Sex Differences Among Older Adults With Bipolar Disorder: Results From the Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) Project.

OBJECTIVE: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD. METHODS: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept. RESULTS: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders. CONCLUSION: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further.

Decreased emotion recognition and reduced focus on facial hallmarks in behavioral variant frontotemporal dementia compared to primary psychiatric disorders and controls.

BACKGROUND AND PURPOSE: Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD. METHODS: The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons. RESULTS: Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76). CONCLUSIONS: In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.

Long-term Outcome Following Electroconvulsive Therapy for Late-Life Depression: Five-Year Follow-up Data From the MODECT Study.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for late-life depression (LLD). Research addressing long-term outcome following an acute course of ECT for LLD is limited. We aimed to describe relapse, cognitive impairment and survival 5 years after a treatment with ECT for severe LLD, and assess the association of clinical characteristics with all three outcome measures. METHODS: This cohort study was part of the Mood Disorders in Elderly treated with ECT (MODECT) study, which included patients aged 55 years and older with major depressive disorder. Data regarding clinical course, cognitive impairment and mortality were collected 5 years after the index ECT course. We used multivariable Cox proportional hazards models and logistic regression models to assess the association of clinical characteristics with relapse and survival, and cognitive impairment, respectively. RESULTS: We studied 110 patients with a mean age of 72.9 years. 67.1% of patients who showed response at the end of the index ECT course relapsed, and the included clinical characteristics were not significantly associated with the risk of relapse. 38.8% of patients with available data showed cognitive impairment at five-year follow-up. 27.5% were deceased; higher age and a higher number of previous psychiatric admissions were significantly associated with increased risk of mortality. CONCLUSIONS: Five-year outcome after a course of ECT for severe LLD seems to be in line with long-term outcome following other acute treatments for severe LLD in terms of relapse, cognitive impairment and survival. Additional studies aimed at improving long-term outcome in severe LLD are warranted.

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT. Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc. Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT. Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change. Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.

Transient Cognitive Impairment and White Matter Hyperintensities in Severely Depressed Older Patients Treated With Electroconvulsive Therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) is a safe and effective treatment for patients with severe late life depression (LLD), transient cognitive impairment can be a reason to discontinue the treatment. The aim of the current study was to evaluate the association between structural brain characteristics and general cognitive function during and after ECT. METHODS: A total of 80 patients with LLD from the prospective naturalistic follow-up Mood Disorders in Elderly treated with Electroconvulsive Therapy study were examined. Magnetic resonance imaging scans were acquired before ECT. Overall brain morphology (white and grey matter) was evaluated using visual rating scales. Cognitive functioning before, during, and after ECT was measured using the Mini Mental State Examination (MMSE). A linear mixed-model analysis was performed to analyze the association between structural brain alterations and cognitive functioning over time. RESULTS: Patients with moderate to severe white matter hyperintensities (WMH) showed significantly lower MMSE scores than patients without severe WMH (F(1,75.54) = 5.42, p = 0.02) before, during, and post-ECT, however their trajectory of cognitive functioning was similar as no time × WMH interaction effect was observed (F(4,65.85) = 1.9, p = 0.25). Transient cognitive impairment was not associated with medial temporal or global cortical atrophy (MTA, GCA). CONCLUSION: All patients showed a significant drop in cognitive functioning during ECT, which however recovered above baseline levels post-ECT and remained stable until at least 6 months post-ECT, independently of severity of WMH, GCA, or MTA. Therefore, clinicians should not be reluctant to start or continue ECT in patients with severe structural brain alterations.

Cognitive performance in older-age bipolar disorder: Investigating psychiatric characteristics, cardiovascular burden and psychotropic medication.

OBJECTIVE: This study aimed to explore a large range of candidate determinants of cognitive performance in older-age bipolar disorder (OABD). METHODS: A cross-sectional study was performed in 172 BD patients aged ≥50 years. Demographics, psychiatric characteristics and psychotropic medication use were collected using self-report questionnaires and structured interviews. The presence of cardiovascular risk factors was determined by combining information from structured interviews, physical examination and laboratory assessments. Cognitive performance was investigated by an extensive neuropsychological assessment of 13 tests, covering the domains of attention, learning/ memory, verbal fluency and executive functioning. The average of 13 neuropsychological test Z-scores resulted in a composite cognitive score. A linear multiple regression model was created using forward selection with the composite cognitive score as outcome variable. Domain cognitive scores were used as secondary outcome variables. RESULTS: The final multivariable model (N = 125), which controlled for age and education level, included number of depressive episodes, number of (hypo)manic episodes, late onset, five or more psychiatric admissions, lifetime smoking, metabolic syndrome and current use of benzodiazepines. Together, these determinants explained 43.0% of the variance in composite cognitive score. Late onset and number of depressive episodes were significantly related to better cognitive performance whereas five or more psychiatric admissions and benzodiazepine use were significantly related to worse cognitive performance. CONCLUSION: Psychiatric characteristics, cardiovascular risk and benzodiazepine use are related to cognitive performance in OABD. Cognitive variability in OABD thus seems multifactorial. Strategies aimed at improving cognition in BD should include cardiovascular risk management and minimizing benzodiazepine use.

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature.

OBJECTIVE: In the last decade, repetitive transcranial magnetic stimulation (rTMS) has been introduced as a non-invasive neuromodulation therapy for depression. Little is known, however, about (serious) adverse events (AE) of rTMS in older adults with a depression. In this article, we want to study what is known about (serious) AE of rTMS in older adults (>60 years) with late-life depression (LLD). METHODS: A systematic search has been performed according to the PRISMA guidelines in PubMed, EMBase and PsycInfo. We have screened 622 articles for eligibility. Eleven studies, evaluating 353 patients in total, were included in this review. RESULTS: AE were reported in 12.4% of the older adults with a LLD treated with rTMS, serious AE in 1.5%. Headache (6.9%) and discomfort at the stimulation site (2.7%) are the most commonly reported AE. Serious AE reported are: psychiatric hospitalization (three times), a combination of posterior vitreous detachment and retinal tear, and increased suicide ideation (both once). CONCLUSIONS: rTMS in older adults with LLD was concluded overall to be safe due to the low frequency of AE reported in trials and observational studies. In case-reports, however, more serious AE have been described. To tailor use of rTMS in older adults with LLD, more research is needed in larger samples to optimize tolerance.

MMSE Changes During and After ECT in Late-Life Depression: A Prospective Study.

OBJECTIVE: There is ongoing concern about the impact of electroconvulsive therapy (ECT) on cognition in patients with late-life depression (LLD), especially in patients for whom pretreatment Mini-Mental State Exam (MMSE) scores are low. Our aim was to examine the evolution of cognitive effects of ECT, using the MMSE in a large group of patients with LLD. METHODS: One hundred nine patients aged 55 years and older with unipolar depression, referred for ECT, were included in our study. The MMSE was assessed before, during, immediately after, and 6 months after ECT. RESULTS: MMSE scores improved significantly during the course of ECT and remained stable during the 6-month period after ending ECT for the total group. In the group of patients with a low MMSE score (<24) at baseline, the MMSE score improved significantly during ECT, whereas in the group of patients with a normal MMSE score (≥24) at baseline, the score did not change significantly during ECT. In both groups, MMSE scores still increased slightly after ECT was discontinued. CONCLUSION: ECT does not cause deleterious cognitive effects, as measured with the MMSE, during and for 6 months after the ECT course in patients with LLD. In the event of a baseline cognitive impairment, MMSE scores tend to improve significantly during and for 6 months after the ECT course. The presence of pretreatment cognitive impairment should not lead clinicians to withhold ECT in older patients with severe depression.

Metabolic syndrome rates in older patients with severe mental illness after five years of follow-up and the association with mortality.

OBJECTIVES: To establish the course of metabolic syndrome (MS) rates in older patients with severe mental illness (SMI) after 5-year follow-up and evaluate whether MS at baseline is associated with mortality or diabetes at follow-up. METHODS: Patients (>60 years of age) with SMI (N = 100) were included at a specialized mental health outpatient clinic. Metabolic parameters were collected from patients' medical files at baseline and after 5-year follow-up. RESULTS: Follow-up data were available of 98 patients (98%); nine patients had died. Parameters of MS were available of 76 patients; 34.2% were diagnosed with MS. This was not significantly different compared with baseline (46.1%). MS at baseline was not significantly associated with mortality or development of diabetes at follow-up. CONCLUSIONS: In older patients with SMI, the rates of MS may reach a plateau. Screening for MS in older patients treated at a specialized mental health outpatient clinic may generate attention for their somatic health and treatment for the components of MS that may in turn have a positive effect on their outcome. However, further research with larger sample sizes is needed in order to confirm these findings.

Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study.

BACKGROUND: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. METHODS: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid ß and tau in cerebrospinal fluid/blood and neurophysiological measures. DISCUSSION: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. TRIAL REGISTRATION: Nederlands Trial Register NTR5867 . Registered 20 May 2016.

Early- and Late-Onset Depression in Late Life: A Prospective Study on Clinical and Structural Brain Characteristics and Response to Electroconvulsive Therapy.

OBJECTIVE: The clinical profile of late-life depression (LLD) is frequently associated with cognitive impairment, aging-related brain changes, and somatic comorbidity. This two-site naturalistic longitudinal study aimed to explore differences in clinical and brain characteristics and response to electroconvulsive therapy (ECT) in early- (EOD) versus late-onset (LOD) late-life depression (respectively onset <55 and ≥55 years). METHODS: Between January 2011 and December 2013, 110 patients aged 55 years and older with ECT-treated unipolar depression were included in The Mood Disorders in Elderly treated with ECT study. Clinical profile and somatic health were assessed. Magnetic resonance imaging (MRI) scans were performed before the first ECT and visually rated. RESULTS: Response rate was 78.2% and similar between the two sites but significantly higher in LOD compared with EOD (86.9 versus 67.3%). Clinical, somatic, and brain characteristics were not different between EOD and LOD. Response to ECT was associated with late age at onset and presence of psychotic symptoms and not with structural MRI characteristics. In EOD only, the odds for a higher response were associated with a shorter index episode. CONCLUSION: The clinical profile, somatic comorbidities, and brain characteristics in LLD were similar in EOD and LOD. Nevertheless, patients with LOD showed a superior response to ECT compared with patients with EOD. Our results indicate that ECT is very effective in LLD, even in vascular burdened patients.

White matter hyperintensities and cognitive impairment during electroconvulsive therapy in severely depressed elderly patients.

OBJECTIVE: Transient cognitive impairment during electroconvulsive therapy (ECT) can be a reason to discontinue ECT in depressed elderly patients. We hypothesized that both white matter hyperintensities and medial temporal lobe atrophy contribute to transient cognitive impairment during ECT. METHODS: In 81 elderly patients with depression, magnetic resonance images (MRI) were recorded before ECT. We rated white matter hyperintensities (WMH) with the Age-Related White Matter Changes scale (ARWMC). Cognitive impairment during ECT was measured weekly with the Mini Mental State Examination (MMSE), 2 days after each session. RESULTS: The mean MMSE score at baseline for all patients was 25.5 points, the lowest MMSE score during ECT was 23.3 points, and the mean MMSE score after ECT was 26.3 points. Stratification for the ECT method showed no significant difference in the lowest MMSE scores of patients with or without WMH, receiving unilateral ECT (22.5 points versus 23.9 points). There was a difference in the lowest MMSE scores in patients who switched from unilateral ECT to bilateral ECT (18.7 points in patients with WMH versus 22.0 points in patients without WMH). CONCLUSION: Depressed elderly patients with WMH who receive bilateral ECT are at increased risk of transient cognitive impairment. Our findings show, however, that cognitive impairment improves when ECT is continued. This implies that ECT does not have to be discontinued when patients experience transient cognitive impairment during ECT.

The pursuit for markers of disease progression in behavioral variant frontotemporal dementia: a scoping review to optimize outcome measures for clinical trials.

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by diverse and prominent changes in behavior and personality. One of the greatest challenges in bvFTD is to capture, measure and predict its disease progression, due to clinical, pathological and genetic heterogeneity. Availability of reliable outcome measures is pivotal for future clinical trials and disease monitoring. Detection of change should be objective, clinically meaningful and easily assessed, preferably associated with a biological process. The purpose of this scoping review is to examine the status of longitudinal studies in bvFTD, evaluate current assessment tools and propose potential progression markers. A systematic literature search (in PubMed and Embase.com) was performed. Literature on disease trajectories and longitudinal validity of frequently-used measures was organized in five domains: global functioning, behavior, (social) cognition, neuroimaging and fluid biomarkers. Evaluating current longitudinal data, we propose an adaptive battery, combining a set of sensitive clinical, neuroimaging and fluid markers, adjusted for genetic and sporadic variants, for adequate detection of disease progression in bvFTD.

Physical comorbidities of older age bipolar disorder (OABD) patients: A global replication analysis of prevalence and sex differences.

OBJECTIVES: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence. METHODS: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems. The analysis used cross-sectional data of OABD participants (n = 878; mean age 60.9 ± 8.0 years, n = 496 (56%) women) from the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset and NC participants recruited at the same sites (n = 355; mean age 64.4 ± 9.7 years, n = 215 (61%) women). RESULTS: After controlling for sex, age, education, and smoking history, the OABD group had more cardiovascular (odds ratio [95% confidence interval]: 2.12 [1.38-3.30]), renal (5.97 [1.31-43.16]), musculoskeletal (2.09 [1.30-3.43]) and endocrine (1.90 [1.20-3.05]) diseases than NC. Women with OABD had more gastrointestinal (1.56 [0.99-2.49]), genitourinary (1.72 [1.02-2.92]), musculoskeletal (2.64 [1.66-4.37]) and endocrine (1.71 [1.08-2.73]) comorbidities than men with OABD, when age, education, smoking history, and study site were controlled. CONCLUSIONS: This replication GAGE-BD study confirms previous findings indicating that OABD present more physical morbidities than matched comparison participants, and that this health burden is significantly greater among women.

Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

BrainAge of patients with severe late-life depression referred for electroconvulsive therapy.

BACKGROUND: Severe depression is associated with accelerated brain aging. BrainAge gap, the difference between predicted and observed BrainAge, was investigated in patients with late-life depression (LLD). We aimed to examine BrainAge gap in LLD and its associations with clinical characteristics indexing LLD chronicity, current severity, prior to electroconvulsive therapy (ECT) and ECT outcome. METHODS: Data was analyzed from the Mood Disorders in Elderly treated with Electroconvulsive Therapy (MODECT) study. A previously established BrainAge algorithm (BrainAge R by James Cole, (https://github.com/james-cole/brainageR)) was applied to pre-ECT T1-weighted structural MRI-scans of 42 patients who underwent ECT. RESULTS: A BrainAge gap of 1.8 years (SD = 5.5) was observed, Cohen's d = 0.3. No significant associations between BrainAge gap, number of previous episodes, current episode duration, age of onset, depression severity, psychotic symptoms or ECT outcome were observed. LIMITATIONS: Limited sample size. CONCLUSIONS: Our initial findings suggest an older BrainAge than chronological age in patients with severe LLD referred for ECT, however with high degree of variability and direction of the gap. No associations were found with clinical measures. Larger samples are needed to better understand brain aging and to evaluate the usability of BrainAge gap as potential biomarker of prognosis an treatment-response in LLD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02667353.

Urine as matrix for analysis of neurofilament light chain is not suitable to distinguish frontotemporal dementia from psychiatric diseases.

The clinical overlap of frontotemporal dementia and primary psychiatric diseases hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. Neurofilament light chain has shown great potential in CSF and blood for the distinction of frontotemporal dementia from primary psychiatric diseases. Measurement of neurofilament light chain in urine would be even more patient-friendly. We aimed to test the performance of neurofilament light chain urine measurements for diagnostics in frontotemporal dementia and to assess their correlation with serum levels. Fifty-five subjects (n = 19 frontotemporal dementia, n = 19 primary psychiatric diseases and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analysed with the ultrasensitive single molecule array neurofilament light chain assay. Neurofilament light chain group comparisons were performed adjusted for age, sex and geriatric depression scale. In the majority of the cohort, neurofilament light chain concentrations were not detectable in urine (n = 6 samples above lower limit of detection (0.038 pg/ml): n = 5 frontotemporal dementia, n = 1 primary psychiatric disease). The frequency of a detectable neurofilament light chain level in urine in the frontotemporal dementia group did not differ from psychiatric disorders (Fisher Exact-test P = 0.180). In the individuals with detectable urine neurofilament light chain values, there was no correlation between the urine and serum neurofilament light chain levels. As expected, serum neurofilament light chain levels were higher in frontotemporal dementia compared to primary psychiatric diseases and controls (P < 0.001), adjusted for age, sex and geriatric depression scale. Receiver operating characteristic curve analysis of serum neurofilament light chain of frontotemporal dementia versus primary psychiatric diseases showed an area under the curve of 0.978 95% confidence interval 0.941-1.000, P < 0.001. Urine is not suitable as a matrix for neurofilament light chain analysis and serum neurofilament light chain is still the most patient-friendly matrix for differentiation between frontotemporal dementia and primary psychiatric diseases.

Electroconvulsive therapy is associated with increased immunoreactivity of neuroplasticity markers in the hippocampus of depressed patients.

Electroconvulsive therapy (ECT) is an effective therapy for depression, but its cellular effects on the human brain remain elusive. In rodents, electroconvulsive shocks increase proliferation and the expression of plasticity markers in the hippocampal dentate gyrus (DG), suggesting increased neurogenesis. Furthermore, MRI studies in depressed patients have demonstrated increases in DG volume after ECT, that were notably paralleled by a decrease in depressive mood scores. Whether ECT also triggers cellular plasticity, inflammation or possibly injury in the human hippocampus, was unknown. We here performed a first explorative, anatomical study on the human post-mortem hippocampus of a unique, well-documented cohort of bipolar or unipolar depressed patients, who had received ECT in the 5 years prior to their death. They were compared to age-matched patients with a depressive disorder who had not received ECT and to matched healthy controls. Upon histopathological examination, no indications were observed for major hippocampal cell loss, overt cytoarchitectural changes or classic neuropathology in these 3 groups, nor were obvious differences present in inflammatory markers for astrocytes or microglia. Whereas the numbers of proliferating cells expressing Ki-67 was not different, we found a significantly higher percentage of cells positive for Doublecortin, a marker commonly used for young neurons and cellular plasticity, in the subgranular zone and CA4 / hilus of the hippocampus of ECT patients. Also, the percentage of positive Stathmin 1 cells was significantly higher in the subgranular zone of ECT patients, indicating neuroplasticity. These first post-mortem observations suggest that ECT has no damaging effects but may rather have induced neuroplasticity in the DG of depressed patients.

Altered brain metabolism in frontotemporal dementia and psychiatric disorders: involvement of the anterior cingulate cortex.

BACKGROUND: Behavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning. RESULTS: Compared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca's area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001). CONCLUSIONS: Our findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.