Michel A. Hofman

Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels

Abstract: Neuropathology is the most reliable criterion for diagnosing Alzheimers disease (AD). A well‐established system for staging the spread of neuropathological changes in AD is available. The clinical use of a biomarker that reflects the neuropathological change occurring in brain tissue has not yet been established. Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in AD. Melatonin levels were determined in ventricular postmortem cerebrospinal fluid (CSF) of 121 subjects. Braak staging and a modified Braak staging for cortex (MBSC) were used to evaluate the severity of AD neuropathology. The present study revealed that not only the Braak stages of AD, but also the MBSC were negatively correlated with CSF melatonin levels. By using MBSC, we now demonstrate for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts. Those individuals that did not have any neurofibrillary tangle (NFT) or neuritic plaque (NP) in the temporal cortex, had much higher melatonin levels (287 ± 68 and 280 ± 64 pg/mL, respectively) than those individuals that had a few NFTs and NPs (82 ± 4 and 39 ± 8 pg/mL, respectively) in the temporal cortex. These results suggest that the decrease in CSF melatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms.

Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation.

Recently, sex differences in the structures of the human hypothalamus and adjacent brain structures have been observed that seem to be related to gender, to gender problems such as transsexuality, and to sexual orientation, that is, heterosexuality and homosexuality. Although these observations have yet to be confirmed, and their exact functional implications are far from clear, they open up a whole new field of physiological structural-functional relationships in human brain research that has so far focused mainly on such relationships in pathology.

VIP neurons in the human SCN in relation to sex, age, and Alzheimer's disease

The brains of 46 control subjects and 21 Alzheimers disease (AD) patients were studied to determine whether there are age-related or AD-related changes in the vasoactive intestinal polypeptide (VIP) neuron population of the human suprachiasmatic nucleus (SCN). The number of VIP expressing neurons in the SCN of females, ranging in age from 10-91 years, did not change during normal aging. In males, however, the number of VIP neurons in the SCN was highest in the young subjects (10-40 years of age), after which, a dramatic decrease occurred in middle-aged subjects. This resulted in an age-dependent sex difference in the VIP cell population of the SCN: young males had twice as many VIP expressing SCN neurons as young females, whereas in the middle-aged groups, the females had twice as many VIP SCN neurons as the males. A significant decrease in the number of VIP expressing neurons in the SCN was found in female presenile AD patients, i.e., those younger than 65 years.

Sexual differentiation of the human hypothalamus: ontogeny of the sexually dimorphic nucleus of the preoptic area

Sexual differentiation of the hypothalamus of the human brain is generally believed to take place around midpregnancy and thought to be related to the development of sexual orientation and gender identity. The present life span study on the human sexually dimorphic nucleus (SDN) of more than a hundred subjects revealed, however, that at the age of 2-4 years the SDN cell number reaches a peak value, and that only after this age sexual differentiation becomes manifest. Furthermore, the SDN cell number in homosexual men was not different from that of the male reference group, but significantly larger than the cell number in age-matched women.

Functional neuroanatomy and neuropathology of the human hypothalamus

The human hypothalamus is involved in a wide range of functions in the developing, adult and aging subject and is responsible for a large number of symptoms of neuroendocrine, neurological and psychiatric diseases. In the present review some prominent hypothalamic nuclei are discussed in relation to normal development, sexual differentiation, aging and a number of neuropathological conditions.The suprachiasmatic nucleus, the clock of the brain, shows seasonal and circadian variations in its vasopressin neurons. During normal aging, but even more so in Alzheimers disease, the number of these neurons decreases. In homosexual men this nucleus is larger than in heterosexual men.The difference between the sexually dimorphic nuclei of men and women arises between the ages of 2–4 to puberty. In adult men this nucleus is twice as large as in adult women. In the process of aging, a sex-dependent decrease in cell number occurs. The vasopressin and oxytocin cells of the supraoptic and paraventricular nucleus are present in adult numbers as early as mid-gestation. Lower oxytocin neuron numbers are found in Prader-Willi syndrome, AIDS and Parkinsons disease. Familial hypothalamic diabetes insipidus is based upon a point mutation in the vasopressin-neurophysin-glycopeptide gene.Parvicellular corticotropin-releasing hormone-containing neurons in the paraventricular nucleus increase in number and are activated during the course of aging.In post-menopausal women, the infundibular or arcuate nucleus contains hypertrophie neurons containing oestrogen receptors. These neurons may be involved in the initiation of menopausal flushes.The nucleus tuberalis lateralis may be involved in feeding behaviour and metabolism. In Huntingtons disease the majority of its neurons is lost; in Alzheimers disease it shows very strong cytoskeletal alterations.Tuberomammillary nucleus neurons contain, e.g., histamine or galanine, and project to the cortex. Strong cytoskeletal changes, as well as plaques and tangles are found in this nucleus in Alzheimers disease.The various hypothalamic nuclei are probably involved in many functions and symptoms of which only a minority has been revealed.

Increased cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid

The hypothalamo‐pituitary‐adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well‐defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF‐cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF‐cortisol levels. The presence or absence of a difference in the cortisol‐CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5‐fold rise of CSF‐cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF‐cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimers disease and CSF cortisol levels.

The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington's disease

Neurons in the hypothalamic lateral tuberal nucleus (NTL) were counted in 16 Huntingtons disease (HD) patients and 12 controls. The control range was 47,500-71,700. In the HD cases the number ranged from 2,800 to 40,600. The log-transformed counts of the HD patients correlated closely with age-at-death (r = 0.66, P less than 0.01) and age-at-onset (r = 0.78, P less than 0.001), but not with duration of disease, nor with the severity of the neostriatal changes. Because of its vulnerability to the effects of the HD gene and its simplicity, the NTL seems fit to study the characteristics of neuronal death in HD.

Vasopressin and the output of the hypothalamic biological clock.

The physiological effects of vasopressin as a peripheral hormone were first reported more than 100 years ago. However, it was not until the first immunocytochemical studies were carried out in the early 1970s, using vasopressin antibodies, and the discovery of an extensive distribution of vasopressin‐containing fibres outside the hypothalamus, that a neurotransmitter role for vasopressin could be hypothesised. These studies revealed four additional vasopressin systems next to the classical magnocellular vasopressin system in the paraventricular and supraoptic nuclei: a sexually dimorphic system originating from the bed nucleus of the stria terminalis and the medial amygdala, an autonomic and endocrine system originating from the medial part of the paraventricular nucleus, and the circadian system originating from the hypothalamic suprachiasmatic nuclei (SCN). At about the same time as the discovery of the neurotransmitter function of vasopressin, it also became clear that the SCN contain the main component of the mammalian biological clock system (i.e. the endogenous pacemaker). This review will concentrate on the significance of the vasopressin neurones in the SCN for the functional output of the biological clock that is contained within it. The vasopressin‐containing subpopulation is a characteristic feature of the SCN in many species, including humans. The activity of the vasopressin neurones in the SCN shows a pronounced daily variation in its activity that has also been demonstrated in human post‐mortem brains. Animal experiments show an important role for SCN‐derived vasopressin in the control of neuroendocrine day/night rhythms such as that of the hypothalamic‐pituitary‐adrenal and hypothalamic‐pituitary‐gonadal axes. The remarkable correlation between a diminished presence of vasopressin in the SCN and a deterioration of sleep‐wake rhythms during ageing and depression make it likely that, also in humans, the vasopressin neurones contribute considerably to the rhythmic output of the SCN.

Diurnal and Seasonal Rhythms of Neuronal Activity in the Suprachiasmatic Nucleus of Humans

The mammalian suprachiasmatic nucleus (SCN) is considered to be a critical component of a neural system implicated in the temporal organization of a wide variety of biological 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 in the SCN by inducing periodic changes in the activity of certain groups of neurons. The present study was conducted to investigate whether the daily light-dark cycle as well as seasonal variations in photoperiod would affect the vasopressin cell population of the human SCN. To that end, the brains of 30 young human subjects (ranging in age from 6 to 47 years) were investigated.

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.