Cortical thinning in patients with late-life minor depression.

OBJECTIVES: Clinically significant minor depression is among the most common mental disorders in the elderly individuals and is associated with considerable medical and psychosocial morbidity. Despite its clinical impact, the biological basis of minor depression in the elderly individuals remains poorly understood. The purpose of our current study was to examine cortical thickness in a sample of patients with late-life minor depression and non-depressed comparison subjects using magnetic resonance imaging (MRI). DESIGN: Cross-sectional analysis. SETTING: Community. PARTICIPANTS: Patients (n = 16; mean age = 76.2 ± 7.5) met modified DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for minor depression and were free of other brain diseases. Healthy comparison subjects (HC; n = 16) were of comparable age and gender distribution. MEASUREMENTS: All subjects were scanned on a 1.5-Tesla GE scanner and brain regions were outlined using Freesurfer Image Analysis. RESULTS: Results show that patients with minor depression have cortical thinning in the right cingulate cortex compared to HC. CONCLUSIONS: These findings indicate that abnormalities in specific structures and associated neural circuitry may underlie minor and major depression in the elderly individuals and the pathophysiological abnormalities are comparable in major and less severe forms of the disorder.

Interleukin-6 and memory functions of encoding and recall in healthy and depressed elderly adults.

Activation of proinflammatory cytokines is associated with depressed mood, feelings of fatigue, and changes in cognitive function. This study examined the relationships between cognitive performance and circulating cellular markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), in moderately depressed and comparison healthy older adults. We conducted a cross-sectional analysis of 87 volunteers (45 nondepressed and 42 depressed) in which participants completed the Structured Clinical Diagnostic Interview and were evaluated by a geriatric psychiatrist for dementia, depression, stroke risk, and neurologic disorders. Volunteers also completed an electrocardiogram, standard battery of laboratory tests, and neuropsychological examination that assessed memory functions of Encoding and Recall, Executive Function, and Attention/Processing. Mid-morning IL-6 and CRP levels were assessed. The data analysis showed that Encoding and Recall were inversely associated with IL-6 across diagnostic groups after controlling for chronological age, Mini-Mental State Examination, body mass index, literacy level, depression severity, and sex. CRP was not associated with cognition. Depression status was associated with recall independent of IL-6 levels. In conclusion, IL-6 serum levels among elderly individuals is a significant correlate of memory performance. Women, in particular, appear sensitive to IL-6 fluctuations across diagnostic groups.

Verbal learning and memory in older adults with minor and major depression.

Late-life minor depression (miD) is a prevalent but poorly understood illness. Verbal learning and memory profiles have commonly been used to characterize neuropsychiatric disorders. This study compared the performance of 27 older adults with miD on the California Verbal Learning Test (CVLT) with 26 age-matched individuals with Major Depressive Disorder (MDD) and 36 non-depressed controls. Results revealed that the miD group performed comparably with controls and significantly better than the MDD group on several CVLT indices. Moreover, cluster analysis revealed three distinct groups, consistent with theoretical representations of "normal," "subcortical," and "cortical" verbal learning and memory profiles. The majority of the miD group showed "normal" profiles (74%), whereas most individuals with MDD displayed "subcortical" profiles (54%). The findings suggest that depression in the elderly is a heterogeneous entity and that the CVLT may be a useful tool for characterizing learning and memory in late-onset depressive disorders.

Protein binding in patients with late-life depression.

CONTEXT: Depression has been identified as a risk factor and a prodrome of dementia. Common neurobiological mechanisms may underlie this clinical and phenomenologic overlap. OBJECTIVE: To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([(18)F]FDDNP) positron emission tomography. DESIGN: A cross-section neuroimaging study using positron emission tomography. SETTING: University of California, Los Angeles. Patients  Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level. Main Outcome Measure  Relative distribution volume in regions of interest was used as the measure of [(18)F]FDDNP binding in all study participants. RESULTS: When compared with controls, [(18)F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group. CONCLUSIONS: These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.

Explicit and implicit memory in late-life depression.

OBJECTIVE: Late-life depression has been associated with memory loss and is frequently assumed to be a risk factor for continued cognitive decline. This study examined cognition in patients with late-life depression with a focus on the assessment of the extent and type of memory loss among elderly depressed patients. METHODS: Two-year cross-sectional study of elderly depressed (N = 112) and nondepressed (N = 138) individuals at or older than 60 years in an urban area surrounding a major medical center in southern California. Participants had little to moderate stroke risk. Volunteers were screened with the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Patients were diagnosed for major depression by a geriatric psychiatrist using DSM-IV criteria. Volunteers completed neuropsychological testing, a standard battery of laboratory tests, and a neurologic and psychiatric evaluation to rule out a medical burden that might contribute to depression or early dementia. RESULTS: Depressed patients showed deficits in attention and processing, executive function, and immediate explicit recall. Implicit learning and episodic recall of the testing procedure, semantic and phonetic fluency, and retention of newly acquired verbal material after a delay period were comparable with controls. CONCLUSION: Moderately depressed patients demonstrate a pattern of cognitive deficits suggestive of mild frontal dysfunction during recall tasks. Their retention of material over a delay period and their intact language skills indicate medial hippocampal function similar to controls. Subcortically mediated implicit memory is also at normal levels. These findings support current efforts to identify pathways of frontal and/or striatal compromise during depressive episodes.

Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression.

The purpose of this study was to examine the effect of type 2 diabetes with major depression on cortical gray matter using magnetic resonance imaging and cortical pattern matching techniques. We hypothesized that diabetic subjects and depressed diabetic subjects would demonstrate decreased cortical gray matter thickness in prefrontal areas as compared to healthy control subjects. Patients with type 2 diabetes (n=26) and patients with diabetes and major depression (n=26) were compared with healthy controls (n=20). Gray matter thickness across the entire cortex was measured using cortical pattern matching methods. All subjects with diabetes demonstrated decreased cortical gray matter thickness in the left anterior cingulate region. Additionally, depressed diabetic subjects showed significant cortical gray matter decreases in bilateral prefrontal areas compared with healthy controls. Correlations between clinical variables and cortical gray matter thickness revealed a significant negative relationship with cerebrovascular risk factors across all three groups, most consistently in the left dorsomedial prefrontal cortex. A significant positive relationship between performance on attention and executive function tasks and cortical gray matter thickness predominantly in left hemisphere regions was also seen across all subjects. Depression and diabetes are associated with significant cortical gray matter thinning in medial prefrontal areas.

Two-dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo.

PURPOSE: To evaluate regional cerebral metabolic and structural changes in patients with minimal hepatic encephalopathy (MHE) using two-dimensional (2D) MR spectroscopy (MRS) and T( (1) )-weighted MRI, to correlate the observed MR changes with neuropsychological (NP) test scores, and to compare the diagnostic accuracy of MRI, 2D MRS, and NP tests in discriminating between patients and healthy subjects. MATERIALS AND METHODS: Thirty-three MHE patients and 30 healthy controls were investigated. The 2D localized correlated spectroscopy (L-COSY) was performed in the frontal and occipital brain on a 1.5 Tesla (T) MR scanner. The NP test battery included 15 tests, grouped into 6 cognitive domains. Globus pallidus signal intensities were calculated from T(1)-weighted images. RESULTS: The 2D MRS showed significant differences in ratios of the following metabolite(s) peaks with respect to creatine (Cr): decreased myo-inositol (mI), choline (Ch), mICh, and increased (glutamate plus glutamine) (Glx) in patients compared with healthy subjects in both occipital and frontal lobes. Frontal lobe taurine also showed a decline in patients. The NP test results revealed declines in cognitive speed, motor function, executive function, and global cognitive status. Significant correlations were found between the altered metabolites and NP tests. Alteration in the mICh/Cr ratio was noted as a powerful discriminant between healthy subjects and the patients. CONCLUSION: The study demonstrates that relative metabolite levels determined by 2D MRS, in particular mICh/Cr, provide the best diagnostic prediction for MHE. The results suggest that depletions of myo-inositol, choline and taurine with respect to creatine correlate with measures of neuropsychological impairment.

Prefrontal brain morphology and executive function in healthy and depressed elderly.

OBJECTIVES: Late-life depression is known to correlate independently with decreased brain volumes in anterior cingulate, gyrus rectus and orbitofrontal cortex and with executive dysfunction, but the relationship between morphometry of reduced volume regions and executive dysfunction has not been well defined. METHODS: Nondepressed and depressed elders completed five executive tests, a standard panel of laboratory tests and magnetic resonance imaging. Images of the prefrontal cortex were manually masked and automatically segmented and regional brain volumes were calculated. Executive scores and error rates were regressed on bilateral white and gray matter volumes of anterior cingulate, gyrus rectus and orbitofrontal. RESULTS: Gyrus rectus was associated positively with scores on sequencing and nonverbal abstract reasoning, and negatively with two fluency error scores. Four positive interactions indicated that performance of controls was more closely associated with increased volume than that of depressed patients. Anterior cingulate was associated positively with two nonverbal reasoning tasks and with three positive interactions. Orbitofrontal volumes were negatively associated with correct responses and errors on two fluency tasks. One interaction showed controls' performance decreased more than depressed patients with increased volume. CONCLUSIONS: Individual executive tasks correlate positively with volumes of anterior cingulate and gyrus rectus regions and negatively with orbitofrontal region. The orbitofrontal relationship suggests a loss of inhibitory control with decreased volume because both correct and incorrect answers on fluency tasks increased per unit decrease in volume.

Biophysical correlates of cognition among depressed and nondepressed type 2 diabetic patients.

OBJECTIVE: Caudate magnetization transfer (MT) ratios have indicated an abnormality in the macromolecular protein pool of diabetic patients. This study examined the relationship between MT ratios of the caudate and cognitive performance. RESEARCH DESIGN AND METHODS: Diabetic patients, diabetic and depressed patients, and healthy comparison subjects completed magnetic resonance imaging and a neuropsychological battery. Magnetization transfer ratios of caudate and three comparison regions were computed. The neuropsychological battery was aggregated into a global index of cognitive function and correlated with MT ratios. RESULTS: MT ratios of the caudate correlated with cognitive performance, and the correlations were stronger among diabetic patients than healthy control subjects. Comorbid depression increased the strength of the correlation compared with diabetes alone. Comparison regions showed no evidence of a diabetes effect on cognition. CONCLUSIONS: One mechanism precipitating cognitive loss during diabetes appears to be associated with cellular changes occurring in the macromolecular protein pool of the caudate.

Prefrontal myo-inositol concentration and visuospatial functioning among diabetic depressed patients.

Patients with diabetes mellitus are reported to be at higher risk for developing neuropsychiatric disorders such as dementia and depression. Myo-inositol (mI), a neuronal/glial metabolite associated with multiple functions in the brain, has been shown to be increased in cognitive disorders, depression and diabetes. This study examined whether elevations in dorsolateral (DL) mI of diabetic patients with depression were associated with visuospatial deficits. Diabetic and depressed patients (n=18) were matched with patients with diabetes but without depression (n=20) and control subjects (n=19). Subjects were scored on both the recall and recognition tasks of the Rey-Osterreith Complex Figure (ROCF). Proton magnetic spectroscopy spectra from bilateral prefrontal white matter voxels were used to obtain concentrations of mI. Controls showed negative correlations between mI in right DL white matter and recall and recognition subtests. No correlation was observed for depressed diabetic patients. Correlations for diabetic controls fell midway between the comparison and depressed diabetic groups. The expected pattern of association between mI and visuospatial impairment in the right DL prefrontal region was seen among healthy controls. Progressive weakening of this association across both diabetic groups might be related to progressive changes in neural activity that underlies visuospatial function.

Neuroanatomical correlates of executive functioning in depressed adults with type 2 diabetes.

Depression is often comorbid with type 2 diabetes. Depression may increase vulnerability to and/or exacerbate existing cognitive deficits. Little is known about the brain pathophysiology underlying depression and cognitive abnormalities in diabetes. The aim of this study was to examine the relationship of orbitofrontal and anterior cingulate volumes with executive functioning and attention/processing speed in type 2 diabetic participants with and without major depression. A total of 21 diabetic participants with major depression, 23 diabetic participants with no depression, and 22 healthy controls were compared. Using brain magnetic resonance imaging, volumetric measures of the prefrontal cortex were examined in relation to executive functioning and attention/processing speed. Partial correlations suggested a significant positive relationship between right orbitofrontal regions and executive functioning in the group with diabetes and depression only, indicating that neurobiological changes in the orbitofrontal region may contribute to observed cognitive dysfunction.

Executive function and MRI prefrontal volumes among healthy older adults.

Brain atrophy and decline in executive functioning have been reported during late life, but the relationship between the 2 phenomena is not clear. To examine associations between executive tasks and morphometry, MRIs of the prefrontal cortex from 23 healthy elders were manually masked and automatically segmented. Total brain matter of the bilateral orbitofrontal, anterior cingulate, gyrus rectus, precentral gyrus, and middle frontal gyrus were computed as ratios of intracranial volume. A neuropsychological battery of five clinical tests of executive function was administered. Better performance on a response inhibition task was associated with larger volume in anterior cingulate, and performance on a nonverbal inductive reasoning task was associated with larger gyrus rectus volumes. In contrast, larger orbitofrontal volumes were associated with lower verbal and nonverbal generative output. An aggregated error index from 4 executive tests correlated negatively with a regional composite brain index. In conclusion, some executive abilities correlate with volumes of specific prefrontal subregions despite a robust neural interconnectedness between the subregions.

Daily functioning and prefrontal brain morphology in healthy and depressed community-dwelling elderly.

OBJECTIVE: Self-perceived emotional vitality, intact mood, physical activity, and social engagement are recognized as important indicators for lowered rates of morbidity and increased longevity in late-life, but little is known about their underlying neural substrates. This study examined relationships between self-reported levels of general functioning and the combined volume of three integrated prefrontal structures associated with self-perception and emotion. DESIGN: Cross-sectional. SETTING: UCLA Semel Institute for Neuroscience, Los Angeles. PARTICIPANTS: Depressed (N = 43) and comparison (N = 41) elderly subjects. MEASUREMENTS: Magnetic resonance images of orbitofrontal, gyrus rectus, and anterior cingulate gray and white matter volumes were corrected for intracranial volume and combined across structures to form white matter and gray matter scales. Subjects completed the RAND Short-Form 36 Questionnaire, a self-report evaluation of daily functioning. Subscales used for analysis were physical function, energy, and general health, which were not correlated with depression. RESULTS: White matter volumes were associated with self-perceptions of Energy for healthy as well as depressed individuals, and gray matter volume was associated with General Health. This latter association was strongest among patients with late-onset of depression, i.e., onset > age 50, although it appeared in all diagnostic groups. CONCLUSIONS: Although mild to moderate atrophy is expected in late-life, prefrontal atrophy may represent changes to neuroanatomic substrates that qualitatively modulate self-perceptions of energy and general health for both depressed and nondepressed persons.

Voxel-based diffusion tensor magnetic resonance imaging evaluation of low-grade hepatic encephalopathy.

PURPOSE: To quantify the changes in brain water diffusivity in hepatic encephalopathy (HE) associated with cirrhosis using diffusion tensor imaging (DTI) and to correlate with neuropsychological (NP) scores. MATERIALS AND METHODS: DTI was performed in 14 patients with low-grade HE and age/gender-comparable 16 healthy controls. Whole brain mean diffusivity (MD) and fractional anisotropy (FA) maps were calculated, normalized to common space, smoothed, and compared voxel-by-voxel between groups using analysis of covariance with age included as a covariate. The average MD and FA values were also calculated from individual subjects for selected brain regions and correlated with the neuropsychological scores. RESULTS: Patients with HE showed increased MD in the cortical gray and white matter and the internal capsule. Less extensive brain regions with decreased FA were observed in the bilateral frontal and occipital white matter. MD values from the corpus callosum correlated inversely with several NP scores among HE patients and controls. Positive correlations were observed with FA values and cognitive scores. CONCLUSION: Voxel-based DTI analysis showed widespread brain regions with increased MD values, indicating enhanced water content and decreased FA in cirrhotic patients with HE. The MD and FA values from selected regions correlated with the NP scores.

Mapping callosal morphology in early- and late-onset elderly depression: an index of distinct changes in cortical connectivity.

There is some evidence of corpus callosum abnormalities in elderly depression, but it is not known whether these deficits are region-specific or differ based on age at onset of depression. Twenty-four patients with early-onset depression (mean age = 68.00, SD+/-5.83), 22 patients with late-onset depression (mean age = 74.50, SD+/-8.09) and 34 elderly control subjects (mean age = 72.38; SD+/-6.93) were studied. Using 3D MRI data, novel mesh-based geometrical modeling methods were applied to compare the midsagittal thickness of the corpus callosum at high spatial resolution between groups. Neuropsychological correlates of midsagittal callosal area differences were additionally investigated in a subsample of subjects. Depressed patients exhibited significant callosal thinning in the genu and splenium compared to controls. Significant callosal thinning was restricted to the genu in early-onset patients, but patients with late-onset depression exhibited significant callosal thinning in both the genu and splenium relative to controls. The splenium of the corpus callosum was also significantly thinner in subjects with late- vs early-onset depression. Genu and splenium midsagittal areas significantly correlated with memory and attention functioning among late-onset depressed patients, but not early-onset depressed patients or controls. Circumscribed structural alterations in callosal morphology may distinguish late- from early-onset depression in the elderly. These findings suggest distinct abnormalities of cortical connectivity in late- and early-onset elderly depression with possible influence on the course of illness. Patients with a late onset of depression may be at higher risk of illness progression and eventually dementia conversion than early-onset depression, with potentially important implications for research and therapy.

Hippocampal morphology and distinguishing late-onset from early-onset elderly depression.

OBJECTIVE: Despite evidence for hippocampal abnormalities in elderly depression, it is unknown whether these changes are regionally specific. This study used three-dimensional mapping techniques to identify regional hippocampal abnormalities in early- and late-onset depression. Neuropsychological correlates of hippocampal morphology were also investigated. METHOD: With high-resolution magnetic resonance imaging, hippocampal morphology was compared among elderly patients with early- (N=24) and late-onset (N=22) depression and comparison subjects (N=34). Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups. RESULTS: Hippocampal volumes differed between depressed patients and comparison subjects but not between patients with early- and late-onset depression. However, statistical mapping results showed that regional surface contractions were significantly pronounced in late- compared to early-onset depression in the anterior of the subiculum and lateral posterior of the CA1 subfield in the left hemisphere. Significant shape differences were observed bilaterally in anterior CA1-CA3 subfields and the subiculum in patients in relation to comparison subjects. These results were similar when each disease group was separately compared to comparison subjects. Hippocampal surface contractions significantly correlated with memory measures among late- but not early-onset depressed patients or comparison subjects. CONCLUSIONS: More pronounced regional volume deficits and their associations with memory in late-onset depression may suggest that these patients are more likely to develop cognitive impairment over time than individuals with early-onset depression. Mapping regional hippocampal abnormalities and their cognitive correlates may help guide research in defining risk profiles and treatment strategies.

Executive dysfunction and memory in older patients with major and minor depression.

Executive function, known to be impaired during late-life depression, is dependent on frontostriatal pathways. Memory is also frequently observed to be impaired among late-life depressed patients, so we assessed the possibility that executive function mediates the learning and recall deficit as a "downstream" effect of the frontostriatal compromise in executive function. A cross-sectional sample of minor and major depressed patients (N = 95) and nondepressed volunteers (N = 71), screened for other Axis I disorders, dementia, medical comorbidity and severity of depression, completed a neuropsychological battery that included the California Verbal Learning Test (CVLT) and other tests selected for convergent and divergent validity testing. Depressed patients differed from controls on learning the word list and on related and unrelated executive tasks. Executive function was a mediator for depressed patients verbal learning scores (z = -2.67, p = .01). A nonverbal executive score also mediated verbal learning (z = -2.18, p = .03) indicating convergent validity of executive dysfunction during verbal learning exercises. In conclusion, the verbal memory deficits typically attributed to late-life depression may result from impaired executive functioning during the learning phase of the recall task.

Cognitive function in adults with type 2 diabetes and major depression.

The aim of this study was to identify characteristics of neuropsychological functioning among type 2 diabetic adults with and without major depression. Twenty type 2 diabetics with major depression, 20 non-depressed type 2 diabetics and 34 controls without diabetes or depression were compared. A mixed effects repeated measures analysis of covariance indicated significant differences in overall cognitive functioning between diagnostic groups, specifically depressed diabetics demonstrated greater cognitive dysfunction than controls. Further comparisons indicated that depressed diabetics performed significantly worse than non-depressed diabetics in attention/information processing speed. Relative to controls, depressed diabetics performed significantly worse in attention/information processing speed and executive functioning, while there was a trend for non-depressed diabetics to perform worse in executive functioning. These findings suggest that depression negatively impacts cognitive performance among adults with type 2 diabetes, which may have implications for neural circuitry underlying cognitive and mood changes in diabetic patients.

Executive dysfunction and memory in older patients with major and minor depression.

Executive function, known to be impaired during late-life depression, is dependent on frontostriatal pathways. Memory is also frequently observed to be impaired among late-life depressed patients, so we assessed the possibility that executive function mediates the learning and recall deficit as a "downstream" effect of the frontostriatal compromise in executive function. A cross-sectional sample of minor and major depressed patients (N=95) and nondepressed volunteers (N=71), screened for other Axis I disorders, dementia, medical comorbidity, and severity of depression, completed a neuropsychological battery that included the California Verbal Learning Test and other tests selected for convergent and divergent validity testing. Depressed patients differed from controls on learning the word list and on verbal and nonverbal executive tasks. Executive function was a mediator for depressed patients verbal learning scores (z=-2.67, p=.01). A nonverbal executive score also mediated verbal learning (z=-2.18, p=.03) indicating convergent validity of executive dysfunction during verbal learning exercises. In conclusion, the verbal memory deficits typically attributed to late-life depression may result from impaired executive functioning during the learning phase of the recall task.

Validity of the Boston qualitative scoring system for the Rey-Osterrieth complex figure among depressed elderly patients.

A recent qualitative scoring method for the Rey-Osterrieth Complex Figure (ROCF), the Boston Qualitative Scoring System (BQSS), purports to assess visuospatial organization, visual memory and executive function by using multiple series of scores with well-defined criteria. The first objective of this study was to determine whether the BQSS cores correlated with scores derived from the tradition Osterrieth scoring method and which method was more efficient at separating the diagnostics groups. The second objective was to correlate the BQSS executive scores to other nonverbal and verbal tests of executive function, working memory, processing speed, and episodic memory to determine what cognitive abilities the BQSS scores were measuring. The subjects, older depressed patients and healthy controls, were free of any clinical sign of incipient dementia or comorbid neurological disease. Their ROCF drawings were scored using both the Osterrieth and BQSS methods. The BQSS summary drawing scores correlated well with the Osterrieth summary scores for the copy and short-delay recall phases, the percent retained over the delay period and recognition. The BQSS executive scores for Planning, which included both copy and recall phases, correlated with Matrix Reasoning indicating that they assessed nonverbal reasoning but they did not correlate with other traditional executive tests. Planning also contributed to the separation of diagnostics groups and was the most effective score for predicting the percent of the ROCF retained over a short delay. The remaining executive scores did not show a pattern of correlations with other nonverbal executive or working memory scores that would satisfy concerns regarding their interpretation or internal validity when used in an older and/or depressed population. No differences emerged between the two scoring methods in their efficiency for predicting depression.