Changes In Late-life Depression Research Articles

The Eight-Item Center for Epidemiological Studies Depression Scale in the English Longitudinal Study of Aging: Longitudinal and Gender Invariance, Sum Score Models, and External Associations.

The disease burden of depression among older populations is high. Detecting changes in late-life depression is predicated on the seldom-examined assumption of longitudinal measurement invariance (MI). Therefore, we investigated longitudinal MI of the 8-item Center for Epidemiological Studies Depression Scale in core members repeatedly assessed in the English Longitudinal Study of Aging, a nine-wave representative study of the English population above 50 years of age (initial N = 11,391). Based on prior literature, we tested MI of a one-factor solution, a one-factor solution with correlated errors of reversely coded items, and a two-factor solution (depressed affect/somatic complaints). For all factor solutions, residual MI was confirmed across nine waves and gender. Sum score models (i.e., all factor loadings constrained to equity) had a good fit. Depression scores correlated with psychiatric diagnoses, ill health, lower life quality, and female gender. Associations slightly differed depending on the factor solutions, signifying their applicability across contexts.

Reliable Cognitive Decline in Late-Life Major Depression.

Major depression in older adults increases the statistical likelihood of dementia. It is challenging to translate statistical evidence of cognitive decline at the group level into knowledge of individual cognitive outcomes. The objective of the current study is to investigate 2-year reliable cognitive change in late-life depression (LLD), which will enhance understanding of cognitive changes in LLD and provide a means to assess individual change. In a sample of non-depressed cognitively normal older adults or NDCN (n = 113), we used linear regression to predict tests of global cognition, processing speed-executive functioning, and memory administered 1 and 2 years later. Stepwise regression was used to select covariates among demographics and raw test scores (either baseline or year 1) and we cross-validated the final models using the predicted residual error sum of squares (PRESS). We then derived a z-change score from the difference between actual and predicted follow-up scores and investigated the proportion of LLD patients (n = 199) and NDCN adults who experienced reliable "decline" (a z-score < -1.645), "stability" (z-scores between + - 1.645), and "improvement" (z scores > +1.645). A greater proportion LLD compared with NDCN experienced cognitive decline in processing speed/executive functioning and global cognition over 2 years. When compared to NDCN, a greater proportion of LLD also significantly improved on one test of processing speed over 2 years. Older adults with LLD are at risk of meaningful cognitive decline over a relatively short period, particularly in the domain of executive functioning and processing speed. This study provides a series of reliable change equations for common neuropsychological tests that can be applied clinically.

Oxidative DNA damage is increased in older adults with a major depressive episode: A preliminary study

BackgroundDNA oxidative damage is a marker of increased oxidative stress activity. Elevated DNA oxidative damage has been associated with major depressive disorder in young adults, but there is no information about DNA oxidative damage in late-life depression. This study aims to evaluate whether older adults with late-life depression (LLD) has increased DNA oxidative damage compared to healthy older adults. MethodsWe included 92 participants (57 with LLD [73.2 ± 7.7 years-old] and 35 non-depressed subjects (Controls) [70.5 ± 7.4 years-old]). We analyzed the plasma 8‑hydroxy-2′-deoxyguanosine (8-oxo-dG), a marker of DNA oxidation, using a commercially-available ELISA assay. ResultsLLD participants had significantly higher 8-oxo-DG levels compared to controls (P<0.001). 8-oxo-dG levels were significantly correlated with depressive symptoms as assessed by the Hamilton Depression Rating Scale (rho=0.34, p<0.001). The plasma levels of 8-OHdG were not significantly correlated with other clinical, neurocognitive, and demographic variables. LimitationsOur current results are limited by the relatively small sample size, cross-sectional design, and the recruitment of participants in tertiary center for assessment and treatment of LLD. ConclusionsOlder adults with LLD have increased DNA oxidative damage. Our findings provide additional evidence for elevated oxidative stress activity in LLD and the possible activation of age-related biological pathways and enhanced biological aging changes in LLD.

Abnormal Voxel-Wise Degree Centrality in Patients With Late-Life Depression: A Resting-State Functional Magnetic Resonance Imaging Study.

ObjectivesLate-life depression (LLD) has negative impacts on somatic, emotional and cognitive domains of the lives of patients. Elucidating the abnormality in the brain networks of LLD patients could help to strengthen the understanding of LLD pathophysiology, however, the studies exploring the spontaneous brain activity in LLD during the resting state remain limited. This study aimed at identifying the voxel-level whole-brain functional connectivity changes in LLD patients.MethodsFifty patients with late-life depression (LLD) and 33 healthy controls were recruited. All participants underwent a resting-state functional magnetic resonance imaging scan to assess the voxel-wise degree centrality (DC) changes in the patients. Furthermore, DC was compared between two patient subgroups, the late-onset depression (LOD) and the early-onset depression (EOD).ResultsCompared with the healthy controls, LLD patients showed increased DC in the inferior parietal lobule, parahippocampal gyrus, brainstem and cerebellum (p < 0.05, AlphaSim-corrected). LLD patients also showed decreased DC in the somatosensory and motor cortices and cerebellum (p < 0.05, AlphaSim-corrected). Compared with EOD patients, LOD patients showed increased centrality in the superior and middle temporal gyrus and decreased centrality in the occipital region (p < 0.05, AlphaSim-corrected). No significant correlation was found between the DC value and the symptom severity or disease duration in the patients after the correction for multiple comparisons.ConclusionsThese findings indicate that the intrinsic abnormality of network centrality exists in a wide range of brain areas in LLD patients. LOD patients differ with EOD patients in cortical network centrality. Our study might help to strengthen the understanding of the pathophysiology of LLD and the potential neural substrates underlie related emotional and cognitive impairments observed in the patients.

Kynurenine pathway changes in late-life depression with memory deficit

Kynurenine pathway (KP) activation is associated with many neuropsychiatric diseases, such as major depressive disorder (MDD) and Alzheimer's disease (AD). Investigations conducted on MDD seldom shed light on KP changes in late-life depression (LLD), though memory deficit (MD) in patients with LLD is a predictable sign of AD. Thus, we aimed to investigate whether tryptophan (TRP) metabolism and kynurenine (KYN) metabolism were imbalanced in patients with LLD with MD and in patients with LLD without MD. We explored KP characteristics between LLD with MD and LLD without MD groups. We investigated 85 patients with LLD and MD, 71 patients with LLD without MD, and 129 healthy controls (HCs). Serum concentrations of TRP, KYN, and kynurenic acid (KYNA) were detected by liquid chromatography-tandem mass spectrometry. Cognition performance was assessed by the Mini-Mental State Examination (MMSE). Language ability was assessed by the Boston Naming Test (BNT). Depressive symptoms were assessed by the 17-item Hamilton Depression Scale (HAMD-17). Lower TRP and KYNA levels, a lower KYNA/KYN ratio and a higher KYN/TRP ratio were found in patients with LLD and MD compared to those in HC. Low levels of TRP and KYN, in the absence of a changed KYN/TRP ratio, were found in patients with LLD without MD. The KYNA/TRP ratio and MMSE, BNT, and HAMD-17 scores were associated with the presence of LLD. MMSE scores and a trend for the KYN/TRP ratio were associated with the presence of MD in patients with LLD. Aside from MMSE scores, there was a trend toward an association between the KYN/TRP ratio and the presence of MD in patients with LLD. In conclusion, profound shifts in TRP metabolism and KYN metabolism were found in patients with LLD and MD but not in patients with LLD without MD.

Kynurenine pathway changes in late-life depression

BackgroundKynurenine pathway (KP) activation is associated with several neuropsychiatric diseases, including major depression disorder (MDD). Although several investigations have been conducted on MDD, these have seldom shed light on KP changes in late-life depression (LLD). ObjectiveWe aimed to investigate whether tryptophan (TRP) metabolism and kynurenine (KYN) metabolism are imbalanced in LLD patients and to explore the differences in KP characteristics between early onset depression (EOD) and late onset depression (LOD) patients. MethodsWe investigated 170 LLD patients (EOD 90, LOD 80) and 135 normal controls. Serum concentrations of TRP, KYN and kynurenic acid (KYNA) were detected by the liquid chromatography-tandem mass spectrometry method. Depressive symptoms were assessed by the 17-item Hamilton Depression Scale (HAMD-17). ResultsLLD patients exhibited lower levels of TRP, KYN, KYNA and KYNA/KYN ratio and a higher level of KYN/TRY ratio than normal controls. The decrease in TRP and the increase in KYN/TRP ratio were found in LOD patients. A low TRP level without increased KYN/TRP ratio was found in EOD patients. The “Depression” factor, which was extracted from HAMD-17 by the principal component factor analysis, was correlated with the TRP level and KYNA/KYN ratio in the EOD group, but no such correlation was found in the LOD group. ConclusionsKP changes were observed in LLD patients; LOD patients showed profound shifts in TRP metabolism, while EOD patients showed low TRP level and a shift in KYN metabolism.

Plasma Amyloid-β and Alzheimer's Disease-Related Changes in Late-Life Depression.

To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer's disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40, but not Aβ42 nor Aβ40/Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

Neuroinflammatory and morphological changes in late-life depression: the NIMROD study.

We studied neuroinflammation in individuals with late-life depression, as a risk factor for dementia, using [11C]PK11195 positron emission tomography (PET). Five older participants with major depression and 13 controls underwent PET and multimodal 3T magnetic resonance imaging (MRI), with blood taken to measure C-reactive protein (CRP). We found significantly higher CRP levels in those with late-life depression and raised [11C]PK11195 binding compared with controls in brain regions associated with depression, including subgenual anterior cingulate cortex, and significant hippocampal subfield atrophy in cornu ammonis 1 and subiculum. Our findings suggest neuroinflammation requires further investigation in late-life depression, both as a possible aetiological factor and a potential therapeutic target.

Brain connectivity in late-life depression and aging revealed by network analysis.

To use novel methods to examine age associations across an integrated brain network in healthy older adults (HOA) and individuals with late-life depression (LLD). Graph theory metrics describe the organizational configuration of both the global network and specified brain regions. Cross-sectional data were acquired. Graph theory was used to explore diffusion tensor imaging-derived white matter networks. Forty-eight HOA and 28 adults with LLD were recruited from the community. Global and local metrics in prefrontal, cingulate, and temporal regions were calculated. Group differences and associations with age were explored. Group differences were noted in local metrics of the right prefrontal and temporal regions, but no significant differences were observed on global metrics. Local (not global) metrics were associated with age differently across groups. For HOA, local metrics across all regions correlated with age, whereas in adults with LLD, correlations were only observed within temporal regions. In keeping with hypothesized regions impacted by LLD, stronger hubs in right temporal regions were observed among HOA, whereas LLD individuals were characterized by robust hubs in frontal regions. We demonstrate widespread age-related changes in local network properties among HOA with different and more restricted local changes in LLD. Although a preliminary analysis, different patterns of correlations in local networks coupled with equivalent global metrics may reflect altered local structural brain networks in patients with LLD.

Imaging and neurobiological changes in late-life depression

Depression was previously thought of as a ‘functional’ illness, without demonstrable pathology, but the advent of sophisticated neuroimaging techniques has changed this perspective. This article reviews the latest structural and functional brain imaging studies, describing the neurobiological changes which underlie this common condition.

Gender differences in the trajectories of late-life depressive symptomology and probable depression in the years prior to death

Gender differences in depression are well established. Whether these differences persist into late life and in the years preceding death is less clear. There is a suggestion that there is no increased likelihood of depression in late life, but that there is an increase in depressive symptomology, particularly with proximity to death. We compared trajectories of probable depression and depressive symptomology between men and women over age and distance-to-death metrics to determine whether reports of depressive symptoms are more strongly related to age or mortality. Participants (N = 2,852) from the Dynamic Analyses to Optimise Ageing (DYNOPTA) project had a mean age of 75 years (SD = 5.68 years) at baseline and were observed for up to 16 years prior to death. Multi-level regression models estimated change in depressive symptomology and probable depression over two time metrics, increasing age, and distance-to-death. Increases in depressive symptomology were reported over increasing age and in the years approaching death. Only male participants reported increased probable depression in the years preceding death. Models that utilized distance-to-death metrics better represented changes in late-life depression, although any changes in depression appear to be accounted for by co-varying physical health status. As death approaches, there are increases in the levels of depressive symptomology even after controlling for socio-demographic and health covariates. In line with increases in suicide rates in late life, male participants were at greater risk of reporting increases in depressive symptomology.

Morphometric analysis of vascular pathology in the orbitofrontal cortex of older subjects with major depression

Late-life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late-life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. The present study used a non-specific histological Nissl staining and a more vessel-specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 older subjects with major depressive disorder (MDD) and 9 non-psychiatric comparison subjects. The density of Nissl-stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF-immunoreactive segments with cross-sectional areas greater than 800 µm2 was higher in MDD. In WM, only the density of vWF-immunoreactive segments with patent perivascular spaces and diameters larger than 60 µm was higher in subjects with MDD. Also in the WM, only subjects with late-onset MDD presented a significantly higher density of vWF-positive segments than comparison subjects. In older subjects with MDD, there appear to be morphological changes that increase visibility of medium-sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles.

Relationship Between Cognition, Magnetic Resonance White Matter Hyperintensities, and Cardiovascular Autonomic Changes in Late-Life Depression

To explore the relationship between specific aspects of cognition, white matter hyperintensities (WMHs), and cardiovascular autonomic parameters in late-life depression (LLD). Cross-sectional analysis. Secondary care psychiatry. Forty-one individuals older than 60 years, with current or previous history of major depression, and 32 age-matched comparison subjects. Cognition was assessed by a standardized computer battery of tasks (Cognitive Drug Research) that measured processing speed, attention, episodic memory, and working memory. Cardiovascular autonomic parameters were estimated by a noninvasive device that calculated blood pressure, heart rate variability, and baroreflex sensitivity (Task Force Monitor). Magnetic resonance imaging was performed on a 3-T magnetic resonance imaging system, and WMH volume was estimated using an automated validated method. As expected, cognitive deficits in all tested domains were present in LLD subjects compared with comparison subjects. In the LLD group, processing speed was correlated with scores on memory and working memory tasks. Attentional deficits were correlated with total and periventricular WMH volume, and episodic memory was associated with heart rate variability. There were no associations between cognitive variables and traditional vascular risk factors or between cognitive variables and any of these parameters in the comparison subjects. This study suggests that processing speed may be an important factor underlying deficits in LLD, but it also indicates that other factors, including those related to vascular disease, are important and thus provide further support for the vascular depression hypothesis.

Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden

A first episode of depression after 65 years of age has long been associated with both severe macrovascular and small microvascular pathology. Among the three more frequent forms of depression in old age, post-stroke depression has been associated with an abrupt damage of cortical circuits involved in monoamine production and mood regulation. Late-onset depression (LOD) in the absence of stroke has been related to lacunes and white matter lesions that invade both the neocortex and subcortical nuclei. Recurrent late-life depression is thought to induce neuronal loss in the hippocampal formation and white matter lesions that affect limbic pathways. Despite an impressive number of magnetic resonance imaging (MRI) studies in this field, the presence of a causal relationship between structural changes in the human brain and LOD is still controversial. The present article provides a critical overview of the contribution of neuropathology in post-stroke, late-onset, and late-life recurrent depression. Recent autopsy findings challenge the role of stroke location in the occurrence of post-stroke depression by pointing to the deleterious effect of subcortical lacunes. Despite the lines of evidences supporting the association between MRI-assessed white matter changes and mood dysregulation, lacunes, periventricular and deep white matter demyelination are all unrelated to the occurrence of LOD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of aging-related neurodegenerative changes in the human brain. However, they also provide data in favor of the neurotoxic theory of depression by showing that neuronal loss occurs in the hippocampus of chronically depressed patients. These three paradigms are discussed in the light of the complex relationships between psychosocial determinants and biological vulnerability in affective disorders.

Biological Basis of Late Life Depression

Late life depression (LLD) is an important area of research given the growing elderly population. The purpose of this review is to examine the available evidence for the biological basis of LLD. Structural neuroimaging shows specific gray matter structural changes in LLD as well as ischemic lesion burden via white matter hyperintensities. Similarly, specific neuropsychological deficits have been found in LLD. An inflammatory response is another possible underlying contributor to the pathophysiology of LLD. We review the available literature examining these multiple facets of LLD and how each may affect clinical outcome in the depressed elderly.

Depressive Symptoms and Mild Cognitive Impairment in the Elderly: An Ominous Combination

Depressive Symptoms and Mild Cognitive Impairment in the Elderly: An Ominous Combination

Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression?

Cardiovascular risk factors and diseases are important etiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham Stroke Risk Profile (FSRP), a well-validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesized that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes. Thirty-six participants with major depression (age 71.8 ± 7.7 years, mean FSRP 10.3 ± 7.6) and 25 controls (age 71.8 ± 7.3 years, mean FSRP 10.1 ± 7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools (www.fmrib.ox.ac.uk/fsl) to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p < 0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group. Participants in the depressed group showed highly significant correlations between FSRP and FA within the body of corpus callosum (r = -0.520, p = 0.002), genu of corpus callosum (r = -0.468, p = 0.005), splenium of corpus callosum (r = -0.536, p = 0.001), and cortico-spinal tract (r = -0.473, p = 0.005). In controls, there was only one significant correlation in the body of corpus callosum (r = -0.473, p = 0.023). FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.

Reduction of dorsolateral prefrontal cortex gray matter in late-life depression

Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non-depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression.

Cortical thickness and VBM-DARTEL in late-life depression

Numerous studies have revealed structural brain changes in late life depression, mainly in white matter or whole lobes with few focussing just on grey matter (GM). The objective was to investigate GM changes in older depressed and similar aged healthy subjects using two different methods, cortical thickness in frontal lobe structures and voxel-based morphometry (VBM). Sixty eight subjects participated (30 healthy comparison subjects, 38 depressed) and underwent 3T T1 MR imaging as well as clinical and cognitive assessments. Frontal cortical thickness was measured using FreeSurfer while VBM was undertaken using the DARTEL algorithm in SPM8. Group differences in cortical thickness and GM volumes were assessed using ANCOVA. Effects of cortical thickness and VBM results on cognitive and depression variables were also investigated. No significant differences in frontal lobe cortical thickness were observed between groups (F(1, 62) ≤ 2.7, p ≥ 0.1). In addition, no significant relationships of cortical thickness on cognitive and depression scores were identified (partial correlation |r'|=0.01-0.31, p ≥ 0.06). VBM showed that GM volumes were indistinguishable between groups but significant age effects were apparent, independent of diagnosis. Results suggest that cortical GM changes in late life depression (LLD) are similar to healthy older subjects and appear to be related to age rather than cognitive or depressive symptoms. Changes to white matter and subcortical GM structures may be more relevant in explaining the underlying neurobiology of LLD.

Electrophysiological changes in late life depression and their relation to structural brain changes

Late life depression is often accompanied by slowed information processing during neuropsychological testing, and this has been related to underlying cerebrovascular disease. We investigated whether changes in electrophysiological markers of information processing might share the same pathological correlates. Differences in power spectra frequency, contingent negative variation (CNV), post-imperative negative variation (PINV), and auditory P300a amplitude and latency in 19 patients with DSM-IV major depression aged ≥ 60 years were compared with 25 recordings in age-matched healthy controls. Associations with total brain volume and degree of white matter hyperintensities (WMH) were examined in those who had undergone additional magnetic resonance imaging (MRI). Compared with healthy controls, patients had more slow-wave delta (group difference: p = 0.024) and theta activity (p = 0.015) as well as alpha activity (p = 0.005) but no decrease in beta band frequency (p = 0.077). None of these changes related differently to brain volume or WMH in patients or controls. Patients further showed prolonged P300a latencies (p = 0.027), which were associated with decreased total brain volume in patients but not controls (interaction by group: p = 0.004). While there were no overall differences in PINV between both groups, patients showed a decrease in PINV magnitude with increasing WMH, a relation that was not seen in controls (interaction by group: p = 0.024). Patients with late life depression show changes in several electrophysiological markers of cerebral arousal and information processing, some of which relate to brain atrophy and WMH on MRI.