Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus.

Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. Several genomic screens have suggested that a region between chromosome 12p13 and 12q22 contains at least one additional locus underlying the susceptibility of AD. However, localization of this locus has been difficult. We performed a 5 cM microsatellite marker screen across 74 cM on chromosome 12 with 15 markers in 585 multiplex families consisting of 994 affected sibpairs and 213 other affected relative pairs. Analyses across the entire data set did not reveal significant evidence of linkage. However, suggestive linkage was observed in several subsets. In the 91 families where no affected individuals carry an ApoE varepsilon4 allele, an HLOD score of 1.55 was generated at D12S1042. We further examined the linkage data considering the proposed linkages to chromosome 9 (D9S741) and chromosome 10 (alpha-catenin gene). There was a modest (P=0.20) increase in the LOD score for D12S368 (MLOD=1.70) when using the D9S741 LOD scores as a covariate and a highly significant (P<0.001) increase in the MLOD score (4.19) for D12S1701 in autopsy-confirmed families (n=228) when using alpha-catenin LOD scores as a covariate. In both cases, families with no evidence of linkage to D9S741 or alpha-catenin demonstrated most of the evidence of linkage to chromosome 12, suggesting locus heterogeneity. Taken together, our data suggest that the 16 cM region between D12S1042 and D12S368 should be the subject of further detailed genomic efforts for the disease.

Steroid receptor-mediated modulation of CD4+CD62L+ cell homing. Implications for drug abusers.

Naive human T cells home to peripheral lymph nodes via the leukocyte endothelial cell adhesion molecule-1 (LECAM-1, l-selectin, CD62L, Leu8 antigen) they express. We enriched populations of CD4+CD62L+ cells (attachment of Leu8+ T cells to flasks coated with anti-mouse IgG (AIS); Leu8+ T cells, 82.3% pure (+/- 2.3%), enriched for CD4+ cells by incubation over flasks coated with anti-CD4 antibody--this 3-4-day procedure yields an 88 +/- 1.4% recovery. Cells were treated with dexamethasone in vitro for 24-48 h, and monitored by flow cytometry. We found severe toxicity by this steroid at high concentration (10(-6) M: 35% decrease in CD62L+ T cells, 22% drop specifically in CD4+CD62L+ cells), suggesting the onset of receptor-mediated apoptotic events. The toxicity was dose dependent (5% and 7% drop in CD62L+ T and CD4+CD62L+ cells, respectively, at 10(-9) M, the concentration found in plasma 10 h following the administration of 1 mg dexamethasone). One mg of dexamethasone given to normal subjects leads to a 15-20% decrease in circulating CD4+CD62L+ cells at 10 h. This tends to be correlated with a drop in the number of glucocorticoid cytosolic receptors. Thus, steroids seem to modulate CD4+CD62L+ cell homing by means of receptor-mediated mechanisms.

Disruption of circadian MHPG rhythmicity in major depression.

Plasma concentrations of total (free plus conjugated) 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined every 3 hr for a 24-hr period in 32 unipolar depressed patients, 11 bipolar depressed patients, and 12 healthy subjects. Each subject's circadian MHPG rhythmicity was modeled by a sinusoidal function. Temporal parameters were estimated by linear least squares regression with a fixed 24-hr period. The variabilities associated with estimates of circadian amplitude and acrophase were roughly twice as large in the patients compared to healthy subjects. Phase advances were associated most significantly with the agitated rather than the retarded subtype of depression, and with first episode depressions. Treatment with desipramine (n = 26) did not alter significantly any of the model parameters and had no effect on circadian variability in any patient group. The data overall support a dysregulation theory for depressive illness with phase advances representing one manifestation of such dysregulation.

Binge eating disorder affects outcome of comprehensive very-low-calorie diet treatment.

To determine the effects of binge eating disorder (BED) on weight loss and maintenance in women undergoing treatment for obesity, we studied the weight changes of 38 women (body mass index > 30 kg/m2), 21 of whom met proposed criteria for BED and 17 of whom reported few problems with binge eating, during and after a 26-week comprehensive very-low-calorie diet (VLCD) treatment program. All 17 subjects without and 16/21 subjects with BED returned for four follow-up visits over 12 months (p = 0.05). While a similar proportion of subjects with and without BED reported absolute adherence to both the modified fast and refeeding, those with BED showed a significantly different distribution in energy intake from those without BED, with fewer small and more large lapses among those who deviated from the diet (p < 0.05). There was no significant difference in mean weight loss over the 26 weeks of treatment, but subjects with BED showed significantly diminished weight loss during the middle third of treatment (p < 0.05). Black subjects, regardless of the presence of BED, lost significantly less weight during treatment than white subjects (p < 0.005). Although there was no significant difference in mean weight loss at any of the four follow-up visits between subjects with and without BED, 25% of subjects with BED had regained > 50% of their lost weight by three-month follow-up, vs. no subjects without the disorder (p < 0.05). One year after completing treatment, approximately half of BED (+) and BED (-) subjects had a good outcome, maintaining a weight loss > or = 10% of initial body weight. However, 35% of subjects with BED, and none of the subjects without BED, had a poor outcome (p < 0.05). We conclude that many individuals with BED will respond well to a medically supervised comprehensive VLCD program, attaining medically significant weight loss. However, this subgroup appears to be at risk for early major regain of lost weight and for poor outcome one year following weight-loss treatment.

The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate.

Standard tricyclic antidepressant (TCA) treatment usually entails response latencies of 2 to 4 weeks. To accelerate the antidepressant response, methylphenidate (MPH) was administered together with standard antidepressants in an open label trial. Twenty inpatients (9 females, 11 males) met DSM-III-R criteria for major depressive episode (15 unipolar and 2 bipolar), depression NOS (n = 2), or Research Diagnostic Criteria for schizoaffective illness, depressed type (n = 1). Following evaluation for depression, patients received an open-label oral MPH stimulation trial (MST), in 1 or 2 dosages of 5 to 15 mg at 0900 and 1000 hours. Twenty patients with positive MST response were treated with TCAs combined with MPH (5-15 mg/d). Therapeutic response was defined as 50 percent decline in the Hamilton Rating Scale for Depression. Six of 20 (30%) patients responded after 1 week of combination TCA-MPH, and 10 of 16 (63%) after 2 weeks. Adverse effects of the combination treatment included: dizziness and orthostatic blood pressure changes (n = 3), dry mouth (n = 3), increased anxiety (n = 3), and hypomania (n = 1). The severity of adverse effects required cessation of the MPH in 3 patients. Elevated self-ratings of anxiety were associated with lack of improvement after both 1 and 2 weeks. Adjunctive MPH appears to accelerate response to tricyclics in this systematically conducted open trial, and adverse effects of the TCA-MPH combination were usually tolerable. Positive response on the MST may be predictive of beneficial therapeutic outcome, especially in depressed patients without high anxiety levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid function in bulimia nervosa.

Bulimia nervosa is characterized by episodes of binge eating. Bulimic patients have diminished caloric requirements and reduced metabolic rate. Because thyroid function is an important modulator of metabolic rate, we sought to clarify conflicting reports concerning this parameter in bulimic patients. Thyroid indices were examined in 18 bulimics at admission and after 3 weeks of abstinence. Patients had thyroid indices in the normal range at admission but slightly diminished triiodothyronine (T3) compared with control subjects (n = 28). Significant declines in T3 and thyroxine and increases in thyrotropin were noted after 3 weeks of abstinence. At abstinence, T3 was positively correlated with caloric intake, protein, fat, and carbohydrate consumption and inversely correlated with percent ideal body weight. We hypothesize that binge-purge behavior may transiently increase thyroid indices and, consequently, metabolic rate in patients with bulimia nervosa. Furthermore, decreases in T3 following abstinence may be related to diminished caloric consumption or may reflect hypothalamic-pituitary dysregulation in these patients.

Normal dexamethasone suppression in obese binge and nonbinge eaters with rapid weight loss.

Natural or experimental starvation is frequently associated with hypercortisolism, reflected as incomplete suppression of serum cortisol after dexamethasone. To determine whether rapid weight loss per se or some other aspect of starvation induces disruption of the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated 2 categories of obese women (body mass index > 30 kg/m2) undergoing rapid weight loss: binge eaters (n = 12) and nonbinge eaters (n = 8). We performed psychometric evaluation and 1 mg overnight dexamethasone suppression tests in the obese subjects, as well as in 12 race- and age-matched normal-weight women. The obese women were tested before and after 12 weeks of a 3349 kJ/day (800 kcal/day) liquid formula diet, and lost an average of 19.3 kg, which represented 17.3% of their total body weight. Binge eaters, who were initially more depressed than either nonbinge eaters or normal-weight controls, had a significant amelioration of their symptoms with weight loss. Neither group had evidence of disruption of the HPA axis before or after weight loss. Thus, the rate of failure to suppress cortisol after dexamethasone was approximately 10% in each of the obese and control groups, and did not differ between the pre- and postweight loss condition or between binge eaters and nonbinge eaters. Serum free T4 was unchanged, whereas T3 fell significantly with weight loss. We conclude that weight loss may improve affect in the obese without altering HPA axis activity, and postulate that one of the concomitants of restricted energy intake, perhaps in combination with a threshold body weight, may be of greater importance in causing abnormalities of dexamethasone suppression testing than rapid weight loss per se.

Case report of anorexia nervosa associated with Wilson's disease.

Wilson's disease is a recessively inherited disorder of copper metabolism with prominent hepatic, hematopoietic, central nervous system (CNS), and ocular involvement. Psychiatric manifestations are notoriously variable. The following case history of a patient with both anorexia nervosa and Wilson's disease is presented and discussed in the context of organic CNS lesions associated with anorexia nervosa-like syndromes.

The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins.

We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low weight patients with anorexia nervosa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding.

Altered serotonin activity in anorexia nervosa after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level correlate with rigid and obsessive behavior?

To avoid the confounding influences of malnutrition or weight loss, we studied patients with anorexia nervosa at normal weight and stable dietary intake. Compared with 15 controls, 17 long-term weight-restored anorectic subjects had elevated concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid, the major serotonin metabolite, whereas levels of cerebrospinal fluid homovanillic acid, the major dopamine metabolite, were normal. Elevated levels of cerebrospinal fluid 5-hydroxyindoleacetic acid may indicate increased serotonin activity. Such activity could contribute to pathological feeding behavior. Most importantly, this study raises the question as to whether increased cerebrospinal fluid 5-hydroxyindoleacetic acid levels are associated with overly inhibited, anxious, or obsessive traits.

High levels of thyrotropin-releasing hormone precursor peptide immunoreactivity and binding substance occur in human cerebrospinal fluid.

A thyrotropin-releasing hormone (TRH) precursor peptide, pGlu-His-Pro-Gly (TRH-Gly) and related peptides were measured in human cerebrospinal fluid (CSF) with a TRH-Gly radiommunoassay and the levels of immunoreactivity (IR) were found to be 136- to 352-fold higher than the corresponding levels of TRH-IR. TRH-IR levels in CSF are elevated during the active phase of multiple sclerosis (MS). We have used this TRH-Gly RIA to determine whether this TRH precursor peptide is also elevated in CSF from MS and Alzheimer's (ALZ) disease patients in comparison with the corresponding levels in non-central nervous system disease (control) patients. A highly significant increase in TRH-Gly-IR was observed in MS and ALZ CSF samples compared to control CSF. Cation exchange and exclusion chromatography of extracts of mixtures of CSF and synthetic TRH-Gly revealed two peaks of TRH-Gly-IR. One cochromatographed with synthetic TRH-Gly and the other was attributable to the formation of a complex between TRH-Gly and a binding substance originating in CSF. Corresponding studies with extracts of mixtures of CSF and synthetic TRH revealed no evidence for TRH binding with any component of CSF. Reverse-phase high-pressure liquid chromatography of pooled extracts of normal CSF revealed that about a third of the total TRH-Gly-IR coeluted with synthetic TRH-Gly. The half-time for in vitro metabolism of synthetic TRH-Gly in fresh CSF was 5 times longer than for synthetic TRH at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary-adrenal-immune system in normal subjects and in patients with anorexia nervosa: the number of circulating helper T lymphocytes (CD4) expressing the homing receptor Leu8 is regulated in part by pituitary-adrenal products.

The association between plasma pituitary-adrenal (PA) hormones and the number of certain populations of peripheral blood lymphocytes (PBL) was examined in subjects with normal PA function and in patients with anorexia nervosa (AN). AN patients display several neuroendocrine dysfunctions, including hypercortisolemia. In the normal subjects there were positive correlations between adrenocorticotropic hormone (ACTH) and the number of PBL and helper T lymphocytes expressing the homing receptor Leu8 (CD4+Leu8+); there was a negative relationship between cortisol and these lymphocyte populations. These latter, inverse correlations did not occur in the AN patients, either while underweight or after weight recovery, with some persistence of hypercortisolemia. Administration of dexamethasone (DEX) suppressed cortisol levels and reduced, perhaps via a receptor-mediated mechanism, the number of circulating PBL and CD4+Leu8+ in the normal subjects but not in the AN patients. These results support the physiological relevance of PA-CMI interaction in subjects with normal PA function and indicate that the PA-CMI interrelationship is disrupted in AN patients with hypercortisolemia.

Fluoxetine treatment of anorexia nervosa: an open clinical trial.

Six patients with chronic, refractory anorexia nervosa were treated with fluoxetine. Depressive symptoms diminished in all patients, and this was associated with weight gain. Subjects, despite frequent medical comorbidity, tolerated fluoxetine well, even in dosages greater than those used for depression.

Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa.

The related central nervous system peptides neuropeptide Y and peptide YY have been found to be among the most potent endogenous stimulants of feeding behavior. We measured these neuropeptides in cerebrospinal fluid to determine whether they contributed to the pathophysiologic characteristics of anorexia and bulimia nervosa. Cerebrospinal fluid neuropeptide Y concentrations were significantly elevated in underweight anorectic patients and in many of the anorectic patients studied at intervals after weight restoration. These levels normalized in long-term weight-restored anorectic patients who had a return of normal menstrual cycles. Increased neuropeptide Y activity may contribute to several characteristic disturbances in anorexia, including menstrual dysregulation. Cerebrospinal fluid peptide YY concentrations were significantly elevated in normal-weight bulimic patients abstinent from pathological eating behavior for a month compared with themselves when actively bingeing and vomiting or compared with healthy volunteers. Increased peptide YY activity may contribute to a drive to overfeed in normal-weight bulimic patients.

Disturbances of noradrenergic systems in normal weight bulimia: relationship to diet and menses.

Several lines of evidence suggest that noradrenergic (NE) disturbances occur in normal-weight bulimic patients. The purpose of this study was to investigate factors that may be related to noradrenergic disturbances. First, we measured plasma NE during bingeing and vomiting. We found that this behavior activated the sympathetic nervous system. Bingeing produced a significant increase in the duration and the peak increase of plasma NE when compared with normal controls eating a large meal. Second, we assessed basal peripheral and central NE levels near in time (within several days of hospital admission) to chronic bingeing and vomiting. At this time, bulimics had normal basal plasma and CSF NE levels. Finally, we restudied the same patients after 30 days of inpatient hospitalization and observed abstinence from bingeing and vomiting. In this last state, bulimics had a reduction of basal plasma and cerebrospinal fluid (CSF) NE levels compared with themselves on admission and compared with healthy controls. This study confirms that reduced noradrenergic activity occurs in normal-weight bulimic women and suggests that this abnormality may emerge during abstinence from bingeing. We hypothesize that dietary intake is related to noradrenergic activity, but cause and effect remain uncertain. Noradrenergic disturbances did not appear to be related to weight, depression, physical activity, or amino acid precursors. Lower CSF NE levels were found in amenorrheic bulimic women in both states, suggesting that a noradrenergic disturbance may be associated with the frequent incidence of amenorrhea in bulimic women.