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Background Known risk factors for Alzheimer's disease and other dementias include medical conditions, genetic vulnerability, depression, demographic factors and mild cognitive impairment. The role of feelings of loneliness and social isolation in dementia is less well understood, and prospective studies including these risk factors are scarce. Methods We tested the association between social isolation (living alone, unmarried, without social support), feelings of loneliness and incident dementia in a cohort study among 2173 non-demented community-living older persons. Participants were followed for 3 years when a diagnosis of dementia was assessed (Geriatric Mental State (GMS) Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT)). Logistic regression analysis was used to examine the association between social isolation and feelings of loneliness and the risk of dementia, controlling for sociodemographic factors, medical conditions, depression, cognitive functioning and functional status. Results After adjustment for other risk factors, older persons with feelings of loneliness were more likely to develop dementia (OR 1.64, 95% CI 1.05 to 2.56) than people without such feelings. Social isolation was not associated with a higher dementia risk in multivariate analysis. Conclusions Feeling lonely rather than being alone is associated with an increased risk of clinical dementia in later life and can be considered a major risk factor that, independently of vascular disease, depression and other confounding factors, deserves clinical attention. Feelings of loneliness may signal a prodromal stage of dementia. A better understanding of the background of feeling lonely may help us to identify vulnerable persons and develop interventions to improve outcome in older persons at risk of dementia.

Recent longitudinal neuroimaging studies in patients with electroconvulsive therapy (ECT) suggest local effects of electric stimulation (lateralized) occur in tandem with global seizure activity (generalized). We used electric field (EF) modeling in 151 ECT treated patients with depression to determine the regional relationships between EF, unbiased longitudinal volume change, and antidepressant response across 85 brain regions. The majority of regional volumes increased significantly, and volumetric changes correlated with regional electric field (t = 3.77, df = 83, r = 0.38, p=0.0003). After controlling for nuisance variables (age, treatment number, and study site), we identified two regions (left amygdala and left hippocampus) with a strong relationship between EF and volume change (FDR corrected p<0.01). However, neither structural volume changes nor electric field was associated with antidepressant response. In summary, we showed that high electrical fields are strongly associated with robust volume changes in a dose-dependent fashion. Electroconvulsive therapy, or ECT for short, can be an effective treatment for severe depression. Many patients who do not respond to medication find that their symptoms improve after ECT. During an ECT session, the patient is placed under general anesthesia and two electrodes are attached to the scalp to produce an electric field that generates currents within the brain. These currents activate neurons and make them fire, causing a seizure, but it remains unclear how this reduces symptoms of depression. For many years, researchers thought that the induced seizure must be key to the beneficial effects of ECT, but recent studies have cast doubt on this idea. They show that increasing the strength of the electric field alters the clinical effects of ECT, without affecting the seizure. This suggests that the benefits of ECT depend on the electric field itself. Argyelan et al. now show that electric fields affect the brain by making a part of the brain known as the gray matter expand. In a large multinational study, 151 patients with severe depression underwent brain scans before and after a course of ECT. The scans revealed that the gray matter of the patients’ brains expanded during the treatment. The patients who experienced the strongest electric fields showed the largest increase in brain volume, and individual brain areas expanded if the electric field within them exceeded a certain threshold. This effect was particularly striking in two areas, the hippocampus and the amygdala. Both of these areas are critical for mood and memory. Further studies are needed to determine why the brain expands after ECT, and how long the effect lasts. Another puzzle is why the improvements in depression that the patients reported after their treatment did not correlate with changes in brain volume. Disentangling the relationships between ECT, brain volume and depression will ultimately help develop more robust treatments for this disabling condition.

Loneliness and social network size have been found to be predictors of mortality in older adults. The objective of this study was to investigate whether loneliness and small social network size are associated with an increased mortality risk and to review the evidence for either network size, or loneliness that constitutes the higher mortality risk. A systematic literature search was performed in PubMed, EMBASE and PsychInfo in January/February 2018 and March/April 2021. Studies that mentioned outcome data were included in the meta-analysis and coded using the Newcastle–Ottawa Quality Assessment Scale for Cohort Studies. The meta-analysis showed that both loneliness and small social network size are associated with mortality risk in older adults (Hazard Ratio 1.10 (95% Confidence Interval 1.06–1.14) for loneliness and 0.96 (95% Confidence Interval 0.93–0.99) for larger network size). Sensitivity analyses according to the Newcastle–Ottawa Quality Assessment Scale yielded varying results. Heterogeneity was large. In conclusion, both loneliness and small social network size in older adults are associated with increased mortality, although the effect size is small. Targeting subjective and objective aspects of older adults’ social contacts should be on the agenda of preventive as well as personalized medicine. In order to be able to compare the association between loneliness and network size and mortality, more studies are needed that include both these risk factors.

Recent structural imaging studies have described hippocampal volume changes following electroconvulsive therapy (ECT). It has been proposed that serum brain-derived neurotrophic factor (sBDNF)-mediated neuroplasticity contributes critically to brain changes following antidepressant treatment. To date no studies have investigated the relationship between changes in hippocampal volume, mood, and sBDNF following ECT. Here, we combine these measurements in a longitudinal study of severe late-life unipolar depression (LLD). We treated 88 elderly patients with severe LLD twice weekly until remission (Montgomery-Åsberg Depression Rating Scale (MADRS) <10). sBDNF and MADRS were obtained before ECT (T0), after the sixth ECT (T1), 1 week after the last ECT (T2), 4 weeks after the last ECT (T3), and 6 months after the last ECT (T4). Hippocampal volumes were quantified by manual segmentation of 3T structural magnetic resonance images in 66 patients at T0 and T2 and in 23 patients at T0, T2, and T4. Linear mixed models (LMM) were used to examine the evolution of MADRS, sBDNF, and hippocampal volume over time. Following ECT, there was a significant decrease in MADRS scores and a significant increase in hippocampal volume. Hippocampal volume decreased back to baseline values at T4. Compared with T0, sBDNF levels remained unchanged at T1, T2, and T3. There was no coevolution between changes in MADRS scores, hippocampal volume, and sBDNF. Hippocampal volume increase following ECT is an independent neurobiological effect unrelated to sBDNF and depressive symptomatology, suggesting a complex mechanism of action of ECT in LLD.

Severe depression is associated with high morbidity and mortality. Neural network dysfunction may contribute to disease mechanisms underlying different clinical subtypes. Here, we apply resting-state functional magnetic resonance imaging based measures of brain connectivity to investigate network dysfunction in severely depressed in-patients with and without psychotic symptoms. A cohort study was performed at two sites. Older patients with major depressive disorder with or without psychotic symptoms were included (n = 23 at site one, n = 26 at site two). Resting state 3-Tesla functional MRI scans, with eyes closed, were obtained and Montgomery-Åsberg Depression Rating Scales were completed. We denoised data and calculated resting state networks in the two groups separately. We selected five networks of interest (1. bilateral frontoparietal, 2.left lateralized frontoparietal, 3.right lateralized frontoparietal, 4.default mode network (DMN) and 5.bilateral basal ganglia and insula network) and performed regression analyses with severity of depression, as well as presence or absence of psychotic symptoms. The functional connectivity (FC) patterns did not correlate with severity of depression. Depressed patients with psychotic symptoms (n = 14, 61%) compared with patients without psychotic symptoms (n = 9, 39%) from site one showed significantly decreased FC in the right part of the bilateral frontoparietal network (p = 0.002). This result was not replicated when comparing patients with (n = 9, 35%) and without (n = 17, 65%) psychotic symptoms from site two. Psychotic depression may be associated with decreased FC of the frontoparietal network, which is involved in cognitive control processes, such as attention and emotion regulation. These findings suggest that FC in the frontoparietal network may be related to the subtype of depression, i.e. presence of psychotic symptoms, rather than severity of depression. Since the findings could not be replicated in the 2nd sample, replication is needed before drawing definite conclusions.

Loneliness is highly prevalent among older people, has serious health consequences and is an important predictor of mortality. Loneliness and depression may unfavourably interact with each other over time but data on this topic are scarce. To determine whether loneliness is associated with excess mortality after 19 years of follow-up and whether the joint effect with depression confers further excess mortality. Different aspects of loneliness were measured with the De Jong Gierveld scale and depression with the Centre for Epidemiologic Studies Depression Scale in a cohort of 2878 people aged 55-85 with 19 years of follow-up. Excess mortality hypotheses were tested with Kaplan-Meier and Cox proportional hazard analyses controlling for potential confounders. At follow-up loneliness and depression were associated with excess mortality in older men and women in bivariate analysis but not in multivariate analysis. In multivariate analysis, severe depression was associated with excess mortality in men who were lonely but not in women. Loneliness and depression are important predictors of early death in older adults. Severe depression has a strong association with excess mortality in older men who were lonely, indicating a lethal combination in this group.

Background We aimed to examine the course of depression during 2-year follow-up in a group clinically depressed older persons. Subsequently, we studied which socio-demographic and clinical characteristics predict a depression diagnoses at 2-year follow-up. Methods Data were used from the Netherlands Study of Depression in Older persons (NESDO; N = 510). Diagnoses of depression DSM-IV-TR criteria were available from 285 patients at baseline and at 2-year follow-up. Severity of the depressive symptoms, as assessed with the Inventory of Depressive Symptoms (IDS), was obtained from 6-monthly postal questionnaires. Information about socio-demographic and clinical variables was obtained from the baseline measurement. Result From the 285 older persons who were clinically depressed at baseline almost half (48.4%) also suffered from a depressive disorder two years later. Patients with more severe depressive symptoms, comorbid dysthymia, younger age of onset and more chronic diseases were more likely to be depressed at 2-year follow-up. 61% of the persons that were depressed at baseline had a chronic course of depressive symptoms during these two years. Conclusions Late-life depression often has a chronic course, even when treated conform current guidelines for older persons. Our results suggest that physical comorbidity may be candidate for adjusted and intensified treatment strategies of older depressed patients with chronic and complex pathology.

ObjectivesThe chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course.MethodsOut of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.ResultsEducation, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having ‘fixed behavioural patterns in daily life’ and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.ConclusionThis is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.

Severe depression can be a life-threatening disorder, especially in elderly patients. A fast-acting treatment is crucial for this group. Electroconvulsive therapy (ECT) may work faster than medication. To compare the speed of remission using ECT v. medication in elderly in-patients. The speed of remission in in-patients with a DSM-IV diagnosis of major depression (baseline MADRS score ≥20) was compared between 47 participants (mean age 74.0 years, s.d. = 7.4) from an ECT randomised controlled trial (RCT) and 81 participants (mean age 72.2 years, s.d. = 7.6) from a medication RCT (nortriptyline v. venlafaxine). Mean time to remission was 3.1 weeks (s.d. = 1.1) for the ECT group and 4.0 weeks (s.d. = 1.0) for the medication group; the adjusted hazard ratio for remission within 5 weeks (ECT v. medication) was 3.4 (95% CI 1.9-6.2). Considering the substantially higher speed of remission, ECT deserves a more prominent position in the treatment of elderly patients with severe depression.

Background To address the lack of social interaction and meaningful activities for persons with dementia (PWD) in nursing homes an artistic Photo-Activity was designed. The present study aims to develop a digital version of the Photo-Activity and to investigate its implementation and impact on nursing home residents with advanced dementia, and their (in)formal carers. Methods First, within a user-participatory design, a digital-app version of the Photo-Activity will be developed and pilot-tested, in co-creation with (in)formal carers and PWD. Next, the feasibility and effectiveness of the Photo-Activity versus a control activity will be explored in a randomized controlled trial with nursing home residents ( N =90), and their (in)formal carers. Residents will be offered the Photo-Activity or the control activity by (in)formal carers during one month. Measurements will be conducted by independent assessors at baseline (T0), after one month (T1) and at follow up, two weeks after T1 (T2). Qualitative and quantitative methods will be used to investigate the effects of the intervention on mood, social interaction and quality of life of the PWD, sense of competence of informal carers, empathy and personal attitude of the formal carers, and quality of the relationship between the PWD, and their (in)formal carers. In addition, a process evaluation will be carried out by means of semi-structured interviews with the participating residents and (in)formal carers. Finally, an implementation package based on the process evaluation will be developed, allowing the scaling up of the intervention to other care institutions. Discussion Results of the trial will be available for dissemination by Spring 2023. The digital Photo-Activity is expected to promote meaningful connections between the resident with dementia, and their (in)formal carers through the facilitation of person-centered conversations. Trial registration Netherlands Trial Register: NL9219 ; registered (21 January 2021); NTR (trialregister.nl)