Late-life Major Depressive Disorder Research Articles

Causes of death in individuals with lifetime major depression: a comprehensive machine learning analysis from a community-based autopsy center

BackgroundDepression can be associated with increased mortality and morbidity, but no studies have investigated the specific causes of death based on autopsy reports. Autopsy studies can yield valuable and detailed information on pathological ailments or underreported conditions. This study aimed to compare autopsy-confirmed causes of death (CoD) between individuals diagnosed with major depressive disorder (MDD) and matched controls. We also analyzed subgroups within our MDD sample, including late-life depression and recurrent depression. We further investigated whether machine learning (ML) algorithms could distinguish MDD and each subgroup from controls based on their CoD.MethodsWe conducted a comprehensive analysis of CoD in individuals who died from nontraumatic causes. The diagnosis of lifetime MDD was ascertained based on the DSM-5 criteria using information from a structured interview with a knowledgeable informant. Eleven established ML algorithms were used to differentiate MDD individuals from controls by simultaneously analyzing different disease category groups to account for multiple tests. The McNemar test was further used to compare paired nominal data.ResultsThe initial dataset included records of 1,102 individuals, among whom 232 (21.1%) had a lifetime diagnosis of MDD. Each MDD individual was strictly paired with a control non-psychiatric counterpart. In the MDD group, the most common CoD were circulatory (67.2%), respiratory (13.4%), digestive (6.0%), and cancer (5.6%). Despite employing a range of ML models, we could not find distinctive CoD patterns that could reliably distinguish individuals with MDD from individuals in the control group (average accuracy: 50.6%; accuracy range: 39-59%). These findings were consistent even when considering factors within the MDD group, such as late-life or recurrent MDD. When comparing groups with paired nominal tests, no differences were found for circulatory (p=0.450), respiratory (p=0.790), digestive (p=1.000), or cancer (p=0.855) CoD.ConclusionsOur analysis revealed that autopsy-confirmed CoD exhibited remarkable similarity between individuals with depression and their matched controls, underscoring the existing heterogeneity in the literature. Future research should prioritize more severe manifestations of depression and larger sample sizes, particularly in the context of CoD related to cancer.

Exploration-Exploitation and Suicidal Behavior in Borderline Personality Disorder and Depression

Clinical theory and behavioral studies suggest that people experiencing suicidal crisis are often unable to find constructive solutions or incorporate useful information into their decisions, resulting in premature convergence on suicide and neglect of better alternatives. However, prior studies of suicidal behavior have not formally examined how individuals resolve the tradeoffs between exploiting familiar options and exploring potentially superior alternatives. To investigate exploration and exploitation in suicidal behavior from the formal perspective of reinforcement learning. Two case-control behavioral studies of exploration-exploitation of a large 1-dimensional continuous space and a 21-day prospective ambulatory study of suicidal ideation were conducted between April 2016 and March 2022. Participants were recruited from inpatient psychiatric units, outpatient clinics, and the community in Pittsburgh, Pennsylvania, and underwent laboratory and ambulatory assessments. Adults diagnosed with borderline personality disorder (BPD) and midlife and late-life major depressive disorder (MDD) were included, with each sample including demographically equated groups with a history of high-lethality suicide attempts, low-lethality suicide attempts, individuals with BPD or MDD but no suicide attempts, and control individuals without psychiatric disorders. The MDD sample also included a subgroup with serious suicidal ideation. Behavioral (model-free and model-derived) indices of exploration and exploitation, suicide attempt lethality (Beck Lethality Scale), and prospectively assessed suicidal ideation. The BPD group included 171 adults (mean [SD] age, 30.55 [9.13] years; 135 [79%] female). The MDD group included 143 adults (mean [SD] age, 62.03 [6.82] years; 81 [57%] female). Across the BPD (χ23 = 50.68; P < .001) and MDD (χ24 = 36.34; P < .001) samples, individuals with high-lethality suicide attempts discovered fewer options than other groups as they were unable to shift away from unrewarded options. In contrast, those with low-lethality attempts were prone to excessive behavioral shifts after rewarded and unrewarded actions. No differences were seen in strategic early exploration or in exploitation. Among 84 participants with BPD in the ambulatory study, 56 reported suicidal ideation. Underexploration also predicted incident suicidal ideation (χ21 = 30.16; P < .001), validating the case-control results prospectively. The findings were robust to confounds, including medication exposure, affective state, and behavioral heterogeneity. The findings suggest that narrow exploration and inability to abandon inferior options are associated with serious suicidal behavior and chronic suicidal thoughts. By contrast, individuals in this study who engaged in low-lethality suicidal behavior displayed a low threshold for taking potentially disadvantageous actions.

Altered activation of the dorsal anterior cingulate cortex during oddball performance in individuals at risk for Alzheimer's disease

IntroductionThe neural mechanisms underlying neurodegenerative disorders in the elderly remain elusive, despite extensive neuroimaging research in recent decades. Amnestic type mild cognitive impairment (aMCI) and late-life major depressive disorder (MDD) are two such conditions characterized by intersecting cognitive and affective symptomatology, and they are at a higher risk for Alzheimer's disease. Materials and methodsThis study analyzed the neural underpinnings of cognitive and depressive symptoms in a cohort comprising 12 aMCI subjects, 24 late-life MDD patients, and 26 healthy controls (HCs). Participants underwent a detailed neuropsychological assessment and completed a visual attentional oddball task during functional magnetic resonance imaging (fMRI), with evaluations at baseline and at 2-year follow-up. ResultsInitial findings showed that aMCI subjects had reduced dACC activation during oddball (target) stimulus detection, a pattern that persisted in longitudinal analyses and correlated with cognitive functioning measures. For HCs, subsequent dACC activation was linked to depression scores. Furthermore, in the affective-cognitive altered groups, later dACC activation correlated with oddball and memory performance. ConclusionsThese findings enhance our comprehension of the neurobiological basis of cognitive and depressive disturbances in aging, indicating that dACC activation in response to a visual attentional oddball task could serve as a neural marker for assessing cognitive impairment and depression in conditions predisposing to Alzheimer's disease.

Effective connectivity of the locus coeruleus in patients with late-life Major Depressive Disorder or mild cognitive impairment

IntroductionWe compared effective connectivity from the locus coeruleus (LC) during the resting-state in patients with late-life Major Depressive Disorder (MDD), individuals with amnestic Mild Cognitive Impairment (aMCI), and Healthy Controls (HCs). Participants23 patients with late-life MDD, 22 patients with aMCI, and 28 HCs. Material and methodsParticipants were assessed in two time-points, 2 years apart. They underwent a resting-state functional magnetic resonance imaging and a high-resolution anatomical acquisition, as well as clinical assessments. Functional imaging data were analyzed with dynamic causal modeling, and parametric empirical Bayes model was used to map effective connectivity between 7 distinct nodes: 4 from the locus coeruleus and 3 regions displaying gray matter decreases during the two-year follow-up period. ResultsLongitudinal analysis of structural data identified three clusters of larger over-time gray matter volume reduction in patients (MDD+aMCI vs. HCs): the right precuneus, and the visual association and parahippocampal cortices. aMCI patients showed decreased effective connectivity from the left rostral to caudal portions of the LC, while connectivity from the left rostral LC to the parahippocampal cortex increased. In MDD, there was a decline in effective connectivity across LC caudal seeds, and increased connectivity from the left rostral to the left caudal LC seed over time. Connectivity alterations with cortical regions involved cross-hemisphere increases and same-hemisphere decreases. ConclusionsOur discoveries provide insight into the dynamic changes in effective connectivity in individuals with late-life MDD and aMCI, also shedding light on the mechanisms potentially contributing to the onset of neurodegenerative disorders.

P6: Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance: a longitudinal study

P6: Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance: a longitudinal study

55 Hoarding Behaviors in Late Life Depression are Associated with Increased Burden of Executive Dysfunction, Disability, and Poorer Response to Depression Treatment

Objective:Late Life Major Depressive Disorder (LLD) and Hoarding Disorder (HD) are common in older adults with prevalence estimates up to 29% and 7%, respectively. Both LLD and HD are characterized by executive dysfunction and disability. There is evidence of overlapping neurobiological dysfunction in LLD and HD suggesting potential for compounded executive dysfunction and disability in the context of comorbid HD and LLD. Yet, prevalence of HD in primary presenting LLD has not been examined and potential compounded impact on executive functioning, disability, and treatment response remains unknown. Thus, the present study aimed to determine the prevalence of co-occurring HD in primary presenting LLD and examine hoarding symptom severity as a contributor to executive dysfunction, disability, and response to treatment for LLD.Participants and Methods:Eighty-three adults ages 65-90 participating in a psychotherapy study for LLD completed measures of hoarding symptom severity (Savings Inventory-Revised: SI-R), executive functioning (WAIS-IV Digit Span, Letter-Number Sequencing, Coding; Stroop Interference; Trail Making Test-Part B; Letter Fluency), functional ability (World Health Organization Disability Assessment Schedule-II-Short), and depression severity (Hamilton Depression Rating Scale) at post-treatment. Pearson's Chi-squared tests evaluated group differences in cognitive and functional impairment rates and depression treatment response between participants with (HD+LLD) and without (LLD-only) clinically significant hoarding symptoms. Linear regressions were used to examine the association between hoarding symptom severity and executive function performance and functional ability and included as covariates participant age, years of education, gender, and concurrent depression severity.Results:At post-treatment, 24.1% (20/83) of participants with LLD met criteria for clinically significant hoarding symptoms (SI-R.41). Relative to LLD-only, the LLD+HD group demonstrated greater impairment rates in Letter-Number Sequencing (χ2(1)=4.0, p=.045) and Stroop Interference (χ2(1)=4.8, p=.028). Greater hoarding symptom severity was associated with poorer executive functioning performance on Digit Span (t(71)=-2.4, β=-0.07, p=.019), Letter-Number Sequencing (t(70)=-2.1, β=-0.05, p=.044), and Letter Fluency (t(71)=-2.8, β=-0.24, p=.006). Rates of functional impairment were significantly higher in the LLD+HD (88.0%) group compared to the LLD-only (62.3%) group, (χ2(1)=5.41, p=.020). Additionally, higher hoarding symptom severity was related to greater disability (t(72)=2.97, β=0.13, p=.004). Furthermore, depression treatment response rates were significantly lower in the LLD+HD group at 24.0% (6/25) compared to 48.3% (28/58) in the LLD-only group, χ2(1)=4.26, p=.039.Conclusions:The present study is among the first to report prevalence of clinically significant hoarding symptoms in primary presenting LLD. The findings of 24.1% co-occurrence of HD in primary presenting LLD and increased burden on executive functioning, disability, and depression treatment outcomes have important implications for intervention and prevention efforts. Hoarding symptoms are likely under-evaluated, and thus may be overlooked, in clinical settings where LLD is identified as the primary diagnosis. Taken together with results indicating poorer depression treatment response in LLD+HD, these findings underscore the need for increased screening of hoarding behaviors in LLD and tailored interventions for this LLD+HD group. Future work examining the course of hoarding symptomatology in LLD (e.g., onset age of hoarding behaviors) may provide insights into the mechanisms associated with greater executive dysfunction and disability.

Atrophy, hypometabolism and implication regarding pathology in late-life major depression with suspected non-alzheimer pathophysiology (SNAP)

BackgroundA substantial proportion of individuals with late-life major depression could be classified as having a suspected non-Alzheimer disease pathophysiology (SNAP), as indicated by a negative test for the biomarker β-amyloid (Aβ-) but a positive test for neurodegeneration (ND+). This study investigated the clinical features, characteristic patterns of brain atrophy and hypometabolism, and implications regarding pathology in this population. MethodsForty-six amyloid-negative patients with late-life major depressive disorder (MDD) patients, including 23 SNAP (Aβ-/ND+) and 23 Aβ-/ND- MDD subjects, and 22 Aβ-/ND-healthy control subjects were included in this study. Voxel-wise group comparisons between the SNAP MDD, Aβ-/ND- MDD and control subjects were performed, adjusting for age, gender and level of education. For exploratory comparisons, 8 Aβ+/ND- and 4 Aβ+/ND + MDD patients were included in the Supplementary Material. ResultsThe SNAP MDD patients had atrophy extending to regions outside the hippocampus, predominately in the medial temporal, dorsomedial and ventromedial prefrontal cortex; hypometabolism involving a large portion of the lateral and medial prefrontal cortex in addition to the bilateral temporal, parietal and precuneus cortex within typical Alzheimer disease regions were observed. Metabolism ratios of the inferior to the medial temporal lobe were significantly elevated in the SNAP MDD patients. We further discussed the implications with regards to underlying pathologies. ConclusionThe present study demonstrated characteristic patterns of atrophy and hypometabolism in patients with late-life major depression with SNAP. Identifying individuals with SNAP MDD may provide insights into currently unspecified neurodegenerative processes. Future refinement of neurodegeneration biomarkers is essential in order to identify potential pathological correlates while in vivo reliable pathological biomarkers are not forthcoming.

Links between electroconvulsive therapy responsive and cognitive impairment multimodal brain networks in late-life major depressive disorder

BackgroundAlthough electroconvulsive therapy (ECT) is an effective treatment for depression, ECT cognitive impairment remains a major concern. The neurobiological underpinnings and mechanisms underlying ECT antidepressant and cognitive impairment effects remain unknown. This investigation aims to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks and assesses whether they are associated with the ECT-induced electric field (E-field) with an optimal pulse amplitude estimation.MethodsA single site clinical trial focused on amplitude (600, 700, and 800 mA) included longitudinal multimodal imaging and clinical and cognitive assessments completed before and immediately after the ECT series (n = 54) for late-life depression. Another two independent validation cohorts (n = 84, n = 260) were included. Symptom and cognition were used as references to supervise fMRI and sMRI fusion to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks. Correlations between ECT-induced E-field within these two networks and clinical and cognitive outcomes were calculated. An optimal pulse amplitude was estimated based on E-field within antidepressant-response and cognitive-impairment networks.ResultsDecreased function in the superior orbitofrontal cortex and caudate accompanied with increased volume in medial temporal cortex showed covarying functional and structural alterations in both antidepressant-response and cognitive-impairment networks. Volume increases in the hippocampal complex and thalamus were antidepressant-response specific, and functional decreases in the amygdala and hippocampal complex were cognitive-impairment specific, which were validated in two independent datasets. The E-field within these two networks showed an inverse relationship with HDRS reduction and cognitive impairment. The optimal E-filed range as [92.7–113.9] V/m was estimated to maximize antidepressant outcomes without compromising cognitive safety.ConclusionsThe large degree of overlap between antidepressant-response and cognitive-impairment networks challenges parameter development focused on precise E-field dosing with new electrode placements. The determination of the optimal individualized ECT amplitude within the antidepressant and cognitive networks may improve the treatment benefit–risk ratio.Trial registrationClinicalTrials.gov Identifier: NCT02999269.

Prevalence of Comorbid Dementia in Late-life Depression and Bipolar Disorder: A Retrospective Inpatient Study.

Background:Dementia in patients with late-life mood disorders is clinically important.Objective:We aimed to investigate the prevalence of dementia in patients with late-life major depressive disorder (MDD) or bipolar disorder (BD) and to clarify the clinical characteristics associated with the diagnosis of dementia.Methods:The prevalence of dementia at hospital discharge and the clinical characteristics at hospitalization who are diagnosed with MDD or BD over 65 years of age, from the medical records of 684 patients who had been admitted from 2015 to 2020 were investigated.Results:A total of 66 patients with MDD (n = 50) and BD (n = 16) were analyzed. The prevalence of dementia was significantly higher in MDD than in BD (24.0% versus 0%; p = 0.026). The mean age at onset of MDD was significantly older in the MDD with dementia group than in the MDD without (76.9±6.3 years versus 62.2±14.0 years; p < 0.001). The rate of first depressive episode at this admission was significantly higher in the MDD with dementia group (91.7% versus 30.3%; p < 0.001). The diagnosis of dementia was significantly associated with lower scores for “insomnia early” (p = 0.019) and higher scores for “insight” (p = 0.049) on the 17-item Hamilton Depression Rating (HAMD-17) subscales and lower scores for “recall” (p = 0.003) on the MMSE subscales.Conclusion:The older age of first onset of depression, “insomnia early”, “insight” and “recall” may be useful indicators for a diagnosis of dementia in late-life depression.

Network structure of time-varying depressive symptoms through dynamic time warp analysis in late-life depression.

ObjectivesLate‐life major depressive disorder (MDD) can be conceptualized as a complex dynamic system. However, it is not straightforward how to analyze the covarying depressive symptoms over time in case of sparse panel data. Dynamic time warping (DTW) analysis may yield symptom networks and dimensions both at the patient and group level.MethodsIn the Netherlands Study of Depression in Older People (NESDO) depressive symptoms were assessed every 6 months using the 30‐item Inventory of Depressive Symptomatology (IDS) with up to 13 assessments per participant. Our sample consisted of 182 persons, aged ≥ 60 years, with an IDS total score of 26 or higher at baseline. Symptom networks dimensions, and centrality metrics were analyzed using DTW and Distatis analyses.ResultsThe mean age was 69.8 years (SD 7.1), with 69.0% females, and a mean IDS score of 38.0 (SD = 8.7). DTW enabled visualization of an idiographic symptom network in a single NESDO participant. In the group‐level nomothetic approach, four depressive symptom dimensions were identified: “core symptoms”, “lethargy/somatic”, “sleep”, and “appetite/atypical”. Items of the “internalizing symptoms” dimension had the highest centrality, whose symptom changes over time were most similar to those changes of other symptoms.ConclusionsDTW revealed symptom networks and dimensions based on the within‐person symptom changes in older MDD patients. Its centrality metrics signal the most influential symptoms, which may aid personalized care.

Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.

Cognitive outcomes are differentially associated with depression severity trajectories during psychotherapy treatment for late life major depressive disorder.

Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD. 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance. Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed. The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD.

Abnormalities in the default mode network in late-life depression: A study of resting-state fMRI

Background/ObjectiveNeuroimaging studies have reported abnormalities in the examination of functional connectivity in late-life depression (LLD) in the default mode network (DMN). The present study aims to study resting-state functional connectivity within the DMN in people diagnosed with late-life major depressive disorder (MDD) compared to healthy controls (HCs). Moreover, we would like to differentiate these same connectivity patterns between participants with high vs. low anxiety levels. MethodThe sample comprised 56 participants between the ages of 60 and 75; 27 of them were patients with a diagnosis of MDD. Patients were further divided into two samples according to anxiety level: the four people with the highest anxiety level and the five with the lowest anxiety level. Clinical aspects were measured using psychological questionnaires. Each participant underwent functional magnetic resonance imaging (fMRI) acquisition in different regions of interest (ROIs) of the DMN. ResultsThere was a greater correlation between pairs of ROIs in the control group than in patients with LLD, being this effect preferentially observed in patients with higher anxiety levels. ConclusionsThere are differences in functional connectivity within the DMN depending on the level of psychopathology. This can be reflected in these correlations and in the number of clusters and how the brain lateralizes (clustering).

Decreased Cerebral Amyloid-β Depositions in Patients With a Lifetime History of Major Depression With Suspected Non-Alzheimer Pathophysiology.

Cerebral amyloid-β (Aβ) depositions in depression in old age are controversial. A substantial proportion of individuals with late-life major depressive disorder (MDD) could be classified as having suspected non-Alzheimer’s disease pathophysiology (SNAP) by a negative test for the biomarker amyloid-β (Aβ−) but positive neurodegeneration (ND+). This study aimed to evaluate subthreshold Aβ loads in amyloid-negative MDD, particularly in SNAP MDD patients. This study included 46 amyloid-negative MDD patients: 23 SNAP (Aβ−/ND+) MDD and 23 Aβ−/ND− MDD, and 22 Aβ−/ND− control subjects. All subjects underwent 18F-florbetapir PET, FDG-PET, and MRI. Regions of interest (ROIs) and voxel-wise group comparisons were performed with adjustment for age, gender, and level of education. The SNAP MDD patients exhibited significantly deceased 18F-florbetapir uptakes in most cortical regions but not the parietal and precuneus cortex, as compared with the Aβ−/ND− MDD and control subjects (FDR correction, p < 0.05). No correlations of neuropsychological tests or depression characteristics with global cortical uptakes, but significant positive correlations between cognitive functions and adjusted hippocampal volumes among different groups were observed. The reduced Aβ depositions in the amyloid-negative MDD patients might be attributed mainly to the SNAP MDD patients. Our results indicated that meaningfully low amounts of subclinical Aβ might contain critical information on the non-amyloid-mediated pathogenesis.

Graph analysis of fMRI resting-state in patients with late life major depressive disorder or mild cognitive impairment

Graph analysis of fMRI resting-state in patients with late life major depressive disorder or mild cognitive impairment

Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance

Brain alterations in patients with late-life major depressive disorder and amnestic type mild cognitive impairment during oddball performance

The diagnostic accuracy of late-life depression is influenced by subjective memory complaints and educational level in an older population in Southern Italy

The prevalence of late-life depression (LLD) depends on the study sample, measurements, and diagnostic approaches. We estimated the 30 item-Geriatric Depression Scale (GDS-30) accuracy against the gold standard LLD diagnosis made with the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders, focusing on the prevalence of a late-life major depressive disorder (MDD), in a population-based sample of 843 subjects aged>65 years, subdivided into three groups: normal cognition, subjective memory complaints, and mild cognitive impairment. At the optimal cut-off score (≥4), the GDS-30 showed 65.1% sensitivity and 68.4% specificity for LLD (63% and 66% for late-life MDD, respectively). Using the standard cut-off score (≥10), the GDS-30 specificity reached 91.2%, while sensitivity dropped to 37.7%, indicating a lower screening accuracy [area under the curve(AUC):0.728, 95% confidence interval(CI):0.67–0–78]. The GDS-30 performance was associated with educational level, but not with age, gender, cognition, apathy, and somatic/psychiatric multimorbidity. For subjective memory complaints subjects, at the optimal cut-off score (≥7), the GDS-30 showed better discrimination performances (AUC=0.792,95%CI:0.60–0.98), but again the educational level affected the diagnostic performance. In subjective memory complaints subjects, symptom-based scales like the GDS-30 may feature a better performance for diagnosing depression in older age, but the GDS-30 seems to require adjustment to the patient's educational level.

Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression

AbstractBackgroundCognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.MethodsWe recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.ResultsMDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p &lt; 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p &lt; 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.ConclusionsLate-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

BackgroundInflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. MethodsBasal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. ResultsWe found moderate level of evidence for an association of lower CSF levels of sTREM2 at 3 years follow up with MDD (Bayes factor in favor of an effect = 7.9). This level of evidence prevailed when controlling for overall antidepressant treatment and CSF levels of markers of AD pathology, i.e., Aβ42/Aβ40, ptau181 and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LimitationsThe sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. ConclusionsOur data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD.

Associations between worse executive control and greater fall risk in Geriatric Major Depressive Disorder

<h3>Introduction</h3> Psychomotor disturbances (e.g. psychomotor retardation/agitation) are a core feature of major depressive disorder (MDD) and when present, predict poor treatment outcomes. Psychomotor impairment in late life MDD (LLD) reflect deficits in motor and sensorimotor function, which impair balance control in older adults (OAs). When compared to healthy OAs, those with LLD are ∼35% more likely to fall, develop a fear of falling, and avoid physical activity, all of which predict early mortality. OAs who fall lose their independence and have a worse quality of life, and the rate of deaths from falls is rising. The association between LLD and fall-risk is complicated by pharmacologic treatments that intensify fall-risk; anti-depressants decrease walking speed and increase fall-risk equivalent to antipsychotic and benzodiazepine medications. A poor understanding of <i>when, why, and how</i>falls occur in LLD has led to a knowledge gap regarding relationships between psychomotor disturbance, LLD and fall-risk. Complicating matters, roughly 40% of patients with LLD suffer from cognitive difficulty called cognitive control deficits (CCD) that predispose them to poor clinical outcomes like disability, SSRI treatment resistance, relapse, and suicide. Converging evidence suggests a common neurobiological etiology underlie LLD, CCD and fall-risk. OAs with CCD are three times more likely to fall than their healthy peers and are more susceptible to recurrent falls. OAs with CCD are more likely to exhibit worse health outcomes and mobility deficits suggesting greater fall-risk. The co-occurrence and clinical relevance of these phenomena provides a unique opportunity for investigation. The purpose of this study was to quantify associations between CCD and fall-risk in treatment resistant LLD. Our hypothesis was LLD patients who fail to respond to treatment with SSRI/SNRI would be more likely to exhibit CCD, which would be negatively associated with fall history. <h3>Methods</h3> Participants were aged ≥ 65 years and met DSM-IV-TR/Research Diagnostic criteria for unipolar MDD (Hamilton Depression Rating Scale (HDRS)>19) in an interview with a licensed clinician (SM) despite treatment with SSRI/SNRI antidepressants for ≥8 weeks. Data collection was part of screening for a larger intervention study at Weill Cornell Medical College. Exclusion criteria included: No diagnosis or evidence of dementing disorder (Mini-Mental State Examination (MMSE) score <25), reporting psychotic features/disorders or acute suicidal ideation, severe medical illness, or neurological disorders. Fall history was determined with a brief survey. Participants completed a neuropsychological battery including the Trail Making Test; a test of cognitive flexibility that is associated with fall risk in OA. Participants who reported a fall one or more times in the preceding year were classified as a ‘faller', those that had not fallen were ‘non-fallers'. Group differences (fallers, non-fallers) in CCD were compared with independent t-tests. Logistic regression predicted fall status with CCD performance outcomes, while controlling for gender. <h3>Results</h3> A total of 30 OA participants with MDD were included in the analysis. Approximately 1/3 of our OA participants with MDD reported falling within the last year (<i>n</i> = 9). Fallers exhibited significantly poorer cognitive control as determined by TMT B and D TMT (both <i>p <</i> 0.001). Logistic regression including gender as a covariate showed D TMT significantly predicted fall status, Gender ß = -0.014, <i>p</i> = 0.918, and Faller status: ß = 0.746, <i>p</i> < 0.001. <h3>Conclusions</h3> The purpose of this study was to estimate the risk of falling in treatment resistant LLD and examine the relationship between CCD and fall risk in depressed OA. Our results demonstrate that in treatment resistant LLD, patients on adequate dosages of SSRI/SNRI antidepressants, roughly one third of patients have fallen within the last year, and that CCD may have a strong independent influence on rates of falling. This rate of falls is consistent with existing reports of fall-risk in community dwelling OAs and OAs with MDD. Our preliminary results suggest that CCD is an important factor that catalyzes fall-risk in LLD, and highlight yet another vulnerability of treatment resistant LLD patients. Though this is a preliminary retrospective study, our results suggest that clinicians may improve prediction of fall risk in LLD patients by assessing CCD, with a short, paper-pencil test that can be administered bedside. Given the new NIMH mandate to quantify features of sensorimotor function across psychiatric conditions, we propose that future investigations of LLD include objective, dimensional, large-scale assessment of motor behavior that can be integrated with other objective assessments (e.g. cognitive, functional, affective). If the associations between CCD and falls prove robust in LLD patients, CCD could serve as an intervention target to reduce fall-risk, depression, and other related negative clinical sequalae. <h3>Funding</h3> Morimoto: K 23 MH 095830, UL1TR000457 Alexopolous: R01 MH065653, P50 MH113838