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

Six-year trajectories of core depressive symptoms and insomnia symptoms in depressed older adults:a NESDO study

OBJECTIVES: This study aimed to identify trajectories of core depressive symptoms and insomnia symptoms in depressed older adults, their prevalence and association, and predictors of unfavorable trajectories.METHOD: We examined 6-year follow-up data of 329 depressed older adults from the Netherlands Study of Depression in Older persons. Core depressive symptoms and insomnia symptoms were assessed with the Inventory of Depressive Symptomatology. We applied growth mixture modeling to identify classes of participants with similar trajectories of core depressive symptoms and insomnia symptoms. The association between core depressive and insomnia symptom trajectories and predictors of these trajectories were examined.RESULTS: We identified three core depressive symptom trajectories: low and declining (40.4%), moderate and declining (37.4%), and high and stable (22.2%); and four insomnia symptom trajectories: moderate and declining (13.7%), low and increasing (7.6%), moderate and stable (55.6%), and high and stable (23.1%). Participants with favorable core depressive symptom trajectories often had unfavorable insomnia symptom trajectories. Older age, chronic diseases, and functional limitations predicted unfavorable core depressive symptom trajectories. Functional limitations predicted unfavorable insomnia symptom trajectories.CONCLUSION: Trajectories of core depressive and insomnia symptoms in depressed older adults were partly associated, but insomnia symptoms often persisted despite improving core depressive symptoms, highlighting the importance of different targeted interventions.</p

BrainFit: improving executive and subjective cognitive functioning in late-life mood disorders - a double-blind randomized active-controlled study evaluating the effect of online cognitive training

Introduction: Unipolar and bipolar mood disorders in older adults are accompanied by cognitive impairment, including executive dysfunction, with a severe impact on daily life. Up and till now, strategies to improve cognitive functioning in late-life mood disorders (LLMD) are sparse. Therefore, we aimed to assess the efficacy of adaptive, computerized cognitive training (CT) on executive and subjective cognitive functioning in LLMD. Methods: In this double-blind, randomized controlled study we enrolled patients over the age of 50 with partly remitted LLMD. Over 8 weeks, patients participated in 24 45-minute sessions of computerized multi-domain training (CT) or an active control condition (ACC) (nonspecific cognitive activity). The primary outcome was executive functioning based on the interference score on the STROOP task (not incorporated in the training). Secondary outcomes were subjective cognitive functioning, depressive symptoms and quality of life. Outcomes were assessed before and after training (T1) and at a 3-month follow-up (T2) and analyzed with linear mixed-model analyses. Results: Thirty-eight patients were included in the study, 22 in the experimental CT and 16 in the ACC. Mean age was 67.3 years and 52.6% was female. Linear mixed-model analyses showed small within-group effect sizes, corresponding to no statistically significant improvement of executive functioning or depression severity in either group. In both groups we did observe an improvement on subjective cognitive functioning over time. From T0 to T1 the mean score of the Cognitive Functioning Questionnaire (CFQ) of the CT group decreased from 52.7 to 46.8 points (p=0.003) and the mean CFQ score of the ACC group decreased from 52.7 to 45.7 points (p<0.001). This effect remained in both groups at follow-up (T2); respectively p=0.002 and p<0.001.The patients in the AAC also showed an improvement of quality of life directly after the training (T1); i.e. the mean quality of life scores improved from 53 to 57 points (p=0.011), but this effect did not remain at follow-up. Conclusions: This study shows no beneficial effect of an 8-week computerized CT on the primary outcome, i.e, executive functioning. Subjective cognitive functioning did improve in both groups, indicating that frequent cognitive training is advantageous. Future studies with more intensive training could be designed to explore this result further. Clinical trial registration: clinicaltrials.gov, identifier NCT04006756

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

Musicality and social cognition in dementia: clinical and anatomical associations

Human musicality might have co-evolved with social cognition abilities, but common neuroanatomical substrates remain largely unclear. In behavioural variant frontotemporal dementia, social cognitive abilities are profoundly impaired, whereas these are typically spared in Alzheimer's disease. If musicality indeed shares a neuroanatomical basis with social cognition, it could be hypothesized that clinical and neuroanatomical associations of musicality and social cognition should differ between these causes of dementia. We recruited 73 participants from the Amsterdam Dementia Cohort (n = 30 female; aged 50-78), of whom 23 had behavioural variant frontotemporal dementia, 22 Alzheimer's disease and 28 were healthy controls. Musicality was assessed using a music-emotion recognition test, melody, tempo, accent and tuning subscores, a musicality summed score, the identification of auditory hedonic phenotypes and music emotion induction using skin conductance responses. Social cognition was assessed across multiple levels, including emotion recognition, theory of mind, socio-emotional sensitivity and understanding of social norms. We used ANCOVA to investigate subgroup differences in musicality and social cognition and linear regressions to investigate associations between musicality and social cognition. All analyses were adjusted for age, sex, musical training and mini mental state examination. Finally, we performed voxel-based morphometry analyses on T1-weighted MRI to study whether regions for musicality and social cognition overlapped anatomically. We found that patients with behavioural variant frontotemporal dementia performed worse on music-emotion recognition (all P < 0.001) and tempo recognition (all P < 0.05) compared with Alzheimer's disease and on musicality summed score (all P = 0.02) compared to controls only. Furthermore, patients with behavioural variant frontotemporal dementia had lower mean skin conductance responses during emotion-inducing music, compared to Alzheimer's disease (all P < 0.045). Worse music emotion recognition scores were associated with worse facial emotion recognition (P < 0.0001), worse theory of mind (P = 0.0005) and worse understanding of social norms (P = 0.01). Melody and tempo recognition were associated with facial emotion recognition and theory of mind, and accent recognition was associated with the theory of mind. Music emotion recognition and tempo recognition were also associated with executive functions. Worse music emotion recognition, melody recognition, tempo recognition, facial emotion recognition and theory of mind scores were all related to atrophy in the anterior temporal regions and the fusiform gyri, which play a role in multisensory integration, and worse tempo recognition was associated with atrophy of the anterior cingulate cortex. These results support the idea that musicality and social cognition may share a neurobiological basis, which may be vulnerable in behavioural variant frontotemporal dementia

Musicality and social cognition in dementia:clinical and anatomical associations

Human musicality might have co-evolved with social cognition abilities, but common neuroanatomical substrates remain largely unclear. In behavioural variant frontotemporal dementia, social cognitive abilities are profoundly impaired, whereas these are typically spared in Alzheimer’s disease. If musicality indeed shares a neuroanatomical basis with social cognition, it could be hypothesized that clinical and neuroanatomical associations of musicality and social cognition should differ between these causes of dementia. We recruited 73 participants from the Amsterdam Dementia Cohort (n = 30 female; aged 50–78), of whom 23 had behavioural variant frontotemporal dementia, 22 Alzheimer’s disease and 28 were healthy controls. Musicality was assessed using a music–emotion recognition test, melody, tempo, accent and tuning subscores, a musicality summed score, the identification of auditory hedonic phenotypes and music emotion induction using skin conductance responses. Social cognition was assessed across multiple levels, including emotion recognition, theory of mind, socio-emotional sensitivity and understanding of social norms. We used ANCOVA to investigate subgroup differences in musicality and social cognition and linear regressions to investigate associations between musicality and social cognition. All analyses were adjusted for age, sex, musical training and mini mental state examination. Finally, we performed voxel-based morphometry analyses on T1-weighted MRI to study whether regions for musicality and social cognition overlapped anatomically. We found that patients with behavioural variant frontotemporal dementia performed worse on music–emotion recognition (all P &lt; 0.001) and tempo recognition (all P &lt; 0.05) compared with Alzheimer’s disease and on musicality summed score (all P = 0.02) compared to controls only. Furthermore, patients with behavioural variant frontotemporal dementia had lower mean skin conductance responses during emotion-inducing music, compared to Alzheimer’s disease (all P &lt; 0.045). Worse music emotion recognition scores were associated with worse facial emotion recognition (P &lt; 0.0001), worse theory of mind (P = 0.0005) and worse understanding of social norms (P = 0.01). Melody and tempo recognition were associated with facial emotion recognition and theory of mind, and accent recognition was associated with the theory of mind. Music emotion recognition and tempo recognition were also associated with executive functions. Worse music emotion recognition, melody recognition, tempo recognition, facial emotion recognition and theory of mind scores were all related to atrophy in the anterior temporal regions and the fusiform gyri, which play a role in multisensory integration, and worse tempo recognition was associated with atrophy of the anterior cingulate cortex. These results support the idea that musicality and social cognition may share a neurobiological basis, which may be vulnerable in behavioural variant frontotemporal dementia.</p

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

Electric field causes volumetric changes in the human brain

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

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. Methods: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R 2) at the optimal p-value threshold is reported. Results: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R 2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R 2 = 8.18%, p = .0013), Belgium (R 2 = 6.83%, p = .016), and the Netherlands (R 2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R 2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R 2 = 4.42%, p = .0024) and unipolar MDE only (R 2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. Conclusions: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry

Volume of the human hippocampus and clinical response following electroconvulsive therapy

BACKGROUND: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome. METHODS: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice. RESULTS: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 +/- 2.2%, d = 1.5; right unilateral, 1.6 +/- 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 +/- 1.7%, d = 1.8; right unilateral, 2.7 +/- 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Asberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069). CONCLUSIONS: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome