Dkk-3 is elevated in CSF and plasma of Alzheimer's disease patients

Biomarkers in CSF can offer improved diagnostic accuracy for Alzheimer's disease (AD). The present study investigated whether the glycoprotein and putative tumor suppressor Dickkopf homolog 3 (Dkk-3) is secreted into CSF and evaluated its applicability as a diagnostic marker for AD. Using our highly specific immunoenzymometric assay, Dkk-3 levels were measured in plasma and/or CSF of patients suffering from depression, mild cognitive impairment (MCI), or AD and compared with healthy subjects. Dkk-3 identity was verified by western blot and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)/MS. High concentrations of Dkk-3 were detected in CSF compared with plasma (28.2 ± 1.3 vs. 1.22 ± 0.04 nmol/L, respectively). Consistently Dkk-3 expression was demonstrated in neurons of the cortex and epithelial cells of the choroid plexus, the major source of CSF. Significantly increased Dkk-3 levels in plasma and CSF were observed for AD patients compared with healthy subjects but not patients suffering from MCI or depression. In summary, our data indicate that elevated Dkk-3 levels are specifically associated with AD and might serve as a potential non-invasive AD biomarker in plasma.     

Neuropeptides in Alzheimer's disease: a postmortem study

The concentration of 5 neuropeptides, neurotensin (NT), somatostatin (SRIF), corticotropin-releasing factor (CRF), bombesin and thyrotropin-releasing hormone (TRH) was measured in 3 cerebrocortical areas and several subcortical regions in post-mortem brains obtained from patients with histologically verified Alzheimer's disease and from controls without neurological or psychiatric disorders using sensitive and specific radioimmunoassay procedures. In Alzheimer's disease, reductions in the concentration of SRIF and CRF were observed in frontal and temporal cortex. In addition, in Alzheimer's disease, SRIF was also reduced in concentration in the hypothalamus, whereas CRF concentrations were reduced in the caudate nucleus. Neurotensin was reduced in concentration in the amygdala in Alzheimer's disease. No alterations in TRH or bombesin/gastrin-releasing peptide were found. These findings provide further evidence for the pathological involvement of certain neuropeptide-containing neurons in Alzheimer's disease.     

Blood-based neurochemical diagnosis of vascular dementia: a pilot study

Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.     

Potassium stimulated calcium dependent release of immunoreactive somatostatin from incubated rat hypothalamus

S omatostatin (somatotropin release inhibiting factor, SRIF) is present in the median eminence of the hypothalamus in high concentration (K ronheim et al., 1976), is visualized in nerve endings (H ökfelt et al., 1974) and has been found to be concentrated in the synaptosome fraction of hypothalamic homogenates (E pelbaum et al., 1977; B erelowitz et al., 1978), suggesting a true neurosecretory role. To further explore this possibility we have studied the release of immunoreactive SRIF from the incubated rat hypothalamus (B radbury et al., 1974: R otsztein et al., 1977), basally and in response to depolarising concentrations of potassium, and have assessed the calcium dependence of this release.     

5-Hydroxyindoleacetic acid and homovanillic acid concentrations in cerebrospinal fluid in patients with Alzheimer's disease, depression and mild cognitive impairment

In this study we investigated the cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in Alzheimer (AD) patients (n=75), patients with mild cognitive impairment (MCI, n=9) and patients with depression (n=7). CSF HVA was significantly elevated in AD with depression (Geriatric Depression Scale, 15 point version GDS>5) in comparison to AD without depression (p<0.05, ANOVA) and CSF HVA showed a significant positive correlation with the GDS score of AD-patients (p=0.03, Spearman Rho: 0.38, Spearman Rank Correlation). In the group of AD patients CSF 5-HIAA was positively correlated with cerebrospinal fluid beta-amyloid 1-42 (Abeta42), p<0.05, Spearman Rho: 0.3, Spearman Rank Correlation, but not with CSF tau. Additionally, there was a significant positive correlation between cerebrospinal fluid 5-HIAA and HVA in the group of AD patients (p<0.0001, Rho: 0.47, Spearman Rank correlation). Neither 5-HIAA nor HVA in CSF could differentiate between mild cognitive impairment, depression and AD. The results of this study support the hypothesis that the serotonergic system plays a role in the course of AD. They further suggest an important role of dopamine metabolism in depression within AD patients.     

CSF total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease

With the arrival of effective symptomatic treatments and the promise of drugs that may delay progression, we now need to identify Alzheimer’s disease (AD) at an early stage of the disease. To diagnose AD earlier and more accurately, attention has been directed toward peripheral biochemical markers. This article reviews promising potential cerebrospinal fluid (CSF) biomarkers for AD focussing on their role in clinical diagnosis. In particular, two biochemical markers, CSF total tau (t-tau) protein and the 42 amino acid form of β-amyloid (Aβ42), perform satisfactorily enough to achieve a role in the clinical diagnostic settings of patients with dementia together with the cumulative information from basic clinical work-up, genetic screening, and brain imaging. These CSF markers are particularly useful to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias. In order to discriminate AD from other primary dementia disorders, however, more accurate and specific markers are needed. Preliminary evidence strongly suggests that quantification of tau phosphorylated at specific sites in CSF improves early detection, differential diagnosis, and tracking of disease progression in AD.     

The impact of cerebrospinal fluid biomarkers on the diagnosis of Alzheimer's disease

The cerebrospinal fluid (CSF) biomarkers β-amyloid(1-42) (Aβ(1-42)), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau(181P)) are gradually finding their way into routine clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria for AD. The combination of the CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P) leads to high (around 80%) levels of sensitivity, specificity, and diagnostic accuracy for discrimination between AD and controls (including psychiatric disorders like depression) and can be applied for diagnosing AD in the predementia phases of the disease (mild cognitive impairment). The added value of CSF biomarkers could lie within those cases in which the clinical diagnostic work-up is not able to discriminate between AD and non-AD dementias. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers, especially those that are reflective of the pathology of non-AD dementia etiologies, could improve the accuracy of differential dementia diagnosis. CSF biomarkers will be of help to establish a correct and early AD diagnosis, even in the preclinical stages of the disease, which will be of importance once disease-modifying drugs for AD become available. Variation in biomarker measurements still jeopardize the introduction of CSF biomarkers into routine clinical practice and clinical trials, but several national and international standardization initiatives are ongoing.     

Increased lipoprotein oxidation in Alzheimer's disease

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.     

Decreased expression of the mRNA for somatostatin in the periventricular nucleus of depression-model rats.

Expression of the mRNA for somatostatin (SRIF) in the periventricular nucleus (PeN), the level of SRIF in the stalk-median eminence (SME) and the concentration of growth hormone (GH) in the plasma were examined in depression-model rats in an attempt to confirm the hypothesis that SRIF neurons in the hypothalamus are hypofunctional in this model. We exposed male Wistar rats to intermittent walking stress for two weeks and then we measured their spontaneous running activity for 12 days. We divided the rats into a depression-model group and a partial-recovery group according to the spontaneous running activity of each rat after the termination of exposure to stress. Expression of SRIF mRNA in the PeN of the hypothalamus was monitored by in situ hybridization and relative levels were determined with an image analysis system. The relative level of expression of SRIF mRNA in the PeN was lower in rats in the depression-model group than in the control group and the partial-recovery group. The level of SRIF in the SME was lower and the plasma concentration of GH was higher in the depression-model group than in the other groups. Our findings suggest that reduced expression of mRNA for SRIF in the PeN might be associated with the pathophysiology of rats with this particular model of depression.     

Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease.

Because increased oxidation is an important feature of Alzheimer's disease (AD) and low concentrations of antioxidant vitamins C and E have been observed in cerebrospinal fluid (CSF) of AD patients, supplementation with these antioxidants might delay the development of AD. Major targets for oxidation in brain are lipids and lipoproteins. We studied whether supplementation with antioxidative vitamins E and C can increase their concentrations not only in plasma but also in CSF, and as a consequence decrease the susceptibility of lipoproteins to in vitro oxidation. Two groups, each consisting of 10 patients with AD, were for 1 month supplemented daily with either a combination of 400 IU vitamin E and 1000 mg vitamin C, or 400 IU vitamin E alone. We found that supplementation with vitamin E and C significantly increased the concentrations of both vitamins in plasma and CSF. Importantly, the abnormally low concentrations of vitamin C were returned to normal level following treatment. As a consequence, susceptibility of CSF and plasma lipoproteins to in vitro oxidation was significantly decreased. In contrast, the supplementation with vitamin E alone significantly increased its CSF and plasma concentrations, but was unable to decrease the lipoprotein oxidizability. These findings document a superiority of a combined vitamin E + C supplementation over a vitamin E supplementation alone in AD and provide a biochemical basis for its use.     

Sphingolipid Metabolism Correlates with Cerebrospinal Fluid Beta Amyloid Levels in Alzheimer’s Disease

Sphingolipids are important in many brain functions but their role in Alzheimer’s disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β₄₂ concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β₄₂ concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.     

Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease

We investigated the lipoprotein distribution and composition in cerebrospinal fluid (CSF) in a group of patients with Alzheimer's disease (AD) or affected by other types of dementia in comparison to non-demented controls. We found slightly decreased apolipoprotein (apo)E and cholesterol concentrations in CSF of AD patients and moderately increased apoA-I concentrations, while in patients suffering from other types of dementia the apoA-I CSF concentration was increased. ApoA-IV concentrations varied widely in human CSF, but were not associated with any clinical condition. HDL(2)-like apoE-containing lipoproteins represent the major lipoprotein fraction. In CSF of normal controls, only a minor HDL(3)-like apoA-I-containing lipoprotein fraction was observed; this fraction was more prevalent in AD patients. ApoA-II was recovered mostly in the HDL(3) density range, while apoA-IV was not associated with lipoproteins but appeared in a lipid-free form, co-localizing with LCAT immunoreactivity. Bi-dimensional analysis demonstrated pre-beta and alpha apoA-I-containing particles; apoE and apoA-II were detected only in alpha-migrating particles. ApoA-IV distributed both to pre-beta and gamma-migrating particles; the LCAT signal was co-localized in this gamma-migrating fraction. Enzymatically active LCAT was present in human CSF as well as PLTP activity and mass; no CETP mass was detected. In CSF from AD patients, LCAT activity was 50% lower than in CSF from normal controls. CSF lipoproteins induced a significant cholesterol efflux from cultured rat astrocytes, suggesting that they play an active role in maintaining the cholesterol homeostasis in brain cells.     

Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer’s disease and other neurodegenerative diseases

Introduction: Neuroinflammation is a crucial mechanism in the pathophysiology of neurodegenerative diseases pathophysiology. Cerebrospinal fluid (CSF) YKL-40 – an indicator of microglial activation ? has recently been identified by proteomic studies as a candidate biomarker for Alzheimer’s disease (AD).

Areas covered: We review the impact of CSF YKL-40 as a pathophysiological biomarker for AD and other neurodegenerative diseases. CSF YKL-40 concentrations have been shown to predict progression from prodromal mild cognitive impairment to AD dementia. Moreover, a positive association between CSF YKL-40 and other biomarkers of neurodegeneration – particularly total tau protein ? has been reported during the asymptomatic preclinical stage of AD and other neurodegenerative diseases. Albeit preliminary, current data do not support an association between APOE-ε4 status and CSF YKL-40 concentrations. When interpreting the diagnostic/prognostic significance of CSF YKL-40 concentrations in neurodegenerative diseases, potential confounders – including age, metabolic and cardiovascular risk factors, diagnostic criteria for selecting cases/controls – need to be considered.

Expert opinion/commentary: CSF YKL-40 represents a pathophysiological biomarker reflecting immune/inflammatory mechanisms in neurodegenerative diseases, associated with tau protein pathology. Besides being associated with tau pathology, CSF YKL-40 adds to the growing array of biomarkers reflecting distinct molecular brain mechanisms potentially useful for stratifying individuals for biomarker-guided, targeted anti-inflammatory therapies emerging from precision medicine.     

Effect of somatostatin and octreotide on proliferation and vascular endothelial growth factor secretion from murine endothelial cell line (HECa10) culture

Angiogenesis, development of new blood vessels, is required for normal tissue repair and also for tumor cell proliferation, extracellular matrix invasion, and hematogenous metastases. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that has been shown to play a key role in neovascularization. Inhibition of angiogenesis in vitro and in vivo was documented by administration of native neuropeptide somatostatin and its analog octreotide. We have studied the effect of somatostatin-14 (SRIF) and ocreotide (sandostatin) on proliferation activity and VEGF release from cultured murine endothelial cells HECa10 in vitro. SRIF in concentrations from 10(-9) to 10(-5) M and ocreotide in concentrations from 10(-9) to 10(-5) M diminished the proliferative activity of cultured cells vs controls. SRIF and ocreotide in concentrations from 10(-14) to 10(-6) M did not change the release of VEGF into supernatants of 24 or 72 h endothelial cell cultures. Although we showed the antiproliferative effect of SRIF and ocreotide on mouse endothelial cells, we were unable to demonstrate the inhibitory effect of tested peptides on VEGF secretion in vitro.     

Effect of streptozotocin administration on somatostatin content of pancreas and hypothalamus in rats.

A radioimmunoassay (RIA) method for somatostatin (SRIF) utilizing rabbit antiserum against synthetic SRIF coupled with human serum alpha-globulin is described. Synthetic N alpha-tyrosylated SRIF was labelled with 125I using the lactoperoxidase method and purified on a Sephadex G-10 column. This assay system was highly specific for SRIF and did not cross-react with hypothalamic trophic hormones, pituitary trophic hormones or gastrointestinal hormones. The effect of streptozotocin induced diabetes on the SRIF content was examined in the pancreas, the pancreatic islets, as well as the hypothalamus of rats. SRIF content in both the pancreas and islets of the diabetic rats was shown by RIA to have significantly increased. However, content in the hypothalamus of the diabetic rats did not differ from that of the control. The physiological and pathophysiological significance of the SRIF changes remains to determined.     

Reduced Somatostatin in Hypothalamus of Young Male Mouse Increases Local but not Circulatory GH

The release of growth hormone (GH) from the pituitary gland is primarily inhibited by somatostatin (SRIF) from the hypothalamus via interactions with five types of SRIF receptors (SSTRs). However, the inhibition mechanism of SRIF on GH has not been fully examined. In this study, we repressed the hypothalamic SRIF in young male mice by stereotaxic injection of the lentiviral-shRNA against SRIF to investigate the role of hypothalamic SRIF on hormone secretion in the GH/IGF-1 axis. We found that the reduction of SRIF in hypothalamus was associated with an increase in the protein, but not the mRNA level, of the GH in the pituitary where SSTR 2 and SSTR 5 act importantly. Interestingly, the level of blood circulatory SRIF, GH, IGF-1 and the body weight were not significantly influenced by the downregulation of hypothalamic SRIF. Our findings provide insights into the mechanisms underlying the inhibition of SRIF on GH secretion.     

Measurement of Aβ1-42 in cerebrospinal fluid is influenced by matrix effects

Aβ1-42 measurement in CSF is an important biochemical marker for Alzheimer disease (AD). However, our understanding of why this biomarker is predictive and why it is often difficult to measure in a reproducible fashion is still lacking. To study these questions, the concentration of Aβ1-42 in CSF was compared before and after denaturation with 6M guanidine and reverse-phase HPLC. Measurement of the Aβ1-42 after denaturation and reverse-phase HPLC demonstrated that considerably more Aβ1-42 was present in CSF than revealed when assaying non-denatured CSF. A comparison of Aβ1-42 concentrations before and after HPLC in AD CSF with that in normal controls suggested that matrix interference may affect the differentiation between the diagnostic groups. A similar effect was observed with dilutions of crude CSF. Together, these results suggested that at least part of the mechanism by which low Aβ1-42 concentrations in CSF function as a biomarker of AD is related to matrix components which preferentially hide a portion of the Aβ1-42 from detection in AD CSF. In contrast, we show that the association of the APOEε4 allele with lower Aβ1-42 concentrations in CSF is preserved even after denaturation and HPLC. A similar relationship between the presence of the APOEε4 allele and lower concentrations of Aβ1-40 was also apparent, thereby generating similar ratios of Aβ1-42/ Aβ1-40 across the APOE genotypes. The results from the present study suggested that Aβ1-42 in CSF functions as a biomarker of AD in tandem with other CSF matrix components that are increased in AD CSF. Further studies are needed to identify which matrix factors (e.g. binding of Aβ to proteins) underlie the increased detection of Aβ1-42 concentrations after denaturation and HPLC. The data also suggested that denaturation and HPLC of CSF may be a useful approach for studies using Aβ1-42 as a pharmacodynamic marker or in other paradigms where measurement of total non-covalently bound Aβ1-42 is required.     

Intrahypothalamic pituitary grafts elevate prolactin in the cerebrospinal fluid and attenuate prolactin release following ether stress

Anterior pituitary (AP) tissue grafted into the hypothalamus of female rats inhibits the luteotrophic prolactin (PRL) secretion which normally follows mating. Dopamine blockade has been shown to overcome this inhibition, suggesting that the grafts suppress PRL release from the in situ pituitary by the action of graft PRL increasing dopamine activity in the hypothalamus. To examine whether PRL levels in the cerebrospinal fluid (CSF) were elevated by the AP grafts, CSF samples were taken from 5 control rats and 10 rats bearing intrahypothalamic AP grafts. Mean PRL concentrations in the CSF of the control rats were 3.0 +/- 0.8 ng/ml. The grafted rats had significantly higher concentrations of PRL in their CSF, averaging 23.2 +/- 4.2 ng/ml (P less than 0.005). Plasma PRL concentrations were similar in the control and grafted rats. PRL release in response to 5 min of ether stress was examined in 8 control and 11 grafted rats. In control animals, PRL rose from 4.2 +/- 1.5 to 44.7 +/- 9.0 ng/ml following exposure to ether, but the response was significantly attenuated in the grafted rats, peaking at 9.3 +/- 1.4 ng/ml (P less than 0.001). This inhibition of response due to the grafts was evident within 1 week of graft placement. The results confirm that the presence of intrahypothalamic AP grafts led to the accumulation of supranormal PRL concentrations in the CSF. This elevated PRL suppressed pituitary PRL release in response to ether stress, probably by an autoregulatory feedback activation of the inhibitory tuberoinfundibular dopaminergic neurons in the hypothalamus.     

Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer's disease

Postmortem demonstration of increased expression of biologically active S100B in Alzheimer's disease (AD) and its relation to progression of neuropathological changes across the cortical regions suggests involvement of this astrocytic cytokine in the pathophysiology of AD. The hypothesis that the overexpression of S100B in Alzheimer brain is related to the progression of clinical symptoms was addressed in living persons by measuring S100B concentrations in cerebrospinal fluid (CSF) from AD patients with a broad range of clinical dementia severity and from healthy older persons. The effect of normal aging on CSF S100B concentrations also was estimated. CSF S100B did not differ between all 68 AD subjects (0.98±0.09 ng/ml (mean±S.E.M.)) and 25 healthy older subjects (0.81±0.13 ng/ml). When AD subjects were divided into mild/moderate stage and advanced stage clinical dementia severity by the established Clinical Dementia Rating Scale (CDR) criteria, S100B was significantly higher in the 46 mild/moderate stage AD subjects (1.17±0.11 ng/ml) than in either the 22 advanced stage AD subjects (0.60±0.12 ng/ml) or the healthy older subjects. Consistent with higher CSF S100B in mild to moderate AD, there was a significant correlation among all AD subjects between CSF S100B and cognitive status as measured by the Mini Mental State Exam (MMSE) score. CSF S100B did not differ between healthy older subjects and healthy young subjects. These results suggest increased CNS expression of S100B in the earlier stages of AD, and are consistent with a role for S100B in the initiation and/or facilitation of neuritic plaque formation in AD brain.     

Transition metal abnormalities in progressive dementias

Abnormal distributions of transition metals inside the brain are potential diagnostic markers for several central nervous system diseases, including Alzheimer’s disease (AD), Parkinson’s disease, dementia with Lewy bodies (DLB), bipolar disorders and depression. To further explore this possibility, the total concentrations of iron, zinc, copper, manganese, aluminum, chromium and cadmium were measured in post-mortem hippocampus and amygdala tissues taken from AD, DLB and Control patients. A statistically significant near fifty percent reduction in the total copper levels of AD patients was observed in both the hippocampus and amygdala. The statistical power of the hippocampus and amygdala copper analysis was found to be 86 and 74% respectively. No statistically significant deviations in the total metal concentrations were found for zinc, manganese, chromium or aluminum. Iron was found to be increased by 38% in AD amygdala tissues, but was unchanged in AD hippocampus tissues. Accounting for differences in tissue water content, as a function of both tissue type and disease state, revealed more consistencies with previous literature. To aid in the design of future experiments, the effect sizes for all tissue types and metals studied are also presented.