Introduction to the sixteenth C.U. Ariëns Kappers lecture.
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Awards and Prizes↗
Biomedical subjects
M A Hofman
Publications and source records attributed to M A Hofman.
ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus.
We previously found apolipoprotein (apoE) epsilon4-dependent lower metabolic activity in nucleus basalis of Meynert (NBM) neurons in Alzheimer disease (AD). In the present study we examined the metabolic activity in the NBM of 39 mentally intact control subjects with different APOE genotype. The control subjects had either no AD pathology (Braak stage 0) or the very beginning of AD pathology (Braak stage I-II). We used the Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Control subjects carrying an apoE epsilon4 allele showed reduced neuronal metabolism; they had significantly more neurons with smaller GA sizes compared to control subjects not carrying an apoE epsilon4 allele. Only control subjects not carrying an apoE epsilon4 allele had increased neuronal metabolism in Braak I-II subjects. They had more neurons with larger GA sizes compared to Braak 0 subjects, which may reflect a compensatory mechanism. Our data indicate that APOE epsilon4 may act by a lower neuronal metabolism as a risk factor for cognitive impairment in normal aging and early prodromal AD. As the disease progresses into later stages of AD (Braak V-VI) neuronal metabolism strongly diminishes, resulting in neurons with extremely small GA sizes, irrespective of APOE genotype.
Aged↗
Circadian oscillations of neuropeptide expression in the human biological clock.
The mammalian suprachiasmatic nucleus is the principal component of a neural timing system implicated in the temporal organization of circadian and seasonal processes. The present study was performed to analyze the circadian profiles of two major neuropeptidergic cell groups in the human suprachiasmatic nucleus. To that end the brains of 40 human subjects collected at autopsy were investigated. The populations of arginine vasopressin- and vasoactive intestinal polypeptide-expressing neurons, located in the shell and core of the suprachiasmatic nucleus, respectively, showed marked circadian rhythms with an asymmetrical, bimodal waveform. Time series analysis revealed that these circadian cycles in neuronal activity could be described by a composite model consisting of a nonlinear periodic function, with mono- and diphasic cycles. The findings suggest that the 24-h biosynthesis of neuropeptides in the human suprachiasmatic nucleus, being part of the neural output pathway of the clock, is driven by a complex pacemaker system consisting of coupled nonlinear oscillators, in accordance with a multioscillator model of circadian timekeeping.
Adolescent↗
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↗
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↗
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↗
The human circadian clock and aging.
The suprachiasmatic nucleus (SCN) of the hypothalamus is implicated in the timing of a wide variety of circadian processes. Since the environmental light-dark cycle is the main zeitgeber for many of the rhythms, photic information may have a synchronizing effect on the endogenous clock of the SCN by inducing periodic changes in the biological activity of certain groups of neurons. By studying the brains obtained at autopsy of human subjects, marked diurnal oscillations were observed in the neuropeptide content of the SCN. Vasopressin, for example, one of the most abundant peptides in the human SCN, exhibited a diurnal rhythm, with low values at night and peak values during the early morning. However, with advancing age, these diurnal fluctuations deteriorated, leading to a disrupted cycle with a reduced amplitude in elderly people. These findings suggest that the synthesis of some peptides in the human SCN exhibits an endogenous circadian rhythmicity, and that the temporal organization of these rhythms becomes progressively disturbed in senescence.
Adult↗
Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression.
Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.
Aged↗
Male-to-female transsexuals have female neuron numbers in a limbic nucleus.
Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis (BSTc) was based on a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin-expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity, and past or present hormonal status. Regardless of sexual orientation, men had almost twice as many somatostatin neurons as women (P < 0.006). The number of neurons in the BSTc of male-to-female transsexuals was similar to that of the females (P = 0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.
Adult↗
Lack of association between depression and loss of neurons in the locus coeruleus in Alzheimer disease.
BACKGROUND: Depression, one of the most frequent psychiatric disturbances in Alzheimer disease (AD), is proposed to have its neurobiological basis in neuron loss in the noradrenergic locus coeruleus, although this is not the case in idiopathic depression. METHODS: We performed image analyzer-assisted morphometry of the locus coeruleus in 6 depressed, 6 transiently depressed, and 6 nondepressed patients with AD and in 8 control subjects, emphasizing longitudinal psychiatric evaluations and matching for the clinical and neuropathological severity of dementia. RESULTS: The mean (+/-SD) number of pigmented neurons in the locus coeruleus in controls (11 607+/-946) was higher than in patients with AD, regardless of being depressed (5165+/-928; P=.001), transiently depressed (5647+/-1163; P=.003), or nondepressed (3717+/-661; P=.001). No significant difference was found in the number of pigmented neurons between patients with AD who were depressed, transiently depressed, and nondepressed. Patients who had depression at the onset of AD had a higher pigmented neuron number than other patients with AD. CONCLUSIONS: We confirmed the loss of pigmented neurons in the locus coeruleus of patients with AD; however, no supplementary loss of pigmented neurons in the locus coeruleus was found in patients with depression and AD. This finding resembles the situation in idiopathic depression, but is in contrast with earlier studies on depression in AD.
Aged↗
Activity of vasopressinergic neurones of the human supraoptic nucleus is age- and sex-dependent.
In the human hypothalamus, arginine-vasopressin (AVP) is produced for a major part by the neurones of the supraoptic nucleus (SON). Since plasma AVP levels in men were reported to be higher than those of women and we did not find a sex difference in the neurone number, a higher vasopressinergic neurone activity was supposed to be present in the SON of men. Therefore we studied the size of the Golgi-apparatus (GA), which has been demonstrated previously to be a sensitive parameter for protein synthetic ability of neurones, in 15 men and 17 women ranging in age from 29 to 94 years. A polyclonal antibody against immunoaffinity purified MG-160, a sialoglycoprotein of the medial cisternae of the GA was applied on paraffin-embedded sections containing the dorsolateral SON (dl-SON) from which 90-95% of neurones are vasopressinergic. SON areas that contain oxytocin (OT) cells were excluded on the basis of adjacent sections stained with a monoclonal antibody against OT. By means of an image analysis system the size of the GA and the cellular profile area were determined in dl-SON neurones with a nucleolus. Our results showed indeed an age-dependent sex difference in the size of the GA that appeared to be twice as large in young men (< or = 50 years old) than in young women of the same age. The size of the GA increased with age in women but not in men. In addition, the mean cell profile area, another measure for neuronal activity, was significantly larger in young men than in young women and was in old women larger than in young women. In conclusion, these data show the presence of a sex-dependent age-difference in the activity of vasopressinergic neurones in dl-SON which may relate to differences in AVP and sex hormone levels and kidney AVP receptors.
Adult↗
Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype.
Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.
Aged↗
Depression in Parkinson's disease is not accompanied by more corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus.
BACKGROUND: Depression is frequently encountered in Parkinson's disease (PD). In addition, more than half of the PD patients have a disturbed dexamethasone suppression test, which is associated with increased activity of corticotropin-releasing hormone (CRH) neurons. We recently found an increase in CRH neuron number, CRH-messenger RNA, and vasopressin colocalization in CRH neurons in the paraventricular nucleus (PVN) of depressed patients, which may be involved in the pathogenesis of depression. METHODS: The number of neurons expressing CRH was determined in the PVN of 6 depressed PD patients with a high score (> or = 13) on the Hamilton Depression Rating Scale, 6 nondepressed PD patients, and 6 controls. RESULTS: The three groups did not differ in the number of neurons expressing CRH. CONCLUSIONS: We hypothesize that activation of CRH neurons in the PVN, as we recently observed in idiopathic depression, does not play an essential role in depression in PD.
Aged↗
Unchanged amounts of vasopressin mRNA in the supraoptic and paraventricular nucleus during aging and in Alzheimer's disease.
The paraventricular (PVN) and supraoptic nucleus (SON) demonstrate a striking stability with respect to cell numbers during aging and Alzheimer's disease (AD). Vasopressin (AVP) neurons even become activated during aging as judged from several parameters for neuronal activity, such as increased AVP plasma levels, enlarged nucleolar as well as cell size and an increased size of the Golgi apparatus in AVP-neurons. The activation possibly occurs as compensation for an age-related loss of AVP-receptors in the kidney. As a specific marker for AVP synthesis, we used quantitative in situ hybridization and estimated total amounts of AVP-mRNA in the entire SON and PVN of 14 control subjects and 14 AD patients that were matched for age, fixation time, postmortem delay and storage time of the tissue in paraffin. Following quantification, no differences were observed in total amounts of AVP-mRNA in the SON or PVN between young and old controls or between young and old AD patients, nor between the entire group of controls and AD patients. A significant negative correlation was found between the volume of the AVP-mRNA signal in the AD SON and age while the total amount of mRNA remained the same. This suggests a redistribution of cells or cell compartments in aging. A significant positive relation in both SON and PVN of AD patients was found between storage time of the paraffin-embedded tissue and the total amount of AVP-mRNA. A significant positive relation was present in the PVN, but not SON between pH of the cerebrospinal fluid, which is a marker for agonal state and the total amount of AVP mRNA. The present unchanged AVP-mRNA levels in SON and PVN confirm earlier observations on the stability of cell numbers in these nuclei in aging and AD. Although on the basis of other parameters, AVP-mRNA upregulation was expected, gradual, chronic stimulation over prolonged periods of time may, possibly, induce alternative mechanisms of regulation such as changes in translatability or in mRNA stability.
Adult↗
Morphometric analysis of vasopressin and vasoactive intestinal polypeptide neurons in the human suprachiasmatic nucleus: influence of microwave treatment.
The vasopressin (VP) and vasoactive intestinal polypeptide (VIP)-expressing neurons in the human suprachiasmatic nucleus (SCN) were morphometrically determined with or without microwave (MW) treatment. Both an enlarged volume and an increased number of neurons were found in the VP and VIP subnucleus of the SCN following MW treatment. The staining of VIP neurons by MW treatment improved much more than that of the VP neurons. Without MW treatment the VP- and VIP-expressing neurons were localized mainly in the central part of the subnuclei, whereas by increasing the sensitivity of the staining by MW treatment more neurons became visible, particularly in the peripheral areas of the subnuclei.
Adult↗
No evidence for a diurnal vasoactive intestinal polypeptide (VIP) rhythm in the human suprachiasmatic nucleus.
The mammalian suprachiasmatic nucleus (SCN) is implicated in the temporal organization of circadian rhythms in a variety of physiological, endocrine and behavioral processes. Since the environmental light-dark cycle is the main zeitgeber for many of these rhythms, photic information may have a synchronizing effect on the endogenous clock of the SCN by inducing periodic changes in the activity of certain groups of neurons. The present study was performed to investigate the diurnal profile of the vasoactive intestinal polypeptide (VIP)-producing neurons in the SCN of humans. No significant diurnal variations were found in the volume of the VIP subdivision of the SCN nor in the number of VIP-producing neurons. In contrast with the VIP cell population, the subdivision of the human SCN containing vasopressin-producing neurons has previously been reported to exhibit a distinct diurnal rhythm, with low values during the night and peak values during the early morning. These findings suggest that the expression of vasopressin, but not that of VIP, in the human SCN exhibits an endogenous circadian rhythm.
Adolescent↗
Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression.
BACKGROUND: Cerebrospinal fluid levels of arginine vasopressin (AVP) and oxytocin (OXT) have been found to change in mood disorders. In the present study, the numbers of AVP-immunoreactive (IR) and OXT-IR neurons were determined in the paraventricular nucleus (PVN) of the human hypothalamus. METHODS: Postmortem brain tissue was fixed in formalin, embedded in paraffin, and stained for AVP and OXT using immunocytochemical techniques. The number of IR neurons in the PVN was estimated by morphometry in eight depressed patients ranging in age from 21 to 85 years and eight age-matched controls ranging in age from 23 to 88 years. RESULTS: The numbers of AVP-IR and OXT-IR neurons in the PVN of patients with mood disorder were increased by 56% and 23%, respectively. No differences were found in AVP-IR or OXT-IR cell numbers between three patients with major depression and three patients with bipolar depression. The numbers of AVP-IR and OXT-IR neurons in two patients with depression not otherwise specified were within the same range as in the six other patients with a mood disorder. CONCLUSIONS: The AVP and OXT neurons were activated in the PVN in patients with major depression or bipolar disorder. This activation may be associated with activation of the hypothalamic-pituitary-adrenal axis in these patients, since both AVP and OXT are known to potentiate the effects of corticotropin-releasing hormone. Because of their central effects, activation of AVP and OXT neurons may also be related to symptoms of major depression or bipolar disorder.
Adult↗
Suprachiasmatic nucleus of the human brain: an immunocytochemical and morphometric analysis.
BACKGROUND: The present paper describes the immunocytochemical and morphometric characteristics of two major cell groups of the suprachiasmatic nucleus (SCN) in the human hypothalamus: the vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neuronal subdivisions. The dimensions (volume and length) and the number of neurons expressing each peptide in the two subdivisions were obtained, as well as the mean diameter of the cell nuclei. All morphometric parameters were studied in relation to sex and age. METHODS: Brains of 42 human subjects (22 males and 20 females) ranging in age from 10 to 92 years were obtained at autopsy. The hypothalamic area containing the SCN was dissected from each brain, dehydrated, and embedded in paraffin. Serial sections of 6 microns were cut in a coronal plane and stained with thionin for general orientation. To determine the architectonic boundaries of the VP- and VIP-expressing cell populations every 25th section was immunocytochemically stained by means of antibodies against arginine VP or VIP using the peroxidase-antiperoxidase method. The VP- and VIP-expressing cell numbers in the SCN of each subject were estimated by unilaterally counting the number of nuclear profiles with the aid of a Zeiss microscope under x 500 magnification, using a deconvolution procedure and a correction for section thickness. RESULTS: The main portion of the VP positive neurons is located in the dorsomedial part of the SCN and is rostrocaudally longer in females than in males (1.76 +/- 0.12 mm and 1.40 +/- 0.10 mm, respectively). The volume of the VP subdivision is 0.244 +/- 0.017 mm3 and contains 6,890 +/- 520 VP-immunoreactive neurons, with a mean density of about 29,000 neurons/mm3. No significant sexual dimorphism or age-related alterations in the population of VP neurons is found. The VIP positive neurons are mainly located in the ventral and central part of the SCN and extend rostrocaudally in a similar way in females and males (1.07 +/- 0.08 mm and 1.02 +/- 0.11 mm, respectively). The volume of the VIP subdivision is 0.034 +/- 0.004 mm3 and contains 1,700 +/- 140 VIP-immunoreactive neurons, with a mean density of about 63,000 neurons/mm3. An age-dependent sexual dimorphism is observed in the number of VIP-expressing neurons in the SCN: young males have about twice as many VIP neurons as females of the same age, whereas in middle-aged subjects this sexual difference is reversed, and less robust, with females now having about 1.7 times as many VIP neurons as males. In old subjects the difference in VIP cell number between men and women disappears. CONCLUSIONS: The present study clearly shows that the population of VP neurons in the human SCN is considerably larger than the population of VIP neurons. Furthermore, the age-related sexual differences in the VIP cell number reinforces the idea that the SCN is not only involved in the timing of circadian rhythms but also in the temporal organization of reproductive functions.
Adolescent↗