rs638944, rs600491, rs718265, and rs7374) in 414 Finnish AD cases and 459 controls and calculated the allelic and genotypic distribution of both cases and controls. The single locus association analysis indicated that men carrying the T allele of rs600491 had an increased risk of AD (OR 1.7 95% CI 1.2-2.4; P = 0.004, Bonferroni corrected P = 0.048 with 12 tests). We estimated haplotypes of SNPs rs638944 and rs600491 between cases and controls and found overall distribution of haplotypes highly significant (P < 0.001). There was a common protective haplotype TC with frequency of 0.22 in cases and 0.30 in controls (P < 0.001) and a risk haplotype GC with frequency of 0.10 in cases and 0.05 in controls (P < 0.001). We also measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of AD cases (n = 44) and controls (n = 10) and found that AD cases that carry rs718265 GG had lower levels of Abeta(42) than other genotype carriers. Our findings indicate that DHCR24 gene may be associated with AD risk.