Deutsches Zentrum für Neurodegenerative Erkrankungen
Recent publications
Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.
Abnormal deposition of α-synuclein aggregates in Lewy bodies and Lewy neurites is the hallmark lesion in Parkinson’s disease (PD). These aggregates, thought to be the culprit of disease pathogenesis, spread throughout the brain as the disease progresses. Agents that inhibit α-synuclein aggregation and/or spread of aggregates would thus be candidate disease-modifying drugs. Here, we found that Chicago sky blue 6B (CSB) may be such a drug, showing that it inhibits α-synuclein aggregation and cell-to-cell propagation in both in vitro and in vivo models of synucleinopathy. CSB inhibited the fibrillation of α-synuclein in a concentration-dependent manner through direct binding to the N-terminus of α-synuclein. Furthermore, both seeded polymerization and cell-to-cell propagation of α-synuclein were inhibited by CSB treatment. Notably, CSB alleviated behavioral deficits and neuropathological features, such as phospho-α-synuclein and astrogliosis, in A53T α-synuclein transgenic mice. These results indicate that CSB directly binds α-synuclein and inhibits its aggregation, thereby blocking α-synuclein cell-to-cell propagation.
Background In severe cases, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS), often treated by extracorporeal membrane oxygenation (ECMO). During ECMO therapy, anticoagulation is crucial to prevent device-associated thrombosis and device failure, however, it is associated with bleeding complications. In COVID-19, additional pathologies, such as endotheliitis, may further increase the risk of bleeding complications. To assess the frequency of bleeding events, we analyzed data from the German COVID-19 autopsy registry (DeRegCOVID). Methods The electronic registry uses a web-based electronic case report form. In November 2021, the registry included N = 1129 confirmed COVID-19 autopsy cases, with data on 63 ECMO autopsy cases and 1066 non-ECMO autopsy cases, contributed from 29 German sites. Findings The registry data showed that ECMO was used in younger male patients and bleeding events occurred much more frequently in ECMO cases compared to non-ECMO cases (56% and 9%, respectively). Similarly, intracranial bleeding (ICB) was documented in 21% of ECMO cases and 3% of non-ECMO cases and was classified as the immediate or underlying cause of death in 78% of ECMO cases and 37% of non-ECMO cases. In ECMO cases, the three most common immediate causes of death were multi-organ failure, ARDS and ICB, and in non-ECMO cases ARDS, multi-organ failure and pulmonary bacterial ± fungal superinfection, ordered by descending frequency. Interpretation Our study suggests the potential value of autopsies and a joint interdisciplinary multicenter (national) approach in addressing fatal complications in COVID-19.
Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood–brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.
Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2 , contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response . These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1 , as well as its relevance to non-neuronal cell types.
Study objective Early post-operative delirium is a common perioperative complication in the post anesthesia care unit. To date it is unknown if a specific anesthetic regime can affect the incidence of delirium after surgery. Our objective was to examine the effect of volatile anesthetics on post-operative delirium. Design Single Center Observational Study. Setting Post Anesthesia Care Units at a German tertiary medical center. Patients 30,075 patients receiving general anesthesia for surgery. Measurements Delirium was assessed with the Nursing Delirium Screening Scale at the end of the recovery period. Subgroup-specific effects of volatile anesthetics on post-operative delirium were estimated using generalized-linear-model trees with inverse probability of treatment weighting. We further assessed the age-specific effect of volatiles using logistic regression models. Main results Out of 30,075 records, 956 patients (3.2%) developed delirium in the post anesthesia care unit. On average, patients who developed delirium were older than patients without delirium. We found volatile anesthetics to increase the risk (Odds exp. (B) for delirium in the elderly 1.8-fold compared to total intravenous anesthesia. Odds increases with unplanned surgery 3.0-fold. In the very old (87 years or older), the increase in delirium is 6.2-fold. This result was confirmed with internal validation and in a logistic regression model. Conclusions Our exploratory study indicates that early postoperative delirium is associated with the use of volatile anesthetics especially in the sub-cohort of patients aged 75 years and above. Further studies should include both volatile and intravenous anesthetics to find the ideal anesthetic in elderly patients.
Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.
Background Reliable estimates of frequency, severity and associated factors of both fatigue and cognitive impairment after COVID-19 are needed. Also, it is not clear whether the two are distinct sequelae of COVID-19 or part of the same syndrome." Methods In this prospective multicentre study, frequency of post-COVID fatigue and cognitive impairment were assessed in n = 969 patients (535 [55%] female) ≥6 months after SARS-CoV-2 infection with the FACIT-Fatigue scale (cut-off ≤30) and Montreal Cognitive Assessment (≤25 mild, ≤17 moderate impairment) between November 15, 2020 and September 29, 2021 at University Medical Center Schleswig-Holstein, Campus Kiel and University Hospital Würzburg in Germany. 969 matched non-COVID controls were drawn from a pre-pandemic, randomised, Germany-wide population survey which also included the FACIT-Fatigue scale. Associated sociodemographic, comorbid, clinical, psychosocial factors and laboratory markers were identified with univariate and multivariable linear regression models. Findings On average 9 months after infection, 19% of patients had clinically relevant fatigue, compared to 8% of matched non-COVID controls (p < 0.001). Factors associated with fatigue were female gender, younger age, history of depression and the number of acute COVID symptoms. Among acute COVID symptoms, altered consciousness, dizziness and myalgia were most strongly associated with long-term fatigue. Moreover, 26% of patients had mild and 1% had moderate cognitive impairment. Factors associated with cognitive impairment were older age, male gender, shorter education and a history of neuropsychiatric disease. There was no significant correlation between fatigue and cognitive impairment and only 5% of patients suffered from both conditions. Interpretation Fatigue and cognitive impairment are two common, but distinct sequelae of COVID-19 with potentially separate pathophysiological pathways. Funding German Federal Ministry of Education and Research (BMBF).
Aim Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. Methods In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Results Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). Conclusions ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.
Nimodipine prevents cerebral vasospasm and improves functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). The beneficial effect is limited by low oral bioavailability of nimodipine, which resulted in an increasing use of nanocarriers with sustained intrathecal drug release in order to overcome this limitation. However, this approach facilitates only a continuous and not an on-demand nimodipine release during the peak time of vasospasm development. In this study, we aimed to assess the concept of controlled drug release from nimodipine-loaded copolymers by ultrasound application in the chicken chorioallantoic membrane (CAM) model. Nimodipine-loaded copolymers were produced with the direct dissolution method. Vasospasm of the CAM vessels was induced by means of ultrasound (Physiomed, continuous wave, 3 MHz, 1.0 W/cm ² ). The ultrasound-mediated nimodipine release (Physiomed, continuous wave, 1 MHz, 1.7 W/cm ² ) and its effect on the CAM vessels were evaluated. Measurements of vessel diameter before and after ultrasound-induced nimodipine release were performed using ImageJ. The CAM model could be successfully carried out in all 25 eggs. After vasospasm induction and before drug release, the mean vessel diameter was at 57% (range 44–61%) compared to the baseline diameter (set at 100%). After ultrasound-induced drug release, the mean vessel diameter of spastic vessels increased again to 89% (range 83–91%) of their baseline diameter, which was significant ( p = 0.0002). We were able to provide a proof of concept for in vivo vasospasm induction by ultrasound application in the CAM model and subsequent resolution by ultrasound-mediated nimodipine release from nanocarriers. This concept merits further evaluation in a rat SAH model. Graphical abstract
Purpose Benzodiazepines are recommended as first line sedative agent in ventilated cardiogenic shock patients, although data regarding the optimal sedation strategy are sparse. The aim of this study was to investigate the hemodynamic effects of propofol versus midazolam sedation in our cardiogenic shock registry. Materials and methods Mechanically ventilated patients suffering from cardiogenic shock were retrospectively enrolled from the cardiogenic shock registry of the university hospital of Munich. 174 patients treated predominantly with propofol were matched by propensity-score to 174 patients treated predominantly with midazolam. Results Catecholamine doses were similar on admission but significantly lower in the propofol group on days 1–4 of ICU stay. Mortality rate was 38% in the propofol and 52% in the midazolam group after 30 days (p = 0.002). Rate of ≥BARC3 bleeding was significantly lower in the propofol group compared to the midazolam group (p = 0.008). Sedation with midazolam was significantly associated with ICU mortality. Conclusion In this observational cohort study, sedation with propofol in comparison to midazolam was linked to a reduced dose of catecholamines, decreased mortality and bleeding rates for patients with cardiogenic shock. Based on this study and in contrast to current recommendations, propofol should be given consideration for sedation in cardiogenic shock patients.
We previously identified a subgroup of schizophrenia cases (~40 %) with heightened inflammation in the neurogenic subependymal zone (SEZ) (North et al., 2021b). This schizophrenia subgroup had changes indicating reduced microglial activity, increased peripheral immune cells, increased stem cell dormancy/quiescence and reduced neuronal precursor cells. The present follow-up study aimed to replicate and extend those novel findings in an independent post-mortem cohort of schizophrenia cases and controls from Australia. RNA was extracted from SEZ tissue from 20 controls and 22 schizophrenia cases from the New South Wales Brain Tissue Resource Centre, and gene expression analysis was performed. Cluster analysis of inflammation markers (IL1B, IL1R1, SERPINA3 and CXCL8) revealed a high-inflammation schizophrenia subgroup comprising 52 % of cases, which was a significantly greater proportion than the 17 % of high-inflammation controls. Consistent with our previous report (North et al., 2021b), those with high-inflammation and schizophrenia had unchanged mRNA expression of markers for steady-state and activated microglia (IBA1, HEXB, CD68), decreased expression of phagocytic microglia markers (P2RY12, P2RY13), but increased expression of markers for macrophages (CD163), monocytes (CD14), natural killer cells (FCGR3A), and the adhesion molecule ICAM1. Similarly, the high-inflammation schizophrenia subgroup emulated increased quiescent stem cell marker (GFAPD) and decreased neuronal progenitor (DLX6-AS1) and immature neuron marker (DCX) mRNA expression; but also revealed a novel increase in a marker of immature astrocytes (VIM). Replicating primary results in an independent cohort demonstrates that inflammatory subgroups in the SEZ in schizophrenia are reliable, robust and enhance understanding of neuropathological heterogeneity when studying schizophrenia.
Proteins that contain repeat phenylalanine-glycine (FG) residues phase separate into oncogenic transcription factor condensates in malignant leukaemias, form the permeability barrier of the nuclear pore complex and mislocalize in neurodegenerative diseases. Insights into the molecular interactions of FG-repeat nucleoporins have, however, remained largely elusive. Using a combination of NMR spectroscopy and cryoelectron microscopy, we have identified uniformly spaced segments of transient β-structure and a stable preformed α-helix recognized by messenger RNA export factors in the FG-repeat domain of human nucleoporin 98 (Nup98). In addition, we have determined at high resolution the molecular organization of reversible FG–FG interactions in amyloid fibrils formed by a highly aggregation-prone segment in Nup98. We have further demonstrated that amyloid-like aggregates of the FG-repeat domain of Nup98 have low stability and are reversible. Our results provide critical insights into the molecular interactions underlying the self-association and phase separation of FG-repeat nucleoporins in physiological and pathological cell activities.
Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).
Background: Limiting the ability to engage in social interaction, aphasia increases the risk of poststroke depression and may prevent classical forms of psychotherapy. Our parallel-group, blinded-assessment, quasi-randomized controlled trial explores the feasibility and potential efficacy of intensive social interaction as a means to alleviate poststroke depression in subacute aphasia. Methods: We adopted a linguistically validated treatment program based on massed practice and conversational turn-taking (Intensive Language-Action Therapy). In a routine outpatient setting, 60 individuals with poststroke depression and subacute aphasia (0.5-6 months following left-hemispheric ischemia or hemorrhage) were assigned to Intensive Language-Action Therapy combined with standard care (Group I) or standard care alone (Group II). End points included feasibility (primary outcome) alongside change on self-report and clinician-rated measures of depression severity (co-primary outcomes: Beck's Depression Inventory; Hamilton Rating Scale for Depression) after a 1-month treatment period (5 weekly 1-hour sessions), controlled for progress in language performance (secondary outcome: Aachen Aphasia Test, AAT). Results: 100% treatment participation demonstrated feasibility of Intensive Language-Action Therapy in poststroke depression. Analyses (n=60) revealed significant between-group differences on the Beck's Depression Inventory (change in Group I [95% CI]: -12.6 [±4.9]; in Group II: -5.8 [±3.2]; P=0.040) and Hamilton Rating Scale for Depression (change in Group I: -5.0 [±1.4]; in Group II: -3.3 [±1.2]; P=0.002), indicating small-to-medium effect sizes in reducing depression severity with Intensive Language-Action Therapy (η2≤0.101). No significant between-group differences emerged on expressive AAT subscales. Conclusions: Our results confirm the feasibility and potential efficacy of intensive social interaction for treatment of poststroke depression in subacute aphasia. Registration: URL: www. Clinicaltrials: gov; Unique identifier: NCT04318951.
The locus coeruleus (LC) in the brainstem as the main regulator of brain noradrenaline gains increasing attention because of its involvement in neurologic and psychiatric diseases and its relevance in general to brain function. In this study, we created a structural connectome of the LC nerve fibers based on in vivo MRI tractography to gain an understanding into LC connectivity and its impact on LC-related psychological measures. We combined our structural results with ultra-high field resting-state functional MRI to learn about the relationship between in vivo LC structural and functional connections. Importantly, we reveal that LC brain fibers are strongly associated with psychological measures of anxiety and alertness indicating that LC-noradrenergic connectivity may have an important role on brain function. Lastly, since we analyzed all our data in subject-specific space, we point out the potential of structural LC connectivity to reveal individual characteristics of LC-noradrenergic function on the single-subject level.
Exploration of bias has significant impact on the transparency and applicability of deep learning pipelines in medical settings, yet is so far woefully understudied. In this paper, we consider two separate groups for which training data is only available at differing image resolutions. For group H, available images and labels are at the preferred high resolution while for group L only deprecated lower resolution data exist. We analyse how this resolution-bias in the data distribution propagates to systematically biased predictions for group L at higher resolutions. Our results demonstrate that single-resolution training settings result in significant loss of volumetric group differences that translate to erroneous segmentations as measured by DSC and subsequent classification failures on the low resolution group. We further explore how training data across resolutions can be used to combat this systematic bias. Specifically, we investigate the effect of image resampling, scale augmentation and resolution independence and demonstrate that biases can effectively be reduced with multi-resolution approaches.
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487 members
Martin Reuter
  • Image Analysis
N. Ahmad Aziz
  • Department of Population Health Sciences
Dan Ehninger
  • RG Molecular and Cellular Cognition (Bonn)
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Pierluigi Nicotera
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www.dzne.de
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