Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia

Recently, we showed that the circulating levels of insulin-related peptides and the secretory granule protein chromogranin A were increased in small cohorts of first onset schizophrenia patients. Assuming that this effect was associated with impaired insulin signalling, we investigated the possibility that secretion of other hormones is also affected in schizophrenia. Multiplex immunoassay analysis of 21 hormones and hormone-related molecules was carried out using sera from 236 first and recent onset schizophrenia patients and 230 matched controls. Serum concentrations of insulin and chromogranin A were increased in schizophrenia subjects, consistent with our previous study. In addition, we found elevated concentrations of pancreatic polypeptide, prolactin, progesterone and cortisol, and decreased levels of growth hormone. We also found that growth hormone levels were decreased in post-mortem pituitaries obtained from chronic schizophrenia patients. It will be important to determine whether any of these molecules are involved in the pathosphysiology of schizophrenia or if they reflect the associated insulin resistance. We conclude that function of multiple components of the hypothalamic-pituitary-adrenal-gonadal axis may be affected in schizophrenia. This could have important implications for future biomarker discovery efforts and personalized medicine strategies based on patient stratification for the treatment of this debilitating disorder.     

Nonconvulsive status epilepticus in metastatic CNS disease

The authors describe the clinical and diagnostic characteristics of four patients with metastatic CNS disease presenting in de novo nonconvulsive status epilepticus (NCSE). Treatment with anticonvulsants resulted in resolution of NCSE in two patients and a brief improvement in mental status in the other two patients. NCSE should be considered in the differential diagnosis of acute mental status change in patients with metastatic CNS disease.     

Altered antigen expression of microglia in the aged rodent CNS

Microglia, the resident macrophages of the central nervous system, are characterised by a highly specialized morphology and unusual antigenic phenotype. Microglia appear to be downregulated by their microenvironment when compared to other tissue macrophages. We have studied the microglia in brains of healthy, aged rats with a panel of monoclonal antibodies. We have found that microglia in the brains of these aged rats express antigens that are downregulated or absent from microglia of juvenile rats. The stimuli which give rise to this upregulated phenotype are not known. Age related changes in the phenotype of microglia should be taken into account when considering the possible role of microglia in neuropathological conditions.     

Altered olfactory function in the MRL model of CNS lupus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that damages several bodily systems, including the CNS. Brain atrophy and diverse neuropsychiatric manifestations are common and serious complications of SLE. Recently, it has been reported that many patients with CNS involvement also present with olfactory deficits of unknown etiology. Similar to CNS SLE, spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by neurodegeneration in periventricular regions and a constellation of behavioral deficits dependent on olfaction. To test the possibility that olfactory dysfunction also occurs in autoimmune mice, we presently examine odor-guided behaviors using a battery of paradigms. Indeed, lupus-prone males spent less time exploring unfamiliar conspecifics and demonstrated age-dependant performance deficits when exposed to low concentrations of attractant and repellant odors. The emergence of olfactory changes was associated with a skewed distribution of DCX(+) cells in the proximal portion of the rostral migratory stream (RMS). The present results are consistent with the hypothesis that the onset of a SLE-like condition affects periventricular regions, including the RMS, as evidenced by disrupted migration of neuronal precursor cells toward the olfactory bulb. If so, ensuing hyposmia and/or olfactory memory deficit may contribute to altered performance in other behavioral tasks and reflect a prodrome of brain damage induced by chronic autoimmune disease.     

Inflammatory bowel disease: psychiatric status of patients before and after disease onset

Compared to normal controls, individuals with Crohn's Disease manifest an increased prevalence of anxiety, depression and panic disorder occurring at any time in their life. Only panic disorder had an excess prevalence in Crohn's disease relative to community dwelling normals prior to the time of disease onset. Individuals with ulcerative colitis did not demonstrate an increased prevalence of psychiatric disorder before or after disease onset. The results suggest that there is a higher prevalence of psychiatric disorder in patients with Crohn's Disease relative to the normal population and that a small but significant percentage of individuals with Crohn's Disease may have a psychiatric disturbance which predates their medical illness.     

Age at menopause predicts age at onset of Parkinson's disease.

We investigated the association between age at onset of Parkinson's disease (PD) and fertile life characteristics in 145 women. Linear regression analyses showed a significant correlation between age at PD onset and age at menopause (P = 0.003), between age at PD onset and fertile life duration (P = 0.008), and a nonsignificant correlation between PD onset and cumulative duration of pregnancies (P = 0.23). These results support the possible role of estrogens in PD.     

Disturbed distribution of proliferative brain cells during lupus-like disease

Brain atrophy and neuronal degeneration of unknown etiology are frequent and severe concomitants of the systemic autoimmune disease lupus erythematosus (SLE). Using the murine MRL/lpr model, we examined populations of proliferative brain cells during the development of SLE-like disease and brain atrophy. The disease onset was associated with reduced expression of Ki67 and BrdU proliferation markers in the dorsal part of the rostral migratory stream, enhanced Fluoro Jade C staining in the subgranular zone of the dentate gyrus, and paradoxical increase in density of Ki67⁺/BrdU⁻ cells in the paraventricular nucleus. Protuberances containing clusters of BrdU⁺ cells were frequent along the lateral ventricles and in some cases were bridging ventricular walls. Cells infiltrating the choroid plexus were Ki67⁺/BrdU⁺, suggesting proliferative leukocytosis in this cerebrospinal fluid-producing organ. The above results further support the hypothesis that systemic autoimmune disease induces complex CNS pathology, including impaired neurogenesis in the hippocampus. Moreover, changes in the paraventricular nucleus implicate a metabolic dysfunction in the hypothalamus–pituitary-adrenal axis, which may account for altered hormonal status and psychiatric manifestations in SLE.     

Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia

Objectives. Oxygen-free radicals and lipid hydroperoxides may have an aetiological role in the development of lesions in the central nervous system in patients with Alzheimer's disease and in those with vascular dementia. This study aimed to make a cross-sectional comparison of blood markers of oxidative stress in two groups of patients with these disorders and a control group. Design. Cross-sectional comparative study. Setting. Established memory clinics in Cardiff organized by a University Department of Geriatric Medicine within an acute care NHS Trust. Methods. Following a dietary assessment, postprandial venous blood samples were obtained from the following: 25 subjects with probable Alzheimer's disease (AD) (mean age 74.3; 10 F, 15 M); 17 subjects with probable vascular dementia (VD) (mean age 75.5; 5 F, 12 M); and 41 controls (mean age 73.4; 24 F, 17 M) for measurement of circulating lipid peroxides (LP), total antioxidant capacity (TAC), vitamin C (VitC), vitamin E (VitE) and beta-carotene (BC). Results. Plasma levels of VitC were significantly lower in subjects with vascular dementia compared with controls (VD, 6.5 (4.8, 8.2); controls, 10.0 (8.38, 11.6); VD vs controls, p=0.015), but no significant difference was seen between controls and patients with Alzheimer's disease (AD, mean 8.3 (6.2, 10.4)). VitE levels were significantly lower in subjects with AD compared with controls (31.1 (28.2, 34.0) vs 36.0 (32.8, 39.2), p=0.035). BC levels were similar in subjects with AD and controls, but significantly elevated in those with VD (AD, 0.28 (0.2, 0.34); VD, 0.40, (0.27, 0.53); controls, 0.28 (0.22, 0.34); VD vs controls, p=0.046). There were no significant differences in LP or TAC between the three groups. Conclusions. Subjects with dementia attributed to Alzheimer's disease or to vascular disease have a degree of disturbance in antioxidant balance which may predispose to increased oxidative stress. This may be a potential therapeutic area for antioxidant supplementation. Copyright © 1998 John Wiley & Sons, Ltd.     

Microglial cell activation and proliferation precedes the onset of CNS autoimmunity

Microglial cells are central nervous system (CNS) resident cells that are thought to become activated and contribute to the inflammation that occurs in the human autoimmune disease multiple sclerosis (MS). This has never been proven, however, because microglial cells cannot be phenotypically distinguished from peripheral macrophages that accumulate in MS inflammatory lesions. To study the kinetics and nature of microglial cell activation in the CNS, we used the animal model of MS, experimental autoimmune encephalomyelitis (EAE), and induced EAE in bone marrow (BM) chimera mice generated using major histocompatibility complex (MHC)-mismatched donor BM, allowing the separation of microglial cells and peripheral monocytes/macrophages. We found that microglial cell activation was evident before onset of disease symptoms and infiltration of peripheral myeloid cells into the CNS. Activated microglial cells underwent proliferation and upregulated the expression of CD45, MHC class II, CD40, CD86, and the dendritic cell marker CD11c. At the peak of EAE disease, activated microglial cells comprised 37% of the total macrophage and dendritic cell populations and colocalized with infiltrating leukocytes in inflammatory lesions. Our findings thus definitively demonstrate that during EAE, microglial cells become activated early in EAE disease and then differentiate into both macrophages and dendritic-like cells, suggesting they play an active role in the pathogenesis of EAE and MS.     

Panayiotopoulos syndrome with convulsive status epilepticus at the onset: A long-term study

PurposeTo better define the convulsive status epilepticus (CSE) as a possible manifestation at the onset of Panayiotopoulos syndrome (PS) and to assess its prognostic value in these children.MethodsChildren with CSE and diagnostic criteria of PS were identified, followed clinically and compared with a group of patients with PS without CSE from 1993 to 2012.ResultsWe identified 37 patients with CSE at the onset of PS. During the same period we identified 72 children with autonomic symptoms of PS without CSE. The first episode of CSE occurred at a mean age of 6.5 years. Generalized clonic seizures were the most common ictal event and one-third of the patients required admission to Intensive Care Units. Interictal EEGs showed occipital spike activity in 31 (83.7%) subjects. Only 14 (37.8%) patients were treated with valproic acid and for two of them (5.40%) it was necessary to administer other drugs. There were no intractable cases. The overall prognosis was excellent. After the first event, 15 subjects (40.54%) experienced at least another typical PS seizure, but all patients were seizure free at the last follow-up.ConclusionCSE is not uncommon in PS and it may occur at the onset of benign childhood epilepsy, without leading to a poor prognosis.     

Relation of occupational stress to the age at onset of Huntington''s disease

Two hypotheses were tested to determine whether occupational stress was related to the age at onset of Huntington's disease. Using case material drawn from four kindreds in southern Norway, occupations of affected persons were graded into three categories according to their degree of physical stress. Adjusting for the effects of related factors, grade of stress was found to be a significant contributor to the variation in onset age. Minor and severe stress were associated with earlier onset ages than moderate stress; the difference between minor and moderate grades was 9 years. The results are interpreted as conforming to the psychosocial concept of Levi, whereby both under- and overstimulation of sensory functions are more stressful and more potent precipitants of illness than intermediate levels of stimulation.     

Age at onset: the major determinant of outcome in Parkinson's disease

Factors at presentation which influenced the course of the disease and response to treatment were assessed in 125 de novo patients with Parkinson's disease. Ninety-eight patients were available for re-assessment at 5 years. Older patients presented earlier after the onset of symptoms, deteriorated more rapidly, and were significantly more likely to develop dementia and impairment of balance. Increasing age and symmetrical disease predicted the new appearance of imbalance. Age of onset did not predict dyskinesia or end of dose failure. A low tremor score at baseline and female gender were predictive of the early appearance of dyskinesia. Patients who experienced end of dose failure were taking a significantly higher dose of levodopa. Once dose and duration of treatment were corrected for, no baseline features were predictive of end of dose failure. The dose of levodopa at 5 years was positively correlated to baseline disease severity as measured by the Columbia score. We conclude that the age of onset of symptoms of Parkinson's disease is a major determinant of the course of the disease and response to treatment.     

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat

In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24-h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.