Serum neurotrophins—A study on the time course and influencing factors in a large old age sample
Introduction
The neurotrophin nerve growth factor (NGF) and its effects on the regulation of different parts of the nervous system, namely the survival, differentiation and maintenance of function of peripheral, neural crest-derived sensory and sympathetic neurons as well as of the basal forebrain cholinergic neurons have been well established [1], [26], [50], [80]. Under physiologic conditions cerebral NGF synthesis in the rat and similarly human brain is highest in the hippocampus, the cortex and the basal forebrain. NGF is retrogradely transported to the basal forebrain by NGF-sensitive neurons, thus increasing cholinergic transmission. Nevertheless, there seems to be some additional autochtonous NGF expression capacity in the basal forebrain under pathophysiological conditions [26], [63], [76]. Increasing evidence of NGF production by peripheral immune cells and the immunomodulatory capacities of NGF provide a possible link between the function of the brain on one side and the function of the immune system on the other [2], [63]. In this context autocrine or paracrine NGF stimulation of leucocytes seems to be an important step in the “protective autoimmunity” processes mediating repair and regeneration of damaged neurons [16].
Along with NGF, brain-derived neurotrophic factor (BDNF) has been implicated in the development of the nervous system (namely, neuronal growth, differentiation, synaptic connectivity) and in neuronal survival and repair [50], [80]. Only recently neurogenesis under the influence of BDNF [59] and its effects on neuronal morphology have been demonstrated [32], [56]. Taken together, BDNF may play a key role in the activity dependent modulation of synapses and has therefore been implicated in long-term potentiation, a form of synaptic plasticity associated with memory formation, and specific behavioural patterns in social environments [8], [46], [63], [80], [81].
In line with the wide distribution of NGF and BDNF and their functions under physiological circumstances, there has been considerable interest in the role of neurotrophins in the pathophysiology of several diseases. NGF has been implicated in inflammatory, autoimmune and allergic conditions such as systemic lupus erythematosus and chronic juvenile arthritis [26], [63], diabetes mellitus type I [6], allergic asthma [11], [19], [62], symptomatic hay fever [44], multiple sclerosis [23], psoriasis [69], Kaposi's sarcoma [67], and bacterial meningitis in children [12]. Moreover, there seems to be a link between NGF availability and neuronal axonal repair in traumatic and neuropathic nerve damage [26], [63]. Considerable attention has been paid to the role of NGF in ageing and neurodegeneration. That NGF might reduce cholinergic cell loss in neurodegenerative diseases such as Alzheimer's disease has been appreciated for some time. Recently a preliminary human gene therapy trial has demonstrated neuroprotective qualities of NGF in neurodegeneration [84].
In contrast to NGF which has been implicated mainly in inflammatory responses, autoimmunity and neuronal repair [for reviews see 63], BDNF has been linked to a wide variety of conditions. Some inflammatory conditions such as multiple sclerosis [22], [41], inflammatory airway diseases [9], [11], [51], [53], and pediatric meningoencephalitis [12] have been associated with enhanced BDNF production. While in multiple sclerosis BDNF seems to be a protective factor [31], its role as a pathophysiological factor in neuronal hyperreactivity and pathological bronchoconstriction in asthma seems to be related to its abundance [52], [53]. Other conditions that have been linked to increased BDNF production include dependence [42]. A decreased production of BDNF has been found in neurodegenerative disorders such as Parkinson's and Alzheimer's disease [13], [34], [57], [66], in patients with metabolic syndrome and acute coronary syndromes [10], [54], as well as with adult and childhood-onset depression [38], [79] and even schizophrenia [35], [36], [37], [75], [87].
In contrast to the wealth of information pertaining to tissue-related BDNF and NGF concentrations in different animal models and in studies comparing groups of patients with control subjects, there is very little information about what could be regarded a normal range in healthy and diseased community dwelling human subjects and how those levels are influenced by different external factors. Since NGF is the first neurotrophin to be discovered, there is somewhat more information about NGF than about BDNF. Our group examined sera of 126 middle-aged healthy volunteers (21–71 years) and found that NGF concentrations were not normally distributed (skewed to the left) with 50% of values being between 11.06 and 41.74 pg/ml and 10% lying above 100 pg/ml [45]. In this age group there was no correlation between age and NGF, and no gender differences could be found. Although there is large interindividual variability, NGF concentrations seem to be intraindividually stable [45]. This is of particular importance since under physiological conditions only about 10% of NGF receptors are thought to be saturated so that little changes of NGF levels in an individual might have considerable impact downstream [see 26 for review].
As for blood-derived BDNF levels information what has to be regarded normal is even scarcer since existing studies on humoral BDNF levels in different diseases also included only small numbers of healthy subjects (mostly n < 35, one study n = 50) [38], [39], [43], [61], [64], [68], [74], [82]. Only a very recent study specifically addressed this question and the important question of influencing factors in healthy younger to middle-aged adults (age range: 20–60 years, median age 39 years, n = 140) [52]. Most importantly, this study reported a significant decrease of BDNF levels in plasma with age, while there was no decline in platelet levels. This is particularly interesting since humoral BDNF derived from different sources has been shown to be taken up by platelets which are the major pool of BDNF in blood and which can release BDNF [see 52 for further discussion]. Neuronal and glial cells seem to be a major source for BDNF stored in platelets with BDNF circulating freely between blood and brain compartments [39], [65]. Moreover, there is a striking correlation between serum and cortical BDNF levels in the rat [39]. Although age seems to be an important influence factor on neurotrophin levels at least in experimental animal models [33], [76] there are no published data in large groups of subjects over the age of 60 years. In the light of the importance of NGF and BDNF in terms of normal and pathological physiology, we present the hitherto largest set of data on serum neurotrophin levels in healthy and diseased community dwelling elderly subjects supplementing this way data on younger and middle-aged healthy adults published previously [45], [52].
Section snippets
Study participants
All subjects were recruited from the Berlin Aging Study [30], [88]. In brief, the Berlin Aging Study is a representative, community based, cross-sectional study of the old and very old (70 years and over; n = 516). All subjects in this study underwent a physical and psychiatric evaluation. If psychiatric disorders were found to be present diagnoses were made according to DSM-III-R and, if applicable, the Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's
General results
In the sample of subjects 70 years and over the mean serum BDNF concentration was 23198.7 ± 10649.2 pg/ml (n = 465) and the mean NGF level was 24.2 ± 7.3 pg/ml (n = 175). Neither BDNF nor NGF serum levels were distributed normally as proven by the Kolmogorov–Smirnov test. For the characterization of sub-groups see Table 1.
Relationship between neurotrophin serum levels and age
There was a negative correlation between serum BDNF levels and age in healthy old adults (r = −0.149, p = 0.017, see Fig. 1). By enlarging this sample to include all healthy and diseased
Discussion
The measured NGF and BDNF concentrations in human serum proved to be not normally distributed and there is a small group of healthy individuals with extreme neurotrophin concentrations (outliers) [45], [52]. To our knowledge, this study is the first to specifically address the question of NGF and BDNF serum levels in a large sample of healthy and diseased elderly subjects. The mean serum BDNF levels of 23198.7 pg/ml in the whole sample and of 23331.0 pg/ml in the healthy sub-sample are in keeping
Acknowledgements
Part of this work has been done as a medical doctoral thesis (DA and MM) at the Free University of Berlin. Parts of this work were supported by the Bundesministerium für Bildung, Forschung und Technologie (Verbund Klinische Pharmakologie Berlin-Brandenburg, Teilprojekt C6). We gratefully acknowledge the excellent technical assistance of Mrs. Pickersgill and Mrs. Bunge.
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