Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression.

BACKGROUND: Altered metabolism of acylcarnitines - transporting fatty acids to mitochondria - may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. METHODS: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. RESULTS: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02-1.07) and C10 (OR = 1.05, 95%CIs = 1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. DISCUSSION: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature.

It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite's effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 "Predictors of Antidepressant Treatment Response: The Emory CIDAR" https://clinicaltrials.gov/ct2/show/NCT00360399 .

Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment.

Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called "state-dependent" biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight "co-expressed" metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.

Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.

Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.

A knowledge network for a dynamic taxonomy of psychiatric disease.

Current taxonomic approaches in medicine and psychiatry are limited in validity and utility. They do serve simple communication purposes for medical coding, teaching, and reimbursement, but they are not suited for the modern era with its rapid explosion of knowledge from the "omics" revolution. The National Academy of Sciences published a report entitled Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. The authors advocate a new taxonomy that would integrate molecular data, clinical data, and health outcomes in a dynamic, iterative fashion, bringing together research, public health, and health-care delivery with the interlinked goals of advancing our understanding of disease pathogenesis and thereby improving health. As the need for an information hub and a knowledge network with a dynamic taxonomy based on integration of clinical and research data is vital, and timely, this proposal merits consideration.

Los enfoques taxonómicos actuales tanto en medicina como en psiquiatría son limitados en validez y utilidad. Ellos sirven para fines de una comunicación simple en la codificación médica, la enseñanza y el reembolso, pero no se adaptan a la era moderna con su rápida explo-sión del conocimiento a partir de la revolución de los "ómicos". La Academia Nacional de Ciencias publicó un informe titulado: "Hacia la Precisión en Medicina: Cons-truyendo una Red de Conocimiento para Investigación Biomédica y una nueva Taxonomía de la Enfermedad". Los autores abogan por una nueva taxonomía que pueda integrar datos moleculares, información clínica y resul

Les stratégies taxonomiques actuelles en médecine et en psychiatrie sont limitées en validité et en utilité. Elles servent des objectifs simples de communication pour le codage médical, l'enseignement et le remboursement, mais ne conviennent pas à l'époque contemporaine avec son explosion rapide de connaissance issue de la révolution « omics ¼. L'Académie Nationale des Sciences aux États-Unis a publié un rapport intitulé « Vers une médecine de précision : Construire un réseau de connaissance pour la recherche biomédicale et une nouvelle taxonomie de la maladie.¼ Les auteurs prônent une nouvelle taxonomie qui intégrerait des données moléculaires, cliniques et des résultats des thérapeutiques de façon dynamique, itérative, en rassemblant la recherche, la santé publique et les pres-tations de soins avec des objectifs interdépendants visant à faire progresser notre compréhension de la pathogenèse de la maladie et donc à améliorer la santé. Le besoin d'un centre d'information et d'un réseau de connaissance doté d'une taxonomie dynamique fondée sur l'intégration de données cliniques et de recherche étant vital et opportun, cette suggestion mérite d'être examinée.

Incubating the research independence of a medical scientist training program graduate: a case study.

PROBLEM: Physician-scientists play a critical role in discovering new biological knowledge and translating findings into medical practices that can improve clinical outcomes. Collectively, the National Institutes of Health (NIH) and its affiliated Medical Scientist Training Programs (MSTPs) invest upwards of $500,000 to fully train each of the 900+ MD/PhD students enrolled in these programs. Nevertheless, graduates face the challenges of navigating fragmented intervals of clinical training and research engagement, reinitiating research upon completing their residencies, managing financial pressures, and competing for funding following what is typically four or more years of research inactivity. Together, these barriers contribute to the high attrition rate of MSTP graduates from research careers. APPROACH: The authors designed and implemented (2009-2014), for a single trainee, an alternative postgraduate training model characterized by early research engagement, strategic mentoring, unyoked clinical and research milestones, and dedicated financial support. OUTCOMES: The pilot training experiment was so successful that the trainee secured an NIH project grant and completed his transition to research independence 3.5 years after starting the experimental training schedule-nearly 9 years earlier (based on age) than is typical for MD/PhDs transitioning from mentored to independent research. This success has demonstrated that unyoking research engagement from conventional calendar-based clinical training milestones is a feasible, effective means of incubating research independence in MSTP graduates. NEXT STEPS: The authors encourage the design and application of similar unconventional approaches that interweave residency training with ongoing research activity for appropriate candidates, especially in subspecialties with increased MSTP graduate enrollment.

Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway.

Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ(2)(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.

Fiber tract-specific white matter lesion severity Findings in late-life depression and by AGTR1 A1166C genotype.

Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. The 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F((1,86)) = 4.62, P = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.

Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile.

Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n = 14; dMDD) or remitted MDD subjects (n = 14; rMDD) were compared against those in healthy controls (n = 18; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion.

AGTR1 gene variation: association with depression and frontotemporal morphology.

The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors, but its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1, the gene coding for the type 1 angiotensin II receptor (AT(1)R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. Participants comprised 257 depressed and 116 nondepressed elderly Caucasian subjects who completed clinical assessments and provided blood samples for genotyping. We used a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. For measurement of hyperintense lesions, 1.5 Tesla magnetic resonance imaging (MRI) data were available on 33 subjects. For measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC), 3 Tesla MRI data were available on 70 subjects. Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports the idea that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology.

Association of depression and survival in patients with chronic heart failure over 12 Years.

OBJECTIVE: To examine the relationship between depression and survival in patients with chronic heart failure (HF) over a 12-year follow-up period. BACKGROUND: The survival associated with depression has been demonstrated in HF patients for up to 7 years. Longer-term impact of depression on survival of these patients remains unknown. METHODS: Prospectively conducted observational study examining adults with HF who were admitted to a cardiology service at Duke University Medical Center between March 1997 and June 2003 and completed the Beck depression inventory (BDI) scale. The national death index was queried for vital status. Cox proportional hazards modeling was used to determine the association of survival and depression. RESULTS: During a mean follow-up of 1792.33 ± 1372.82 days (median 1600; range 0-4683), 733 of 985 participants with HF died of all causes, representing 80% of those with depression (BDI > 10) and 73% of those without (P = 0.01). Depression was significantly and persistently associated with decreased survival over follow-up (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.15-1.57), and was independent of conventional risk factors (HR 1.40, 95% CI 1.16-1.68). Furthermore, survival was inversely associated with depression severity (BDI (continuous) HR 1.02, 95% CI 1.006-1.025, P = 0.001). CONCLUSIONS: The impact of co-morbid depression during the index hospitalization on significantly increased mortality of HF patients is strong and persists over 12 years. These findings suggest that more investigation is needed to understand the trajectory of depression and the mechanisms underlying the impact of depression as well as to identify effective management strategies for depression of patients with HF.

Treatment course with antidepressant therapy in late-life depression.

OBJECTIVE: In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial. METHOD: In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time. RESULTS: Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not. CONCLUSIONS: These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.

Amygdala volume in late-life depression: relationship with age of onset.

OBJECTIVES: Depression is common in the elderly population. Although numerous neuroimaging studies have examined depressed elders, there is limited research examining how amygdala volume may be related to depression. DESIGN: A cross-sectional examination of amygdala volume comparing elders with and without a diagnosis of major depressive disorder, and between depressed subjects with early and later initial depression onset. SETTING: An academic medical center. PARTICIPANTS: Ninety-one elderly patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major depression (54 early-onset depressed and 37 late-onset depressed) and 31 elderly subjects without any psychiatric diagnoses. MEASUREMENTS: Amygdala and cerebral volumes were measured using reliable manual tracing methods. RESULTS: In models controlling for age, sex, and cerebral volume, there was a significant difference between diagnostic cohorts in amygdala volume bilaterally (left: F[2, 116] = 16.28, p < 0.0001; right: F[2, 116] = 16.28, p < 0.0001). Using least squares mean group analyses, both early- and late-onset depressed subjects exhibited smaller bilateral amygdala volumes than did the nondepressed cohort (all comparisons p < 0.0001), but the two depressed cohorts did not exhibit a statistically significant difference. LIMITATIONS: Limitations include missing antidepressant treatment data, recall bias, inability to establish a causal relationship between amygdala size and depression given the cross-sectional nature of the design. CONCLUSIONS: Depression in later life is associated with smaller amygdala volumes, regardless of age of initial onset of depression.

Comprehensive model of how reality distortion and symptoms occur in schizophrenia: could impairment in learning-dependent predictive perception account for the manifestations of schizophrenia?

Conventional wisdom has not laid out a clear and uniform profile of schizophrenia as a unitary entity. One of the key first steps in elucidating the neurobiology of this entity would be to characterize the essential and common elements in the group of entities called schizophrenia. Kraepelin in his introduction notes 'the conviction seems to be more and more gaining ground that dementia praecox on the whole represents, a well characterized form of disease, and that we are justified in regarding the majority of the clinical pictures which are brought together here as the expression of a single morbid process, though outwardly they often diverge very far from one another'. But what is that single morbid process? We suggest that just as the uniform defect in all types of cancer is impaired regulation of cell proliferation, the primary defect in the group of entities called schizophrenia is persistent defective hierarchical temporal processing. This manifests in the form of chronic memory-prediction errors or deficits in learning-dependent predictive perception. These deficits account for the symptoms that present as reality distortion (delusions, thought disorder and hallucinations). This constellation of symptoms corresponds with the profile of most patients currently diagnosed as suffering from schizophrenia. In this paper we describe how these deficits can lead to the various symptoms of schizophrenia.

One-year change in anterior cingulate cortex white matter microstructure: relationship with late-life depression outcomes.

OBJECTIVE: differences in white matter structure measured with diffusion tensor imaging (DTI) are associated with late-life depression, but results examining how these differences relate to antidepressant remission are mixed. To better describe these relationships, the authors examined how 1-year change in DTI measures are related to 1-year course of depression. DESIGN: one-year cross-sectional follow-up to a 12-week clinical trial of sertraline. SETTING: outpatients at an academic medical center. PARTICIPANTS: twenty-nine depressed and 20 never-depressed elderly subjects. Over the 1-year period, 16 depressed subjects achieved and maintained remission, whereas 13 did not. MEASUREMENTS: one-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI. RESULTS: contrary to our hypotheses, depressed subjects who did not remit over the study interval exhibited significantly less change in anterior cingulate cortex (ACC) white matter FA than did never-depressed or depressed-remitted subjects. There were no group differences in other frontal or central white matter regions. Moreover, there was a significant positive relationship between change in Montgomery-Asberg Depression Rating Scale (MADRS) and change in ACC FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS. CONCLUSION: older depressed individuals who remit exhibit white matter changes comparable with what is observed in never-depressed individuals, whereas nonremitters exhibit significantly less change in ACC FA. Such a finding may be related to either antidepressant effects on brain structure or the effects of chronic stress on brain structure. Further work is needed to better understand this relationship.

Support for the vascular depression hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial.

CONTEXT: Research on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity. OBJECTIVE: To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression. DESIGN: Two-site, prospective, nonrandomized controlled trial. SETTING: Outpatient clinics at Washington University and Duke University. PARTICIPANTS: A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time. RESULTS: Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores. CONCLUSIONS: Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045773.

Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia.

BACKGROUND: TOR1A encodes a chaperone-like AAA-ATPase whose Delta GAG (Delta E) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late onset, focal dystonia has been suggested. RESULTS: A novel TOR1A missense mutation (c.613T-->A, p.F205I) in a patient with late onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or Delta E, but not wildtype TOR1A, produced frequent intracellular inclusions. CONCLUSIONS: A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late onset, focal dystonia.

Reductions in neuronal density in elderly depressed are region specific.

OBJECTIVE: Frontal regions, including the orbitofrontal cortex (ORB) and dorsolateral prefrontal cortex (dlPFC) have been implicated in the neuropathology of geriatric depression. Prominent reductions in pyramidal neuron density have been recently reported in the ORB of older depressed subjects. However, the cellular pathology of the dlPFC has not yet been examined in these subjects. METHODS: Postmortem tissue from the dlPFC (Brodmann's area 9, BA9) was collected from 10 older (>60 years old) subjects diagnosed with major depression and 10 age-matched non-psychiatric controls (CTRL). The majority of the subjects were the same as those used for our previous study on neuronal reductions in the ORB in older depressed. Overall (all six layers combined), and laminar density of pyramidal (presumably glutamatergic), and non-pyramidal (GABAergic) neurons as well as cortical and laminar width were measured using linear optical disector of Stereoinvestigator software. RESULTS: Neither the overall nor laminar density of pyramidal or non-pyramidal neurons was significantly different between groups. The cortical and laminar widths were also not affected. CONCLUSIONS: These results suggest that neuronal prefrontal pathology in elderly depressed is region specific. No significant changes were detected in the density of any type of neurons in the dlPFC of elderly depressed subjects (present study) whereas, prominent reductions in the density of pyramidal glutamatergic neurons were observed previously in the ORB.