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Biomedical subjects

D F Swaab

Publications and source records attributed to D F Swaab.

At least 19 recordsLinked to original sources
PubMed2003

Early social stress in male Guinea-pigs changes social behaviour, and autonomic and neuroendocrine functions.

The present study was undertaken to investigate the effects of pre- and early postnatal social stress on the functioning of hormonal, autonomic and behavioural systems, by studying the distribution of sex hormone receptors in limbic brain systems. Dams had either lived in groups with a constant composition (= stable social environment) or in groups with changing compositions, i.e. every third day, two females from different groups were exchanged (= unstable social environment). The subjects were male offspring of dams who had either lived in a stable social environment during pregnancy and lactation (= control males) or in an unstable social environment during this period of life (= early stressed males). From days 20-80, the spontaneous behaviour of control males and early stressed males was recorded in their home cages. Five control males and five early stressed males were killed at 75 days, and five control males and five early stressed males at 120 days. Blood samples were taken to determine serum concentrations of cortisol, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate and oestrogen. The adrenals were prepared to determine tyrosine hydroxylase activities and the brains were used to investigate the distribution of sex-hormone receptors in specific hypothalamic and hippocampal brain areas. Early stressed males showed a behavioural infantilization that was accompanied by significantly decreased adrenal tyrosine hydroxylase activities and dehydroepiandrosterone levels. Furthermore, early stressed males showed a down-regulation of androgen receptors in the medial preoptic area and the nucleus arcuatus of the hypothalamus, as well as of oestrogen receptor alpha in the hippocampus compared to control males. Thus, the present study provides clear evidence that early social stress induces changes in endocrine, autonomic and limbic brain function, which is mirrored by changes in male social behaviour.

Animals↗
PubMed2002

Co-localization of histamine with GABA but not with galanin in the human tuberomamillary nucleus.

The presence of GABA and galanin in histaminergic neurons was previously reported in the rodent brain but whether such co-localizations also occur in the human brain was not known. We used in situ hybridization histochemistry and immunohistochemistry to study the co-localization of histamine with GABA and galanin in neurons of the tuberomamillary nucleus of adult human posterior hypothalamus. On consecutive formalin-fixed paraffin-embedded sections, co-localization was assessed using the in situ hybridization for L-histidine decarboxylase mRNA and immunocytochemistry for glutamate decarboxylase-67 kDa or galanin in the two profiles of same cell. The pattern of distribution and number of histaminergic neurons identified by in situ hybridization of the synthesizing enzyme gene transcripts were in accordance with data reported for histamine immunoreactivity. The great majority of neurons within the main divisions of the tuberomamillary nucleus containing L-histidine decarboxylase mRNA was also immunoreactive for glutamate decarboxylase-67 kDa. The range of co-localization of the two markers varied from 72% in the lateral part, to 75-87% in the medial part and 83-88% in the ventral part. In contrast, no cell containing L-histidine decarboxylase mRNA was immunoreactive for galanin. We conclude that tuberomamillary neurons in human co-express histamine with GABA but, unlike the neurons in rodents, do not express galanin, indicating that neurotransmitter co-localization patterns differ in the two species.

Adult↗
PubMed2002

Cranial electrostimulation (CES) in patients with probable Alzheimer's disease.

In one study, behavioral disorders of patients with vascular dementia reacted positively to cranial electrostimulation (CES). In the present study, it was examined whether CES could improve cognition and (affective) behavior in patients with probable Alzheimer's disease (AD). Eighteen AD patients, divided into an experimental and a placebo group, were treated for 30 min per day, 5 days a week, for 6 weeks. No improvements in cognition and (affective) behavior were found after CES.

Aged↗
PubMed2002

Brain aging and Alzheimer's disease; use it or lose it.

(1) Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. (2) The neuropathological hallmarks of AD, i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but may occur independently. (3) In brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. The decreased metabolic rate appears not to be induced by the presence of pretangles, NFT or NPs. (4) Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of AD, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in AD patients also supports the view that AD has a metabolic basis. (5) Moreover, several observations in postmortem brain indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as 'use it or lose it'. (6) It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in AD. A number of pharmacological and non-pharmacological studies support the concept that activation of the brain has beneficial effects and may, to a certain degree, restore several aspects of cognition and other central functions. For instance, the circadian system may be restimulated in AD patients by exposing them to more light or transcutaneous nerve stimulation. A procedure has been developed to culture human postmortem brain tissue that allows testing of the efficacy of putative stimulatory compounds such as neurotrophins.

Aging↗
PubMed2002

Senescence, sleep, and circadian rhythms.

The goal of this review article is to summarize our knowledge and understanding of the overlapping (interdisciplinary) areas of senescence, sleep, and circadian rhythms. Our overview comprehensively (and visually wherever possible), emphasizes the organizational, dynamic, and plastic nature of both sleep and circadian timing system (CTS) during senescent processes in animals and in humans. In this review, we focus on the studies that deal with sleep and circadian rhythms in aged animals and how these studies have closely correlated to and advanced our understanding of similar processes in ageing humans. Our comprehensive summary of various aspects of the existing research on animal and human ageing, both normal and pathological, presented in this review underscores the invaluable advantage of close collaboration between clinicians and basic research scientists and the future challenges inherent in this collaboration. First, our review addresses the common age-related changes that occur in sleep and temporal organization of both animals and humans. Second, we examine the specific modifications that often accompany sleep and CTS during aging. Third, we discuss the clinical epidemiology of sleep dysfunctions during ageing and their current clinical management, both pharmacological and non-pharmacological. Finally, we predict the possible future promises for complementary and alternative medicine (CAM) that pave the way to the emergence of a "Holistic Sleep Medicine" approach to the treatment of sleep disorders in the ageing population. Further studies will provide additional valuable insights into the understanding of both sleep and circadian rhythms during senescence.

Aging↗
PubMed2002

Cortisol is increased in postmortem cerebrospinal fluid of multiple sclerosis patients: relationship with cytokines and sepsis.

Hypothalmo-pituitary-adrenal (HPA) axis activity is altered in patients with multiple sclerosis (MS), resulting in elevated basal levels and enhanced response of cortisol in stimulation tests. HPA axis hyperactivation in MS is thought to be the result of complex interactions of genetic, immunologic, and neuroendocrinological mechanisms. In order to investigate whether cytokine levels in the central nervous system are associated with the activation of the HPA axis in MS, we measured cortisol, interleukin (IL)-6, IL-10 and TNF-alpha levels in postmortem cerebrospinal fluid (CSF) of 18 patients with severe MS and 50 controls. We also investigated the cortisol and cytokine levels in the CSF of a group of MS patients and controls who died with sepsis, in order to see whether acute infectious situations affect the association between cortisol and cytokines. The cortisol levels in MS patients were increased by 80% in comparison to controls (p=0.008). There was no difference in IL-6 levels between the groups, while IL-10 and TNF-alpha levels of the majority of subjects were below detection limits. There was a positive correlation between cortisol and IL-6 only in control patients with sepsis (r=0.89, p=0.019), but not within the MS patents with sepsis or MS and control groups without sepsis. Cortisol levels in postmortem serum and CSF were highly correlated (r>0.78, p<0.001). We concluded that the basal level of cortisol is significantly increased in the CSF of MS patients and that IL-6 is not responsible for this rise. The relationship between cortisol and IL-6 in sepsis is discussed.

Aged↗
PubMed2002

Glucocorticoid treatment is associated with decreased expression of processed AVP but not of proAVP, neurophysin or oxytocin in the human hypothalamus: are PC1 and PC2 involved?

OBJECTIVES: We reported earlier that vasopressin (AVP) peptide expression is significantly decreased in the postmortem hypothalamus of glucocorticoid (GC) treated patients, while such a decrease was not observed in AVP prohormone (proAVP) expression. This indicated a GC-induced suppression of AVP synthesis at the posttranslational level. Here, we investigated in detail whether this decreased levels of AVP expression in GC treated patients might be due to the down regulation of the prohormone convertases PC-1 and PC-2, and the molecular chaperone 7B2, as was reported previously in some AVP-related disorders. MATERIALS & METHODS: An immunocytochemical study was performed on post-mortem hypothalami of GC exposed patients and controls, in which quantification of proAVP, AVP, neurophysin (NP) and oxytocin (OXT) expression were done along with the quantification of PC1, PC2 and 7B2 expression in the paraventricular nucleus, by using a computerized image analysis system. RESULTS: Expression of processed AVP in GC exposed patients was significantly decreased (p=0.021), while the amount of proAVP expression was unchanged. Despite the strong correlation between AVP and NP (the other cleavage product of proAVP) expression in the GC group (r=0.917, p=0.004), the mean NP immunoreactivity did not show a significant decrease in this group. Also the OXT expression was similar in both groups. Although in most of the GC treated patients, the expression intensities of PC1 and PC2 were decreased parallel to the decrease in AVP, the mean expression levels of neither of PC1 and PC2, nor of 7B2 were statistically different between the groups (p=0.20-0.80). CONCLUSION: We conclude that the suppression of AVP expression by GCs is not mediated solely by the down regulation of PC1, PC2 or 7B2. Other mechanisms, which may contribute to the GC-induced posttranslational suppression of AVP, are discussed.

Adult↗
PubMed2001

Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock.

Abnormalities in autonomic activity resulting in disturbances of the diurnal rhythm of many physiologic processes were recently revealed in hypertensive patients. These findings suggest deteriorations in the functioning of the suprachiasmatic nucleus (SCN), which is known to be the biological clock of mammals. To test this hypothesis, we carried out an immunocytochemical study of the SCN of primary hypertension patients who had died due to myocardial infarction or brain hemorrhage, and compared them with those of individuals with a normal blood pressure who had never had any autonomic disturbances and died from myocardial infarction after chest trauma or from hypothermia. We found that the staining for the three main neuronal populations of the SCN; i.e., vasopressin, vasoactive intestinal polypeptide, and neurotensin, reduced by more than 50% in the hypertensives compared with controls. The present data indicate a serious dysregulation of the biological clock in hypertensive patients. Such a disturbance may cause a harmful hemodynamic imbalance with a negative effect on circulation, especially in the morning, when the inactivity-activity balance changes. The difficulty in adjusting from inactivity to activity might be involved in the morning clustering of cardiovascular events.

Adult↗
PubMed2001

Metabolic activity of the human ventromedial nucleus neurons in relation to sex and ageing.

The ventromedial nucleus (VMN) in animals is involved in a number of sexually dimorphic behaviors, including reproduction, and is a well-documented target for sex steroids. In rats and in lizards, it is also characterized by the presence of structural sexual dimorphisms. In the present study, we determined whether the metabolic activity of human ventromedial nucleus neurons was sex- or age-related. The size of the immunocytochemically defined Golgi apparatus (GA) and cell profiles were determined as measures for neuronal metabolic activity in 12 male and 16 female control brains sub-divided into four groups with the dividing line being the age of 50. It appeared that the size of the GA relative to cell size was 34% larger in young women (<50 years old) than in young men and was 25% larger in elderly men (> or = 50 years old) than in young men. In addition, the GA/cell size ratio correlated significantly with age in men and not in women. Our data suggest that androgens play an inhibitory role with respect to the metabolic activity of the human VMN neurons.

Adult↗
PubMed2001

Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression.

BACKGROUND: Circadian rhythm disturbances are frequently found in depressed subjects. Although it has been presumed that these disturbances may reflect a disorder of the circadian pacemaker, this has never been established. The suprachiasmatic nucleus (SCN) is the pacemaker of the circadian timing system in mammals, and arginine vasopressin (AVP) is one of its major neuropeptides. As peptide content is often taken as a measure for activity, we hypothesized that a decreased number of AVP-immunoreactive (AVP-IR) neurons and amount of AVP-messenger RNA (mRNA) would be present in the SCN of depressed subjects. METHODS: Brains of 11 subjects suffering from major depression (8 cases) and bipolar disorder (3 cases), and of 11 controls, matched for sex, age, and clock time at death, were collected. The number of AVP-IR neurons in the SCN was determined by means of a digitizer (CalComp Inc, Reading, England). The amount of AVP-mRNA expression in the SCN was quantified with the Interaktive Bild Analyse System image analysis system (Kontron, Munich, Germany). RESULTS: In depressed subjects, the number of AVP-IR neurons in the SCN was more than one and a half times higher than in controls, while the total masked area of silver grains, as an estimate of the amount of AVP-mRNA, was about one half that of controls. CONCLUSIONS: Contrary to our hypothesis, an increase in the number of AVP-IR neurons in the SCN in depression was found, together with an expected decrease in AVP-mRNA. These findings suggest that, in depressed patients, both the synthesis and release of AVP in the SCN is reduced, resulting in an impaired functional ability. A disbalance between AVP production and transport needs further investigation in future studies.

Age of Onset↗
PubMed2001

Structural and functional sex differences in the human hypothalamus.

Sex differences in the brain may be the basis not only for sex differences in reproduction, gender identity (the feeling of being male or female), and sexual orientation (heterosexuality vs homosexuality), but also for the sex difference in prevalence of psychiatric and neurological diseases ( Swaab and Hofman, 1995 ). In this brief article we discuss a few examples of structural and functional sex differences in the human brain.

Aging↗
PubMed2001

Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure.

Glucocorticoid (GC) overexposure in animals has been implicated in hippocampal dysfunctioning and neuronal loss. In major depression, hypercortisolemia, hypothalamic-pituitary-adrenocortical-axis alterations, and reduced hippocampal volumes are commonly observed; hence, hippocampal neurodegeneration is also expected. To study possible GC-related pathology, we investigated hippocampal tissue of 15 major-depressed patients, 16 matched controls, and 9 steroid-treated patients, using in situ-end-labeling for DNA fragmentation and apoptosis, and heat-shock protein 70 and nuclear transcription factor kappaB immunocytochemistry for damage-related responses. No obvious massive cell loss was observed in any group. In 11 of 15 depressed patients, rare, but convincing apoptosis was found in entorhinal cortex, subiculum, dentate gyrus, CA1, and CA4. Also in three steroid-treated patients, apoptosis was found. Except for several steroid-treated patients, heat-shock protein 70 staining was generally absent, nor was nuclear transcription factor-kappaB activation found. The detection in 11 of 15 depressed patients, in three steroid-treated, and in one control patient, demonstrates for the first time that apoptosis is involved in steroid-related changes in the human hippocampus. However, in absence of major pyramidal loss, its rare occurrence, that notably was absent from areas at risk for GC damage such as CA3, indicates that apoptosis probably only contributes to a minor extent to the volume changes in depression.

Adolescent↗
PubMed2001

Decreased neuropeptide Y (NPY) expression in the infundibular nucleus of patients with nonthyroidal illness.

In patients with a variety of illnesses, serum concentrations of T3 decrease without giving rise to elevated serum levels of TSH, a phenomenon known as the sick euthyroid syndrome or nonthyroidal illness (NTI). Our previous studies in postmortem brain material showed decreased thyrotropin-releasing hormone (TRH) messenger RNA (mRNA) in the paraventricular nucleus (PVN) of patients with NTI, suggesting a role for TRH cells in the persistence of low TSH levels in NTI. In the present study, we hypothesized that changes in neuropeptide Y (NPY) input from the infundibular nucleus (IFN) to TRH cells in the PVN might be a determinant of decreased TRH expression in NTI. We investigated the hypothalamus of nine patients whose endocrine status had been assessed in a serum sample taken less than 24h before death and we examined NPY expression in the IFN by means of immunocytochemistry and mRNA in situ hybridization using an image analysis system. There was a negative correlation (r = -0.88; p = 0.01) between serum leptin concentrations and total NPY mRNA in the IFN. The total amount of NPY immunoreactivity in the IFN correlated with total NPY mRNA (r = 0.69; p = 0.04). In contrast to the situation in food-deprived rodents, total NPY immunoreactivity in the IFN showed a positive correlation with total TRH mRNA in the PVN (r = 0.77; p = 0.02). The results suggest a role for decreased NPY input from the IFN in the resetting of thyroid hormone feedback on hypothalamic TRH cells in NTI.

Adult↗
PubMed2001

Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus.

In major depression, decreased hippocampal volume has been attributed to hypercortisolemia, a frequent sign of the disorder, because in animals an excess of corticosteroids has led to dendritic atrophy, astrogliosis and loss of neurons in this brain region. The present study is the first to investigate the structural integrity of the human hippocampus in major depression and following glucocorticoid treatment. Post-mortem hippocampal tissue from 15 patients who had had major depression or bipolar affective disorder, 10 patients who had been treated with glucocorticoids and 16 controls was assessed using haematoxylin-eosin, Nissl and Bodian staining. The patterns of reactive astrogliosis (glial fibrillary acidic protein, GFAP), synaptic density (synaptophysin), synaptic reorganization (growth-associated protein B-50) and early signs of Alzheimer's disease (Alz-50) were examined immunocytochemically. Multivariate analysis, with the patients' age, tissue fixation time and postmortem delay as covariates, was performed. There was no evidence of neuronal cell loss or other major morphological alterations in any of the groups, nor was there a significant change in the distribution pattern of synaptophysin or Alz-50. Changes in B-50 and GFAP staining were observed in the steroid-treated and depressed patients in areas CA1 and CA2 only. The human hippocampus in major depression and after glucocorticoid treatment does not reveal any major morphological changes or signs of neuronal cell death, but does show subtle alterations in B-50 and GFAP expression in selected parts of the pyramidal cell layer.

Adult↗
PubMed2001

Hypothalamic lesions in multiple sclerosis.

Demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e. the fornix. anterior commissure, internal capsule, and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients. Therefore we investigated the presence and immunological activity of lesions in hypothalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed demyelinated lesions. The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the internal capsule (p = 0.005). In 4 of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients grey matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score (r = -0.72, p = 0.001). Since comparison of hypothalamic lesions with MS lesions in other areas of the brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02). In the median eminence region that lacks a blood-brain barrier, all controls showed a strong HLA expression around the blood vessels. We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.

Adult↗
PubMed2001

Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality.

In a previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally, men had stronger nuclear AR immunoreactivity (AR-ir) than women. The strongest nuclear labeling was found in the caudal hypothalamus in the mamillary body complex (MBC), which is known to be involved in aspects of cognition and sexual behavior. The present study was carried out to investigate whether the sex difference in AR-ir of the MBC is related to sexual orientation or gender identity (i.e. the feeling of being male or female) or to circulating levels of androgens, as nuclear AR-ir is known to be up-regulated by androgens. Therefore, we studied the MBC in postmortem brain material from the following groups: young heterosexual men, young homosexual men, aged heterosexual castrated and noncastrated men, castrated and noncastrated transsexuals, young heterosexual women, and a young virilized woman. Nuclear AR-ir did not differ significantly between heterosexual and homosexual men, but was significantly stronger than that in women. A female-like pattern of AR-ir (i.e. no to weak nuclear staining) was observed in 26- to 53-yr-old castrated male-to-female transsexuals and in old castrated and noncastrated men, 67--87 yr of age. In analogy with animal studies showing strong activational effects of androgens on nuclear AR-ir, the present data suggest that nuclear AR-ir in the human MBC is dependent on the presence or absence of circulating levels of androgen. The group data were, moreover, supported by the fact that a male-like AR-ir (i.e. intense nuclear AR-ir) was found in a 36-yr-old bisexual noncastrated male-to-female transsexual and in a heterosexual virilized woman, 46 yr of age, with high levels of circulating testosterone. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be clearly related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these alterations are discussed in relation to reproduction, cognition, and neuroprotection.

Adult↗
PubMed2001

[Increased activity of stress-regulating systems in Alzheimer disease].

Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.

Aged↗