Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer's disease, and related to neuropathological disease stage

OBJECTIVE: It is currently unknown whether cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimer's disease (AD), but it is unclear whether CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. DESIGN: DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by HPLC. Frozen CSF and temporal cortex specimens were provided by the Alzheimer's Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. RESULTS: CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak) (r = 0.42, P = 0.007). CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001) and tend to be correlated with neuropathological disease stage (Braak) (r = 0.30, P = 0.06). CSF DHEA levels are elevated (P = 0.032), and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD, compared with cognitively intact control subjects. CONCLUSIONS: These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.     

Dementia without cholinergic deficit

We examined the role of cholinergic system in multi-infarct dementia (MID) by measuring acetylcholinesterase (AChE) activities in cerebrospinal fluid (CSF) of clinically diagnosed MID patients, Alzheimer's disease (AD) patients and controls. In spite of the similar clinical severity of dementia, MID patients had unaltered AChE levels, whereas AD patients had significantly reduced AChE levels in CSF when compared to controls. In the autopsy study we analyzed choline acetyltransferase (ChAT) levels in four cortical brain areas from clinically and neuropathologically studied AD patients, demented non-AD patients and controls. ChAT activities in the cerebral cortex in non-AD patients were on the same level as in controls, but AD patients had a marked loss of ChAT activity in all four cortical brain areas studied. Although cholinergic deficit is a usual phenomenon associated with cognitive failure, severe dementia can exist without cholinergic dysfunction.     

Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia

Changes in the hypothalamus-pituitary-adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer's disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.     

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.     

Plasma dihydroxyphenylalanine and total body and regional noradrenergic activity in humans

Dihydroxyphenylalanine (DOPA) is the immediate product of the rate-limiting step in catecholamine biosynthesis, hydroxylation of tyrosine. This study examined whether plasma concentrations of DOPA are related to tyrosine hydroxylase activity. Plasma concentrations of DOPA, norepinephrine, and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in arterial blood and blood draining the heart, brain, and forearm of 21 patients undergoing cardiac catheterization. Rates of entry of norepinephrine into arterial plasma and plasma draining the heart were estimated using infusions of radioactive norepinephrine. Arterial plasma DOPA correlated positively with arterial plasma DHPG (r = 0.63), MHPG (r = 0.47), norepinephrine (r = 0.67), and the rate of entry of norepinephrine into arterial plasma (r = 0.62). There were significant arteriovenous increments in plasma DOPA: 28% across the heart, 18% across the brain, and 32% across the forearm. Arteriovenous increments in plasma DOPA across the brain correlated positively with increments in plasma DHPG (r = 0.83), but not with increments in norepinephrine or MHPG. In the arm, where MHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in MHPG (r = 0.52) and with the combined increments in MHPG, DHPG, and norepinephrine (r = 0.60). In the heart, where DHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in DHPG (r = 0.72) and the combined increments in DHPG, MHPG, and norepinephrine (r = 0.62). The rate at which norepinephrine entered the great cardiac venous plasma from tissues of the heart correlated positively with the rate at which DOPA overflowed from the heart into the systemic circulation (r = 0.56). The relationships between plasma DOPA and norepinephrine metabolism and the rates of norepinephrine entry into plasma support the view that plasma DOPA reflects tyrosine hydroxylase activity.     

Dexamethasone effects on cortisol secretion in Alzheimer's disease: some clinical and hormonal features in suppressor and nonsuppressor patients

Alterations in the hypothalamic-pituitary-adrenal axis (HPAA) and failure of dexamethasone (DXT) to suppress cortisol secretion occur in Alzheimer's disease (AD). This study was aimed to settle possible differences in some clinical (age, body weight, body mass index, dementia severity) and hormonal parameters in AD patients non-responders to overnight 1 mg-DXT suppression test compared with the responder subjects. ACTH, cortisol and dehydroepiandrosterone sulphate (DHEAS) day-time levels were assessed in 25 AD patients and in 12 age-matched healthy controls before DXT administration. In view of their neuroprotective effects, plasma levels of Insulin-like Growth Factor-I (IGF-I) and of IGF-Binding Proteins (IGFBPs) were also determined. After DXT, 8 AD subjects (32%) showed cortisol levels above the conventional cut-off of 140 nmol/L. No significant differences were found in clinical parameters in suppressor vs nonsuppressor patients. AD subjects showed higher cortisol, cortisol/DHEAS ratios, and lower DHEAS levels in comparison with controls. Both ACTH and cortisol levels were not different in suppressor and nonsuppressor patients, but DHEAS levels were significantly lower in nonsuppressor cases, who also exhibited ACTH and cortisol periodicities more altered than in suppressor and in control subjects. IGF-I and IGFBP-3 levels were lower and those of IGFBP-1 higher in nonsuppressor than in suppressor cases and in healthy controls. IGF-I/IGFBPs system data were correlated with cognitive impairment and adrenal steroid levels in AD patients.     

Biomarkers,mild cognitive impairment and early diagnosis of Alzheimer's disease

Elderly people are concerned about changes in their cognitive functioning. Since cholinergic therapies for Alzheimer's disease have been developed and become widely accepted, elderly people have come to visit clinics to seek medical advice about whether such a subtle change in cognitive ability may represent an early manifestation of Alzheimer's disease (AD). If they are likely to develop dementia or AD, they want to receive immediate medical treatment as soon as possible to prevent further loss of cognitive functioning so that they can live independently as long as possible. The first priority in the clinical application of a biomarker is that biomarker should contribute to early diagnosis of dementia. Among such biomarkers, we believe that cerebrospinal fluid markers and functional brain imaging are clinically the most applicable procedures. Since 1993, we have collected 623 cerebrospinal fluid (CSF) samples at The Tohoku University Hospital for evaluation of dementia (age: 42-93). We found that CSF/phospho-tau measures produced the most adequate sensitivity (85.2%) and specificity (85.0%) in the diagnosis of AD as a sole bio-marker. The CSF levels of A beta 1-42 showed a strong positive correlation with the Mini-mental state examination score and brain glucose metabolism by positron emission tomography. The baseline levels of both total-tau and phospho-tau in CSF increased in approximately 70% of patients with mild cognitive impairment who later developed AD, suggesting that pathological change in the brain might start years before dementia becomes clinically manifested. A combined use of CSF-tau and IMP-SPECT improved the predictability of the transition from mild cognitive impairment into AD.     

Acute beta-interferon or thymopentin administration increases plasma growth hormone and cortisol levels in children.

The interaction between the immune and endocrine systems has recently been investigated. Hodgkin's disease represents a model of immune disturbance frequently associated with endocrine impairment. The present study evaluated the effect of the acute administration of beta-interferon or thymopentin on plasma growth hormone, prolactin and cortisol levels in children with Hodgkin's disease (N = 8) and age- and sex-matched healthy controls (N = 8). beta-interferon (1,000,000 IU), thymopentin (50 mg) or placebo (saline) were injected after two basal blood samples (-15 and 0) and further samples were drawn at 15, 30, 45, 60, 90 and 120 min. Plasma growth hormone, prolactin and cortisol levels were measured by specific RIAs. Plasma prolactin levels did not show significant change following beta-interferon or thymopentin injection in either the controls or the patients. In the patients with Hodgkin's disease, beta-interferon injection induced a significant increase in both plasma growth hormone and cortisol levels, while thymopentin was not effective. In controls both thymopentin and beta-interferon administration increased plasma growth hormone and cortisol levels. These results indicate that beta-interferon and thymopentin are immune substances active on the release of growth hormone and cortisol in healthy children. The lack of effect of thymopentin in children with Hodgkin's disease suggests an impairment of the immune-endocrine interaction in these patients.     

Elevation of plasma soluble amyloid precursor protein beta in Alzheimer’s disease

IntroductionBeta-amyloid is considered to be a pathophysiological marker in Alzheimer's disease (AD). Soluble amyloid precursor proteins (sAPPs) –α (sAPPα) and –β (sAPPβ), which are the byproducts of non-amyloidogenic and amyloidogenic process of APP, respectively, have been repeatedly observed in the cerebrospinal fluids (CSF) of AD patients. The present study focused on the determination of sAPP levels in peripheral blood.MethodsThe plasma protein levels of sAPPα and sAPPβ were measured with ELISA. Plasma from 52 AD patients, 98 amnestic mild cognitive impairment (MCI) patients, and 114 cognitively normal controls were compared.ResultsThe plasma level of sAPPβ was significantly increased in AD patients than in cognitively healthy controls. However, no significant change in plasma sAPPα was observed among the three groups. Furthermore, the plasma sAPPβ levels significantly correlated with cognitive assessment scales, such as clinical dementia rating (CDR), and mini-mental status examination (MMSE). Interestingly, sAPPα and sAPPβ had a positive correlation with each other in blood plasma, similar to previous studies on CSF sAPP. This correlation was stronger in the MCI and AD groups than in the cognitively healthy controls.ConclusionsThese results suggest that individuals with elevated plasma sAPPβ levels are at an increased risk of AD; elevation in these levels may reflect the progression of disease.     

Neurochemical Correlates of Sympathetic Activation during Severe Alcohol Withdrawal

Cerebrospinal fluid (CSF) was obtained from 17 patients during acute alcohol withdrawal. Eight of these 17 patients had a second lumbar puncture a mean of 11.9 ± 8.1 ( sd ) days later, when the clinical signs of alcohol withdrawal had subsided. CSF 3-methoxy-4-hydroxyphen-ylglycol concentrations declined significantly ( p < 0.05) during the course of alcohol withdrawal from 52.0 ± 22.1 ( sd ) to 39.6 ± 12.6 pM/ml. In early withdrawal, there was a significant positive correlation between CSF norepinephrine (NE) and corticotropin releasing hormone (CRH) concentrations ( r = 0.95, p <0.001). Both NE and CRH concentrations correlated positively with diastolic blood pressure ( r = 0.88, p < 0.001 and r = 0.62, p < 0.05, respectively). In all samples, CSF 5-hydroxyindole acetic acid concentrations correlated positively with CSF-homovanillic acid concentrations ( r = 0.83, p < 0.001). These findings indicate significant perturbations of the noradrenergic neuronal system and a change in CRH-NE interactions during acute alcohol withdrawal.     

The Cholinergic Neuronal Phenotype in Alzheimer's Disease

The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer’s disease (AD), and AD brains are characterized by amyloid deposits composed primarily of Aβ peptides. Although Aβ peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic Aβ peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of Aβ peptides.     

Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's disease: a pilot study

Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers Aβ(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group.     

胱抑素C与老年2型糖尿病患者认知功能障碍的相关性探讨

目的：探讨血清胱抑素C（Cys C）水平与老年2型糖尿病患者认知功能障碍的相关性。方法选取老年2型糖尿病患者352例,其中认知功能正常组（NC组）146例、轻度认知功能障碍组（MCI组）112例,阿尔茨海默病组（AD组）94例。采用简易智能状态检查量表（MMSE）、蒙特利尔认知评估量表（MoCA）评定患者认知功能。检测所有患者血糖、血脂、Cys C水平和肝肾功能等,比较3组间临床特征及Cys C水平差异。结果3组间血清Cys C水平差异具有统计学意义（均P＜0.05）。NC、MCI、AD组血清Cys C水平依次升高。相关分析表明,血清Cys C水平与年龄、糖尿病病程、甘油三酯（TG）、血肌酐（Cr）、糖化血红蛋白（HbA1c）呈正相关（r＝0.352,0.199,0.177,0.616,0.368,均P＜0.05）,与MMSE分数、MoCA分数、高密度脂蛋白胆固醇（HDL-C）呈负相关（r＝-0.186,-0.237,-0.185,均P＜0.05）。logistic回归分析显示Cys C（P＝0.011,OR＝2.120）、年龄（P＝0.021,OR＝3.401）、病程（P＝0.033, OR＝3.102）、HbA1c（P＝0.010,OR＝2.691）是老年2型糖尿病患者认知功能障碍的独立危险因素。结论血清Cys C水平与老年2型糖尿病患者认知功能障碍相关,老年2型糖尿病患者高血清 Cys C水平提示认知功能障碍患病风险增加。     

对内嗅皮质和内侧颞叶萎缩的阿尔茨海默病与遗忘型轻度认知功能障碍患者的研究

目的探讨阿尔茨海默痛(AD)与遗忘型轻度认知功能障碍(aMCD)患者内嗅皮质和内侧颞叶萎缩(MTA)的关系。方法选择轻中度AD患者18例(AD组),aMC1患者1 7例(aMCI组)。认知功能通过长谷川痴呆量表修订版(HDS-R)和AD评定量表认知部分(ADAS-cog)评价。通过基于体素的AD特异性局部分析系统的Z评分来评价内嗅皮质的萎缩程度。同时视觉评分系统对MTA程度进行分级。结果 AD组HDS R评分明显低于aMCI组,ADAS-cog和MTA评分明显高于aMCI组(P<0.01)。AD组Z评分与MTA评分呈正相关(P<0.01)。aMCI组Z评分与年龄、MTA评分呈正相关(P<0.01),MTA评分与年龄呈正相关(P<0.05)。结论 aMCI患者中,内嗅皮质萎缩与认知功能改变相关;而AD患者中;MTA更可能的与认知功能相关。MTA评分比Z评分能更有效地区别aMCI和AD患者。在aMCI阶段,内嗅皮质萎缩起了主要的作用;而AD阶段海马等结构作用更突出。     

Adrenal steroid dysregulation in dystrophia myotonica.

OBJECTIVE: To evaluate circulating adrenal steroid hormones, cortisol diurnal rhythm and the negative feedback function of the cortisol axis in patients with dystrophia myotonica (DyM), a disease where metabolic disturbances, peripheral insulin insensitivity and cognitive dysfunction are common features. DESIGN: Morning serum levels of dehydroepiandrosterone sulphate, androstenedione, 17 alpha-hydroxy progesterone and cortisol; morning serum levels of testosterone and insulin; diurnal rhythm of saliva cortisol; and an overnight dexamethasone suppression test, together with a cognitive screening test in men with DyM and in controls. SETTING: Outpatient clinic in co-operation with Ume? University Hospital. SUBJECTS: Fifteen men with DyM and 13 age-matched controls. MAIN OUTCOME MEASURES: Adrenal steroid hormone levels, diurnal rhythm of saliva cortisol, dexamethasone suppression test and Mini Mental State Examination scores. RESULTS: Morning serum levels of dehydroepiandrosterone sulphate, androstenedione and 17 alpha-hydroxy progesterone were significantly decreased in DyM after inclusion of age and body mass index in multiple regression analyses (48, 26 and 32% decreases, respectively). An abnormal diurnal rhythm of saliva cortisol was present in all patients, mean saliva cortisol levels being significantly increased (33%) in DyM patients. Dexamethasone suppressibility did not differ between groups. DyM patients scored significantly lower on the Mini Mental State Examination (P < 0.001). CONCLUSIONS: These results indicate an abnormal adrenal steroid hormone secretion in DyM, which may contribute to peripheral insulin sensitivity as well as cognitive impairment in these patients.     

Dementia of the Alzheimer type and multi-infarct dementia: a clinical description and diagnostic problems

Patients who had Alzheimer's disease-senile dementia of the Alzheimer type (AD/SDAT) or multi-infarct dementia (MID) were compared with a group of controls. Demented patients had approximately the same degree of dementia and the same duration of illness. The MID group had a significantly higher mean age than the AD/SDAT group. Sixty-three per cent of the AD/SDAT patients were free of other diseases, while 65 per cent of the MID patients had cardiovascular disease. Thirty per cent of the MID patients had a history of previous depression, while only 5 per cent of the AD/SDAT patients had had depression. At the time of the investigation, however, AD/SDAT patients showed significantly more signs of depression than the MID patients. Focal neurologic signs were found in 70 per cent of the MID patients and only 6 per cent of the AD/SDAT patients. The electrocardiogram was normal for every AD/SDAT patient, while 75 per cent of the MID patients had abnormal ECGs. Electroencephalography showed generalized slow frequencies in 79 per cent of the AD/SDAT patients and localized slow frequencies and abnormalities in 65 per cent of the MID patients. Computed tomography of the brain showed that MID patients had significantly greater dilation of the ventricular system, while cortical atrophy did not differ significantly among the three groups. Homovanillic acid in the cerebrospinal fluid was significantly lower in the AD/SDAT group as compared with controls.     

Stress and dementia: the role of the hypothalamicpituitary-adrenal axis

Hippocampus plays a crucial role in learning and memory and, in spite of its remarkable plasticity, it is also particularly sensitive to stress hormones due to its high concentration of corticosteroid receptors. Indeed, adrenal steroids modulate hippocampal plasticity, acting on excitability and long term potentiation or depression. By a chronobiological approach, we studied the cortisol and DHEAS secretion in clinically healthy old subjects and in age-matched demented patients, including both the degenerative and the vascular type. When compared to young controls, both clinically healthy elderly subjects and demented patients, particularly those with AD, had significantly higher cortisol levels at night time, i.e. at the moment of the maximal sensitivity of HPA axis to stimulatory or inhibitory inputs. At the same time, a clear age- and disease-dependent reduction of DHEAS secretion was found. Thus the cortisol to DHEAS molar ratio was significantly higher in healthy old subjects, and even more in demented patients, when compared to young controls, and significantly linked to both age and cognitive impairment. Finally, the quantitative and qualitative changes of the adrenal secretory pattern were significantly correlated with the decline of hippocampal volumes, measured by MRI. In conclusion, several lines of evidence deal with a pathogenetic role of stress hormones in the occurrence and progression of cognitive disorders in elderly subjects. The consequent hippocampal neuronal impairment may in turn be responsible for the continuous activation of HPA axis and the increased hypothalamic expression of vasopressin and corticotropin releasing hormone.     

Endogenous sex hormone levels in postmenopausal women with Alzheimer's disease

A cross-sectional study examined whether there was a difference in endogenous serum sex hormone levels between community-dwelling postmenopausal women with Alzheimer's disease (AD) and healthy controls. Total morning levels of serum estrone, estradiol, androstenedione, testosterone, and cortisol were measured in 52 nondepressed women with AD and 60 postmenopausal women who were neither depressed nor cognitively impaired. Estradiol was undetectable in 35.7% of cases, but detectable hormone was found in 96-100% of cases otherwise. After adjustment for potential confounds, serum levels were significantly higher for estrone (P = 0.0057) and androstenedione (P = 0.02), but not testosterone (P = 0.086) or estradiol (P = 0.59), in subjects with AD. Sex hormone levels did not correlate with cognitive scores in either group. Although the failure to detect estradiol in a third of cases limits the conclusions that can be drawn for this hormone, the possibility that AD is associated with abnormalities in certain serum sex hormone levels should be considered and warrants further research.     

Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)?

Even in its incipient stage, late-onset sporadic dementia of the Alzheimer type (SDAT) is characterized by an abnormal reduction in brain glucose consumption and energy formation. Gathering evidence indicates that cerebral glucose metabolism is controlled by brain insulin/insulin receptors. This led us to hypothesize that the abnormal reduction in glucose utilization found in Alzheimer brains is preceded by a desensitization of cerebral insulin receptors which might be due to enhanced levels of stress factors such as cortisol and catecholamines. The hypothesis is supported by clinical findings of an abnormal response to the oral glucose tolerance test in AD patients. Furthermore, experimental desensitization of the cerebral insulin receptor resulted in both cognitive deficits and metabolic abnormalities in cerebral oxidative glucose metabolism resembling those described in incipient late-onset SDAT. Glucose is the major source of energy in the CNS, and any impairment in cerebral glucose oxidation can be expected to result in deficits in both acetylcholine synthesis and ATP formation, which might contribute to altered APP processing and enhanced susceptibility to neurotoxicity.     

重症病毒性脑炎患者血清甲状腺激素和皮质醇变化的临床意义

目的探讨重症病毒性脑炎（SVE）患者血清甲状腺激素、皮质醇变化的临床意义。方法采用化学发光分析法检测SVE患者（SVE组）及查体健康者（对照组）的血清甲状腺激素、皮质醇水平,比较治疗前后SVE患者血清甲状腺激素、皮质醇变化及其与病情改善程度的相关性。结果与对照组比较,SVE组治疗前血清甲状腺激素水平下降（P〈0．05）,血清皮质醇水平明显升高（P〈0．01）;治疗10d后,除4例死亡者外,其余病情改善者的血清甲状腺激素水平升高,且与病情改善程度呈正比（r=0．76,P〈0．05）;血清皮质醇水平明显下降,且与病情改善程度呈反比（r=-0．81,P〈0．05）。结论及时检测SVE患者的血清甲状腺激素及皮质醇变化,对指导患者治疗及评估预后有重要临床意义