Psychiatric disorders are currently classified, in the majority of cases, by clinical syndromes. However, advances over the last decade in imaging and biochemical biomarkers in several Central ...Nervous System (CNS) disorders anticipate the incorporation of some of these markers in the diagnostic work-up of psychiatric conditions. In particular, CSF biomarkers offer the possibility of detecting a wide range of pathophysiological processes in the CNS. Newer CSF markers can measure axonal and synaptic damage, glial activation, and oxidative stress in CNS disorders with high precision. The possibility that these markers can be applied in the differential diagnosis of common psychiatric disorders such as Schizophrenia, Major Depressive or Bipolar Disorders not only to rule out neurodegenerative diseases but also to identify specific biomarker signatures has yet to be explored. In particular, synaptic proteins in CSF could be useful as markers of synaptic and neurotransmitter transmission impairment since these are key molecular features of psychiatric conditions. In this paper we outline the current and potential applications of CSF biomarkers in psychiatric disorders.
•CSF biomarkers offer the possibility of detecting a wide range of pathophysiological processes in the CNS.•Newer CSF markers can measure axonal and synaptic damage, glial activation, and oxidative stress in CNS disorders.•These newer markers can be informative in the differential diagnosis of common psychiatric disorders.•Synaptic proteins in CSF could be markers of synaptic and neurotransmitter transmission impairment in psychiatric disorders.
After the beginning of the COVID-19 pandemic in 2020, digital teaching had to be implemented by most universities at short notice and widely replaced classroom teaching. As a consequence, digital ...teaching further reduced direct social interaction for students. One year after the introduction of digital teaching formats at our university medical center (department of psychiatry and psychotherapy), teaching evaluation of students from summer semesters 2020 and 2021 (SS20, SS21) were compared. The main objective of this study was to objectify whether students evaluate digital teaching less favorably after one year of its implementation. Ratings of 311 medical students on (1) knowledge gain, (2) teaching contents and (3) subjective advantages of digital teaching were analyzed for the two separate cohorts SS20 (n = 175) and SS21 (n = 136). Students also rated their pandemic-related stress level, and if learning progress had been reduced by the pandemic in general. Significant knowledge gain was achieved for all included domains in psychiatry (all p < .001), and did not differ between SS20/SS21. Teaching contents in SS21 were rated worse in six out of eight domains compared to SS20 (p < .001 to .05). Also, subjective advantages of digital teaching vanished in most domains comparing the cohorts of SS21 and SS20 (p < .001 to .05). No differences were found for pandemic-related stress level and subjective learning progress. Limitations include the post-hoc design, possible bias from individual exam grades, and sampling bias. The present study showed that knowledge gain can be considered to be stable one year after the pandemic-related implementation of digital teaching. However, sustainability of this teaching format should be monitored critically: The subject of psychiatry and psychotherapy thrives on direct communication, which can be compromised when using digital formats only. In this light, implementation of more interactive formats in digital teaching is discussed.
Alzheimer's disease (AD) diagnosis requires invasive CSF analysis or expensive brain imaging. Therefore, a minimal-invasive reliable and cost-effective blood test is requested to power large clinical ...AD trials at reduced screening failure.
We applied an immuno-infrared sensor to measure the amyloid-β (Aβ) and tau secondary structure distribution in plasma and CSF as structure-based biomarkers for AD (61 disease controls, 39 AD cases).
Within a first diagnostic screening step, the structure-based Aβ blood biomarker supports AD identification with a sensitivity of 90%. In a second diagnostic validation step, the combined use of the structure-based CSF biomarkers Aβ and tau excluded false-positive cases which offers an overall specificity of 97%.
The primary Aβ-based blood biomarker funnels individuals with suspected AD for subsequent validation of the diagnosis by structure-based combined analysis of the CSF biomarkers Aβ and tau. Our novel two-step recruitment strategy substantiates the diagnosis of AD with a likelihood of 29.
GAD65 autoimmunity is reported to be associated with schizophrenia and bipolar disorder. However, there has been no evidence that glutamic acid decarboxylase 65 (GAD65) autoantibodies in ...cerebrospinal fluid (CSF) are associated with akinetic catatonia in schizophrenia patients.
We report the case of a 28-year-old man who underwent diagnostics including brain MRI, neuropsychological testing, and electroencephalography (EEG) as well as a tumor search
CT of the abdomen and thorax, as well as colonoscopy and gastroscopy. For clinical characterization, his patient files were retrospectively examined.
Our patient presented catatonia that responded somewhat to benzodiazepines in combination with previously taken antipsychotics such as risperidone for prediagnosed paranoid schizophrenia. Diagnostics revealed GAD65 autoantibodies in his serum and CSF. MRI revealed no brain lesion, and the tumor search had no malignancy. We diagnosed catatonic schizophrenia. Furthermore, as he had not fully recovered, he was given immunotherapy entailing two cycles of intravenous immunoglobulins. Subsequent neuropsychological testing due to subjective cognitive complaints after immunotherapy revealed no objective cognitive deficits.
We present the novel finding of an association between GAD65 autoantibodies in the serum and CSF with catatonia in a patient suffering from prediagnosed chronic schizophrenia. Due to the presence of CSF GAD65 antibodies and the catatonia factor in prediagnosed schizophrenia, we suspect that his catatonia has an autoimmune origin. Immunotherapy stabilized the catatonia that had initially responded to lorazepam treatment. Further research should be done to characterize patients' responses to immunotherapy and standard treatment in a large cohort of patients with GAD65 antibody-associated catatonia and schizophrenia.
Alzheimer's disease (AD) is an irreversible, devastating neurodegenerative brain disorder characterized by the loss of neurons and subsequent cognitive decline. Despite considerable progress in the ...understanding of the pathophysiology of AD, the precise molecular mechanisms that cause the disease remain elusive. By now, there is ample evidence that activated microglia have a critical role in the initiation and progression of AD. The present study describes the identification of Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel AD-related factor in both transgenic mice and sporadic AD patients by expression profiling, immunohistochemistry and ELISA measurements. We show that GPNMB levels increase in an age-dependent manner in transgenic AD models showing profound cerebral neuron loss and demonstrate that GPNMB co-localizes with a distinct population of IBA1-positive microglia cells that cluster around amyloid plaques. Our data further indicate that GPNMB is part of a microglia activation state that is only present under neurodegenerative conditions and that is characterized by the up-regulation of a subset of genes including TREM2, APOE and CST7. In agreement, we provide in vitro evidence that soluble Aβ has a direct effect on GPNMB expression in an immortalized microglia cell line. Importantly, we show for the first time that GPNMB is elevated in brain samples and cerebrospinal fluid (CSF) of sporadic AD patients when compared to non-demented controls.The current findings indicate that GPNMB represents a novel disease-associated marker that appears to play a role in the neuroinflammatory response of AD.
The metabolic syndrome (MetS) comprises abdominal obesity, preclinical or full diabetes type 2, arterial hypertension, and dyslipidemia and affects a significant proportion of the general population ...with a remarkably higher prevalence in patients suffering from psychiatric disorders. However, studies exploring the pathogenetic link between MetS and psychiatric diseases are rare. Here, we aim to narrow this gap in knowledge by providing a narrative review on this topic that focuses on two psychiatric diseases, namely on schizophrenia and posttraumatic stress disorder (PTSD) since we assume them to be associated with two different main causalities of MetS: in schizophrenia, MetS evidently develops or aggravates in response to antipsychotic drug treatment while it assumingly develops in response to stress-induced endocrine and/or epigenetic alterations in PTSD. First, we compared the prevalences of MetS and associated pathologies (which we took from the latest meta-analyses) among different psychiatric disorders and were surprised that the prevalences of arterial hypertension and hyperglycemia in PTSD almost doubles those of the other psychiatric disorders. Next, we performed a literature search on the neurobiology of MetS and found numerous articles describing a role for proopiomelanocortin (POMC) in MetS. Thus, we concentrated further analysis on POMC and one of its downstream effector hormones, α-melanocyte-stimulating hormone (α-MSH). We found some evidence for a role of POMC in both PTSD and schizophrenia, in particular in antipsychotic-induced MetS, as well as for α-MSH in schizophrenia, but, surprisingly, no study on α-MSH in PTSD. Taken together, our synopsis reveals, first, a potential interaction between the POMC system and stress in the assumingly at least partially shared pathogenesis of psychiatric disorders and MetS, second, that modulation of the POMC system, in particular of the melanocortin 3 and 4 receptors, might be a promising target for the treatment of MetS and, third, that the DNA methylation status of
POMC
might speculatively be a promising biomarker for MetS in general and, possibly, in particular in the context of stress-related psychiatric conditions such as PTSD. To best of our knowledge, this is the first review on the role of the POMC system in MetS in psychiatric disorders.
The Covid-19 pandemic highly impacts mental health worldwide. Patients with psychiatric disorders are a vulnerable risk population for worsening of their condition and relapse of symptoms. This study ...investigates the pandemic-related course of psychosocial burden in patients with pre-existing mental disorders. With the newly developed Goettingen psychosocial Burden and Symptom Inventory (Goe-BSI) psychosocial burden has been traced
retrospectively
(1) before the pandemic (beginning of 2020), (2) at its beginning under maximum lockdown conditions (March 2020), and (3) for the
current state
after maximum lockdown conditions (April/May 2020). The Goe-BSI also integrates the Adjustment Disorder New Module (ADNM-20), assesses general psychiatric symptoms, and resilience. A total of 213 patients covering all major psychiatric disorders (ICD-10 F0-F9) were interviewed once in the time range from April, 24th until May 11th, 2020. Across all diagnoses patients exhibited a distinct pattern with an initial rise followed by a decline of psychosocial burden (
p
< 0.001, partial η
2
= 0.09; Bonferroni-corrected pairwise comparisons between all three time-points:
p
< 0.05 to 0.001). Female gender and high ADNM-20 scores were identified as risk factors for higher levels and an unfavorable course of psychosocial burden over time. Most psychiatric symptoms remained unchanged. Trajectories of psychosocial burden vary in parallel to local lockdown restrictions and seem to reflect an adaptive stress response. For female patients with pre-existing mental disorders and patients with high-stress responses, timely and specific treatment should be scheduled. With the continuation of the pandemic, monitoring of long-term effects is of major importance, especially when long incubation times for the development of mental health issues are considered.
Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if ...there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.
Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.
Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD.
Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD.
This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).
Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation ...tools. The test–retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test–retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5–2) when possible. We acquired across-session test–retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test–retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.
•We implemented a multi-site 3T MRI protocol for brain morphometry on 8EU sites.•We acquired across-session test-retest data on 40 healthy elderly subjects.•We calculated the reproducibility of cortical and volumetric FreeSurfer estimates.•Longitudinal segmentation was more reliable than cross-sectional on all sites.
Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study ...we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.
PDF
