Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C.

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aß) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and ß (sAPPα, sAPPß), Aß oligomers 38, 40, 42, and Aß-total; phosphorylated tau (P-tau181), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aß-42 and Hulstaert (P-tau181) index were lower in HIV1-C than B (p = 0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau181 (p < 0.001), and sAPPα (p = 0.041); HIV(+) had higher CSF Aß-42 (p = 0.002) and higher CSF indexes: [Aß-42/(240 + 1.18 T-tau)], P-tau181/Aß-42, T-tau/Aß-42, P-tau181/T-tau, sAPPα/ß (all p ≤ 0.01) than AD. Compared to HIV(-), HIV(+) had lower CSF Aß-42, and T-tau (all p ≤ 0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau181) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.

Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer's disease.

Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 ± 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.

Abnormal APP processing in platelets of patients with Alzheimer's disease: correlations with membrane fluidity and cognitive decline.

RATIONALE: Previous studies have implicated platelet amyloid precursor protein (APP) as a candidate biomarker for Alzheimer's disease (AD). Platelets contain more than 95% of the circulating APP and enclose the enzymatic machinery for the APP metabolism yielding both soluble APP and amyloid-beta peptides. OBJECTIVES: The objective of this study is to compare the ratio of 130- to 110-kDa fragments of APP in platelets from patients with AD, mild cognitive impairment (MCI), and elderly controls. MATERIALS AND METHODS: After subjects were grouped according to diagnosis, APP ratio in platelets was evaluated by means of Western blot analysis. RESULTS: The APP ratio was significantly lower in AD patients (1.01 +/- 0.21) as compared to controls (1.24 +/- 0.21, p = 0.001) and MCI patients (1.18 +/- 0.21, p = 0.027), but no significant differences were found between MCI and controls (p = 0.904). In addition, we found positive correlations between the APP ratio and 1,6-diphenyl-1,3,5-hexatriene anisotropy (r = 0.3, p = 0.01), as well as with certain parameters of cognitive decline, namely, the mini-mental state examination score (r = 0.33, p = 0.003), the total Cambridge cognitive test (CAMCOG) score (r = 0.37, p = 0.001), and the score on the memory subscale of the CAMCOG (r = 0.38, p = 0.001). CONCLUSIONS: The pattern of platelet APP fragments was altered in patients with AD but not in patients with MCI. The alteration of APP fragments was correlated with membrane fluidity and the cognitive decline.

Altered beta-amyloid precursor protein isoforms in Mexican Alzheimer's Disease patients.

OBJECTIVE: To determine the beta-amyloid precursor protein (betaAPP) isoforms ratio as a risk factor for Alzheimer's Disease and to assess its relationship with demographic and genetic variables of the disease. METHODS: Blood samples from 26 patients fulfilling NINCDS-ADRDA diagnostic criteria for AD and 46 healthy control subjects were collected for Western blotting for betaAPP. A ratio of betaAPP isoforms, in optical densities, between the upper band (130 Kd) and the lower bands (106-110 Kd) was obtained. Odds ratios were obtained to determine risk factor of this component. RESULTS: betaAPP ratio on AD subjects was lower than that of control subjects: 0.3662 +/- 0.1891 vs. 0.6769 +/- 0.1021 (mean +/- SD, p<0.05). A low betaAPP ratio (<0.6) showed an OR of 4.63 (95% CI 1.45-15.33). When onset of disease was taken into account, a betaAPP ratio on EOAD subjects of 0.3965 +/- 0.1916 was found vs. 0.3445 +/- 0.1965 on LOAD subjects (p>0.05). CONCLUSIONS: Altered betaAPP isoforms is a high risk factor for Alzheimer's disease, although it has no influence on the time of onset of the disease.