Birgitta Näsman

Histochemical detection of 4-hydroxynonenal protein in Alzheimer amyloid.

The presence of lipid peroxidation product in amyloid deposits from seven patients with Alzheimer disease and nine with non-Alzheimer disease was examined immunohistochemically by means of an affinity purified anti-HNE antibody to hydroxynonenal (HNE), a marker of lipid peroxidation. A positive reaction was found in amyloid deposits in all the specimens examined: most of the perivascular areas (89%) where amyloid deposition was confirmed by Congo red staining, showed immunoreactivity with the antibody in the specimens of Alzheimer disease. Twenty-one percent of senile plaques which were also stained by Congo red staining reacted with this antibody. Several perivascular cells were also stained by anti-HNE antibody. In other neurons both in Alzheimer and non-Alzheimer disease patients, only a few percent reacted with this antibody and no statistical difference was observed between them. These results verify that lipid peroxidation via free radical injury occurs in amyloid deposits in Alzheimer amyloid. Since HNE has been identified as a cytotoxic metabolite of free radical injury, amyloid deposits in the tissue may exhibit a toxic effect during the generation process of HNE.

Abnormalities at different levels of the hypothalamic-pituitary-adrenocortical axis early after stroke.

Background and Purpose: Hypercortisolism is common in stroke patients. The aim of this study was to investigate possible disturbances at different sites within the hypothalamic-pituitary-adrenal axis. We also studied possible associations between hypercortisolism and clinical manifestations of brain dysfunction. Methods: Patients with an acute ischemic stroke (n=16; mean±SD age, 71±11 years) were compared with healthy elderly subjects (n=9). We performed a short adrenocorticotropic hormone (ACTH) test with 0.25 mg 1-24 ACTH injected intravenously and an overnight dexamethasone suppression test with 1 mg dexamethasone given orally at 11 PM. Results: Serum cortisol levels after dexamethasone at 8 AM were significantly higher in stroke patients (p=0.003). The area under the curve for the cortisol response to ACTH was elevated in seven (47%) of stroke patients, and the centered cumulative cortisol response was elevated in three (20%) patients. The area under the curve response correlated significantly to the presence of an acute confusional state and male sex in stroke patients (rs=0.63 and rs=0.62, respectively; p<0.05), whereas the centered cumulative cortisol response diminished with increasing age (rs=−0.62;p<0.05). Postdexamethasone cortisol levels were significantly correlated to the presence of an acute confusional state and to extensive limb paresis (rs=0.66 and rs=0.62, respectively;p<0.05). Conclusions: There are abnormalities in the cortisol axis both at the central level and at the adrenal level early after stroke. Hypercortisolism is closely associated with cognitive disturbances and extensive motor impairment.

Cognitive Dysfunction, Hippocampal Atrophy and Glucocorticoid Feedback in Alzheimer’s Disease

BACKGROUND The hippocampal formation is damaged early in Alzheimers disease (AD). An association between temporal lobe volume and cognitive function has been shown in several studies. Increased limbic-hypothalamic-pituitary-adrenal (LHPA) axis function has been suggested to be related to hippocampal atrophy and cognitive impairment. Our hypothesis was that there is a clear link between hippocampal volume -- notably of the CA1 region -- memory (episodic and visuospatial) and decreased feedback sensitivity in the LHPA axis in AD. METHODS Sixteen medication-free outpatients with mild to moderate AD were included. Hippocampal volume was measured with magnetic resonance imaging. Dexamethasone suppression tests were performed using .5 mg and .25 mg dexamethasone. Three different components in the neuropsychological battery -- Rey 15 item memory test, Alzheimers Disease Assessment Scale (ADAS) word recall and spatial span from Wechsler Adult Intelligence Scale - Revised neuropsychological instrument (WAIS-R NI) -- were found to represent episodic and visuospatial memory. RESULTS Low hippocampal CA1 volume and high post-dexamethasone cortisol levels in combination were significantly associated with Rey 15 item memory and spatial span test outcomes. No association was found between LHPA feedback and hippocampal volume. CONCLUSIONS Low hippocampal volume and a disturbed negative feedback in the LHPA axis link to specific cognitive impairments in Alzheimers disease.

Increased Levels of Adrenocortical and Gonadal Hormones in Mild to Moderate Alzheimer’s Disease

Hormonal changes during normal aging include decreasing levels of gonadal hormones and adrenal androgens. These hormones influence multiple nervous functions, including cognition and mood. Related to this, abnormalities at several levels of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in patients with Alzheimer’s disease (AD). We studied steroid hormones in 33 patients with mild to moderate AD (12 men; 21 women, 76.4 ± 7.8 years) and 22 healthy elderly controls (10 men; 12 women, 75.4 ± 7.5 years old, respectively). Basal levels of serum cortisol, dehydroepiandrosterone (DHEA) and androstenedione were significantly increased in AD patients. Women with AD had significantly higher levels of DHEA and androstenedione. Serum estradiol levels were non-significantly increased in women with AD. After adjustment for age and BMI women with AD had significantly increased levels of androstenedione and DHEA. Increased gonadal hormone levels in mild to moderate AD may reflect an increased secretion, and/or alterations in metabolism of these hormones. This may influence the symptomatology and progression of the disease.

Regulation of circulating leptin in humans.

In the early 1950s, the ob/ob mouse was described (I). Later extensive metabolic studies have shown that the syndrome of this mouse consists of massive obesity in conjunction with hyperphagia, insulin resistance, hyperinsulinemia, development of noninsulin-dependent diabetes mellitus (NIDDM), cold intolerance, and infertility (2). Parabiosis studies in the 1950s and 1960s also revealed that the cause of the syndrome is the deficiency of a circulatory factor, rather than overproduction of a factor, since lean mice in parabiosis with obese mice were found to reduce the weight of the obese animals (2-4). Finally, by the end of 1994, the gene coding for the factor lacking in the ob/ob mice was cloned (5) and in 1995 it was shown that administration of the protein product of this gene, leptin, normalized the hyperphagia, the massive obesity and the huge hyperinsulinemia in these animals (6-8).

Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease

BACKGROUND Abnormalities at several levels of the hypothalamic-pituitary-adrenal axis, which may promote glucocorticoid dependent neurodegeneration, have been reported in patients with Alzheimers disease. In this study we have explored the possibility that peripheral cortisol metabolism is enhanced and glucocorticoid production is increased compensatory in patients with mild to moderate Alzheimers disease. METHODS Urinary excretion of cortisol and its principal conjugated metabolites was studied in ten women with mild to moderate Alzheimers disease, seven healthy elderly women and seven young women. RESULTS There was an age-related fall in glucocorticoid production (median, 2009 [range 1828--4201] vs. 9315 [range 3613--16,244] microg/24 hours in elderly vs. young control subjects). A-ring metabolism (i.e., the irreversible inactivation of cortisol by 5 alpha- and 5 beta-reductases) was reduced in old age. However, patients with Alzheimers disease showed persistence of cortisol metabolite excretion. Glucocorticoid production was significantly increased in patients with Alzheimers disease versus healthy elderly control subjects (median, 7269 [range 6005-15,335] vs. 2009 [range 1828--4201] microg/24 hours), and patients with Alzheimers disease had increased A-ring reduction of cortisol. CONCLUSIONS An increased glucocorticoid production is an early feature of Alzheimers disease and may be secondary to enhanced metabolic clearance of cortisol by A-ring reduction.

Blunted adrenocorticotropin and increased adrenal steroid response to human corticotropin-releasing hormone in Alzheimer's disease

Previous studies suggest disturbances in the central regulation of the hypothalamic-pituitary-adrenocortical axis (HPA) in advanced Alzheimers disease (AD). In this study the reactivity of the HPA axis was evaluated by stimulation with corticotropin-releasing hormone (CRH) of patients with mild to moderate AD. Twenty-three patients with AD (aged 61-88 yr) and 19 healthy elderly (aged 62-84 yr) received an intravenous bolus injection of human CRH (1 microgram/kg) at 3:00 PM. CRH-stimulated plasma ACTH levels were significantly lower in AD patients, while serum cortisol, dehydroepiandrosterone, and androstenedione responses relative to the amount of ACTH released were higher in AD patients. Significant correlations were found between low basal plasma ACTH levels and temporal lobe atrophy (p=0.02) and between peak plasma ACTH levels and hippocampal atrophy (p = 0.01). These findings suggest abnormalities at several levels of HPA axis in AD.

Cortisol axis abnormalities early after stroke – relationships to cytokines and leptin

Abstract. Johansson Å, Ahrén B, Näsman B, Carlström K, Olsson T (Umeå University Hospital, Umeå; Malmö University Hospital, Malmö; Karolinska Instituitet, Huddinge University Hospital, Huddinge, Sweden). Cortisol axis abnormalities early after stroke – relationships to cytokines and leptin. J Intern Med 2000; 247: 179–187.

A subtle disturbance in the feedback regulation of the hypothalamic-pituitary-adrenal axis in the early phase of Alzheimer's disease

In an attempt to find if a disturbance in the function of the feedback regulation of the hypothalamic-pituitary-adrenal axis is an early feature in Alzheimers disease (AD), 35 outpatients (mean age 76.8 years) with a mild to moderate AD were compared to 20 controls (mean age 73.8 years) in their response to different doses of dexamethasone. After 0.5 mg dexamethasone, serum cortisol levels were significantly less suppressed in patients with early AD (p = .03) and these patients were significantly more often dexamethasone nonsuppressors (serum cortisol > or = 138 nmol/l) than controls (14/35 vs. 2/20; p = .03). Nonsuppression to 1 mg dexamethasone did not differ between groups (2/35 vs. 0/20). Plasma adrenocorticotropin levels were significantly lower in patients with Alzheimers disease (n = 16) after 0.5 mg as well as after 1.0 mg dexamethasone (p = .01 and p < .001, respectively). The relationship between cortisol resistance to dexamethasone suppression and pathophysiology of AD is discussed.

Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer's disease

In an attempt to evaluate possible adrenal abnormalities in Alzheimers disease (AD), prestimulus levels and ACTH-stimulated serum levels of steroid hormones, corticosteroid-binding globulin (CBG), and insulin-like growth factor I (IGF-I) were measured in 18 patients with early AD (8 men, 10 women; 74.6 +/- 6.5 years, mean +/- SD) and 19 healthy controls (10 men, 9 women; 74.2 +/- 7.6 years, mean +/- SD). Steroid hormone levels were measured before and after an intravenous bolus injection of 250 micrograms ACTH. AD per se had an independent influence on hormone levels when evaluated in MANOVA models. AD patients had significantly higher prestimulus levels of dehydroepiandrosterone and androstenedione (p = .04 and p = .003, respectively) with accentuated differences after ACTH (p = .02 and p < .001 for peak responses, respectively). Serum levels of cortisol, CBG, free cortisol, 17 alpha-hydroxyprogesterone (17 alpha-OHP), and IGF-I did not differ between groups. These abnormalities may have implications for neuronal degeneration as well as for behavioural symptoms in AD.