Depression is perhaps the most frequent cause of emotional suffering in later life and significantly decreases quality of life in older adults. In recent years, the literature on late-life depression has exploded. Many gaps in our understanding of the outcome of late-life depression have been filled. Intriguing findings have emerged regarding the etiology of late-onset depression. The number of studies documenting the evidence base for therapy has increased dramatically. Here, I first address case definition, and then I review the current community- and clinic-based epidemiological studies. Next I address the outcome of late-life depression, including morbidity and mortality studies. Then I present the extant evidence regarding the etiology of depression in late life from a biopsychosocial perspective. Finally, I present evidence for the current therapies prescribed for depressed elders, ranging from medications to group therapy.

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Depression in Late Life: Review and Commentary

Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings.

Diffuse optical imaging DOI may be a beneficial diagnos- tic method for women with mammographically dense breast tissue. In order to evaluate the utility of DOI, we are developing broadband diffuse optical spectroscopy DOS to characterize the functional ori- gins of optical signals in breast cancer patients. Broadband DOS com- bines multifrequency intensity-modulated and continuous-wave near- infrared light to quantify tissue absorption and scattering spectra from 650 to 1000 nm. Values of intrinsic physiological properties oxy- and deoxy-hemoglobin, water, lipid, and scatter power derived from absorption and scattering spectra provide detailed information on breast physiology. We present the results of clinical studies of 58 stage II/III malignant breast tumors using a noninvasive, handheld, broad- band DOS probe. On average, eight positions were scanned over tumor and contralateral normal breast for each subject. Intrinsic physiological properties were statistically significantly different for malignant vs. normal tissues for all subjects, without patient age or tumor size/type stratification. Breast tissues containing malignant tu- mors displayed reduced lipid content 20% and increased water, deoxy-, and oxy-hemoglobin 50% each compared to normal breast tissues. Functional perturbations by the tumor were signifi- cantly larger than functional variations in normal tissues. A tissue op- tical index TOI derived from intrinsic physiological properties yielded an average two-fold contrast difference between malignant tumors and intrinsic tissue properties. Our results demonstrate that intrinsic optical signals can be influenced by functional perturbations characteristic of malignant transformation; cellular metabolism, extra- cellular matrix composition, and angiogenesis. Our findings further underscore the importance of broadband measurements and patient age stratification in breast cancer DOI. © 2006 Society of Photo-Optical Instru-

http://www.bli.uci.edu/profiles/editor/userfiles/acerussi/cerussi.jbo06.pdf

In vivo absorption, scattering, and physiologic properties of 58 malignant breast tumors determined by broadband diffuse optical spectroscopy

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton (1H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus (31P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research.

Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder

OBJECTIVE: Neuroanatomical abnormalities have been identified in patients with late-life mood disorders by using magnetic resonance imaging. This study examined the biochemical correlates of late-life major depression in the frontal gray and white matter by using single-voxel proton spectroscopy. METHOD: Twenty elderly patients with major depression and 18 comparison subjects similar in age and gender to the patients were scanned on a 1.5-T magnetic resonance scanner with head coil. Voxels were placed in the left dorsolateral white matter and bilaterally in the anterior cingulate gray matter. Absolute levels of N-acetylaspartate, choline, myo-inositol, and creatine were estimated with the LC-Model algorithm. Ratios of metabolite to creatine levels were computed from the absolute values. RESULTS: myo-Inositol/creatine and choline/creatine ratios were significantly higher in the frontal white matter in the major depression group than in the comparison group. The groups had no significant differences in the ...

Frontal White Matter Biochemical Abnormalities in Late-Life Major Depression Detected With Proton Magnetic Resonance Spectroscopy

Objective: The diagnosis of bipolar disorder in juveniles is controversial. This study was designed to compare proton magnetic resonance spectroscopy ( 1 H MRS) in patients with bipolar disorder or intermittent explosive disorder, two groups with symptomatic overlap but categorical distinction. Children with intermittent explosive disorder designate patients whose illness clinically resembles pediatric bipolar disorder but does not satisfy DSM-IV criteria for mania. Based on the authors’ previous report of higher levels of 1 H MRS cingulate myo-inositol/ creatine in youngsters with bipolar disorder than in normal comparison subjects, they hypothesized that patients with bipolar disorder would have higher cingulate myo-inositol/creatine-phosphocreatine measurements than patients with intermittent explosive disorder and normal comparison subjects. Method: Myo-inositol levels were measured with a 2× 2× 2 cm 3 voxel placed in the anterior cingulate for acquisition of 1 H MRS in 10 patients with bipolar disorder, 10 patients with intermittent explosive disorder, and 13 normal comparison subjects. N-Acetylaspartate, choline moieties, creatine-phosphocreatine, and glutamate-glutamine metabolite levels were also measured. Results: The patients with bipolar disorder showed significantly higher anterior cingulate myo-inositol/creatine-phosphocreatine and myo-inositol (mmol/liter) levels than the patients with intermittent explosive disorder and the normal comparison subjects. No significant differences were found across groups for myoinositol or other metabolites in the occipital cortex. Conclusions: These data provide evidence that differences in the concentration of myo-inositol (mmol/liter) in the anterior cingulate cortex in 1 H MRS may differentiate these two populations. Follow-up studies involving larger samples may conclusively estimate the biological specificity between pediatric bipolar disorder and other disorders, which overlap clinically.

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.160.8.1442

Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents

A localized 2D correlation spectroscopic sequence (L-COSY) was implemented and applied in human breast cancer in vivo to evaluate the water to fat (both saturated and unsaturated) ratios and also to identify choline. Being in agreement with the conventional 1D magnetic resonance spectroscopy (MRS) results, elevated water to lipids ratios were found in breast cancers and choline was observed only in a few cancer patients. J. Magn. Reson. Imaging 2001;14:181–186. © 2001 Wiley-Liss, Inc.

Volume-localized two-dimensional correlated magnetic resonance spectroscopy of human breast cancer

The test-retest reliability of two-dimensional (2D) correlated spectroscopy (COSY) was studied on a whole-body 1.5T MRI scanner. Single-voxel localized 2D proton spectra were recorded in vitro as well as in vivo using a recently implemented localized chemical shift correlated spectroscopic (L-COSY) sequence. A total of 40 in vitro and 40 human brain (10 volunteers, four times each) 2D L-COSY spectra were recorded. The coefficients of variation (CVs) of selected brain metabolites (raw volume integrals) recorded in 10 healthy volunteers were less than 9% for creatine, choline, and N-acetyl aspartate, and less than 17% for myo-inositol, glutamine/glutamate, aspartate, and threonine/lactate. The 2D metabolite ratios and the raw volume integrals of 2D diagonal and cross peaks in healthy human brain were very well reproduced. The intraclass correlation coefficients were greater than 0.4 (P < 0.05) for the major metabolites, indicating that the 2D peak volumes were stable enough within individuals to detect reliable differences between normal subjects.

Kenneth Yue

Papers

Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder

Frontal White Matter Biochemical Abnormalities in Late-Life Major Depression Detected With Proton Magnetic Resonance Spectroscopy

Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents

Volume-localized two-dimensional correlated magnetic resonance spectroscopy of human breast cancer

Reproducibility of localized 2D correlated MR spectroscopy