Structural imaging in late-life depression: association with mood and cognitive responses to antidepressant treatment.

OBJECTIVES: Recent positron emission tomography studies of cerebral glucose metabolism have identified the functional neural circuitry associated with mood and cognitive responses to antidepressant treatment in late life depression (LLD). The structural alterations in these networks are not well understood. The present study used magnetic resonance (MR) imaging and voxel-based morphometry to evaluate the association between gray matter volumes and changes in mood symptoms and cognitive function with treatment with the antidepressant citalopram. DESIGN: Open-label trial with baseline brain MR scan. Mood and cognitive assessments performed at baseline and during citalopram treatment. SETTING: Outpatient clinics of an academic medical center. PARTICIPANTS: 17 previously unmedicated patients age 55 years or older with a major depressive episode and 17 non-depressed comparison subjects. INTERVENTION: 12-week trial of flexibly dosed citalopram. MEASUREMENTS: Gray matter volumes, Hamilton Depression Rating Scale, California Verbal Learning Test, Delis-Kaplan Executive Function System. RESULTS: In LLD, higher gray matter volumes in the cingulate gyrus, superior and middle frontal gyri, middle temporal gyrus, and precuneus was associated with greater mood improvement. Higher gray matter volumes in primarily frontal areas were associated with greater improvement in verbal memory and verbal fluency performance. CONCLUSIONS: Associations with antidepressant induced improvements in mood and cognition were observed in several brain regions previously correlated with normalization of glucose metabolism after citalopram treatment in LLD. Future studies will investigate molecular mechanisms underlying these associations (e.g., beta-amyloid, inflammation, glutamate).

Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial.

BACKGROUND: Anorexia nervosa is characterised by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder. Deep brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results. We aimed to assess the safety of DBS to modulate the activity of limbic circuits and to examine how this might affect the clinical features of anorexia nervosa. METHODS: We did a phase 1, prospective trial of subcallosal cingulate DBS in six patients with chronic, severe, and treatment-refractory anorexia nervosa. Eligible patients were aged 20-60 years, had been diagnosed with restricting or binge-purging anorexia nervosa, and showed evidence of chronicity or treatment resistance. Patients underwent medical optimisation preoperatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation. Patients were followed up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit. Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals. This trial is registered with ClinicalTrials.gov, number NCT01476540. FINDINGS: DBS was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious. Other related adverse events were panic attack during surgery, nausea, air embolus, and pain. After 9 months, three of the six patients had achieved and maintained a BMI greater than their historical baselines. DBS was associated with improvements in mood, anxiety, affective regulation, and anorexia nervosa-related obsessions and compulsions in four patients and with improvements in quality of life in three patients after 6 months of stimulation. These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder. INTERPRETATION: Subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory anorexia nervosa. FUNDING: Klarman Family Foundation Grants Program in Eating Disorders Research and Canadian Institutes of Health Research.

A multidimensional home-based care coordination intervention for elders with memory disorders: the maximizing independence at home (MIND) pilot randomized trial.

OBJECTIVES: To assess whether a dementia care coordination intervention delays time to transition from home and reduces unmet needs in elders with memory disorders. DESIGN: 18-month randomized controlled trial of 303 community-living elders. SETTING: 28 postal code areas of Baltimore, MD. PARTICIPANTS: Age 70+ years, with a cognitive disorder, community-living, English-speaking, and having a study partner available. INTERVENTION: 18-month care coordination intervention to systematically identify and address dementia-related care needs through individualized care planning; referral and linkage to services; provision of dementia education and skill-building strategies; and care monitoring by an interdisciplinary team. MEASUREMENTS: Primary outcomes were time to transfer from home and total percent of unmet care needs at 18 months. RESULTS: Intervention participants had a significant delay in time to all-cause transition from home and the adjusted hazard of leaving the home was decreased by 37% (Hazard ratio: 0.63, 95% Confidence Interval: 0.42-0.94) compared with control participants. Although there was no significant group difference in reduction of total percent of unmet needs from baseline to 18 months, the intervention group had significant reductions in the proportion of unmet needs in safety and legal/advance care domains relative to controls. Intervention participants had a significant improvement in self-reported quality of life (QOL) relative to control participants. No group differences were found in proxy-rated QOL, neuropsychiatric symptoms, or depression. CONCLUSIONS: A home-based dementia care coordination intervention delivered by non-clinical community workers trained and overseen by geriatric clinicians led to delays in transition from home, reduced unmet needs, and improved self-reported QOL.

Measurement of micronutrient deficiency associated biomarkers in dried blood spots using a multiplexed immunoarray.

Simplifying blood collection is often critical when collecting specimens in remote and/or austere settings. The use of dried blood spots (DBS) offers a practical collection method suitable for a wide variety of analytes. A small volume of whole blood can be obtained rapidly through a minimally invasive heel- or finger-stick using a disposable safety lancet. Once dried, the samples require no further processing, are stable for months or longer, pose minimal risk of disease transmission, and are easy to ship. DBS are often used in demographic health surveys to assess infectious disease status in vulnerable populations. These samples can be used to screen biomarkers of micronutrient deficiency (MND) and inflammation. We recently described a multiplexed immunoarray, the Q-plex human micronutrient array, which can simultaneously quantify seven biomarkers related to MND, inflammation and malarial antigenemia using plasma (alpha-1-acid glycoprotein, C-reactive protein, ferritin, histidine-rich protein 2, retinol binding protein, soluble transferrin receptor, and thyroglobulin). In this work, we present a protocol for preparing eluates from DBS samples and their measurement using a modified protocol for this new tool. We evaluated the concordance of analyte concentrations (excluding ferritin) from a panel ninety samples of DBS prepared from anticoagulated venous blood and paired K2-EDTA plasma. The results show high correlation between DBS eluates and wet plasma for five of the six analytes screened, suggesting the Q-plex human micronutrient array can be used with DBS samples, but also highlighting that anticoagulants can have a negative effects on some test components.

Simultaneous assessment of iodine, iron, vitamin A, malarial antigenemia, and inflammation status biomarkers via a multiplex immunoassay method on a population of pregnant women from Niger.

Deficiencies of vitamin A, iron, and iodine are major public health concerns in many low- and middle-income countries, but information on their status in populations is often lacking due to high costs and logistical challenges associated with assessing micronutrient status. Accurate, user-friendly, and low-cost analytical tools are needed to allow large-scale population surveys on micronutrient status. We present the expansion of a 7-plex protein microarray tool for the simultaneous measurement of up to seven biomarkers with relevance to the assessment of the key micronutrients iron, iodine, and vitamin A, and inflammation and malaria biomarkers: α-1-acid glycoprotein, C-reactive protein, ferritin, retinol binding protein 4, soluble transferrin receptor, thyroglobulin, and histidine-rich protein II. Assay performance was assessed using international reference standards and then verified by comparing the multiplexed and conventional immunoassay results on a training panel of plasma samples collected from US adults. These data were used to assign nominal concentrations to the calibrators of the assay to further improve performance which was then assessed by interrogating plasma samples from a cohort of pregnant women from Niger. The correlation between assays for each biomarker measured from this cohort was typically good, with the exception of thyroglobulin, and the sensitivity ranged from 74% to 93%, and specificity from 81% to 98%. The 7-Plex micronutrient assay has the potential for use as an affordable tool for population surveillance of vitamin A, iron, and iodine deficiencies as well as falciparum malarial parasitemia infectivity and inflammation. The assay is easy-to-use, requires minimal sample volume, and is scalable, rapid, and accurate-needing only a low-cost reader and basic equipment present in most reference laboratory settings and so may be employed by low and middle income countries for micronutrient surveillance to inform on status in key populations. Micronutrient deficiencies including iron, iodine, and vitamin A affect a significant portion of the world's population. Efforts to assess the prevalence of these deficiencies in vulnerable populations are challenging, partly due to measurement tools that are inadequate for assessing multiple micronutrients in large-scale population surveys. We have developed a 7-plex immunoassay for the simultaneous measurement of seven biomarkers relevant to assessing iodine, iron, and vitamin A status, inflammation and Plasmodium falciparum parasitemia by measuring levels of thyroglobulin, ferritin, soluble transferrin receptor, retinol binding protein 4, α-1-acid glycoprotein, C-reactive protein, and histidine-rich protein II. This 7-plex immunoassay technique has potential as a rapid and effective tool for use in large-scale surveys and assessments of nutrition intervention programs in low- and middle-income countries.

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease.

BACKGROUND: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. OBJECTIVE: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD). METHODS: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. RESULTS: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. CONCLUSION: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging.

Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer׳s disease (AD). The underlying neurobiological mechanisms are poorly understood. Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD. Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD. Fasting serum glucose (FSG) in non-diabetic young (YC; n=20) and elderly controls (EC; n=12) and LLD patients (n=16) was correlated with PET scans of cerebral glucose metabolism on a voxel-wise basis. The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions. Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.

Risk models for predicting chemotherapy-induced neutropenia.

Neutropenia and its complications, including febrile neutropenia, are major dose-limiting toxicities of systemic cancer chemotherapy. A number of studies have attempted to identify risk factors for neutropenia and its consequences to develop predictive models capable of identifying patients at greater risk for such complications and to guide more effective and cost-effective applications of the colony-stimulating factors. A systematic review of the literature showed that age, performance status, nutritional status, chemotherapy dose intensity, and low baseline blood cell counts were associated with the risk of severe and febrile neutropenia or reduced chemotherapy dose intensity in multivariate analysis in two or more studies. Similarly, age, diagnosis of leukemia or lymphoma, high temperature or low blood pressure at admission, and i.v. site infection along with low blood cell counts and organ dysfunction were associated with serious medical complications of febrile neutropenia, including bacteremia and death. The available risk model studies, however, had several limitations, including retrospective analyses of small study populations lacking independent validation, frequent missing values, and differences in the predictive factors considered. To overcome the limitations of previous studies, efforts are under way to develop and validate risk models based on large prospective studies in representative populations of patients receiving systemic chemotherapy.