Elevated spermidine serum levels in mild cognitive impairment, a potential biomarker of progression to Alzheimer dementia, a pilot study.

BACKGROUND/AIMS: There is a close link between iron and polyamine biosynthesis and metabolism. In a recent study, we reported alterations in the serum levels of hepcidin and other iron-related proteins in Alzheimer's disease (AD) patients (Sternberg et al., 2017). Based on these findings, this pilot study compared serum levels of one of the polyamines, Spermidine, between AD, mild cognitive impairment (MCI), and control subjects, correlating the levels with the existing clinical and neuroimaging data. METHODS: This cross-sectional study measured Spermidine levels in frozen serum samples of 43 AD patients, 12 MCI patients, and 21 age-matched controls, provided by the Oregon Alzheimer's Disease Center Bio-repository, using enzyme-linked immunosorbent assay. RESULTS: MCI patients showed significantly higher mean Spermidine serum levels compared to controls (P = 0.01), with a non-significant trend for higher Spermidine serum levels in pure AD (P = 0.08) participants compared to controls. Spermidine serum levels correlated with the values of cognitive assessment tests including MMSE (r = -0.705, P = 0.003), CDR (r = 0.751, P = 0.002), and CDR-SOB (r = 0.704, P = 0.007), in "pure" AD subgroup, suggesting that higher Spermidine serum levels in MCI can be a potential biomarker of conversion to dementia in subjects with AD underlying pathology. Furthermore, Spermidine serum levels correlated with serum levels of the chief iron regulatory protein, hepcidin in AD participants with a more advanced disease stage, indicated by MMSE (strata of 8-19, P = 0.02), and CDR-SOB (strata of 6-12, P = 0.03). CONCLUSION: Studies with larger cohort are warranted for defining the role of Spermidine in AD pathophysiology, and the utility of polyamines as biomarkers of progression of MCI to AD.

Increased free prostate specific antigen serum levels in Alzheimer's disease, correlation with Cognitive Decline.

BACKGROUND/AIMS: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testosterone, the serum levels of which are altered in patients with Alzheimer's disease (AD).This pilot study compared serum levels of the free (f) PSA between AD, mild cognitive impairment (MCI), and control subjects, and evaluated the relationship between fPSA serum levels and cognitive assessment tests and neuroimaging data. In addition, in a subgroup of AD patients, we correlated fPSA serum levels with the existing data on serum levels of amyloid-beta (Aß), and iron-related proteins, including hepcidin and ferritin. METHODS: Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of fPSA using enzyme-linked immunosorbent assay. RESULTS: fPSA serum levels calculated as median ±â€¯SD were higher in AD males (663.6 ±â€¯821.0 pg/ml) compared to control males (152.0 ±â€¯207.0 pg/ml), p = 0.003. A similar Pattern emerged when comparing MCI males (310.7 ±â€¯367.0 pg/ml) to control males (P = 0.02). Correlation studies showed a significant association between fPSA and CDR (r = 0.56, P = 0.006) and CDR-SOB (r = 0.54, P = 0.009) in AD males. CONCLUSION: Additional studies in a larger cohort are required for determining whether fPSA can be used as biomarker of AD disease progression and whether it has the potential to identify male subjects at risk of AD dementia.

Fingolimod anti-inflammatory and neuroprotective effects modulation of RAGE axis in multiple sclerosis patients.

BACKGROUND: We investigated Fingolimod treatment effects on the RAGE (receptor for advanced glycation endproducts) axis in multiple sclerosis (MS) patients. The primary outcome of the study was whether Fingolimod treatment increases serum levels of the soluble RAGE isoforms, sRAGE and esRAGE - both being considered putative endogenous inhibitors of RAGE signaling. Additional variables were serum levels of RAGE ligands, the high mobility group box (HMGB)1 and pentosidine. METHODS: Serum levels of the study variables were measured by ELISA, and compared between baseline (before Fingolimod treatment) and 6 and 12 months post-drug treatment in 17 relapsing MS patients. Fingolimod treatment effects on MS disease progression were assessed by comparing pre- and post-Fingolimod values of the EDSS and rate of clinical relapse, and changes in the T1-and T2-enahncing lesions on the MRI scan.methods RESULTS: Twelve months treatment with Fingolimod increased serum levels of sRAGE and esRAGE by 32.4% (P = 0.004) and 48.5% (P = 0.007) respectively. In addition, Fingolimod treatment reduced serum levels of HMGB1 by 71.6% (P = 0.02) and pentosidine serum levels by 41.3% (P = 0.12). EDSS remained stable (baseline: 3.57 ± 1.56; post-Fingolimod: 3.54 ± 1.2, P = 0.96) and the rate of clinical relapse decreased near significantly (P = 0.094). T1-and T2-enhancing lesions remained stable, showing no significant changes pre-vs. post-Fingolimod treatment. CONCLUSION: Fingolimod mediates modulation of the RAGE axis which apparently contributes to the Fingolimod's anti-inflammatory and neuroprotective effects. These findings may provide a rationale for the clinical efficacy of Fingolimod in pathological states other than MS, where dysregulation of the RAGE axis plays a role.