ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC. METHODS: We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [3H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 µl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [3H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF. RESULTS: We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aß. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.

The association of polysomnographic sleep on posttraumatic stress disorder symptom clusters in trauma-exposed civilians and veterans.

Study Objectives: Self-reported sleep disturbance has been established as a risk factor and predictor for posttraumatic stress disorder (PTSD); however, less is known about the relationship between objective sleep and PTSD symptom clusters, and the specific role of hyperarousal. The present study examined the relationships between sleep continuity and architecture on PTSD symptom clusters. Methods: Participants underwent two in-laboratory sleep studies to assess sleep continuity and architecture. They also completed the Clinician-Administered PTSD-IV scale and the Structured Clinical Interview for the DSM-IV to assess for PTSD diagnosis and other psychiatric disorders. Results: Sleep continuity (i.e. total sleep time, sleep efficiency percent, wake after sleep onset, sleep latency) was significantly related to PTSD Cluster B (reexperiencing) symptom severity (R 2 = .27, p < .001). Sleep architecture, specifically Stage N1 sleep, was significantly associated with PTSD Cluster B (t = 2.98, p = .004), C (Avoidance; t = 3.11, p = .003), and D (Hyperarosual; t = 3.79, p < .001) symptom severity independently of Stages N2, N3, and REM sleep. REM sleep variables (i.e. REM latency, number of REM periods) significantly predicted Cluster D symptoms (R 2 = .17, p = .002). Conclusions: These data provide evidence for a relationship between objective sleep and PTSD clusters, showing that processes active during Stage N1 sleep may contribute to PTSD symptomatology in civilians and veterans. Further, these data suggest that arousal mechanisms active during REM sleep may also contribute to PTSD hyperarousal symptoms.This paper is part of the War, Trauma, and Sleep Across the Lifespan Collection. This collection is sponsored by the Sleep Research Society.

Targeted Plasmalogen Supplementation: Effects on Blood Plasmalogens, Oxidative Stress Biomarkers, Cognition, and Mobility in Cognitively Impaired Persons.

Plasmalogens are a specific type of glycerophospholipid found in especially high levels in neuronal membranes. Decreased blood and brain levels of docosahexaenoic acid (DHA) containing plasmalogens are associated with decreased cognition and neuromuscular function in humans. Administration of 1-O-alkyl-2-acylglycerol (AAG) plasmalogen precursors containing DHA at the sn-2 position dose-dependently increase blood DHA plasmalogens and are neuroprotective in animal models of neurodegeneration at doses between 10 and 50 mg/kg. We conducted an investigational clinical trial in 22 cognitively impaired persons to evaluate the effects of an escalating oral dosing regimen of DHA-AAG from 900 to 3,600 mg/day over a 4-month period on blood serum plasmalogen and non-plasmalogen phospholipids and oxidative stress biomarkers. Safety, tolerability and therapeutic effects on cognition and mobility were also evaluated. DHA plasmalogen levels increased with increasing dose and remained significantly elevated at all treatment doses and durations. DHA plasmalogen levels were positively associated with catalase activity and negatively associated with malondialdehyde (MDA) levels. DHA-AAG supplementation normalized catalase activity in persons with low baseline catalase activity, normalized MDA levels in persons with high baseline MDA levels, and normalized superoxide dismutase activity in persons with high baseline SOD activity. Cognition improved in nine participants, was unchanged in nine, and declined in four. Mobility improved in twelve, was unchanged in five and declined in four participants. Changes in cognition and mobility were statistically significant versus a random outcome. Baseline DHA-plasmalogen levels were not predictive of clinical response. DHA-AAG was well tolerated at all dosages and no adverse reactions were observed.

Circulating ethanolamine plasmalogen indices in Alzheimer's disease: Relation to diagnosis, cognition, and CSF tau.

INTRODUCTION: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability. METHODS: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers. RESULTS: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 × 10-5 ) and PBV (P = 1.99 × 10-4 ), and AD versus LMCI with PL/PE (P = 1.85 × 10-4 ). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 × 10-6 ; PBV: P = 6.92 × 10-5 ) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 × 10-9 ; PBV: P = 6.50 × 10-9 ). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total-tau was negatively associated with PL-PX (P = 5.55 × 10-6 ) and PBV (P = 7.77 × 10-6 ). Additionally, CSF t-tau/Aß1-42 ratio was negatively associated with these same indices (PL-PX, P = 2.73 × 10-6 ; PBV, P = 4.39 × 10-6 ). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/Aß1-42 (P = 0.021). CSF Aß1-42 was not significantly associated with any of these indices in either cohort. DISCUSSION: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.

Correlates and Predictors of Cerebrospinal Fluid Cholesterol Efflux Capacity from Neural Cells, a Family of Biomarkers for Cholesterol Epidemiology in Alzheimer's Disease.

BACKGROUND: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer's disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD. OBJECTIVE: To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects. METHODS: We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis. To measure cerebrospinal fluid (CSF) CECs from neurons, microglia, and astrocytes, CSF was exposed to, correspondingly, neuronal, microglial, and astrocytic cholesterol source cells. Human neuroblastoma SH-SY5Y, mouse microglial N9, and human astroglial A172 cells were used as the cholesterol source cells. CSF samples were screened for contamination with blood. CSF CECs were measured in a small cohort of 22 individuals. RESULTS: CSF CECs from neurons, microglia, and astrocytes were moderately to moderately strongly correlated with CSF concentrations of cholesterol, apolipoprotein A-I, apolipoprotein E, and clusterin (Pearson's r = 0.53-0.86), were in poor agreement with one another regarding CEC of the CSF samples (Lin's concordance coefficient rc = 0.71-0.76), and were best predicted by models consisting of, correspondingly, CSF phospholipid (R2 = 0.87, p < 0.0001), CSF apolipoprotein A-I and clusterin (R2 = 0.90, p < 0.0001), and CSF clusterin (R2 = 0.62, p = 0.0005). CONCLUSION: Characteristics of the CSF CEC metrics suggest a potential for independent association with AD and provision of fresh insight into the role of cholesterol in AD pathogenesis.

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study.

INTRODUCTION: The dynamic range of cerebrospinal fluid (CSF) amyloid ß (Aß1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. METHODS: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). RESULTS: Seven proteins were significantly associated with Aß1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. DISCUSSION: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.

Subjective memory complaints, cognitive performance, and psychological factors in healthy older adults.

OBJECTIVE: To determine whether subjective memory complaints (SMCs) are associated with performance on objective cognitive measures and psychological factors in healthy, community-dwelling older adults. METHOD: The cohort was composed of adults, 65 years and older with no clinical evidence of cognitive impairment (n = 125). Participants were administered: CogState computerized neurocognitive battery, Prospective Retrospective Memory Questionnaire, personality and meaning-in-life measures. RESULTS: SMCs were associated with poorer performance on measures of executive function (p = 0.001). SMCs were also associated with impaired delayed recall (p = 0.006) but this did not remain significant after statistical adjustment for multiple comparisons. SMCs were inversely associated with conscientiousness (p = 0.004) and directly associated with neuroticism (p < 0.001). Higher scores on SMCs were associated with higher perceived stress (p = 0.001), and ineffective coping styles (p = 0.001). Factors contributing to meaning-in-life were associated with fewer SMCs (p < 0.05). CONCLUSIONS: SMCs may reflect early, subtle cognitive changes and are associated with personality traits and meaning-in-life in healthy, older adults.

Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer's disease from normal cognitive aging.

BACKGROUND: A critical and as-yet unmet need in Alzheimer disease (AD) research is the development of novel markers that can identify individuals at risk for cognitive decline due to AD. This would aid intervention trials designed to slow the progression of AD by increasing diagnostic certainty, and provide new pathophysiologic clues and potential drug targets. RESULTS: We used two metabolomics platforms (gas chromatography-time of flight mass spectrometry [GC-TOF] and liquid chromatography LC-ECA array [LC-ECA]) to measure a number of metabolites in cerebrospinal fluid (CSF) from patients with AD dementia and from cognitively normal controls. We used stepwise logistic regression models with cross-validation to assess the ability of metabolite markers to discriminate between clinically diagnosed AD participants and cognitively normal controls and we compared these data with traditional CSF Luminex immunoassay amyloid-ß and tau biomarkers. Aß and tau biomarkers had high accuracy to discriminate cases and controls (testing area under the curve: 0.92). The accuracy of GC-TOF metabolites and LC-ECA metabolites by themselves to discriminate clinical AD participants from controls was high (testing area under the curve: 0.70 and 0.96, respectively). CONCLUSIONS: Our study identified several CSF small-molecule metabolites that discriminated especially well between clinically diagnosed AD and control groups. They appear to be suitable for further confirmatory and validation studies, and show the potential to provide predictive performance for AD.

Association of plasma C-reactive protein levels with the diagnosis of Alzheimer's disease.

C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer's disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual Mini-Mental State Examinations (MMSE) during a 3-year follow-up period to investigate CRP's relationship with diagnosis and progression of cognitive decline. Adjusted for age, sex, and education, subjects with AD had significantly lower levels of plasma CRP than subjects with MCI and normal aging. However, there was no significant association between plasma CRP at baseline and subsequent cognitive decline as assessed by longitudinal changes in MMSE score. Our results support previous reports of reduced levels of plasma CRP in AD and indicate its potential utility as a biomarker for the diagnosis of AD.

Insomnia in alcohol dependence: predictors of symptoms in a sample of veterans referred from primary care.

OBJECTIVE: Patients with alcohol dependence presenting for treatment may have multiple associated co-morbid conditions and limited social supports, which complicate treatment. Each of these factors has been independently associated with complaints of insomnia. In this preliminary study, we investigated the relations between insomnia complaints and socio-demographic factors and psychiatric co-morbidity in treatment-seeking patients with alcohol dependence. METHOD: We conducted a retrospective chart review on 84 consecutive patients referred to the Behavioral Health Laboratory of the Philadelphia Veterans Affairs Medical Center for evaluation of psychiatric and substance use disorders. Patients met DSM-IV diagnostic criteria for alcohol dependence and completed a series of self-assessments of sleep. Univariate and multivariable analyses were used to examine the relations amongst the variables of interest. RESULTS: In multivariable models, Sleep Latency was significantly greater in individuals without partners (p = .01), those with psychiatric disorders (p = .03) and smokers (p = .01), with a non-significant trend for those with past-year suicidal ideation. No significant predictor of Wake Time After Sleep Onset was seen. Poor Sleep Quality was predicted by younger age (OR = .93 [.88, .98], p = .004) and the presence of a psychiatric disorder (OR = 20.80 [4, 102], p = .0002), with a non-significant trend for suicidal ideation. CONCLUSIONS: Insomnia symptoms in treatment-seeking alcohol dependent patients should prompt consideration of the individuals' psychiatric and psychosocial features.

Vascular disease and dementias: paradigm shifts to drive research in new directions.

Vascular disease was once considered the principal cause of aging-related dementia. More recently, however, research emphasis has shifted to studies of progressive neurodegenerative disease processes, such as those giving rise to neuritic plaques, neurofibrillary tangles, and Lewy bodies. Although these studies have led to critical insights and potential therapeutic strategies, interest in the role of systemic and cerebrovascular disease mechanisms waned and has received relatively less attention and research support. Recent studies suggest that vascular disease mechanisms play an important role in the risk for aging-related cognitive decline and disorders. Vascular disease frequently coexists with cognitive decline in aging individuals, shares many risk factors with dementias considered to be of the "Alzheimer type," and is observed more frequently than expected in postmortem material from individuals manifesting "specific" disease stigmata, such as abundant plaques and tangles. Considerable difficulties have emerged in attempting to classify dementias as being related to vascular versus neurodegenerative causes, and several systems of criteria have been used. Despite multiple attempts, a lack of consensus remains regarding the optimal means of incorporating vascular disease into clinical diagnostic, neurocognitive, or neuropathologic classification schemes for dementias. We propose here an integrative, rather than a strictly taxonomic, approach to the study and elucidation of how vascular disease mechanisms contribute to the development of dementias. We argue that, instead of discriminating between, for example, "Alzheimer's disease," "vascular dementia," and other diseases, there is a greater need to focus clinical and research efforts on elucidating specific pathophysiologic mechanisms that contribute to dementia phenotypes and neuropathologic outcomes. We outline a multitiered strategy, beginning with clinical and public health interventions that can be implemented immediately, enhancements to ongoing longitudinal studies to increase their informative value, and new initiatives to capitalize on recent advances in systems biology and network medicine. This strategy will require funding from multiple public and private sources to support collaborative and interdisciplinary research efforts to take full advantage of these opportunities and realize their societal benefits.

Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias.

A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer's disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer's disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer's disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing. More than 77% of subjects with Alzheimer's disease had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43-67%). Age- and sex-adjusted atherosclerosis ratings were highly correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral amyloid angiopathy ratings in the whole sample and within individual groups. We found no associations between atherosclerosis ratings and α-synuclein or TDP-43 lesion ratings. The association between age-adjusted circle of Willis atherosclerosis and Alzheimer's disease-type pathology was more robust for female subjects than male subjects. These results provide further confirmation and specificity that vascular disease and Alzheimer's disease are interrelated and suggest that common aetiologic or reciprocally synergistic pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology.

Unmedicated, remitted patients with major depression have decreased serum immunoglobulin A.

Patents with major depression have evidence of a proinflammatory state with consistent elevations in acute phase proteins and in the levels of inflammatory mediators such as interleukin-6 and tumor necrosis factor-α. We report here a study of the serum levels of immunoglobulin A (IgA) in medication-free patients with major depression in the remitted state (ruMDD). Selective IgA deficiency is the most common form of immunoglobulin abnormality, and is often associated with a higher than expected incidence of proinflammatory and autoimmune phenomena. We measured serum IgG, IgM, and IgA in 28 ruMDD patients and 27 healthy subjects (Ctrl) at 0 (pretreatment), 7, and 24h following sham depletion and tryptophan (TrpD) depletion conducted at least 8 days apart under balanced, randomized, blinded conditions. Immunoglobulins were measured by automated immunonephelometry. Data were analyzed by repeated measures ANOVA with diagnosis as a fixed effect and drug (TrpD vs. sham), and time as repeated measures factors. Serum IgA was consistently lower in ruMDD patients vs. Ctrl at all time points examined (p<0.04 for main effect of diagnosis). Serum IgG and IgM levels did not show significant differences by diagnosis. Medication-free patients with major depression in the remitted state have a significant reduction in serum IgA levels measured on multiple occasions. In the light of the fact that IgA serves many immunomodulatory, anti-inflammatory roles, this finding supports the concept that major depressive illness represents a proinflammatory state.

Acute hydrocortisone treatment increases anxiety but not fear in healthy volunteers: a fear-potentiated startle study.

BACKGROUND: The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as "anxiety," but not relatively similar, briefer aversive states, such as "fear." However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats. METHODS: Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle). RESULTS: Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle. CONCLUSIONS: These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.

Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?

BACKGROUND: Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating. Selective serotonin reuptake inhibitors are commonly prescribed to treat depression, but may not be as effective for more severe or persistent depression. METHODS: The authors review data concerning the effects of corticosteroid synthesis inhibitors (CSIs) in the management of depressive disorders, present a hypothesis as to their possible mechanisms of action based on recent data suggesting synergistic effects of glucocorticoids on extrahypothalamic corticotropin-releasing hormone (CRH), and consider alternative hypotheses. Published reports evaluating the efficacy of CSIs in treating depression are reviewed and presented in light of recent findings regarding actions of glucocorticoids on the central CRH system. RESULTS: Results from open label and double-blind studies by several groups have indicated that CSIs may be efficacious or of adjunctive value in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production. CONCLUSIONS: The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs on glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features.

Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis.

BACKGROUND: Evidence is accumulating that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder and schizophrenia. Cerebrospinal fluid (CSF) concentration of lactate, a product of extra-mitochondrial glucose metabolism, is commonly elevated in individuals with mitochondrial disorders, especially those with neuropsychiatric symptoms. We tested the hypothesis that patients with bipolar disorder and schizophrenia would, on average, have elevated CSF lactate concentrations compared with healthy control subjects. METHODS: The CSF lactate and CSF and plasma glucose concentrations were measured with a YSI (YSI, Yellow Springs, Ohio) 2300 STAT Plus Glucose & Lactate Analyzer in 15 samples from each of three groups of subjects: bipolar I disorder patients, schizophrenic patients, and healthy control subjects. RESULTS: Mean CSF lactate concentrations were significantly higher in bipolar (1.76 +/- .38) and schizophrenic subjects (1.61 +/- .31) compared with control subjects (1.31 +/- .21 mmol/L). These differences persisted after adjusting means for CSF glucose concentration, which correlated positively with CSF lactate concentration. CONCLUSIONS: This is the first report of increased CSF lactate concentrations in patients with bipolar disorder and schizophrenia. Elevated CSF lactate indicates increased extra-mitochondrial and anaerobic glucose metabolism and is consistent with impaired mitochondrial metabolism. Measuring CSF lactate concentration might help identify bipolar and schizophrenic patients with mitochondrial dysfunction who might benefit from research to elucidate and ultimately rectify possible mitochondrial pathology underlying these disorders.

Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression.

In contrast to relapse, the mechanisms of multiple sclerosis (MS) disease progression are less understood and appear not to be exclusively inflammatory in nature. In this pilot study we investigated the relationship between disturbed CNS energy metabolism and MS disease progression. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of sorbitol, fructose, and lactate, all metabolites of extra-mitochondrial glucose metabolism, would be elevated in secondary progressive (SP) MS patients and would be associated with worsening neurologic disability. We measured metabolite concentrations by gas chromatographic/mass spectrometric and enzymatic methods in archived CSF samples from 85 MS patients [31 relapsing-remitting (RR) and 54 SP patients] and 18 healthy controls. We found that concentrations of all three metabolites, but not concentrations of glucose or myoinositol, were significantly increased in CSF from SP and, to a lesser degree, RR patients, compared to controls. Furthermore, CSF concentrations of sorbitol and fructose (polyol pathway metabolites), but not lactate (anaerobic glycolysis metabolite), correlated positively and significantly with Expanded Disability Status Scale (EDSS) score, an index of neurologic disability in MS patients. We conclude that extra-mitochondrial glucose metabolism is increased in MS patients and is associated with disease progression evidenced by increasing EDSS score. As extra-mitochondrial glucose metabolism increases with impaired mitochondrial metabolism of glucose, these findings implicate mitochondrial dysfunction in the pathogenesis of MS disease progression. CSF metabolic profiling may be useful in clarifying the role of mitochondrial pathology in progression and in targeting and monitoring therapies for disease progression that aim to preserve or boost mitochondrial glucose metabolism.

CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques.

CONTEXT: Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence. OBJECTIVE: To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques. DESIGN: We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption. SETTING: National Institutes of Health Animal Center. PARTICIPANTS: Rhesus macaques. MAIN OUTCOME MEASURES: Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH -2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance. RESULTS: We show that -2232C>G alters DNA x protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior. CONCLUSION: Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.