Late-onset Depression Research Articles

Coordinate-Based Network Mapping of Brain Structure in Major Depressive Disorder in Younger and Older Adults: A Systematic Review and Meta-Analysis

Background: Neuroimaging findings in younger and older adults with major depressive disorder (MDD) are highly heterogeneous. It is unclear whether this heterogeneity is due to methodological limitations, lack of distinction between MDD and late-life depression (LLD), or clinical moderators. Methods: We identified all voxel-based and surface-based morphometry studies comparing younger adults with MDD or older adults with LLD to non-psychiatric control participants (updated search: Oct 27, 2020). We used both an Activation Likelihood Estimation (ALE) analysis and a novel coordinate-based network mapping to identify brain circuits affected in MDD and LLD. We then used meta-regressions to examine the impact of age of onset in older patients with LLD and treatment with antidepressants in younger patients with MDD. Results: We analysed 145 comparisons from 143 articles including 14,318 participants (MDD; 6,362; LDD: 535; controls: 7,421). Our ALE results confirmed previous findings implicating the bilateral parahippocampus (z RIGHT =5.2, z LEFT =4.3, p FWE <0.001) and anterior cingulate (z RIGHT =3.6, z LEFT =4.5 p FWE <0.005) in MDD and anterior cingulate (z RIGHT =3.7, z LEFT =3.6 p FWE <0.005) in LLD. In contrast, coordinate-based network mapping showed differences in the frontoparietal, dorsal attention, and visual networks both in MDD and LLD. Meta-regressions showed that late onset was associated with widespread structural abnormalities in LLD and treatment with antidepressants was associated with abnormalities in the anterior cingulate (BA32, t 1,116 =3.8, p FDR =0.03) and dorsolateral prefrontal cortex (BA9, t 1,116 =3.0, p FDR =0.04) in MDD. Conclusions: While ALE identified specific brain regions affected in MDD, coordinate-based network mapping was more sensitive to disruptions in both MDD and LLD. Meta-regression identified additional differences related to age of onset and treatment with antidepressants. These findings help clarify the shared circuitry of depression across the adult lifespan and highlight some unique circuitry relevant to late-onset depression, which may explain some of the risk for cognitive decline and dementia. Funding Statement: Andrea Cipriani is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP- 2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). Declaration of Interests: PZ was funded by the Labatt Family Postdoctoral Fellowship in Depression Biology. JAEA was funded by Canadian Institute of Health Research CIHR fellowship Grant No. CIHR-IRSC: 0093005620. B.H. Mulsant receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; he currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He directly owns stocks of General Electric (less than $5,000). Within the past five years, he has also received research support from Eli Lilly (medications and matching placebo pills for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial) and he has been an unpaid consultant to Myriad Neuroscience. Andrea Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma. ANV currently receives funding from CIHR, the NIH, the National Sciences and Engineering Research Council (NSERC), the CAMH Foundation, and the University of Toronto.

Association of cortical thickness with age of onset in first-episode, drug-naïve major depression.

We previously showed differences in brain grey matter volume changes between patients with early-onset adult depression (EOD) and late-onset adult depression (LOD). Here, we aim to identify whether cortical thickness (CT) is affected by the age of onset in patients with depression. High-resolution MRI images were obtained for 54 major depressive disorder (MDD) patients with EOD, 58 patients with LOD, 57 young healthy controls (HCs), and 58 aged HCs. Depression severity was assessed using the Hamilton Depression Rating Scale 17-item (HDRS17). Associations between CT of patients and clinical scores were analyzed. There was a significant main effect of diagnosis for the left rostal anterior cingulate (rACC), right inferior temporal, right lateral orbitofrontal cortex (lOFC), and bilateral pericalcarine. A remarkable onset age-group effect on CT was observed in the rACC and bilateral caudal anterior cingulate (cACC). The diagnosis-by-onset age interaction effect was found in bilateral rACC and right lOFC. Thinning CT in bilateral rACC was observed in EOD patients compared to young HCs. Compared to older HCs, thicker CT in lOFC was seen in the LOD patient group. Compared with the LOD group, the EOD group showed cortical thinning of the right cACC and posterior cingulate cortex (PCC). There were no significant associations between CT in right cACC or PCC with symptom severity or illness duration. MDD patients with different age at onset show distinct CT alterations, suggesting potentially divergent pathological mechanisms of EOD and LOD.

Five Personality Traits in Late-onset Depression in Hong Kong.

This study aimed to examine the association between five personality traits and late-onset depression in Hong Kong older people. This cross-sectional study included a convenience sample of 40 older people with late-onset depression (LOD) and 54 non-depressed elderly controls. The patients were assessed using the NEO Five Factor Inventory (for personality), the Hamilton Depression Rating Scale (for depression severity), the Mini-Mental State Examination (for cognitive function), the Lawton Instrumental Activities of Daily Living (for functioning), and the Cumulative Illness Rating Scale (for number of physical illnesses). The LOD group had a higher Hamilton Depression Rating Scale score (18.9 vs 3.7, p < 0.001), lower Mini Mental State Examination score (24.9 vs 26.4, p = 0.004), and lower Instrumental Activities of Daily Living scale score (21.9 vs 23.7, p = 0.013). On the NEO Five Factor Inventory, the LOD group had a higher neuroticism score (30.7 vs 17.5, p < 0.001) and lower scores on extraversion (19.0 vs 26.4, p < 0.001), openness (18.9 vs 21.5, p = 0.026), and conscientiousness (29.1 vs 33.8, p < 0.001). Neuroticism was the only significant predictor of LOD (odds ratio = 2.325, p = 0.001) and the only significant factor associated with depression severity (β = 0.581, p = 0.003). The personality trait of neuroticism is associated with LOD and its severity. Assessment of personality traits should be included in the assessment of people with depression.

Selective serotonin reuptake inhibitors and Alzheimer's disease.

Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

APOE4 allele in north Indian elderly patients with dementia or late onset depression-a multiple-disease case control study.

The objective of the study was to analyze the frequency of APOE4 allele in elderly patients with Alzheimer’s or vascular dementia or depression; compare these to age/sex matched controls; compare the results with established literature and highlight new findings. A single center, multiple disease, case-control study was performed with three case groups- probable AD patients (n=36), vascular dementia patients (n=29) and depression patients (n=20) and with a control group (n=32). APOE genotyping was performed in whole blood samples collected from patients and controls by restriction isotyping using the enzymes AflIII and HaeII. There was significant difference in frequency distribution of E4 allele between the AD (12/72; 16.7%) and control groups (3/64; 4.7%) (P=0.03). However, no significant difference was found in any of the other comparisons. The current study demonstrates absence of a significant association between APOE4 positivity and presence of late-onset depression in the north Indian elderly and reinforces the higher APOE4 prevalence in LOAD patients but not in VD patients. It is the first study of its kind from the northern part of India involving multiple disease groups and lays the framework for larger cohort studies.

MicroRNA-140-5p: A novel circulating biomarker for early warning of late-onset post-stroke depression

We aimed to explore the circulating microRNAs biomarkers in the acute stage following cerebral ischemia to earlier warn late-onset post-stroke depression (PSD). A total of 251 consecutive patients with acute ischemic stroke were recruited. They were divided into three groups depending on whether PSD had occurred at 2 weeks or 3 months since stroke: early-onset PSD, late-onset PSD, and non-depressed group. Microarray assay was conducted to identify the different expression profiles of plasma miRNAs. Comprehensive bioinformatics analysis for their integrating putative target genes was performed. The key miRNA was validated in a larger cohort and its function was further studied in ischemic mice brain. We screened three differentially expressed miRNAs in the late-onset PSD individuals, miR-140-5p and miR-221-3p were significantly upregulated while miR-1246 was downregulated. The bioinformatics analysis demonstrated that their predicted target genes were mainly enriched in axon development and Ras signaling pathway. Logistic regression analysis revealed that miR-140-5p was an independent risk factor for late-onset PSD (P = 0.017, OR = 2.313, 95%CI 1.158 to 4.617). The miR-140-5p expression on admission was significantly positively correlated with HDRS scores assessed at 3 months after stroke (P = 0.0007). The predictive value of miR-140-5p for late-onset PSD is 83.3% sensitivity and 72.6% specificity (AUC = 0.8127, P < 0.0001). AAV-mediated overexpression of miR-140-5p decreased the protein level of IL1rap, IL1rapl1, VEGF, and MEGF10 in the ischemic mouse hippocampus and inhibited neurogenesis and capillary density. MiR-140-5p might be involved in the pathogenesis of late-onset PSD and used as a novel early warning biomarker.

Disrupted structural brain connectome underlying the cognitive deficits in remitted late-onset depression.

Cognitive deficit is a key feature of late-onset depression (LOD) and remains after clinical recovery. LOD has been associated with widespread neurobiological difficulties, including atrophy in gray and white matter (WM) tissue in areas distributed throughout the brain. However, little is known about the topological pattern changes of WM structural networks in LOD in the remitted state and its relationship to cognitive deficits. We acquired diffusion tensor images in 37 remitted LOD (rLOD) patients and 30 healthy controls. The tract-based spatial statistics method was employed to investigate WM tract integrity in rLOD. Graph-theory based network models were further used to characterize the topological organization of WM structural networks between the two groups. Compared with controls, rLOD patients showed decreased fractional anisotropy values in the left posterior cingulate bundle, right inferior fronto-occipital fasciculus and superior longitudinal fasciculus. Moreover, rLOD patients showed abnormal small-world architecture (i.e., increased path length and decreased network efficiency) in the WM structural networks. rLOD patients also showed reduced nodal efficiencies predominantly in the frontal-striatal-occipital and posterior default-mode regions. Importantly, these structural connectomic changes significantly correlated with cognitive deficits in the rLOD patients. Finally, rLOD networks showed more vulnerable to targeted attacks compared with healthy controls. These findings provide structural evidence to support the concept of rLOD that the core aspects of the pathophysiology of this disease are associated with disruptive alterations in the coordination of large-scale brain networks and advance our understanding of the neurobiological mechanism underlying cognitive deficits in the rLOD patients.

Association of late-onset postpartum depression of mothers with expressive language development during infancy and early childhood: the HBC study.

BackgroundWhile it has been implied that an infant’s exposure to maternal postpartum depression (PPD) may be associated with delayed development of expressive language, it remains unclear whether such a delay persists into childhood and whether the onset of PPD onset—early (within 4 weeks after childbirth) vs. late (between 5 and 12 weeks postpartum)—is relevant in this context.ObjectiveTo examine whether children of mothers with early- or late-onset PPD have reduced expressive language scores during infancy and early childhood (up to 40 months of age).MethodsThis longitudinal, observational study was conducted as a part of the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), a population-representative sample in Japan. A total of 969 neonates and their mothers were included in the analysis.ExposuresEarly- and late-onset PPD was measured using the Edinburgh Postnatal Depression Scale.Main Outcomes and MeasuresExpressive language development was measured using the Mullen Scales of Early Learning. Six points over time were monitored (10, 14, 18, 24, 32, and 40 months postpartum). The relationship between the exposure variable and any change in expressive language score was evaluated using multiple linear regression analysis and growth curve analysis, both adjusted for covariates.ResultsResults from the adjusted regression analysis showed that children of mothers with late-onset PPD had significantly lower expressive language scores at 18 months of age and beyond, with a score reduction of approximately 0.6 standard deviations from the reference value at 40 months of age (95% CI [−0.888 to −0.265], p < .001). This association was confirmed on growth curve analysis, which revealed a significant, monotonic decline of expressive language development between 10 and 40 months of age among children of mothers with late-onset PPD, but not among children of mothers with early-onset PPD.ConclusionExposure to late-onset PPD may lead to a persistent decline in the rate of expressive language development in offspring during infancy and early childhood, highlighting the significance of monitoring for late-onset PPD to facilitate early detection and intervention.

Aortic Pulsatility Propagates Intracranially and Correlates with Dilated Perivascular Spaces and Small Vessel Compliance

Introduction: To test the hypotheses that changes in the aortic pulse-wave produced by arterial stiffening are (1) propagated into cerebral small vessels, (2) associated with reduced compliance of small cerebral arterial vessels, and (3) associated with the presence of dilated perivascular spaces (PVS). Methods: Fifteen volunteers and 19 patients with late-onset depression (LOD) were prospectively recruited, of which 6 fulfilled the criteria for treatment-resistant depression (TRD). Aortic pulse-wave velocity (PWV) was determined using Carotid-Femoral Doppler. Pulse-wave analysis (PWA) was performed using a SphygmoCor system. White-matter lesion load and PVS were scored on established MRI scales. Cerebral arterial and aqueductal cerebrospinal fluid (CSF) flow patterns were studied using quantitative phase-contrast angiography. Results: Depressed patients had more PVS (P < .05) and prolongation of the width of the arterial systolic pulse-wave in the carotid arteries (P < .01). There was no significant group difference for any PWV or PWA measurement. TRD patients showed more PVS than other LOD patients (P < .05). The fractional width of the arterial systolic peak correlated significantly with augmentation index (AIx) and heart rate-corrected augmentation index (AIx75; R2 = 0.302, P < .01and R2 = 0.363, P < .01 respectively). Arterial–aqueductal delay showed a negative correlation with estimated aortic systolic pressure (PWVsys; R2 = 0.293; P < .01), AIx (R2 = −0.491; P < .01) and AIx75 (R2 = −0.310; P < .01). PVS scores correlated with AIx (R2 = 0.485; P < .01) and AIx75 (R2 = −0.292; P < .01). Conclusion: Our findings support the hypothesis that increased arterial pulsatility resulting from central arterial stiffness propagates directly into cerebral vessels and is associated with the development of microvascular angiopathy, characterized by dilated PVS and decreased compliance of small arterial vessels.

White matter hyperintensities in elderly patients with late-onset and early-onset depression: a comparative study

Background Depression in late life is associated with subtle irreversible cognitive impairment, subtle structural brain damage, and a high frequency of white matter and other lesions, on visualization with MRI. Objectives The objective of this article is to explore the role of white matter hyperintensities (WMH) in elderly patients with depression. A total of 80 elderly patients with depression were recruited from the Geriatric Outpatient Clinic of Psychiatry and Addiction Prevention Hospital, Kasr Al-Ainy, Cairo University. They were divided into two groups according to the age of onset of depression: late-onset group [late-onset depression (LOD)] and early-onset group (early-onset depression). Patients and methods This was a hospital-based, cross-sectional, comparative study with consecutive referral. The patients were subjected to MRI of the brain to assess WMH using modified Fazekas score, Hamilton depression rating scale, and Addenbrooke’s cognitive examination revised. Results The mean total score of modified Fazekas score is significantly higher in the LOD group than in the early-onset depression group, and the periventricular WMH are significantly higher in the LOD. Conclusion WMH are more associated with LOD in elderly patients.

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter.

White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply–demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity—the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply–demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

Apathy in depression: a morphometric analysis

To study structural correlates of apathy in patients with late-life depression. Thirty-five patients (≥60 y.o.) with late-onset depression and 22 age-matched healthy volunteers underwent high resolution brain MRI-scanning, and a comprehensive neuropsychiatric examination including HAM-D and the Apathy Scale. A morphometric analysis showed that apathy was associated with atrophy of the lateral prefrontal cortex and reduced grey matter volume of the caudate nucleus on the right, and the nucleus accumbens on the left. Depression correlated with reduced thickness of the medial orbitofrontal cortex bilaterally, rostral anterior cingulate gyrus on the left, isthmus cingulate gyrus on the right, and larger surface area of the entorhinal cortex. Total grey matter volume, grey/white matter volumes of the cerebellum, and cortical thickness in temporal and occipital regions were negatively correlated with both apathy and depression severity. Thus, atrophy of basal ganglia and lateral prefrontal cortex, well known neuroanatomical correlates of apathy in different psychiatric and neurological conditions, characterized it in late-life depression too. This supports the idea of independent pathophysiology of apathetic syndrome.

Age-Related Hearing Loss.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate age-related auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL.

Aberrant Default Mode Network Underlying the Cognitive Deficits in the Patients With Late-Onset Depression.

Late-onset depression (LOD) is regarded as a risk factor or a prodrome of Alzheimer’s disease (AD). Moreover, LOD patients with cognitive deficits have the higher risk of subsequent AD. Thus, it is necessary to understand the neural underpinnings of cognitive deficits and its pathological implications in LOD. Consistent findings show that the default mode network (DMN) is an important and potentially useful brain network for the cognitive deficits in LOD patients. In recent years, genetics has been actively researched as a possible risk factor in the pathogenesis of LOD. So, in this review, we discuss the current research progress on the cognitive deficits and DMN in LOD through a combined view of brain network and genetics. We find that different structural and functional impairments of the DMN might be involved in the etiological mechanisms of different cognitive impairments in LOD patients.

Investigating the relationship between age of onset of depressive disorder and cognitive function.

Depressive disorder is commonly associated with impaired cognitive function; however, it is unclear whether the age of onset of the first episode of depression, current depression severity, or historical severity of depressive episodes are associated with cognitive performance. This study examined baseline cross-sectional data from the ongoing online PROTECT study. A total of 7344 participants, 50years or older, with a history of depression and no diagnosis of dementia were divided into three groups according to age of onset of their first depressive episode: early-onset, midlife-onset, and late-onset. Performance on measures of visuospatial episodic memory, executive function, verbal working, and visual working memory were evaluated. Demographic and clinical characteristics such as age, education, and severity of symptoms during their worst previous depressive episode and current depression severity were included in multivariate regression models. The late-onset depression group scored significantly lower on the verbal reasoning task than the early-onset group while there were no significant differences found on the other tasks. Midlife-onset depression participants performed better in the visual episodic memory task, but worse on the verbal reasoning task, than early-onset depression participants. Current depression severity was negatively correlated with all four cognitive domains, while historical severity score was found to be significantly associated with cognitive performance on the verbal reasoning and spatial working memory tasks. The most important indicator of cognitive performance in depression appears to be current, rather than historic depression severity; however, late-onset depression may be associated with more executive impairment than an early-onset depression.

Inflammation in older subjects with early- and late-onset depression in the NESDO study: a cross-sectional and longitudinal case-only design

ObjectiveDifferent biological mechanisms may underlie depression beginning in early life (early-onset) and depression beginning later in life (late-onset). Although the relation between inflammation and depression has been studied extensively, the distinct role of inflammation in early and late-onset depression in older patients has not been addressed before. In the cross-sectional part of this study, we explored differences in levels of circulating inflammatory markers and cytokine levels in lipopolysaccharide (LPS) stimulated whole blood between older subjects with a late-life onset depression (≥60 years) and older subjects with an early-onset depression (<60 years). Secondly, in a 2-year follow-up study, we examined if circulating and stimulated inflammatory markers influenced the change in Inventory of Depressive Symptomatology (IDS) scores, and if this relation was different for early- and late-onset depression. MethodsThe study was part of the Netherlands Study of Depression in Older Persons (NESDO). We included 350 patients, all aged 60 and older, with a depressive episode in the previous 6 months: 119 with a late-onset depression and 231 with an early-onset depression. Blood samples were collected and CRP, IL-6, NGAL, GDF15, and, LPS plasma levels were determined and whole blood was LPS stimulated and cytokine levels IL-1β, IL-6, TNFα, IFNγ, IL-10, and IL-1 receptor antagonist (IL-1ra) were determined. ResultsAfter adjustment for demographics, health indicators, and medication use, increased plasma CRP levels were more strongly associated with late-onset depression than early-onset depression (OR [95% CI]: 1.43 [1.05–1.94]). In the longitudinal analyses, higher circulating IL-6 levels were associated with a significantly slower decline in IDS scores in the crude and the adjusted models (p ≤ 0.027). This relation was not different between late- and early-onset depression. Other circulating and stimulated inflammatory markers were not associated with late- and/or early-onset depression. ConclusionsThis study provides preliminary evidence that low-grade inflammation is more strongly associated with late-onset than early-onset depression in older adults, suggesting a distinct inflammatory etiology for late-onset depression. Cytokine production capacity did not distinguish between early- and late-onset depression.

GABAA dysregulation as an explanatory model for late-onset postpartum depression associated with weaning and resumption of menstruation.

It is well established that a subgroup of women are particularly vulnerable to affective dysregulation during times of hormonal fluctuation. One underrecognized reproductive transition may be late-onset postpartum depression (PPD) in the context of weaning from breastfeeding and the resumption of menstruation. The goal of this review is to propose a biologically plausible mechanism for affective dysregulation during these transitions. The relationship between affective symptoms and neurohormonal changes associated with weaning will be investigated through a hypothesis-driven review of relevant literature. Neurosteroids, like allopregnanolone (ALLO), are widely recognized for augmenting GABAergic inhibition and having a powerful anxiolytic effect (Belelli D and Lambert JL, Nature Reviews Neuroscience 6:565-575, 2005). However, when ALLO is administered after prolonged withdrawal, there may be a paradoxical anxiogenic effect (Smith et al., Psychopharmacology 186:323-333, 2006; Shen et al., Nat Neurosci 10:469-477, 2007). Weaning from breastfeeding is a physiologic example of fluctuating levels of ALLO after prolonged withdrawal. We propose that the complex hormonal milieu during weaning and resumption of menstruation may modify GABAA receptors such that ALLO may contribute to rather than ameliorate depressive symptoms in vulnerable individuals. The proposed model provides an initial step for understanding the mechanisms by which the changing hormonal environment during weaning and resumption of menstruation may contribute to an increased risk of depression in a subgroup of women who are hormonally sensitive. Future research investigating this model would be valuable both to identify women at increased risk for developing mood symptoms late in postpartum and to inform treatment for this and related reproductive depressive disorders.

William M. Feinberg Award for Excellence in Clinical Stroke: Small Vessel Disease; a Big Problem, But Fixable.

Like much in stroke, this research journey started with a clot although this clot and this stroke were different.1 Small vessel disease (SVD) is now recognized to cause 20% to 25% of strokes, to be the second commonest cause of dementia, to cause cognitive decline, physical frailty, and late onset depression. In addition to acute small subcortical (lacunar) ischemic strokes, SVD includes lesions seen commonly on brain imaging: white matter hypertensities (WMH), lacunes, microbleeds, perivascular spaces (PVS), brain shrinkage,2 and biomarkers in apparently normal areas (eg, increased tissue fluid volume and mobility).3 However, when this research started, the strokes, cognitive presentations, and neuroimaging features of SVD were thought generally to be unrelated, silent, permanent, and lacunar stroke was a small version of large artery stroke. In 2000 AD, a 70-year-old man presented to our hospital with a recent lacunar stroke. His computed tomographic scan showed a small, low attenuation area, consistent with a recent small subcortical (lacunar) infarct. There were 3 odd features. 1. In the center was a small white dot, like a mini version of the hyperattenuated middle cerebral artery commonly seen in patients with hyperacute cardio- or athero-thromboembolic ischemic stroke, an appearance not described previously. 2. Brain magnetic resonance imaging (MRI) immediately after the computed tomographic scan confirmed the recent lacunar infarct, including the odd central line/dot, except that there also appeared to be some blood in the arteriole wall. Although a few small cardiac or carotid atheromatous emboli can enter the basal perforating arterioles, ≈6% in experimental models,4 and no more than 11% in patients,5 an embolus would not explain the blood in the arteriole wall. 3. The infarct was around the affected arteriolar segment, not at the end of it, as would be expected in, for example, an infarct occurring secondary to an …

The role of neuroinflammation and neurovascular dysfunction in major depressive disorder.

Although depression has generally been explained with monoamine theory, it is far more multifactorial, and therapies that address the disease’s pathway have not been developed. In this context, an understanding of neuroinflammation and neurovascular dysfunction would enable a more comprehensive approach to depression. Inflammation is in a sense a type of allostatic load involving the immune, endocrine, and nervous systems. Neuroinflammation is involved in the pathophysiology of depression by increasing proinflammatory cytokines, activating the hypothalamus–pituitary–adrenal axis, increasing glucocorticoid resistance, and affecting serotonin synthesis and metabolism, neuronal apoptosis and neurogenesis, and neuroplasticity. In future, identifying the subtypes of depression with increased vulnerability to inflammation and testing the effects of inflammatory modulating agents in these patient groups through clinical trials will lead to more concrete conclusions on the matter. The vascular depression hypothesis is supported by evidence for the association between vascular disease and late-onset depression and between ischemic brain lesions and distinctive depressive symptoms. Vascular depression may be the entity most suitable for studies of the mechanisms of depression. Pharmacotherapies used in the prevention and treatment of cerebrovascular disease may help prevent vascular depression. In future, developments in structural and functional imaging, electrophysiology, chronobiology, and genetics will reveal the association between depression and brain lesions. This article aims to give a general review of the existing issues examined in the literature pertaining to depression-related neuroinflammatory and vascular functions, related pathophysiology, applicability to depression treatment, and directions for future research.

Risk factors associated with cognitions for late-onset depression based on anterior and posterior default mode sub-networks

BackgroundAbnormal functional connectivity (FC) in the default mode network (DMN) plays an important role in late-onset depression (LOD) patients. In this study, the risk predictors of LOD based on anterior and posterior DMN are explored. MethodsA total of 27 LOD patients and 40 healthy controls (HC) underwent resting-state functional magnetic resonance imaging and cognitive assessments. Firstly, FCs within DMN sub-networks were determined by placing seeds in the ventral medial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Secondly, multivariable logistic regression was used to identify risk factors for LOD patients. Finally, correlation analysis was performed to investigate the relationship between risk factors and the cognitive value. ResultsMultivariable logistic regression showed that the FCs between the vmPFC and right middle temporal gyrus (MTG) (vmPFC–MTG_R), FCs between the vmPFC and left precuneus (PCu), and FCs between the PCC and left PCu (PCC–PCu_L) were the risk factors for LOD. Furthermore, FCs of the vmPFC-MTG_R and PCC-PCu_L correlated with processing speed (R = 0.35, P = 0.002; R = 0.32, P = 0.009), and FCs of the vmPFC-MTG_R correlated with semantic memory (R = 0.41, P = 0.001). LimitationsThe study was a cross-sectional study. The results may be potentially biased because of a small sample. ConclusionsIn this study, we confirmed that LOD patients mainly present cognitive deficits in processing speed and semantic memory. Moreover, our findings further suggested that FCs within DMN sub-networks associated with cognitions were risk factors, which may be used for the prediction of LOD.