Cindy Dickson

Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia.

A new iron sensitive MR sequence (susceptibility weighted imaging - SWI) enabling the simultaneous quantitation of regional brain iron levels and brain microbleeds (BMB) has been acquired serially to study dementia. Cohorts of mildly cognitively impaired (MCI) elderly (n = 73) and cognitively normal participants (n = 33) have been serially evaluated for up to 50 months. SWI phase values (putative iron levels) in 14 brain regions were measured and the number of BMB were counted for each SWI study. SWI phase values showed a left putaminal mean increase of iron (decrease of phase values) over the study duration in 27 participants who progressed to dementia compared to Normals (p = 0.035) and stable MCI (p = 0.01). BMB were detected in 9 out of 26 (38%) MCI participants who progressed to dementia and are a significant risk factor for cognitive failure in MCI participants [risk ratio = 2.06 (95% confidence interval 1.37-3.12)]. SWI is useful to measure regional iron changes and presence of BMB, both of which may be important MR-based biomarkers for neurodegenerative diseases.

Increased production of inflammatory cytokines in mild cognitive impairment.

Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimers disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.

Proteomic analysis of eccrine sweat: implications for the discovery of schizophrenia biomarker proteins.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and multiple reaction monitoring mass spectrometry (MRM-MS) proteomics analyses were performed on eccrine sweat of healthy controls, and the results were compared with those from individuals diagnosed with schizophrenia (SZ). This is the first large scale study of the sweat proteome. First, we performed LC-MS/MS on pooled SZ samples and pooled control samples for global proteomics analysis. Results revealed a high abundance of diverse proteins and peptides in eccrine sweat. Most of the proteins identified from sweat samples were found to be different than the most abundant proteins from serum, which indicates that eccrine sweat is not simply a plasma transudate and may thereby be a source of unique disease-associated biomolecules. A second independent set of patient and control sweat samples were analyzed by LC-MS/MS and spectral counting to determine qualitative protein differential abundances between the control and disease groups. Differential abundances of selected proteins, initially determined by spectral counting, were verified by MRM-MS analyses. Seventeen proteins showed a differential abundance of approximately 2-fold or greater between the SZ pooled sample and the control pooled sample. This study demonstrates the utility of LC-MS/MS and MRM-MS as a viable strategy for the discovery and verification of potential sweat protein disease biomarkers.

The Heme Degradation Pathway is a Promising Serum Biomarker Source for the Early Detection of Alzheimer's Disease

One of the remaining challenges in Alzheimers disease (AD) research is the establishment of biomarkers for early disease detection. As part of a prospective study spanning a period of five years, we have collected serial serum samples from cognitively normal, mild cognitively impaired (MCI), and mild AD participants, including same patient samples before and after cognitive decline. Using mass spectrometry we identified several promising leads for biomarker development, such as prosaposin, phospholipase D1, biliverdin reductase B, and S100 calcium binding protein A7. Selected candidate markers were verified using reverse phase protein microarray assays. Of 15 protein/protein abundance ratios that were significantly altered in sera from subjects with mild AD compared to Normal or MCI subjects, 14 were composed of ratios containing heme oxygenase-1, biliverdin reductase A, or biliverdin reductase B. Moreover, an increase in the protein abundance ratio of matrix metallopeptidase 9/biliverdin reductase differentiated stable MCI subjects from MCI subjects progressing into mild AD before the onset of cognitive decline. These findings strongly implicate the heme degradation pathway as a promising source of protein biomarkers for the early detection of AD.

A multicenter study of permanent hemodialysis access patency: beneficial effect of clipped vascular anastomotic technique

OBJECTIVE There is an urgent and compelling need to reduce the morbidity and expense of maintaining hemodialysis vascular access patency. This large, long-term, retrospective, multicenter study, which compared access patency of autogenous arteriovenous fistulas (AVF) and synthetic bridge grafts (AVG) created with conventional sutures or nonpenetrating clips, was undertaken to resolve conflicting results from previous smaller studies. DESIGN Patency data for 1385 vascular access anastomoses (clipped or sutured) was obtained from 17 hospitals and dialysis centers (Appendix). Five hundred eighteen AVF (242 clip, 276 suture) and 827 AVG (440 clip, 384 suture) were analyzed. Statistical comparisons were made with Kaplan-Meier survival analysis, log-rank test, two-sample t test, and X(2) test. The Cox proportional hazards model was used to confirm Kaplan-Meier analysis. RESULTS Access patency (primary, secondary, overall, and intention to treat) was significantly improved in access anastomoses constructed with clips. In the intention-to-treat group, primary patency at 24 months was 0.54 for clipped AVF and 0.34 for sutured AVF, and was 0.36 for clipped AVG and 0.17 for sutured AVG. At 24 months, primary patency rate for AVF successfully used for dialysis was 0.67 for clips and 0.48 for sutures, and for AVG was 0.39 for clips and 0.19 for sutured constructs. Interventions necessary to maintain patency were significantly fewer in clipped anastomoses. CONCLUSION Replacing conventional suture with clips significantly reduces morbidity associated with maintaining permanent hemodialysis vascular access. This beneficial effect may be due to the biologic superiority of interrupted, nonpenetrating vascular anastomoses.

The utility of the VCS clip for creation of vascular access for hemodialysis: long-term results and intraoperative benefits.

UNLABELLED The purpose of this study was to compare the effectiveness of the VCS vascular clip approximating system for the creation of hemodialysis access fistulas. 173 new vascular accesses were created, 92 prosthetic grafts and 81 autologous fistulas over a 40-month period. 50 sutured and 42 clipped fistulas comprised the prosthetic graft series, and 33 sutured and 48 clipped cases the autologous series. Risk factors associated with access patency were correlated and the primary patencies compared in the suture versus clipped group. A significant improvement in primary patency was noted for the clipped prosthetic group at all time points studied, with a positive trend also noted for clipped autologous fistulae. CONCLUSIONS The vascular clipping system (the VCS system) provides both long-term and immediate advantages for vascular access construction. Clips have been used successfully to treat seven consecutive patients with upper extremity arterial steal syndrome without the technical difficulties associated with traditional methods of repair.

P2-330: Altered brain iron metabolism as a risk factor for Alzheimer’s disease

amyloid deposition and memory impairment are correlated. Methods: Thirty-one older subjects recruited from longitudinal studies of aging and dementia underwent neuropsychological assessment and PIB PET. There were 9 AD, 6 MCI, and 16 highly intelligent (AMNART mean IQ 127) CDR 0 subjects who were classified as NC (N 8) or IQ-MI (N 8) based on the Buschke SRT memory scores adjusted for IQ. PET was acquired over 60 minutes after injection of 10-15 mCi C11-PIB. PIB binding was calculated using the Logan graphical analysis method in an aggregated cortical region-of-interest comprising superior frontal, anterior cingulate, parietal, and precuneus, which yielded a distribution volume ratio (DVR) with cerebellar gray as reference. Results: Group mean PIB binding was significantly higher in AD than in MCI, IQ-MI, or NC groups (p .001). However, PIB binding within the range of AD (PIB-positive) was seen in 3 of 6 MCI, 4 of 8 IQ-MI, and 1 of 8 NC subjects; the remaining subjects had low PIB retention (DVR 1.0, non-specific binding). Among PIBpositive subjects, greater PIB binding was associated with poorer performance on the SRT memory scores (r 0.59, p .01) and the Boston Naming (r 0.66, p 0.001) test. Conclusions: Our findings support the hypothesis that a subset of highly intelligent adults with subtle memory impairment, who would otherwise be classified as normal, have amyloid deposition. In addition, amyloid burden appears highly correlated with memory and naming ability.