RESUMO
BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. RESULTS: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. CONCLUSION: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
Assuntos
Doença de Alzheimer , Encéfalo , Disfunção Cognitiva , Microglia , Animais , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Disfunção Cognitiva/metabolismo , Humanos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Tomografia por Emissão de Pósitrons , Receptores de GABA/metabolismo , Masculino , Camundongos Transgênicos , Conectoma/métodos , FemininoRESUMO
GRT-X, which targets both the mitochondrial translocator protein (TSPO) and the Kv7.2/3 (KCNQ2/3) potassium channels, has been shown to efficiently promote recovery from cervical spine injury. In the present work, we investigate the role of GRT-X and its two targets in the axonal growth of dorsal root ganglion (DRG) neurons. Neurite outgrowth was quantified in DRG explant cultures prepared from wild-type C57BL6/J and TSPO-KO mice. TSPO was pharmacologically targeted with the agonist XBD173 and the Kv7 channels with the activator ICA-27243 and the inhibitor XE991. GRT-X efficiently stimulated DRG axonal growth at 4 and 8 days after its single administration. XBD173 also promoted axonal elongation, but only after 8 days and its repeated administration. In contrast, both ICA27243 and XE991 tended to decrease axonal elongation. In dissociated DRG neuron/Schwann cell co-cultures, GRT-X upregulated the expression of genes associated with axonal growth and myelination. In the TSPO-KO DRG cultures, the stimulatory effect of GRT-X on axonal growth was completely lost. However, GRT-X and XBD173 activated neuronal and Schwann cell gene expression after TSPO knockout, indicating the presence of additional targets warranting further investigation. These findings uncover a key role of the dual mode of action of GRT-X in the axonal elongation of DRG neurons.
Assuntos
Axônios , Gânglios Espinais , Receptores de GABA , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/citologia , Camundongos , Axônios/metabolismo , Receptores de GABA/metabolismo , Receptores de GABA/genética , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ2/genética , Camundongos Knockout , Camundongos Endogâmicos C57BL , Células Cultivadas , Células de Schwann/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/citologia , Técnicas de Cocultura , Neurônios/metabolismo , Neurônios/efeitos dos fármacosRESUMO
BACKGROUND: Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. OBJECTIVE: We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. METHODS: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. RESULTS: In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (ß = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (ß = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. CONCLUSIONS: Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMO
Recently, the gamma-aminobutyric acid (GABA) system has come into focus for the treatment of anxiety, postpartum depression, and major depressive disorder. Endogenous 3α-reduced steroids such as allopregnanolone are potent positive allosteric modulators of GABAA receptors and have been known for decades. Current industry developments and first approvals by the U.S. food and drug administration (FDA) for the treatment of postpartum depression with exogenous analogues of these steroids represent a major step forward in the field. 3α-reduced steroids target both synaptic and extrasynaptic GABAA receptors, unlike benzodiazepines, which bind to synaptic receptors. The first FDA-approved 3α-reduced steroid for postpartum depression is brexanolone, an intravenous formulation of allopregnanolone. It has been shown to provide rapid relief of depressive symptoms. An orally available 3α-reduced steroid is zuranolone, which also received FDA approval in 2023 for the treatment of postpartum depression. Although a number of studies have been conducted, the efficacy data were not sufficient to achieve approval of zuranolone in major depressive disorder by the FDA in 2023. The most prominent side effects of these 3α-reduced steroids are somnolence, dizziness and headache. In addition to the issue of efficacy, it should be noted that current data limit the use of these compounds to two weeks. An alternative to exogenous 3α-reduced steroids may be the use of substances that induce endogenous neurosteroidogenesis, such as the translocator protein 18 kDa (TSPO) ligand etifoxine. TSPO has been extensively studied for its role in steroidogenesis, in addition to other functions such as anti-inflammatory and neuroregenerative properties. Currently, etifoxine is the only clinically available TSPO ligand in France for the treatment of anxiety disorders. Studies are underway to evaluate its antidepressant potential. Hopefully, neurosteroid research will lead to the development of fast-acting antidepressants.
RESUMO
Securing an accurate autism-spectrum-condition diagnosis, particularly among women, remains challenging for autistic adults. Building upon previous research highlighting the short-story task (SST) as a promising tool for detecting fiction-based mentalizing difficulties in autistic adults, this study expands its scope. We investigated the SST's discriminative capacity across three distinct groups: autistic individuals (n = 32), nonautistic individuals without mental health problems (n = 32), and nonautistic individuals with clinical depression (n = 30). All three groups differed significantly from each other in their SST mentalizing score with the nonautistic group having the highest scores, the nonautistic but depressed group having medium scores and the autistic group showing the lowest scores. Receiver operator curve (ROC) analysis reaffirmed the SST's efficacy as a discriminator. Moreover, a linear regression analysis identified the SST mentalizing score, the SST comprehension score, and the number of books read per month as significant predictors of autism-spectrum-condition diagnosis. These findings bolster the SST's potential as a valuable adjunct in autism diagnostics, highlighting its discriminatory ability across diverse samples.
RESUMO
TSPO ligands are promising alternatives to benzodiazepines in the treatment of anxiety, as they display less pronounced side effects such as sedation, cognitive impairment, tolerance development and abuse potential. In a randomized double-blind repeated-measures study we compare a benzodiazepine (alprazolam) to a TSPO ligand (etifoxine) by assessing side effects and acquiring resting-state fMRI data from 34 healthy participants after 5 days of taking alprazolam, etifoxine or a placebo. To study the effects of the pharmacological interventions in fMRI in detail and across different scales, we combine in our study complementary analysis strategies related to whole-brain functional network connectivity, local connectivity analysis expressed in regional homogeneity, fluctuations in low-frequency BOLD amplitudes and coherency of independent resting-state networks. Participants reported considerable adverse effects such as fatigue, sleepiness and concentration impairments, related to the administration of alprazolam compared to placebo. In resting-state fMRI we found a significant decrease in functional connection density, network efficiency and a decrease in the networks rich-club coefficient related to alprazolam. While observing a general decrease in regional homogeneity in high-level brain networks in the alprazolam condition, we simultaneously could detect an increase in regional homogeneity and resting-state network coherence in low-level sensory regions. Further we found a general increase in the low-frequency compartment of the BOLD signal. In the etifoxine condition, participants did not report any significant side effects compared to the placebo, and we did not observe any corresponding modulations in our fMRI metrics. Our results are consistent with the idea that sedation globally disconnects low-level functional networks, but simultaneously increases their within-connectivity. Further, our results point towards the potential of TSPO ligands in the treatment of anxiety and depression.
Assuntos
Alprazolam , Encéfalo , Imageamento por Ressonância Magnética , Humanos , Alprazolam/farmacologia , Alprazolam/administração & dosagem , Masculino , Adulto , Feminino , Método Duplo-Cego , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Adulto Jovem , Oxazinas/farmacologia , Ansiolíticos/farmacologia , Hipnóticos e Sedativos/farmacologia , DescansoRESUMO
BACKGROUND: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. METHODS: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. DISCUSSION: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. TRIAL REGISTRATION: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).
Assuntos
Antidepressivos , Oxazinas , Estudo de Prova de Conceito , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Método Duplo-Cego , Ligantes , Oxazinas/uso terapêutico , Receptores de GABA/metabolismo , Resultado do TratamentoRESUMO
Depression's link to serotonin dysregulation is well-known. The monoamine theory posits that depression results from impaired serotonin activity, leading to the development of antidepressants targeting serotonin levels. However, their limited efficacy suggests a more complex cause. Recent studies highlight mitochondria as key players in depression's pathophysiology. Mounting evidence indicates that mitochondrial dysfunction significantly correlates with major depressive disorder (MDD), underscoring its pivotal role in depression. Exploring the serotonin-mitochondrial connection, our study investigated the effects of chronic serotonin treatment on induced-pluripotent stem cell-derived astrocytes and neurons from healthy controls and two case study patients. One was a patient with antidepressant non-responding MDD ("Non-R") and another had a non-genetic mitochondrial disorder ("Mito"). The results revealed that serotonin altered the expression of genes related to mitochondrial function and dynamics in neurons and had an equalizing effect on calcium homeostasis in astrocytes, while ATP levels seemed increased. Serotonin significantly decreased cytosolic and mitochondrial calcium in neurons. Electrophysiological measurements evidenced that serotonin depolarized the resting membrane potential, increased both sodium and potassium current density and ultimately improved the overall excitability of neurons. Specifically, neurons from the Non-R patient appeared responsive to serotonin in vitro, which seemed to improve neurotransmission. While it is unclear how this translates to the systemic level and AD resistance mechanisms are not fully elucidated, our observations show that despite his treatment resistance, this patient's cortical neurons are responsive to serotonergic signals. In the Mito patient, evidence suggested that serotonin, by increasing excitability, exacerbated an existing hyperexcitability highlighting the importance of considering mitochondrial disorders in patients with MDD, and avoiding serotonin-increasing medication. Taken together, our findings suggested that serotonin positively affects calcium homeostasis in astrocytes and increases neuronal excitability. The latter effect must be considered carefully, as it could have beneficial or detrimental implications based on individual pathologies.
Assuntos
Astrócitos , Cálcio , Transtorno Depressivo Maior , Células-Tronco Pluripotentes Induzidas , Mitocôndrias , Neurônios , Serotonina , Humanos , Serotonina/metabolismo , Serotonina/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transtorno Depressivo Maior/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Cálcio/metabolismo , Adulto , Masculino , Feminino , Depressão/metabolismo , Antidepressivos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Pessoa de Meia-IdadeRESUMO
The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
Assuntos
Caricaceae , Transtorno Depressivo Maior , Humanos , Astrócitos , Depressão , Mitocôndrias , Neurônios , Fibroblastos , MitomicinaRESUMO
BACKGROUND AND OBJECTIVES: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between ß-amyloid-accumulation and microglial activation in AD. METHODS: 49 patients with AD (29 females, all Aß-positive) and 15 Aß-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and ß-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aß-PET on TSPO-PET was used to determine the Aß-plaque-dependent microglial response (slope) and the Aß-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). RESULTS: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aß-PET z-scores were similar. The Aß-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aß-plaque-dependent microglial response was not different between sexes. The Aß-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aß-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005). CONCLUSION: While microglia response to fibrillar Aß is similar between sexes, women with AD show a stronger Aß-plaque-independent microglia response. This sex difference in Aß-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aß-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.
Assuntos
Doença de Alzheimer , Microglia , Humanos , Feminino , Masculino , Índice de Massa Corporal , Doenças Neuroinflamatórias , Peptídeos beta-Amiloides , Obesidade , Receptores de GABARESUMO
BACKGROUND AND OBJECTIVES: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in ß-amyloid (Aß)-negative CBS. METHODS: We included patients with clinically diagnosed Aß-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). RESULTS: Overall, 21 patients with Aß-negative CBS with â¼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. DISCUSSION: [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aß-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.
Assuntos
Degeneração Corticobasal , Doenças Neurodegenerativas , Tauopatias , Humanos , Filamentos Intermediários , Peptídeos beta-Amiloides , Biomarcadores , Progressão da Doença , Receptores de GABARESUMO
Background: Neurosteroids have recently gained in interest as a treatment strategy for affective disorders. Etifoxine is known for its dual mode of action, one of which is to stimulate endogenous neurosteroid synthesis. The gut microbiome has been studied in affective disorders, but it has not been investigated in the context of human etifoxine or neurosteroid interventions. Methods: We performed a crossover study with 36 healthy male volunteers who received etifoxine versus alprazolam and placebo in a balanced Williams design. Participants were randomized into six sequences and went through three 5-day treatments followed by wash-out phases of 9 days. Bacterial compositions in stool samples were determined by high-throughput 16S rRNA amplicon sequencing. Results: Gut microbiome analyses revealed no relevant effects between treatments with respect to alpha and beta diversity. Differential abundance analyses yielded etifoxine treatment as the only effect related to changes in microbial features with reductions of Faecalibacterium duncaniae, Roseburia hominis and Lactobacillus rogosae (i.e., Bacteroides galacturonicus). Conclusion: Here we report on the first human investigation of the gut microbiome with short-term etifoxine intervention. Differences in diversity and compositional structure of the microbiome were more likely due to between- subject effects rather than medication. However, five-day treatment with etifoxine reduced the abundance of a few bacterial species. These species are currently seen as beneficial components of a healthy intestinal microbiome. This reduction in abundances may be related to elevated endogenous neurosteroids.
RESUMO
INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.
Assuntos
COVID-19 , Humanos , Tratamento Farmacológico da COVID-19 , Prevalência , Psicotrópicos/uso terapêutico , SARS-CoV-2 , Estudos RetrospectivosRESUMO
Alzheimer's disease (AD) is characterized by the accumulation of ß-amyloid peptide (Aß). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aß on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAß). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAß) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aß levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.
Assuntos
Doença de Alzheimer , Doenças do Sistema Nervoso , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Receptores de GABA/metabolismo , Camundongos Transgênicos , Proteínas de Transporte , Peptídeos beta-Amiloides/metabolismo , Ligantes , Cognição , Modelos Animais de DoençasRESUMO
TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing.We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages.In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.
Assuntos
Glioblastoma , Glioma , Células-Tronco Mesenquimais , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Macrófagos Associados a Tumor , Macrófagos , Receptores de GABA/genéticaRESUMO
The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Pessoa de Meia-Idade , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/radioterapia , Prognóstico , Isocitrato Desidrogenase/genética , Temozolomida/uso terapêutico , Tomografia por Emissão de Pósitrons , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Receptores de GABA/genéticaRESUMO
ß-amyloid (Aß) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aß-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aß (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aß (AD: ßT = 0.412 ± 0.196 vs. ßA = 0.142 ± 0.123, p < 0.001; AD-CBS: ßT = 0.385 ± 0.176 vs. ßA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (ßT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aß related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Microglia/patologia , Doenças Neuroinflamatórias , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Atrofia/patologia , Biomarcadores , Proteínas tau , Receptores de GABARESUMO
Background: Anxiety and depressive disorders share common features of mood dysfunctions. This has stimulated interest in transdiagnostic dimensional research as proposed by the Research Domain Criteria (RDoC) approach by the National Institute of Mental Health (NIMH) aiming to improve the understanding of underlying disease mechanisms. The purpose of this study was to investigate the processing of RDoC domains in relation to disease severity in order to identify latent disorder-specific as well as transdiagnostic indicators of disease severity in patients with anxiety and depressive disorders. Methods: Within the German research network for mental disorders, 895 participants (n = 476 female, n = 602 anxiety disorder, n = 257 depressive disorder) were recruited for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) and included in this cross-sectional study. We performed incremental regression models to investigate the association of four RDoC domains on disease severity in patients with affective disorders: Positive (PVS) and Negative Valance System (NVS), Cognitive Systems (CS) and Social Processes (SP). Results: The results confirmed a transdiagnostic relationship for all four domains, as we found significant main effects on disease severity within domain-specific models (PVS: ß = -0.35; NVS: ß = 0.39; CS: ß = -0.12; SP: ß = -0.32). We also found three significant interaction effects with main diagnosis showing a disease-specific association. Limitations: The cross-sectional study design prevents causal conclusions. Further limitations include possible outliers and heteroskedasticity in all regression models which we appropriately controlled for. Conclusion: Our key results show that symptom burden in anxiety and depressive disorders is associated with latent RDoC indicators in transdiagnostic and disease-specific ways.
RESUMO
INTRODUCTION: There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine. METHODS: To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). RESULTS: We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters. DISCUSSION: This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam.