Cerebrospinal Fluid (CSF) 25-Hydroxyvitamin D Concentration and CSF Acetylcholinesterase Activity Are Reduced in Patients with Alzheimer's Disease

Background

Little is known of vitamin D concentration in cerebrospinal fluid (CSF) in Alzheimer´s disease (AD) and its relation with CSF acetylcholinesterase (AChE) activity, a marker of cholinergic function.

Methods

A cross-sectional study of 52 consecutive patients under primary evaluation of cognitive impairment and 17 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 28), other dementias (n = 12), and stable MCI (SMCI, n = 12). We determined serum and CSF concentrations of calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and CSF activities of AChE and butyrylcholinesterase (BuChE).

Findings

CSF 25OHD level was reduced in AD patients (P < 0.05), and CSF AChE activity was decreased both in patients with AD (P < 0.05) and other dementias (P < 0.01) compared to healthy controls. None of the measured variables differed between BuChE K-variant genotypes whereas the participants that were homozygous in terms of the apolipoprotein E (APOE) ε4 allele had decreased CSF AChE activity compared to subjects lacking the APOE ε4 allele (P = 0.01). In AD patients (n=28), CSF AChE activity correlated positively with CSF levels of total tau (T-tau) (r = 0.44, P < 0.05) and phosphorylated tau protein (P-tau) (r = 0.50, P < 0.01), but CSF activities of AChE or BuChE did not correlate with serum or CSF levels of 25OHD.

Conclusions

In this pilot study, both CSF 25OHD level and CSF AChE activity were reduced in AD patients. However, the lack of correlations between 25OHD levels and CSF activities of AChE or BuChE might suggest different mechanisms of action, which could have implications for treatment trials.     

β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis

With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β(3)-adrenergic receptors. However, vast majorities of β(3)-adrenergic agonists have so far not been able to stimulate human β(3)-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β(1)-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β(3)-adrenergic receptors. Wild-type and β(3)-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β(3)-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β(1)-adrenergic receptors. Thus, in the absence of β(3)-adrenergic receptors, β(1)-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β(1)-adrenergic receptors or β(3)-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β(1)-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.     

Testing morphology-based hypotheses of phylogenetic relationships in Parmeliaceae (Ascomycota) using three ribosomal markers and the nuclear RPB1 gene

Parmeliaceae is the largest family of lichen-forming fungi with more than 2000 species and includes taxa with different growth forms. Morphology was widely employed to distinguish groups within this large, cosmopolitan family. In this study we test these morphology-based groupings using DNA sequence data from three nuclear and one mitochondrial marker from 120 taxa that include 59 genera and represent the morphological and chemical diversity in this lineage. Parmeliaceae is strongly supported as monophyletic and six well-supported main clades can be distinguished within the family. The relationships among them remain unresolved. The clades largely agree with the morphology-based groupings and only the placement of four of the genera studied is rejected by molecular data, while four other genera belong to clades previously unrecognised. The classification of these previously misplaced genera, however, has already been questioned by some authors based on morphological evidence. These results support morphological characters as important for the identification of monophyletic clades within Parmeliaceae.     

Vascular development: tracing signals along veins

The plant hormone auxin has been implicated in vascular development, but the molecular details of patterned vascular differentiation have remained elusive. Research in the past year has identified new genes that control vascular patterning, and auxin transport and perception. New experimental strategies have been employed to study vascular development. Together, these findings have generated a conceptual framework and experimental tools for the exploration of vascular-tissue patterning at the molecular level.     

Influence of interelectrode distance and force level on the spectral parameters of surface electromyographic recordings from the lumbar muscles.

In order to study the influence of interelectrode distance and force level on the electromyographic (EMG) spectral parameters and on their reliability, bipolar surface EMG measurements were performed on the lumbar muscles of 15 subjects. Two test contractions (45 s) at 40% of maximal voluntary contraction (MVC) were performed, one with 2 cm interelectrode distance and the other with 4 cm, followed by two contractions at 80% MVC with the same change in interelectrode distance. Increasing the interelectrode distance from 2 to 4 cm caused a significant mean decrease (about 8%) in the initial median frequency. It is shown that this shift is of an order of magnitude that may be expected from the bipolar electrode filter factor, and we further conclude that the observed individual variations in the shift are likely to be connected to fluctuations in the shape of the power spectrum and to variations in conduction velocity. No significant change was found for the median frequency slope when changing the interelectrode distance. Increasing the force (from 40 to 80% MVC) also caused a significant mean decrease (about 10%) in the initial median frequency. The median frequency slope became significantly more negative by more than 200%. We conclude, however, that torque fluctuations during the fatigue contractions should have had only minor influence on the standard error of measurement of the initial median frequency and of the median frequency slope.     

BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.     

Retrospective dosimetry using OSL of tooth enamel and dental repair materials irradiated under wet and dry conditions

Following a radiological or nuclear emergency event, there is a need for quick and reliable dose estimations of potentially exposed people. In situations where dosimeters are not readily available, the dose estimations must be carried out using alternative methods. In the present study, the optically stimulated luminescence (OSL) properties of tooth enamel and different dental repair materials have been examined. Specimens of the materials were exposed to gamma and beta radiation in different types of liquid environments to mimic the actual irradiation situation in the mouth. Measurements were taken using a Ris? TL/OSL reader, and irradiations were made using a ⁹⁰Sr/⁹⁰Y source and a linear accelerator (6 MV photons). Results show that the OSL signal from tooth enamel decreases substantially when the enamel is kept in a wet environment. Thus, tooth enamel is not reliable for retrospective dose assessment without further studies of the phenomenon. Dental repair materials, on the other hand, do not exhibit the same effect when exposed to liquids. In addition, dose–response and fading measurements of the dental repair materials show promising results, making these materials highly interesting for retrospective dosimetry. The minimum detectable dose for the dental repair materials has been estimated to be 20–185?mGy.     

Aminomethyl-2,6-difluorophenols as a novel class of increased lipophilicity GABA(C) receptor antagonists

3- and 4-(Aminomethyl)-2,6-difuorophenols were tested for activity against the three major classes of GABA receptors. 4-(Amninomethyl)-2,6difluorophenol was shown to be a competitive and somewhat selective antagonist at p1 GABA(C) receptors expressed in Xenopus oocytes (K(B) = 75.5 microM with a 95% Confidence Interval range of 75.2 microM to 75.8 microM). This is the first in a novel class of increased lipophilicity GABA(C) receptor antagonists with little activity at alpha1beta2gamma2 GABA(A) and GABA(B) receptors.     

Acute psychological stress raises plasma ghrelin in the rat

Ghrelin is produced by the A-like cells of the stomach and mobilized by food deprivation. It was reported recently that acute psychological stress increases ghrelin gene expression in rat oxyntic mucosa. The aim of this study was to examine the effect of such stress on circulating ghrelin levels. To this end, we measured plasma ghrelin in Wistar Kyoto (WKY) rats (a high-anxiety strain) and Sprague-Dawley (SPD) rats (a low-anxiety strain), exposed to water avoidance stress for 60 min. Blood was collected before and after the stress. Acute stress increased the plasma ACTH concentration approximately 5-fold (p<0.01) in both strains of rats, while plasma ghrelin increased by 85% (p<0.01) in the SPD rats and by 40% (p<0.001) in the WKY rats. Ghrelin levels after acute stress were higher (p<0.05) in the SPD rats than in the WKY rats. Sham stress did not affect plasma ghrelin. We conclude that acute psychological stress mobilizes ghrelin and that the SPD rats respond with a higher plasma ghrelin concentration than the WKY rats.