Dorsal root ganglion magnetic resonance imaging biomarker correlations with pain in Fabry disease.

Fabry disease is a rare monogenetic, X-linked lysosomal storage disorder with neuropathic pain as one characteristic symptom. Impairment of the enzyme alpha-galactosidase A leads to an accumulation of globotriaosylceramide in the dorsal root ganglia. Here, we investigate novel dorsal root ganglia MR imaging biomarkers and their association with Fabry genotype and pain phenotype. In this prospective study, 89 Fabry patients were examined using a standardized 3 T MRI protocol of the dorsal root ganglia. Fabry pain was assessed through a validated Fabry pain questionnaire. The genotype was determined by diagnostic sequencing of the alpha-galactosidase A gene. MR imaging end-points were dorsal root ganglia volume by voxel-wise morphometric analysis and dorsal root ganglia T2 signal. Reference groups included 55 healthy subjects and Fabry patients of different genotype categories without Fabry pain. In patients with Fabry pain, T2 signal of the dorsal root ganglia was increased by +39.2% compared to healthy controls (P = 0.001) and by +29.4% compared to painless Fabry disease (P = 0.017). This effect was pronounced in hemizygous males (+40.7% compared to healthy; P = 0.008 and +29.1% compared to painless; P = 0.032) and was consistently observed across the genotype spectrum of nonsense (+38.1% compared to healthy, P < 0.001) and missense mutations (+39.2% compared to healthy; P = 0.009). T2 signal of dorsal root ganglia and globotriaosylsphingosine levels were the only independent predictors of Fabry pain (P = 0.047; P = 0.002). Volume of dorsal root ganglia was enlarged by +46.0% in Fabry males in the nonsense compared to missense genotype category (P = 0.005) and by +34.5% compared to healthy controls (P = 0.034). In painful Fabry disease, MRI T2 signal of dorsal root ganglia is increased across different genotypes. Dorsal root ganglion MRI T2 signal as a novel in vivo imaging biomarker may help to better understand whether Fabry pain is modulated or even caused by dorsal root ganglion pathology.

Pearls & Oy-sters: INO Plus From Downward Herniation-A Cautionary Tale Regarding Neuro-Ophthalmologic Signatures of Brainstem Compression.

Pupillary assessment is a quintessential part of the clinical examination in neuro-intensive care patients because it provides insight into the integrity of midbrain reflex arcs. Abnormal pupils, particularly anisocoria and later bilateral fixed mydriasis, are classically used to assess expansive intracranial processes because they are frequently considered early indicators of transtentorial midbrain compression due to elevated intracranial pressure. Complex ocular motor deficits mapping to the midbrain are rarely described in the setting of high transtentorial pressure. This is likely because ocular motor deficits typically occur in conjunction with decreased consciousness and corticospinal tract dysfunction reflecting advanced midbrain compromise. We present a case of left midbrain compression due to downward herniation in a patient with acute-on-chronic bilateral subdural hematoma. Ocular motor assessment demonstrated left internuclear ophthalmoplegia (INO) and an ocular tilt reaction, termed INO plus. However, pupillary, mental status, and sensorimotor examinations were unremarkable. Head magnetic resonance imaging revealed acute perforator ischemia in the left pontomesencephalic tegmentum, localizing to the ipsilateral medial longitudinal fasciculus and graviceptive oculocephalic circuits. Microvascular compromise secondary to mechanical pressure is discussed as a causative mechanism. We caution against overreliance on "telltale pupils" in suspected brainstem compression and recommend checking for other oculomotor signs.

MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study.

BACKGROUND: Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). METHODS: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. FINDINGS: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. INTERPRETATION: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. FUNDING: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke.

INTRODUCTION: Blood-based biomarkers may improve prediction of functional outcome in patients with acute ischemic stroke. The role of neurofilament light chain (NfL) and glial fibrillary acidic (GFAP) as potential biomarkers especially in severe stroke patients is unknown. PATIENTS AND METHODS: Prospective, monocenter, cohort study including consecutive patients with severe ischemic stroke in the anterior circulation on admission (NIHSS score ⩾ 6 points or indication for mechanical thrombectomy). Outcome was assessed 3 months after the index stroke by the modified Rankin Scale (mRS). Serum biomarkers levels of NfL and GFAP were determined by ultrasensitive ELISA. Univariate and multivariate logistic regression models were performed to determine the association of biomarker levels and functional disability. Discrimination, calibration, and overall performance were analyzed in different models via AUROC, calibration plots (with Emax and Eavg), Brier-score and R2 using variables, identified as important covariates for functional outcome in previous studies. RESULTS: Between 06/2020 and 08/2021, 213 patients were included [47% female, mean age 76 (SD ± 12) years, median NIHSS score 13 (interquartile range, IQR 9; 17)]. Biomarker serum levels were measured at a median of 1 [IQR, 1; 2] day after admission. Compared to patients with mRS 0-2 at 3 months, patients with mRS 3-6 had higher serum levels of NfL (median: 136 pg/ml vs 41 pg/ml; p < 0.0001) and GFAP (700 ng/ml vs 9.6 ng/ml; p < 0.0001). Both biomarkers were significantly associated with functional outcome [adjusted logistic regression, odds ratio (95% CI) for NfL: 2.63 (1.62; 4.56), GFAP: 2.16 (1.58; 3.09)]. In all models the addition of serum NfL led to a significant improvement in the AUROC, as did the addition of serum GFAP. Calibration plots showed high agreement between the predicted and observed outcomes and after addition of the two blood-based biomarkers there was an improvement of the overall performance. CONCLUSION: Prediction of functional outcome after severe acute ischemic stroke was improved by the blood-based biomarkers serum NfL and GFAP, measured in the acute phase of stroke. These findings have to be replicated in independent external cohorts.Study registration: DRKS00022064.

High-resolution Magnetic Resonance Imaging visualizes intracranial large artery involvement in Giant Cell Arteritis.

OBJECTIVE: Giant Cell arteritis (GCA) is a large vessel vasculitis, typically involving the aorta and its branches with predilection for the scalp arteries. Intracranial involvement is still part of ongoing research. We assess inflammation of the intracranial arteries on 3D-black-blood magnetic resonance imaging (3D-CS-BB-MRI) in patients with GCA and age-matched controls. METHODS: 105 patients with 3D-CS-BB-MRI of the brain were included in this retrospective dual-center case-control study; 55 with diagnosed GCA and 50 age-matched controls. High-resolution 3D-CS-BB-MRI was performed on a 3 Tesla MR scanner with a post-contrast 3D-compressed-sensing (CS) MR pulse sequence, specifically a T1-weighted sampling perfection, application-optimized contrasts using different flip angle evolution (SPACE) pulse sequence with whole-brain coverage and isotropic resolution of 0.55 mm3. Two neuroradiologists blinded to clinical data independently scored the cerebral arteries qualitatively for inflammation; circumferential vessel wall thickening and contrast enhancement were scored positive for vasculitis. RESULTS: 8 of 55 GCA patients (14.5%) showed inflammation of at least one intracranial artery. The internal carotid artery (ICA) was affected in 6/55 (10.9%), the vertebral artery in 4/55 (7.3%) and the basilar artery and posterior cerebral artery in 1/55 (1.8%). All patients with inflammatory changes reported headaches and none showed any focal neurological deficit. Besides headache and general weakness, there was no significant correlation between inflammation of the intracranial arteries and clinical symptoms. No age-matched control patient showed inflammatory changes of the intracranial arteries. CONCLUSION: High-resolution 3D-CS-BB-MRI revealed inflammatory changes of intracranial arteries in 14.5% of GCA patients with the intradural ICA as the most frequently affected vessel.

[Neuralgic amyotrophy: an inflammatory neuropathy and its surgical treatment]. / Neuralgische Amyotrophie ­ eine entzündliche Neuropathie und ihre operative Behandlung.

BACKGROUND: Neuralgic amyotrophy (NA) is a monofocal or oligofocal inflammatory neuropathy whose incidence has been significantly underestimated. A connection between constrictions and torsions of peripheral nerves with this disease has been increasingly established in recent years. Modern imaging techniques such as high-resolution nerve ultrasound and MR neurography have contributed to a better understanding of the pathophysiology and a better assessment of the prognosis of the disease. This has led to the concept of treating patients with such focal changes surgically in order to improve the prognosis. This review presents current ideas on the pathophysiology, clinical presentation, diagnosis and treatment of the disease. PATIENTS AND METHODS: In a retrospective study, pre-, intra- and postoperative findings of 22 patients with 23 constrictions/torsions of peripheral nerves of the upper extremity were analysed. The patients underwent surgery at a nerve surgery centre over a period of 3.5 years (Dec. 2019-May 2023). The median nerve was most frequently affected (N=9), followed by the suprascapular nerve (N=6) and radial nerve (N=4). The axillary nerve (N=3) and the accessory nerve (N=1) were also involved. Surgical exploration revealed nerve torsions (N=9), nerve constrictions (N=5), fascicular torsions (N=12) and fascicular constrictions (N=9). Depending on the intraoperative findings, epineuriotomies (N=1), epi- and perineuriotomies (N=33), end-to-end sutures (N=2), and one epi- and one perineural suture were performed. RESULTS: After an average follow-up of 10 months (3-28 months), 17 patients were re-examined. All of them reported a clear subjective improvement in motor deficits. Clinically and electromyographically, a reinnervation and significant increase in strength from a pre-existing strength grade of M0 to at least M3 in the vast majority of affected muscles was demonstrated in these patients. SUMMARY: The incidence of NA continues to be underestimated and, in a significant proportion of patients, leads to permanent motor deficits, most likely due to constrictions and torsions of affected nerves. Surgical treatment is recommended as early as possible. Very good results can usually be achieved with epi- and perineuriotomy. In rare cases, end-to-end neurorrhaphy or nerve grafting is required.

Heart rate variability, interoceptive accuracy and functional connectivity in middle-aged and older patients with depression.

BACKGROUND AND OBJECTIVE: Major depressive disorder (MDD) is associated with increased cardiac morbidity. Reduced heart rate variability (HRV) as well as lower interoceptive accuracy (IAc) have been observed in MDD as possible sympathomimetic mechanisms related to insula activity. The salience network (SN) anchored by the insula has been posited as a crucial functional network for cardiac sensations and the default mode network (DMN) for MDD. This study aimed to investigate the relation between insula-centered and depression-related brain networks, IAc and HRV in patients with depression as a possible mechanism by which MDD increases cardiac morbidity. METHODS: 30 depressed inpatients and 30 healthy subjects (derived from the population-based "Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression" cohort study, STAAB) all over 50 years were examined. HRV and IAc were assessed via electrocardiogram and a heartbeat perception task prior to a 3 T resting-state functional magnetic resonance imaging. Seed-to-voxel resting-state functional connectivity (FC) analysis was conducted with six seeds in the insula and two seeds in the DMN. RESULTS: Depressed patients on the one hand showed decreased FC between insula cortex and frontal as well occipital cortical brain regions compared to controls. Depressed patients on the other hand exhibited higher FC between the medial prefrontal cortex and the insula cortex compared to controls. However, depressed patients did not differ in HRV nor in IAc compared to controls. CONCLUSION: Thus, differences in insula-related brain networks in depression in our study were not mirrored by differences in HRV and IAc. Future research is needed to define the mechanism by which depression increases cardiac morbidity.

Treating seronegative neuromyelitis optica spectrum disorder with inebilizumab: a case report.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disease of the central nervous system that is often severely disabling from the outset. The lack of pathognomonic aquaporin 4 (AQP4) antibodies in seronegative NMOSD not only hinders early diagnosis, but also limits therapeutic options, in contrast to AQP4 antibody-positive NMOSD, where the therapeutic landscape has recently evolved massively. Case presentation: We report a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as the index events of a seronegative NMOSD, who was successfully treated with inebilizumab. Conclusion: Treatment with inebilizumab may be considered in aggressive seronegative NMOSD. Whether broader CD19-directed B cell depletion is more effective than treatment with rituximab remains elusive.

[Diagnostics and treatment of hourglass-like nerve constrictions and torsions in neuralgic amyotrophy]. / Diagnostik und Therapie sanduhrförmiger Nervenstrikturen und -torsionen bei neuralgischer Amyotrophie.

Neuralgic amyotrophy is a disease of the peripheral nervous system characterized by severe neuropathic pain followed by peripheral paralysis. A distinction is made between a hereditary and an idiopathic form, which is assumed to have an autoimmunological origin. Conservative medicinal treatment mainly consists of nonsteroidal anti-inflammatory drugs (NSAID), opioids and glucocorticoids; however, despite treatment, symptoms in the form of pain or paralysis persist in over 50% of cases. Inflammation can lead to strictures and torsions of peripheral nerves, which can be visualized by imaging using nerve sonography or magnetic resonance (MR) neurography and confirmed intraoperatively during surgical exploration. Based on the currently available data, patients with strictures and torsions of peripheral nerves can benefit from neurosurgical treatment.

Serum ß-synuclein, neurofilament light chain and glial fibrillary acidic protein as prognostic biomarkers in moderate-to-severe acute ischemic stroke.

We aimed to assess the prognostic value of serum ß-synuclein (ß-syn), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with moderate-to-severe acute ischemic stroke. We measured ß-syn, GFAP and NfL in serum samples collected one day after admission in 30 adult patients with moderate-to-severe ischemic stroke due to middle cerebral artery (MCA) occlusion. We tested the associations between biomarker levels and clinical and radiological scores (National Institute of Health Stroke Scale scores, NIHSS, and Alberta Stroke Program Early CT Score, ASPECTS), as well as measures of functional outcome (modified Rankin Scale, mRS). Serum biomarkers were significantly associated with ASPECTS values (ß-syn p = 0.0011, GFAP p = 0.0002) but not with NIHSS scores at admission. Patients who received mechanical thrombectomy and intravenous thrombolysis showed lower ß-syn (p = 0.029) und NfL concentrations (p = 0.0024) compared to patients who received only mechanical thrombectomy. According to median biomarker levels, patients with high ß-syn, NfL or GFAP levels showed, after therapy, lower clinical improvement (i.e., lower 24-h NIHSS change), higher NIHSS scores during hospitalization and higher mRS scores at 3-month follow-up. Elevated serum concentrations of ß-syn (p = 0.016), NfL (p = 0.020) or GFAP (p = 0.010) were significantly associated with 3-month mRS of 3-6 vs. 0-2 even after accounting for age, sex and renal function. In patients with moderate-to-severe acute ischemic stroke, serum ß-syn, NfL and GFAP levels associated with clinical and radiological scores at different timepoints and were able to predict short- and middle-term clinical outcomes.

Endovascular thrombectomy for acute ischaemic stroke with established large infarct: multicentre, open-label, randomised trial.

BACKGROUND: Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice. METHODS: In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715. FINDINGS: From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60-4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46-0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone. INTERPRETATION: Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection. FUNDING: EU Horizon 2020.

Internal carotid artery blood flow and pulsatility index in cognitively impaired people with chronic heart failure.

AIMS: Mild cognitive impairment and dementia are common and serious co-morbidities in people with chronic heart failure (HF) as they increase hospitalization rates, mortality and health care costs. Upon other factors, dysregulated cerebral perfusion might contribute to brain pathology. We aimed to evaluate the association of non-invasively measured blood flow (BF) and pulsatility index (PI) of the internal carotid artery (ICA) with (i) chronic HF parameters, (ii) brain morphologic measures and (iii) cognitive impairment. METHODS AND RESULTS: This post-hoc analysis of the observational, prospective Cognition.Matters-HF study included 107 chronic HF patients without atrial fibrillation or carotid artery stenosis (aged 63 ± 10 years; 19% women). Using extracranial sonography, we measured ICA-BF and ICA-PI 1.5 cm distal of the carotid bifurcation. Brain magnetic resonance imaging was performed on a 3-Tesla scanner to quantify cerebral atrophy, hippocampal atrophy and white matter hyperintensities. Extensive neuropsychological testing tested the cognitive domains intensity of attention, visual/verbal memory and executive function (including its subdomains selectivity of attention, visual/verbal fluency and working memory) using a comprehensive test battery. (i) Neither ICA-BF (median 630 (quartiles 570, 700) mL/min) nor ICA-PI (1.05 (0.96. 1.23)) related to left ventricular ejection fraction, left atrial volume index or NT-proBNP. (ii) Higher ICA-PI (r = 0.25; P = 0.011), but not ICA-BF (r = 0.08; P = 0.409), associated with increased volume of white matter hyperintensities beyond ageing, while neither ICA-PI nor ICA-BF related to cerebral or hippocampal atrophy indices. (iii) ICA-BF, but not ICA-PI, positively correlated with age-adjusted T-scores of executive function (r = 0.38; P < 0.001) and its subdomains working memory (r = 0.32; P < 0.001) and visual/verbal fluency (r = 0.32; P < 0.001). In a multivariate linear model of executive function, only ICA-BF (T = 3.79; P < 0.001), but not HF or magnetic resonance imaging parameters, remained a significant correlate of executive function. CONCLUSIONS: ICA-BF and ICA-PI, measured in broadly available extracranial sonography, independently related to measures of functional and structural brain changes in people with chronic HF, respectively. Due to limitations of this cross-sectional approach without a healthy control group, larger controlled longitudinal studies are needed to further elucidate the role of ICA-BF dysregulation and its implication for clinical care in this vulnerable cohort.

Distinct Alterations in Oxygenation, Ion Composition and Acid-Base Balance in Cerebral Collaterals During Large-Vessel Occlusion Stroke.

PURPOSE: Disturbances of blood gas and ion homeostasis including regional hypoxia and massive sodium (Na+)/potassium (K+) shifts are a hallmark of experimental cerebral ischemia but have not been sufficiently investigated for their relevance in stroke patients. METHODS: We report a prospective observational study on 366 stroke patients who underwent endovascular thrombectomy (EVT) for large-vessel occlusion (LVO) of the anterior circulation (18 December 2018-31 August 2020). Intraprocedural blood gas samples (1 ml) from within cerebral collateral arteries (ischemic) and matched systemic control samples were obtained according to a prespecified protocol in 51 patients. RESULTS: We observed a significant reduction in cerebral oxygen partial pressure (-4.29%, paO2ischemic = 185.3 mm Hg vs. paO2systemic = 193.6 mm Hg; p = 0.035) and K+ concentrations (-5.49%, K+ischemic = 3.44 mmol/L vs. K+systemic = 3.64 mmol/L; p = 0.0083). The cerebral Na+:K+ ratio was significantly increased and negatively correlated with baseline tissue integrity (r = -0.32, p = 0.031). Correspondingly, cerebral Na+ concentrations were most strongly correlated with infarct progression after recanalization (r = 0.42, p = 0.0033). We found more alkaline cerebral pH values (+0.14%, pHischemic = 7.38 vs. pHsystemic = 7.37; p = 0.0019), with a time-dependent shift towards more acidotic conditions (r = -0.36, p = 0.055). CONCLUSION: These findings suggest that stroke-induced changes in oxygen supply, ion composition and acid-base balance occur and dynamically progress within penumbral areas during human cerebral ischemia and are related to acute tissue damage.

Profiles of cognitive impairment in chronic heart failure-A cluster analytic approach.

Background: Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods: The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results: Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion: Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.

Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1.

We analyzed single nucleotide polymorphisms (SNPs) in PKNOX1 (rs2839629) and in the intergenic region between PKNOX1 and CBS (rs915854) by Sanger sequencing in 88 patients with multiple myeloma treated with bortezomib. All patients (n = 13) harboring a homozygous mutation in PKNOX1 (rs2839629) also had a homozygous mutated rs915854 genotype. Homozygous mutated genotypes of rs2839629 and rs915854 were significantly enriched in patients with painful peripheral neuropathy (PNP) (P < 0.0001), and homozygous mutated rs2839629 genotype was significantly enriched in patients with pain compared to patients with no pain (P = 0.04). In summary, both SNPs rs2839629 and/or rs915854 may be potential biomarkers predicting an increased risk to develop painful PNP under bortezomib.

Deep phenotyping as a contribution to personalized depression therapy: the GEParD and DaCFail protocols.

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20-30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case-control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case-control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

[18F]FET-PET in children and adolescents with central nervous system tumors: does it support difficult clinical decision-making?

PURPOSE: Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. METHODS: Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1-19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. RESULTS: The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. CONCLUSION: [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

Vasoactive Soluble Endoglin: A Novel Biomarker Indicative of Reperfusion after Cerebral Large-Vessel Occlusion.

Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-ß co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.