Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological changes of the brain. Great efforts have been undertaken to determine the progression of the disease and to monitor therapeutic interventions. Especially, the analysis of blood plasma had yielded incongruent results. Recently, Ray et al. (Nat. Med. 13, 2007, 1359f) identified changes of 18 signaling proteins leading to an accuracy of 90% in the diagnosis of AD. The aim of the present study was to examine 16 of these signaling proteins by quantitative Searchlight multiplex ELISA in order to determine their sensitivity and specificity in our plasma samples from AD, mild cognitive impairment (MCI), depression with and without cognitive impairment and healthy subjects. Quantitative analysis revealed an increased concentration in Biocoll isolated plasma of 5 out of these 16 proteins in MCI and AD patients compared to healthy subjects: EGF, GDNF and MIP1δ (in AD), MIP4 (in MCI) and RANTES (in MCI and AD). ROC analysis predicted a sensitivity of 65-75% and a specificity of 52-63% when comparing healthy controls versus MCI or AD. Depression without any significant cognitive deficits did not cause any significant changes. Depressed patients with significant cognitive impairment were not different from MCI patients. In conclusion, we detected a number of altered proteins that may be related to a disease specific pathophysiology. However, the overall expression pattern of plasma proteins could not be established as a biomarker to differentiate MCI from AD or from depression.

Cognitive deterioration in Alzheimer's disease is accompanied by increase of plasma neopterin.

The pro-inflammatory reaction of the immune system is a feature of healthy aging and might influence the progression of Alzheimer's disease (AD). Neopterin is a pteridine derivative, released from macrophages upon stimulation with pro-inflammatory cytokine interferon-gamma. Forty-three probable AD patients were investigated at baseline and follow up (14.5+/-0.5 months; mean+/-s.e.m.). We assessed the clinical progression by the Consortium to Establish a Registry for Alzheimer's disease (CERAD) battery and compared cognitive changes to serum concentrations of neopterin, C-reactive protein (CRP) and antibody to cytomegalovirus (CMV). The mean neopterin concentrations increased significantly from 9.8+/-1.0 to 13.6+/-2.1 nM (p=0.04). In contrast, mean CRP concentrations at baseline was 0.46+/-0.1 and non-significantly decreased to 0.28+/-0.04 mg/dl. Of AD patients 70% were CMV IgG-seropositive at baseline and CMV-antibody concentrations correlated with levels of neopterin (Spearman r=0.386, p=0.016). CERAD scores did not correlate with any of immune parameters at baseline. At follow up, the increase of neopterin correlated significantly with the decrease in the total CERAD and MMSE scores, according to the clinical progression (r=-0.353, p<0.05 and r=-0.401, p<0.01, respectively). Subdividing the sample with respect to baseline MMSE scores, neopterin concentrations significantly increased only in the group of MMSE<20. In the multiple testing covariated for age, gender, Apolipoprotein E-epsilon4 allele, time difference between both measurements, neopterin remained significantly associated with cognitive decline. In summary, neopterin concentrations correlated with cognitive decline in AD patients, which might be due to high CMV seropositivity in that population.

Efficacy of donepezil treatment in Alzheimer patients with and without subcortical vascular lesions.

In a pilot study designed as a case control study the efficacy of donepezil treatment was investigated in patients with Alzheimer's disease (AD). Patients were stratified according to radiological criteria into patients without (AD group) and with subcortical vascular lesions (AD+SVD group). Changes in cognition were assessed as the primary outcome measurement after 6 and 18 months of treatment by the Mini-Mental Status Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. After 6 months, patients had improved from baseline by 0.7 points in MMSE score in the AD group and by 1.8 in the AD+SVD group. After 18 months of treatment, the AD+SVD group performed significantly worse in one CERAD subscore, whereas a deterioration in two subscores was observed in the AD group. A comparison between the 2 groups revealed that treatment did not lead to statistically significant differences between the AD and AD+SVD groups in any of CERAD parameters following 6 or 18 months of treatment. These data support previous observations that donepezil therapy is effective in AD patients with and without subcortical vascular lesions.