Concentrations of Matrix Metalloproteinases and their Tissue Inhibitors in the Cerebrospinal Fluid of Patients with Alzheimer's Disease
Barbara MroczkoMagdalena GroblewskaMarzena ZbochAgnieszka Kulczynska‐PrzybikOlga Martyna Koper‐LenkiewiczMaciej SzmitkowskiJohannes KornhuberPiotr Lewczuk
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Background: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistentKeywords:
Neurochemical
Pathophysiology
Background: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent
Neurochemical
Pathophysiology
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Cerebrospinal fluid (CSF) and serum levels of cobalamin were studied in 35 subjects with dementia and in 7 healthy volunteers with no clinical or family history of dementia. The demented patients were classified into three groups according to DSM-III-R: dementia of Alzheimer-type (DAT), multi-infarct dementia (MID) and dementia not otherwise specified (DNOS). The CSF concentrations of cobalamin were significantly reduced in the DAT and MID cases. There were correlations between CSF and serum levels of cobalamin in the patient groups. The cobalamin levels in CSF were not related to cognitive functioning, behavior or degree of dementia, respectively. The subarachnoid spaces, ventricles and white-matter changes in the brain were observed on magnetic resonance imaging. The volumes were calculated in the DAT group, but there were no correlations to CSF or serum concentrations of cobalamin. The significance of low CSF cobalamin is discussed in relation to the metabolism of the brain.
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In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40–84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology. In a large multicentre study, Toledo et al. examine core Alzheimer's disease CSF biomarkers in 1233 cognitively normal subjects aged 40–85 years. Alzheimer disease-like changes in Aβ1-42 are seen as early as middle age, while APOE genotype strongly modifies age-related effects on both Aβ1–42 and phosphorylated/total tau.
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After head injury, many complex neurochemical events occur locally, at the site of initial injury, and globally, as a result of secondary phenomena. Neurochemical alterations in the cerebrospinal fluid after injury can be utilized to reflect these events. The authors review the role of the cerebrospinal fluid in the treatment of head injury as it relates to the diagnosis, prognosis, and further elucidation of the pathophysiological manifestations of head injury at the cellular and biochemical level. (Neurosurgery 18:234-243, 1986)
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Abstract Abstract The incidence of the "closing-in" phenomenon and of the tendency to give "primitive answers" on the Raven's Colored Matrices was studied in 50 normal subjects and in two groups of Alzheimer's type (n = 41) and of vascular (n = 35) dementia patients, carefully matched as for the overall severity of dementia and the degree of visual-spatial impairment. The aims of this research were to determine if these patterns of behavior can be considered as neuropsychological markers of dementia and if their incidence is similar in the two dementia groups. Results show that both the closing-in phenomenon and the tendency to give globalistic and odd responses on the Raven's Colored Matrices are good markers of dementia and that, in particular, they point to a degenerative, rather than to a vascular form of dementia. From the clinical point of view, these data suggest that a qualitative analysis of the patient's behavior can increase the diagnostic efficacy of neuropsychological tests and that neuropsychological markers of dementia point more to Alzheimer's disease (considered as the most prototypic form of dementia) than to a vascular form of dementia even when the two groups of patients are well balanced in terms of visual-spatial impairment and the overall severity of dementia.
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Vascular dementia
Cognitive Decline
Amyloid (mycology)
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The decrease in circulating testosterone and LH titer that occurs in aged male rats may in part be a consequence of decreased excitatory neurochemical signals that promote the episodic discharge of LHRH from the hypothalamus. In view of evidence that neuropeptide Y (NPY) stimulates the release and potentiates the action of LHRH on LH secretion, the present studies investigated age-related changes in the concentrations of NPY in individual hypothalamic nuclei and in the ability of hypothalamic tissues to release NPY in vitro. Compared with tissues of 2.5-month-old male rats, medial basal hypothalamic tissues of 13-month-old rats released significantly less NPY in response to K+ depolarization. In contrast, K+-evoked LHRH release from the same tissues was unimpaired. Aged male rats also exhibited markedly reduced concentrations of NPY in the median eminence and in the arcuate, medial preoptic, suprachiasmatic, paraventricular, dorsomedial, and ventromedial hypothalamic nuclei, which are sites of NPY perikarya and nerve terminal networks. These neurochemical changes occurred in association with decreased serum testosterone and LH levels. These findings demonstrate a widespread age-related decline in NPY levels and release in the hypothalamus, which may be responsible for the reduction in testosterone secretion and may contribute to the decline in reproductive function in aged male rats. (Endocrinology122: 2199–2203, 1988)
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Concentrations of individual free amino acids were determined in lumbar cerebrospinal fluid (CSF) from patients with various complaints including histologically verified Alzheimer9s dementia. Glycine and glutamine in the CSF of Alzheimer9s dementia samples were lower than that of control samples. Only the concentration of glutamic acid in Alzheimer9s dementia patients correlated with psychological measures. The reduction in glycine concentration was not specific for Alzheimer9s dementia.
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The association between cerebrospinal fluid (CSF) and serum concentration of thyroid hormones and pituitary thyrotropin stimulating hormone (TSH) was studied in nine hypothyroid patients (HT) before and in seven after L-thyroxine treatment. With L-thyroxine, median free T4 increased 4-fold in serum (3.5 pmol/L vs 17.5 pmol/L) and 3-fold in CSF, (3.9pmol/L vs 11.5 pmol/L). Correspondingly, total T3 in serum increased two-fold (0.9 nmol/L vs 2.2 nmol/L). Unexpectedly, free T3 concentration in CSF was similar (1.5 pmol/L vs.1.5 pmol/L) before and during treatment. In HT, TSH in serum correlated with TSH in CSF as did free T4 in serum and in CSF. During L-thyroxine, the correlation with TSH in serum and CSF remained. Likewise, the free T4 concentration in serum correlated with that in CSF. However, no correlation was found between T3 in serum and free T3 in CSF. It seems evident that free T4 in serum equilibrates with that in the CSF both in the HT and during L-thyroxine. Despite a two-fold increase in total serum T3, free T3 in CSF remained unchanged, which agrees with previous results in rats showing that T3 is less exchangeable between serum and CSF. Alternatively, an accelerated conversion of T4 to T3 might have maintained the concentration of T3, due to strongly increased levels of TSH found in the hypothyroid state. The notion that free T4 in serum reflects the CSF concentration of free T4 is consistent with previous reports from studies in animals.
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