Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

CSF YKL-40 and GAP-43 are related to suicidal ideation in older women.

OBJECTIVE: To investigate possible relationships between suicidal ideation and cerebrospinal fluid (CSF) levels of glial markers YKL-40 (also known as chitinase-3-like protein 1), growth-associated protein-43 (GAP-43) and myelin basic protein (MBP). METHOD: The sample was obtained from the Prospective Population Study of Women and included 86 women without dementia who underwent both psychiatric examinations and lumbar puncture (LP). Eight of these women reported past-month suicidal ideation. RESULTS: Significantly, higher CSF levels of both YKL-40 and GAP-43 were detected in women with past-month suicidal ideation. Associations with suicidal ideation remained for both YKL-40 and GAP-43 in regression models adjusted for smoking status, BMI and age. CSF levels of YKL-40, GAP-43 and MBP did not differ by depression status. Higher levels of CSF GAP-43 were associated with feelings of worthlessness; a strong relationship was demonstrated in the fully adjusted model (OR 5.95 CI [1.52-23.20], P = 0.01). CONCLUSION: Our findings of elevated CSF concentrations of both YKL-40 and GAP-43 in women with suicidal ideation, compared to those without, suggest that a disrupted synaptic glial functioning and inflammation may be related to the aetiology of suicidal ideation in older adults.

Effects of dietary supplementation of coriander oil, in canola oil diets, on the metabolism of [1-(14)C] 18:3n-3 and [1-(14)C] 18:2n-6 in rainbow trout hepatocytes.

The aim of this study was to investigate the effects of petroselinic acid, found in coriander oil, on the ability of rainbow trout hepatocytes to increase the production of eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA) from [1-(14)C] α-linolenic acid (18:3n-3; ALA) and to reduce the production of arachidonic acid (20:4n-6; ARA) from [1-(14)C] 18:2n-6. Addition of coriander oil increased the production of 22:6n-3, from [1-(14)C] 18:3n-3, at the 0.5 and 1.0% inclusion levels and reduced the conversion of [1-(14)C] 18:2n-6 to 20:4n-6. ß-Oxidation was significantly increased at the 1.5% inclusion level for [1-(14)C] 18:2n-6, however ß-oxidation for [1-(14)C] 18:3n-3 only showed an increasing trend. Acetate, a main breakdown product of fatty acids (FA) via peroxisomal ß-oxidation, decreased three-fold for [1-(14)C] 18:2n-6 and nearly doubled for [1-(14)C] 18:3n-3 when coriander was added at a 1.5% inclusion level. Acyl coenzyme A oxidase (ACO) enzyme activity showed no significant differences between treatments. Relative gene expression of ∆6 desaturase decreased with addition of coriander oil compared to the control. The addition of petroselinic acid via coriander oil to vegetable oil (VO) based diets containing no fishmeal (FM) or fish oil (FO), significantly increased the production of anti-inflammatory precursor 22:6n-3 (P=0.011) and decreased pro-inflammatory precursor 20:4n-6 (P=0.023) in radiolabelled hepatocytes of rainbow trout.

High white matter lesion load is associated with hippocampal atrophy in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition suggested as a prodromal state of Alzheimer's disease (AD) and subcortical vascular dementia (SVD). Recent findings suggest that white matter lesions (WML) may be associated with hippocampal atrophy. The objective of the study was to examine hippocampal and WML volumes in MCI patients and to examine if WML were linked to hippocampal atrophy. METHODS: The Gothenburg MCI study is a clinically based longitudinal study with biennial clinical assessments. The participants (n = 166) consist of 92 patients with stable MCI, 30 patients with converting MCI, and 44 healthy controls. WML volumes was measured manually using MRIcron. Automated segmentation of hippocampal and total white matter volumes was performed using FreeSurfer. RESULTS: The patients converting from MCI to dementia had reduced hippocampal volume. Stable MCI patients had fewer WML and converting MCI patients had more WML compared to controls. Hippocampal volume was only correlated to WML volume (ρ = 0.57; p < 0.01) in the quartile (n = 42) with the most WML. CONCLUSIONS: Hippocampal atrophy is present in both AD and SVD. Hippocampal volume was associated with WML volume only in the high WML quartile, suggesting that the WML volume must reach a threshold before hippocampal atrophy is seen.

Reduced levels of mitochondrial DNA increases the toxicity of 9-beta-D-arabinofuranosylguanine (araG).

Incubation of cells with thymidine (dThd) is known to cause dNTP pool imbalance as well as deletions and depletion of the mtDNA. In order to gain further understanding in the events involved in dThd toxicity over time, H9 cells were cultured for 20 months in the presence or absence of 1 micro M dThd. The level of mtDNA was reduced by 90% in the cells grown in dThd as compared to the control cells. The H9/dThd cells also showed a 100-fold increased sensitivity towards the cytotoxicity of the antileukemic compound 9-beta-D-arabinofuranolsylguanine (araG).

Alterations of mitochondrial DNA in CEM cells selected for resistance toward ddC toxicity.

2 ',3 '-dideoxycytidine (ddC) is a nucleoside analog that has been shown to produce a delayed toxicity which may be due to the depletion of mitochondrial DNA (mtDNA). In order to gain further understanding of the events involved in mitochondrial toxicity, two different CEM cell lines were selected for resistance to the delayed ddC toxicity.

Investigation of the substrate recognition of Drosophila melanogaster nucleoside kinase by site directed mutagenesis.

The deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) has a broad substrate specificity and a higher catalytic rate than other known deoxyribonucleoside kinases. Therefore it is a natural candidate for possible use as a suicide gene in combined gene/chemotherapy of cancer. We have performed site directed mutagenesis and tested different truncated forms of the enzyme in order to increase the affinity for ganciclovir.

A novel assay for examining the molecular reactions at the eukaryotic replication fork: activities of replication protein A required during elongation.

Studies to elucidate the reactions that occur at the eukaryotic replication fork have been limited by the model systems available. We have established a method for isolating and characterizing Simian Virus 40 (SV40) replication complexes. SV40 rolling circle complexes are isolated using paramagnetic beads and then incubated under replication conditions to obtain continued elongation. In rolling circle replication, the normal mechanism for termination of SV40 replication does not occur and the elongation phase of replication is prolonged. Thus, using this assay system, elongation phase reactions can be examined in the absence of initiation or termination. We show that the protein requirements for elongation of SV40 rolling circles are equivalent to complete SV40 replication reactions. The DNA produced by SV40 rolling circles is double-stranded, unmethylated and with a much longer length than the template DNA. These properties are similar to those of physiological replication forks. We show that proteins associated with the isolated rolling circles, including SV40 T antigen, DNA polymerase alpha, replication protein A (RPA) and RF-C, are necessary for continued DNA synthesis. PCNA is also required but is not associated with the isolated complexes. We present evidence suggesting that synthesis of the leading and lagging strands are co-ordinated in SV40 rolling circle replication. We have used this system to show that both RPA-protein and RPA-DNA interactions are important for RPA's function in elongation.

Interhemispheric transfer in normals and acallosals: latency adjusted evoked potential averaging.

Interhemispheric transfer time (IHTT) can be estimated from visual evoked potentials (EPs). Latency adjusted averaging (LAA) produces EPs which have enhanced components. LAA also provides estimates of EP latency variance and signal-to-noise ratio (S/N). LAA was tested in analysis of EP-IHTT in normal and acallosal subjects. It was hypothesized that in normals S/N and latency variance would reveal signal degradation resulting from interhemispheric transfer. LAA in normals replicated IHTT findings for both P1 and N1 latency. Latency variance did not increase for cross-callosal measures, whereas the S/N measure showed significant EP degradation due to callosal transfer. EPs from five subjects with callosal absence (two commissurotomy; two complete and one partial callosal agenesis) showed significantly larger than normal latency variability, as well as decreased S/N ratios, for cross-hemisphere visual EPs. Results support the value of LAA in EP research on adequacy of hemispheric interactions in clinical populations.

A P element containing suppressor of hairy-wing binding regions has novel properties for mutagenesis in Drosophila melanogaster.

P elements are widely used as insertional mutagens to tag genes, facilitating molecular cloning and analyses. We modified a P element so that it carried two copies of the suppressor of Hairy-wing [su(Hw)] binding regions isolated from the gypsy transposable element. This transposon was mobilized, and the genetic consequences of its insertion were analyzed. Gene expression can be altered by the su(Hw) protein as a result of blocking the interaction between enhancer/silencer elements and their promoter. These effects can occur over long distances and are general. Therefore, a composite transposon (SUPor-P for suppressor-P element) combines the mutagenic efficacy of the gypsy element with the controllable transposition of P elements. We show that, compared to standard P elements, this composite transposon causes an expanded repertoire of mutations and produces alleles that are suppressed by su(Hw) mutations. The large number of heterochromatic insertions obtained is unusual compared to other insertional mutagenesis procedures, indicating that the SUPor-P transposon may be useful for studying the structural and functional properties of heterochromatin.

Glutathione transferases in aquatic and terrestrial animals from nine phyla.

Glutathione transferase (GST) was present in 71 of 72 animal species/stages representing nine phyla when measured with 1-chloro-2,4-dinitrobenzene (CDNB). Our hypothesis that all animals have GST was not falsified. Transferase activity towards ethacrynic acid (ETHA) was present in species from all phyla investigated, but some animals seem to be without this activity. Activity towards 1,2-dichloro-4-nitrobenzene (DCNB) was less developed in aquatic animals than in terrestrial ones. The amount of protein binding to GSH-affinity gel matrix was rather uniform, ranging between 0.3 and 0.7% of soluble protein in homogenates of widely diverse animal species, thus being less variable than the enzyme activity. Transferases active towards DCNB did not bind at all or were less firmly bound to the GSH-affinity gel than the activity towards CDNB or ETHA. Fractionation was obtained by using a gradient of GSH. With SDS-electrophoresis it was demonstrated that the proteins with affinity to GSH had monomers in the MW-range 21.500-29.000. Hydra attenuata had one band (MW = 25,000); all other sources gave a complex pattern with up to six bands. It is concluded that GSTs are characteristic major constituents of animal cells, probably with some common basic function. Mutant forms able to aid detoxication are retained in the phylogenesis when they increase the fitness of the animal.