Anand Kumar

Atrophy and high intensity lesions: complementary neurobiological mechanisms in late-life major depression.

The primary objective of our study was to examine the role of atrophy, high intensity lesions and medical comorbidity in the pathophysiology of major depressive disorder in the elderly (late-life MDD). Our sample was comprised of 51 patients with late-life MDD and 30 non-depressed controls. All subjects were scanned on 1.5 tesla magnetic resonance imaging scanner (MRI) and absolute and normalized measures of brain and lesion volumes were obtained and used for comparison between groups. Patients with MDD had significantly smaller frontal lobe volumes, together with larger whole brain lesion volumes when compared with controls (p < .05). Whole brain lesion volumes correlated significantly (r = 0.41, p = .006) with overall medical comorbidity. The odds ratio (OR) for existing MDD increases significantly with a decrease in frontal lobe volume and an increase in whole brain lesion volumes (p < .05). Our findings suggest that atrophy and high intensity lesions represent relatively independent pathways to late-life MDD. While medical disorders lead to neuropathological changes that are captured on MR imaging as high intensity signals, atrophy may represent a relatively autonomous phenomenon. These findings have broad implications for the pathophysiology of mood disorders and suggest that complementary neurobiological processes may lead to cumulative neuronal injury thereby predisposing to clinical depression.The primary objective of our study was to examine the role of atrophy, high intensity lesions and medical comorbidity in the pathophysiology of major depressive disorder in the elderly (late-life MDD). Our sample was comprised of 51 patients with late-life MDD and 30 non-depressed controls. All subjects were scanned on 1.5 tesla magnetic resonance imaging scanner (MRI) and absolute and normalized measures of brain and lesion volumes were obtained and used for comparison between groups. Patients with MDD had significantly smaller frontal lobe volumes, together with larger whole brain lesion volumes when compared with controls (p < .05). Whole brain lesion volumes correlated significantly (r = 0.41, p = .006) with overall medical comorbidity. The odds ratio (OR) for existing MDD increases significantly with a decrease in frontal lobe volume and an increase in whole brain lesion volumes (p < .05). Our findings suggest that atrophy and high intensity lesions represent relatively independent pathways to late-life MDD. While medical disorders lead to neuropathological changes that are captured on MR imaging as high intensity signals, atrophy may represent a relatively autonomous phenomenon. These findings have broad implications for the pathophysiology of mood disorders and suggest that complementary neurobiological processes may lead to cumulative neuronal injury thereby predisposing to clinical depression.

Accurate Measurement of Brain Changes in Longitudinal MRI Scans using Tensor-Based Morphometry

This paper responds to Thompson and Holland (2011), who challenged our tensor-based morphometry (TBM) method for estimating rates of brain changes in serial MRI from 431 subjects scanned every 6 months, for 2 years. Thompson and Holland noted an unexplained jump in our atrophy rate estimates: an offset between 0 and 6 months that may bias clinical trial power calculations. We identified why this jump occurs and propose a solution. By enforcing inverse-consistency in our TBM method, the offset dropped from 1.4% to 0.28%, giving plausible anatomical trajectories. Transitivity error accounted for the minimal remaining offset. Drug trial sample size estimates with the revised TBM-derived metrics are highly competitive with other methods, though higher than previously reported sample size estimates by a factor of 1.6 to 2.4. Importantly, estimates are far below those given in the critique. To demonstrate a 25% slowing of atrophic rates with 80% power, 62 AD and 129 MCI subjects would be required for a 2-year trial, and 91 AD and 192 MCI subjects for a 1-year trial.

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.

Quantitative anatomic measures and comorbid medical illness in late-life major depression

The authors examined the individual and relative roles of atrophy, comorbid medical illness, and cerebrovascular risk factors in the pathogenesis of late-life major depressive disorder (MDD). They used magnetic resonance imaging techniques to study 28 subjects with late-life MDD, 29 healthy control subjects, and 34 subjects with probable dementia of the Alzheimer type (DAT). Depressed subjects showed increases in cerebrospinal fluid volumes comparable to the DAT group but significantly different from control subjects. High-intensity signals, but not measures of atrophy correlated significantly with cerebrovascular risk factor scores. A logistic regression revealed that both brain atrophy and medical illness are associated with an increased risk of developing MDD. Data suggest that both atrophy and comorbid medical illness increase the likelihood of developing MDD in late life.

Cerebral metabolic and cognitive studies in dementia with frontal lobe behavioral features

Three subjects with dementia of the Alzheimer type (DAT) with frontal lobe features of behavioral disinhibition were studied using positron emission tomography with [18F]2-fluoro-2-deoxy-D-glucose (18 FDG) and standardized neuropsychological tests. The three subjects showed significant decrements (p less than .05) in relative glucose metabolism (regional/mean gray metabolism) in the orbitofrontal, prefrontal and anterior cingulate regions when compared to healthy controls. Severity-matched subjects with DAT without the associated frontal lobe features did not show the relative reductions in glucose metabolism in these regions when compared to controls. However, on neuropsychological testing of frontal lobe cognitive functions the three subjects did not show decrements that were more severe than those shown by severity-matched DAT patients without the behavioral features. These data demonstrate physiologic dysfunction in specific cortical regions in subjects with behavioral aberrations attributed to these regions and an apparent dissociation between behavioral and cognitive functions of the frontal lobe.

Prefrontal brain morphology and executive function in healthy and depressed elderly

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.

Explicit and Implicit Memory in Late-Life Depression

OBJECTIVEnLate-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.nnnMETHODSnTwo-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.nnnRESULTSnDepressed 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.nnnCONCLUSIONnModerately 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.

Reductions in parietal and temporal cerebral metabolic rates for glucose are not specific for Alzheimer's disease.

Reduction in the regional cerebral metabolic rate for glucose (rCMRglc) in the parietal and temporal regions has been shown in Alzheimers disease (AD). The specificity of these findings for this disease state is uncertain. We repeatedly measured rCMRglc with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in the resting state in a 68 year old man with slowly progressive dementia who, during life, was initially diagnosed as having dementia of the Alzheimer type, then Parkinson disease with dementia, but was found to have only Parkinsons disease at necropsy. Metabolic ratios (rCMRglc/mean grey CMRglc) were significantly (p < 0.05) reduced in parietal and temporal regions, as well as in the prefrontal and premotor areas. This pattern was similar in regional distribution and magnitude of the defect to that seen in patients with probable AD. These results suggest that reductions of glucose metabolism in association neocortex in AD are not specific to the disease process, but may be related to the dementia state.

Regional cerebral glucose metabolism is normal in young adults with Down syndrome

Regional CMRglc (rCMRglc) values were measured with [18F]2-fluoro-2-deoxy-d-glucose (18FDG) and positron emission tomography (PET), using a Scanditronix PC-1024-7B scanner, in 14 healthy, noninstitutionalized subjects with trisomy 21 (Down syndrome; DS) (mean age 30.0 years, range 25–38 years) and in 13 sex-matched, healthy volunteers (mean age 29.5 years, range 22–38 years). In the DS group, mean mental age on the Peabody Picture Vocabulary Test was 7.8 years and dementia was not present. Resting rCMRglc was determined with eyes covered and ears occluded in a quiet, darkened room. Global gray CMRglc equaled 8.76 ± 0.76 mg/100 g/min (mean ± SD) in the DS group as compared with 8.74 ± 1.19 mg/100 g/min in the control group (p > 0.05). Gray matter regional measurements also did not differ between groups. The ratio of rCMRglc to global CMRglc, calculated to reduce the variance associated with absolute rCMRglc, and right/left ratios did not show any consistent differences. These results show that healthy young DS adults do not have alterations in regional or global brain glucose metabolism, as measured with 18FDG and PET, prior to an age at which the neuropathological changes in Alzheimer disease are reported to occur.

Age of onset of depression and quantitative neuroanatomic measures: absence of specific correlates

The purpose of our study was to examine the relationship between volumetric neuroanatomic measures and age of onset of illness in subjects with late-life major depression. Our sample was composed of 51 elderly subjects with Major Depressive Disorder who were scanned using a 1.5-tesla GE magnetic resonance imaging scanner with head coil. Absolute total and focal brain volumes were obtained together with quantified estimates of high intensity lesions. The relationship of these measures to onset age was examined using a regression while adjusting for subjects current age and total intracranial volume. There was no significant linear relationship between age of onset of the first episode and any of the neuroanatomic measures examined. These data do not support the notion that neuroanatomical contributions to depression increase with a later age of onset of illness.