Late-life depression (LLD) predisposes individuals to cognitive decline, often leading to misdiagnoses as mild cognitive impairment (MCI). Voxel-based morphometry (VBM) can distinguish the profiles of these disorders according to gray matter (GM) volumes. We integrated findings from previous VBM studies for comparative analysis and extended the research into molecular profiles to facilitate inspection and intervention.

We comprehensively searched PubMed and Web of Science for VBM studies that compared LLD and MCI cases with matched healthy controls (HCs) from inception to 31st December 2023. We included 13 studies on LLD (414 LLDs, 350 HCs) and 50 on MCI (1878 MCIs, 2046 HCs). Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) was used for voxel-based meta-analysis to assess GM atrophy, spatially correlated with neuropsychological profiles. We then used multimodal and linear-model analysis to assess the similarities and differences in GM volumetric changing patterns. Partial least squares (PLS) regression and gene enrichment were employed for transcription-neuroimaging associations.

GM volumes in the left hippocampus and right parahippocampal gyrus are more affected in MCI, along with memory impairment. MCI was spatially correlated with a more extensive reduction in the levels of neurotransmitters and a severe downregulation of genes related to cellular potassium ion transport and metal ion transmembrane transporter activity.

Compared to LLD, MCI exhibited more GM atrophy in the hippocampus and parahippocampal gyrus and lower gene expression of ion transmembrane transport. Our findings provided imaging-transcriptomic-genetic integrative profiles for differential diagnosis and precise intervention between LLD and MCI.

Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains.

Older adults with major depressive disorder (N = 228, ages 65–91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning.

Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity.

Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.

The longitudinal course of late-life depression remains under-studied.

To describe transitions along the depression continuum in old age and to identify factors associated with specific transition patterns.

We analysed 15-year longitudinal data on 2745 dementia-free persons aged 60+ from the population-based Swedish National Study on Aging and Care in Kungsholmen. Depression (minor and major) was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; subsyndromal depression (SSD) was operationalised as the presence of ≥2 symptoms without depression. Multistate survival models were used to map depression transitions, including death, and to examine the association of psychosocial (social network, connection and support), lifestyle (smoking, alcohol consumption and physical activity) and clinical (somatic disease count) factors with transition patterns.

Over the follow-up, 19.1% had ≥1 transitions across depressive states, while 6.5% had ≥2. Each additional somatic disease was associated with a higher hazard of progression from no depression (No Dep) to SSD (hazard ratio 1.09; 1.07–1.10) and depression (Dep) (hazard ratio 1.06; 1.04–1.08), but also with a lower recovery (HRSSD−No Dep 0.95; 0.93–0.97 [where ‘HR’ refers to ‘hazard ratio’]; HRDep−No Dep 0.96; 0.93–0.99). Physical activity was associated with an increased hazard of recovery to no depression from SSD (hazard ratio 1.49; 1.28–1.73) and depression (hazard ratio 1.20; 1.00–1.44), while a richer social network was associated with both higher recovery from (HRSSD−No Dep 1.44; 1.26–1.66; HRDep−No Dep 1.51; 1.34–1.71) and lower progression hazards to a worse depressive state (HRNo Dep−SSD 0.81; 0.70–0.94; HRNo Dep−Dep 0.58; 0.46–0.73; HRSSD−Dep 0.66; 0.44–0.98).

Older people may present with heterogeneous depressive trajectories. Targeting the accumulation of somatic diseases and enhancing social interactions may be appropriate for both depression prevention and burden reduction, while promoting physical activity may primarily benefit recovery from depressive disorders.

Late-life depression (LLD) is common and frequently co-occurs with neurodegenerative diseases of aging. Little is known about how heterogeneity within LLD relates to factors typically associated with neurodegeneration. Varying levels of anxiety are one source of heterogeneity in LLD. We examined associations between anxiety symptom severity and factors associated with neurodegeneration, including regional brain volumes, amyloid beta (Aβ) deposition, white matter disease, cognitive dysfunction, and functional ability in LLD.

Older adults with major depression (N = 121, Ages 65–91) were evaluated for anxiety severity and the following: brain volume (orbitofrontal cortex [OFC], insula), cortical Aβ standardized uptake value ratio (SUVR), white matter hyperintensity (WMH) volume, global cognition, and functional ability. Separate linear regression analyses adjusting for age, sex, and concurrent depression severity were conducted to examine associations between anxiety and each of these factors. A global regression analysis was then conducted to examine the relative associations of these variables with anxiety severity.

Greater anxiety severity was associated with lower OFC volume (β = −68.25, t = −2.18, p = .031) and greater cognitive dysfunction (β = 0.23, t = 2.46, p = .016). Anxiety severity was not associated with insula volume, Aβ SUVR, WMH, or functional ability. When examining the relative associations of cognitive functioning and OFC volume with anxiety in a global model, cognitive dysfunction (β = 0.24, t = 2.62, p = .010), but not OFC volume, remained significantly associated with anxiety.

Among multiple factors typically associated with neurodegeneration, cognitive dysfunction stands out as a key factor associated with anxiety severity in LLD which has implications for cognitive and psychiatric interventions.

Conventional treatment methods have limited effectiveness in addressing late-life depression (LLD) that does not respond well. While a new approach called priming repetitive transcranial magnetic stimulation (rTMS) has shown promise in treating depression in adults, its effectiveness in LLD has not been explored. This study aimed to investigate the impact of priming rTMS on LLD.

This study investigated the effectiveness of priming rTMS in 31 patients with LLD who did not improve after an adequate trial of antidepressants. Patients were randomly assigned to receive either active priming rTMS or sham priming rTMS. Active priming rTMS was delivered over the right dorsolateral prefrontal cortex for 10 sessions, lasting 31 minutes each, over a period of 2 weeks.

The group receiving active priming rTMS demonstrated greater improvements in scores on the Hamilton Rating Scale for Depression (p < 0.037; partial η2 0.141) and the Geriatric Depression Rating Scale (p < 0.045; partial η2 0.131) compared to the sham priming group, with a mild effect size. At the end of the second and fourth weeks, the priming rTMS group achieved a response rate of 50%, while the sham priming group had response rates of 26.7% and 6.7%, respectively. No adverse effects requiring intervention were observed.

Priming rTMS is well-tolerated for the treatment of LLD and not only reduces the severity of depression but also maintains the achieved response over time.

Frailty and late-life depression (LLD) often coexist and share several structural brain changes. We aimed to study the joint effect LLD and frailty have on brain structure.

Cross-sectional study

Academic Health Center

Thirty-one participants (14 LLD+Frail and 17 Never-depressed+Robust)

LLD was diagnosed by a geriatric psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition for single episode or recurrent major depressive disorder without psychotic features. Frailty was assessed using the FRAIL scale (0–5), classifying subjects as robust (0), prefrail (1–2), and frail (3–5). Participants underwent T1-weighted magnetic resonance imaging in which covariance analysis of subcortical volumes and vertex-wise analysis of cortical thickness values were performed to access changes in grey matter. Participants also underwent diffusion tensor imaging in which tract-based spatial statistics was used with voxel-wise statistical analysis on fractional anisotropy and mean diffusion values to assess changes in white matter (WM).

We found a significant difference in mean diffusion values (48,225 voxels; peak voxel: pFWER=0.005, MINI coord. (X,Y,Z) = −26,−11,27) between the LLD-Frail group and comparison group. The corresponding effect size (f=0.808) was large.

We showed the LLD+Frailty group is associated with significant microstructural changes within WM tracts compared to Never-depressed+Robust individuals. Our findings indicate the possibility of a heightened neuroinflammatory burden as a potential mechanism underlying the co-occurrence of both conditions and the possibility of a depression–frailty phenotype in older adults.

Slowed information processing speed (IPS) is the core contributor to cognitive impairment in patients with late-life depression (LLD). The hippocampus is an important link between depression and dementia, and it may be involved in IPS slowing in LLD. However, the relationship between a slowed IPS and the dynamic activity and connectivity of hippocampal subregions in patients with LLD remains unclear.

One hundred thirty-four patients with LLD and 89 healthy controls were recruited. Sliding-window analysis was used to assess whole-brain dynamic functional connectivity (dFC), dynamic fractional amplitude of low-frequency fluctuations (dfALFF) and dynamic regional homogeneity (dReHo) for each hippocampal subregion seed.

Cognitive impairment (global cognition, verbal memory, language, visual–spatial skill, executive function and working memory) in patients with LLD was mediated by their slowed IPS. Compared with the controls, patients with LLD exhibited decreased dFC between various hippocampal subregions and the frontal cortex and decreased dReho in the left rostral hippocampus. Additionally, most of the dFCs were negatively associated with the severity of depressive symptoms and were positively associated with various domains of cognitive function. Moreover, the dFC between the left rostral hippocampus and middle frontal gyrus exhibited a partial mediation effect on the relationships between the scores of depressive symptoms and IPS.

Patients with LLD exhibited decreased dFC between the hippocampus and frontal cortex, and the decreased dFC between the left rostral hippocampus and right middle frontal gyrus was involved in the underlying neural substrate of the slowed IPS.

To investigate the relationship between lean muscle mass and treatment response in treatment-resistant late-life depression (TR-LLD). We hypothesized that lower lean muscle mass would be associated with older age, higher physical comorbidities, higher depressive symptom severity, and poorer treatment response.

Secondary analysis of a randomized, placebo-controlled trial.

Three academic hospitals in the United States and Canada.

Adults aged 60+ years with major depressive disorder who did not remit following open treatment with venlafaxine extended-release (XR) (n = 178).

We estimated lean muscle mass using dual-energy X-ray absorptiometry (DEXA) scans prior to and following randomized treatment with aripiprazole or placebo added to venlafaxine XR. Multivariate regressions estimated influence of demographic and clinical factors on baseline lean muscle mass, and whether baseline lean muscle mass was associated with treatment response, adjusted for treatment arm.

Low lean muscle mass was present in 22 (12.4%) participants. Older age and female sex, but not depressive symptom severity, were independently associated with lower lean muscle mass at baseline. Marital status, baseline depressive symptom severity, and treatment group were associated with improvement of depressive symptoms in the randomized treatment phase. Baseline lean muscle mass was not associated with improvement, regardless of treatment group.

As expected, older age and female sex were associated with lower lean muscle mass in TR-LLD. However, contrary to prior results in LLD, lean muscle mass was not associated with depression severity or outcome. This suggests that aripiprazole augmentation may be useful for TR-LLD, even in the presence of anomalous body composition.

clinicaltrials.gov Identifier: NCT00892047.

Priming stimulation, which involves high-frequency repetitive transcranial magnetic stimulation (rTMS) followed by low-frequency, has been shown to enhance neural response and is one of the novel paradigms found beneficial in adult patients with depression and has not been studied in late-life depression (LLD). This study aims to compare the effect of adjunctive priming vis-a-vis no priming rTMS over right dorso-lateral prefrontal cortex (DLPFC), on treatment of LLD.

This trial is registered in Clinical Trial Registry-India (CTRI) on www.ctri.nic.in. CTRI registration number: CTRI/2020/08/027230. Forty patients of LLD who are symptomatic after an adequate antidepressant trial will be randomized into 2 groups (active priming and sham priming rTMS); each receiving 10 sessions of rTMS over 2 weeks. Patients will remain blind to treatment allocation. Assessments will be done using Hamilton rating scale for depression, Geriatric Depression Scale, Hamilton rating scale for Anxiety, Somatic Symptom Severity Scale 8, Hindi Mental Status Examination, and Clinical Global Impression scale at baseline, week 1, 2, and 4. Side effect checklist will be applied after each session in both groups and at the end of 4 weeks.

Data will be analyzed using statistical software Statistical Package for Social Sciences. Both the groups (active and sham groups) will be compared at the four given timepoints. Also, the baseline characteristics will be compared with the 3 follow-up points for any change.

The findings of the study will give an insight to the possible role of priming to augment the effect of low-frequency rTMS in LLD.

Introduction: Residual depressive symptoms are common after a successful acute treatment of late-life depression (LLD), and their presence predicts increased risk of relapse. While electroconvulsive therapy (ECT) is the most effective treatment for LLD, little is known about which particular symptoms remain and impact long-term outcome after a successful acute ECT course.

Objectives: We aimed to assess the association between specific residual depressive symptoms after an effective acute ECT course for LLD and relapse at six-month follow-up.

Methods: In this prospective cohort study, including 110 patients aged 55 years and older with LLD, information about relapse was collected six months after the acute ECT course. Relapse was defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score >15, hospital admission or restart of ECT. We used multivariable stepwise logistic regression models including the scores on the 10 individual MADRS items at the end of the acute ECT course to predict relapse.

Results: Of the 80 responders with available six-month follow-up data, 29 patients (36.25%) had suffered relapse. Higher scores on the MADRS items ‘reduced sleep’ (odds ratio (OR)=2.03, 95% confidence interval (CI)=1.11-3.69, p=0.0214) and ‘lassitude’ (OR=1.62, 95% CI=1.00-2.62, p=0.0497) at the end of the acute ECT course were significantly associated with increased risk of relapse at six-month follow-up.

Conclusions: Some residual depressive symptoms, including sleep disturbance and fatigue, may help better identify patients vulnerable to relapse following a successful acute ECT course for LLD. Future studies assessing interventions that target specific residual symptoms may further reduce post-ECT depressive relapse.

No significant relationships.

No significant relationships.

There are growing concerns about the impact of the COVID-19 pandemic on the mental health of older adults. We examined the effect of the pandemic on the risk of depression in older adults.

We analyzed data from the prospective cohort study of Korean older adults, which has been followed every 2 years. Among the 2308 participants who completed both the third and the fourth follow-up assessments, 58.4% completed their fourth follow-up before the outbreak of COVID-19 and the rest completed it during the pandemic. We conducted face-to-face diagnostic interviews using Mini International Neuropsychiatric Interview and used Geriatric Depression Scale. We performed generalized estimating equations and logistic regression analyses.

The COVID-19 pandemic was associated with increased depressive symptoms in older adults [b (standard error) = 0.42 (0.20), p = 0.040] and a doubling of the risk for incident depressive disorder even in euthymic older adults without a history of depression (odds ratio = 2.44, 95% confidence interval 1.18–5.02, p = 0.016). Less social activities, which was associated with the risk of depressive disorder before the pandemic, was not associated with the risk of depressive disorder during the pandemic. However, less family gatherings, which was not associated with the risk of depressive disorder before the pandemic, was associated with the doubled risk of depressive disorder during the pandemic.

The COVID-19 pandemic significantly influences the risk of late-life depression in the community. Older adults with a lack of family gatherings may be particularly vulnerable.

Emotional cognition and effective interpretation of affective information is an important factor in social interactions and everyday functioning, and difficulties in these areas may contribute to aetiology and maintenance of mental health conditions. In younger people with depression and anxiety, research suggests significant alterations in behavioural and brain activation aspects of emotion processing, with a tendency to appraise neutral stimuli as negative and attend preferentially to negative stimuli. However, in ageing, research suggests that emotion processing becomes subject to a ‘positivity effect’, whereby older people attend more to positive than negative stimuli.

This review examines data from studies of emotion processing in Late-Life Depression and Late-Life Anxiety to attempt to understand the significance of emotion processing variations in these conditions, and their interaction with changes in emotion processing that occur with ageing.

We conducted a systematic review following PRISMA guidelines. Articles that used an emotion-based processing task, examined older persons with depression or an anxiety disorder and included a healthy control group were included.

In Late-Life Depression, there is little consistent behavioural evidence of impaired emotion processing, but there is evidence of altered brain circuitry during these processes. In Late-Life Anxiety and Post-Traumatic Stress disorder, there is evidence of interference with processing of negative or threat-related words.

How these findings fit with the positivity bias of ageing is not clear. Future research is required in larger groups, further examining the interaction between illness and age and the significance of age at disease onset.

Suicide rate tends to peak in old age, and major depression is the most salient risk factor for late-life suicide. However, few studies have focused on the neuroscientific facet of suicide in the context of late-life depression (LLD).

We recruited 114 participants of LLD (28 with history of suicide attempt and 86 without) and 47 elderly controls. They received MRI scanning and behavioral assessment. White matter hyperintensity (WMH) was quantified by an automated segmentation algorithm and graph theoretical analysis was applied to resting-state fMRI. We used ANCOVA to compare group difference in WMH loading and multivariate generalized linear model to compare global and local topological parameters in fMRI signals, controlling for demographics. Partial correlation was conducted between imaging parameters and behavioral data in group of suicide attempters.

We found significant higher WMH in suicide attempters than those of LLD without suicide attempts and elderly controls (F =7.091; p = 0.001). Suicide attempters also had increased betweenness centrality (BC) in right superior occipital gyrus (SOG) (Bonferroni corrected), right precuneus (False positive corrected) and right superior temporal gyrus (uncorrected) and decreased BC in left hippocampus (uncorrected). In suicide attempters, higher BC in right SOG correlated with higher WMH, higher depression severity, higher illness awareness and insight, and lower cognitive function (digit backward), while higher BC in right precuneus correlated with higher decrease awareness and insight and higher cognitive function (digit backward).

Resonating with the vascular hypothesis in LLD, higher WMH was found in those having history of suicide attempts. However, the re-organized brain topology changes are related with divergent cognitive function and convergent heightened disease insight.

Recent research on late-life depression (LLD) pathophysiology suggests the implication of abnormalities in cerebral white matter [1] and particularly in interhemispheric transfer [2]. Corpus callosum (CC) is the main brain interhemispheric commissure [3]. Hence, we investigated the association between baseline CC measures and risk of LDD.

We studied 467 non-demented individuals without LLD at baseline from a cohort of community-dwelling people aged 80 years or younger (the ESPRIT study). LLD was assessed at year 2, 4, 7 and 10 of the study follow-up. At baseline, T1-weighted magnetic resonance images were manually traced to measure the mid-sagittal areas of the anterior, mid and posterior CC. Multivariate Cox proportional hazards models stratified by sex were used to predict LLD incidence over 10 years.

A significant interaction between gender and CC size was found (P = 0.02). LLD incidence in elderly women, but not in men, was significantly associated with smaller anterior (HR 1.37 [1.05–1.79] P = 0.017), mid (HR 1.43 [1.09–1.86] P = 0.008), posterior (HR1.39 [1.12–1.74] P = 0.002) and total (HR 1.53 [1.16–2.00] P = 0.002) CC areas at baseline in Cox models adjusted for age, education, global cognitive impairment, ischemic pathologies, left-handedness, white matter lesion, intracranial volume and past depression.

The main limitation was the retrospective assessment of major depression.

Smaller CC size is a predictive factor of incident LLD over 10 years in elderly women. Our finding suggests a possible role of CC and reduced interhemispheric connectivity in LLD pathophysiology. Extensive explorations are needed to clarify the mechanisms leading to CC morphometric changes in mood disorders.