Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker

PURPOSE: TSPO PET imaging may hold promise as a single-step diagnostic work-up for clinical immunopsychiatry. This review paper on the clinical applicability of TSPO PET for primary psychiatric disorders discusses if and why TSPO PET imaging might become the first clinical immunopsychiatry biomarker and the investment prerequisites and scientific advancements needed to accommodate this transition from bench to bedside. METHODS: We conducted a systematic search of the literature to identify clinical studies of TSPO PET imaging in patients with primary psychiatric disorders. We included both original case-control studies as well as longitudinal cohort studies of patients with a primary psychiatric diagnosis. RESULTS: Thirty-one original studies met our inclusion criteria. In the field of immunopsychiatry, TSPO PET has until now mostly been studied in schizophrenia and related psychotic disorders, and to a lesser extent in mood disorders and neurodevelopmental disorders. Quantitative TSPO PET appears most promising as a predictive biomarker for the transdiagnostic identification of subgroups or disease stages that could benefit from immunological treatments, or as a prognostic biomarker forecasting patients' illness course. Current scanning protocols are still too unreliable, impractical and invasive for clinical use in symptomatic psychiatric patients. CONCLUSION: TSPO PET imaging in its present form does not yet offer a sufficiently attractive cost-benefit ratio to become a clinical immunopsychiatry biomarker. Its translation to psychiatric clinical practice will depend on the prioritising of longitudinal research and the establishment of a uniform protocol rendering clinically meaningful TSPO uptake quantification at the shortest possible scan duration without arterial cannulation

Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review

ObjectiveSchizophrenia poses a tremendous health, social, and economic burden upon patients and society, indicating current treatment options remain inadequate. Recent findings from several lines of evidence have pointed to the importance of immune system involvement in not only premorbid neurodevelopmental but also subsequent symptom generation and aging processes of brain change in schizophrenia. In this meta-review, we use the summarized evidence from recent quantitative systematic reviews (SRs) and meta-analyses of several subspecialties to critically evaluate the hypothesis that immune-related processes shape the symptomatic presentation and illness course of schizophrenia, both directly and indirectly through altered neuroplasticity.MethodsWe performed a data search in PubMed for English language SRs and meta-analyses from 2010 to 2017. The methodological quality of the SRs was assessed with the AMSTAR instrument. In addition, we review in this paper 11 original publications on translocator protein (TSPO) positron emission tomography (PET) imaging in schizophrenia.ResultsWe reviewed 26 SRs and meta-analyses. Evidence from clinical observational studies of inflammatory or immunological markers and randomized controlled drug trials of immunomodulatory compounds as add-on in the treatment of schizophrenia suggests psychotic exacerbations are accompanied by immunological changes different from those seen in non-acute states, and that the symptoms of schizophrenia can be modified by compounds such as non-steroidal anti-inflammatory drug and minocycline. Information derived from post-mortem brain tissue analysis and PET neuroimaging studies to evaluate microglial activation have added new perspectives to the available evidence, yet these results are very heterogeneous. Each research domain comes with unique opportunities as well as inherent limitations. A better understanding of the (patho-)physiology of microglial cells and their role in neuroplasticity is key to interpreting the immune-related findings in the context of schizophrenia illness exacerbations and progression.ConclusionEvidence from clinical studies analyzing patients’ blood and cerebrospinal fluid samples, neuroimaging and post-mortem brain tissue suggests that aberrant immune responses may define schizophrenia illness’ course through altered neuroplasticity representing abnormal aging processes. Most findings are however prone to bias and confounding, and often non-specific to schizophrenia, and a multidisciplinary translational approach is needed to consolidate these findings and link them to other schizophrenia hypotheses

Microglia and brain plasticity in acute psychosis and schizophrenia illness course: a meta-review

OBJECTIVE: Schizophrenia poses a tremendous health, social, and economic burden upon patients and society, indicating current treatment options remain inadequate. Recent findings from several lines of evidence have pointed to the importance of immune system involvement in not only premorbid neurodevelopmental, but also subsequent symptom generation and ageing processes of brain change in schizophrenia. In this meta-review, we use the summarized evidence from recent quantitative systematic reviews and meta-analyses of several subspecialties to critically evaluate the hypothesis that immune-related processes shape the symptomatic presentation and illness course of schizophrenia, both directly and indirectly through altered neuroplasticity.METHODS: We performed a data search in PubMed for English-language systematic reviews and meta-analyses from 2010 to 2017. The methodological quality of the systematic reviews was assessed with the AMSTAR instrument. In addition, we review in this paper 11 original publications on TSPO PET imaging in schizophrenia.RESULTS: We reviewed 26 systematic reviews and meta-analyses. Evidence from clinical observational studies of inflammatory or immunological markers and randomized controlled drug trials of immunomodulatory compounds as add-on in the treatment of schizophrenia suggests psychotic exacerbations are accompanied by immunological changes different from those seen in non-acute states, and that the symptoms of schizophrenia can be modified by compounds such as NSAID and minocycline. Information derived from post-mortem brain tissue analysis and PET neuroimaging studies to evaluate microglial activation have added new perspectives to the available evidence, yet these results are very heterogeneous. Each research domain comes with unique opportunities as well as inherent limitations. A better understanding of the (patho-)physiology of microglial cells and their role in neuroplasticity is key to interpreting the immune-related findings in the context of schizophrenia illness exacerbations and progression.CONCLUSIONS: Evidence from clinical studies analyzing patients’ blood and cerebrospinal fluid samples, neuroimaging and post-mortem brain tissue suggests that aberrant immune responses may define schizophrenia illness’ course through altered neuroplasticity representing abnormal ageing processes. Most findings are however prone to bias and confounding, and often nonspecific to schizophrenia, and a multidisciplinary translational approach is needed to consolidate these findings and link them to other schizophrenia hypotheses

Stable schizophrenia patients learn equally well as age-matched controls and better than elderly controls in two sensorimotor Rotary Pursuit tasks

Objective: To compare sensorimotor performance and learning in stable schizophrenia patients, healthy age- and sex-matched controls and elderly controls on two variations of the Rotary Pursuit: Circle Pursuit (true motor learning) and Figure Pursuit (motor and sequence learning).Method: In the Circle Pursuit a target circle, rotating with increasing speed along a predictable circular path on the computer screen, must be followed by a cursor controlled by a pen on a writing tablet. In the eight-trial Figure Pursuit, subjects learn to draw a complex figure by pursuing the target circle that moves along an invisible trajectory between and around several goals. Tasks were administered thrice (day 1, day 2, day 7) to 30 patients with stable schizophrenia (S), 30 healthy age- and sex-matched controls (C) and 30 elderly participants (>65y; E) and recorded with a digitizing tablet and pressure-sensitive pen. The outcome measure accuracy (% of time that cursor is within the target) was used to assess performance.Results: We observed significant group differences in accuracy, both in Circle and Figure Pursuit tasks (E<S<C, p<0.01). Strong learning effects were found in each group. Learning curves were similar in Circle Pursuit but differed between groups in Figure Pursuit. When corrected for group differences in starting level, the learning gains over the three sessions of schizophrenia patients and age-matched controls were equal and both were larger than those of the elderly controls. Conclusion: Despite the reduced sensorimotor performance that was found in the schizophrenia patients their sensorimotor learning seems to be preserved. The relevance of this finding for the evaluation of procedural learning in schizophrenia is discussed. The better performance and learning rate of the patients compared to the elderly controls was unexpected and deserves further study

Implicit motor sequence learning in schizophrenia and in old age: reduced performance only in the third session

Although there still is conflicting evidence whether schizophrenia is a neurodegenerative disease, cognitive changes in schizophrenia resemble those observed during normal aging. In contrast to extensively demonstrated deficits in explicit learning, it remains unclear whether implicit sequence learning is impaired in schizophrenia and normal aging. Implicit sequence learning was investigated using a computerized drawing task, the 'implicit pattern learning task (IPLT)' in 30 stable patients with schizophrenia, 30 age-matched controls and 30 elderly subjects on two consecutive days and after 1 week (sessions 1, 2 and 3). Fixed sequence trials were intermixed with random trials, and sequence learning was assessed by subtraction of the response time in fixed sequence trials from random trials. Separate analyses of response times and movement accuracy (i.e., directional errors) were performed. Explicit sequence knowledge was assessed using three different awareness tasks. All groups learned equally during sessions 1 and 2. In session 3, control subjects showed significantly larger learning scores than patients with schizophrenia (p = .012) and elderly subjects (p = .021). This group difference is mainly expressed in movement time and directional errors. Patients with schizophrenia demonstrated less subjective sequence awareness, and both patients with schizophrenia and elderly subjects had less explicit sequence recall. Explicit recall was positively correlated with task performance in all groups. After a short 24 h interval, all subjects showed similar improvements in implicit sequence learning. However, no benefit of prior task exposure 1 week later was observed in patients with schizophrenia and elderly subjects compared to controls. As patients with schizophrenia and elderly both display less explicit sequence recall, the control group superiority after 1 week could be explained by an explicit learning component. The few patients with schizophrenia and elderly subjects who had some sequence recall could possibly utilize this explicit knowledge to improve their task performance but did this by distinct mechanism

TSPO PET brain inflammation imaging: a transdiagnostic systematic review and meta-analysis of 156 case-control studies

Introduction: The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity.Methods: we searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P &lt; 0.05.Results: 156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR &lt; 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer’s disease (SMD = 0.693, PFDR &lt; 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR &lt; 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P &lt; 0.001, I2 = 67%) were most prominent for Alzheimer’s disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P &lt; 0.001, I2 = 71%) was observed for Alzheimer’s disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR &lt; 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P &lt; 0.001), patient age (9% of variance), and radioligand generation (5% of variance).Conclusion: this study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method