Neuropathy in ARSACS is demyelinating but without typical nerve enlargement in nerve ultrasound.

BACKGROUND: To specify peripheral nerve affection in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) by correlating high-resolution nerve ultrasound and nerve conduction studies. METHODS: We assessed a cohort of 11 ARSACS patients with standardized nerve conduction studies and high-resolution ultrasound of peripheral nerves and compared nerve ultrasound findings to a healthy control group matched for age, sex, size and weight. RESULTS: Mean age of patients was 39.0 (± 14.1) years and disease duration at assessment 30.6 (± 12.5) years. All patients presented with a spasticity, ataxia and peripheral neuropathy. Neuropathy appeared to be primarily demyelinating in 9/11 cases and was not classifiable in 2/11 cases due to not evocable potentials. Nerve ultrasound revealed a normal ultrasound pattern sum score (UPSS) in each ARSACS patient and no significant nerve enlargement compared to the control group. CONCLUSIONS: Peripheral neuropathy in ARSACS showed primarily demyelinating rather than axonal characteristics and presented without nerve enlargement. As demyelinating neuropathies do commonly present enlarged nerves we recommend further genetic testing of the SACS gene in patients who present with this combination of demyelinating neuropathy without nerve enlargement. ARSACS cases that initially presented only with neuropathy without spasticity or ataxia and therefore were misdiagnosed as Charcot-Marie-Tooth disease are supporting this suggestion.

Nerve Ultrasound of Peripheral Nerves in Patients Treated with Immune Checkpoint Inhibitors.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have enriched tumor therapy, improving overall survival. Immunotherapy adverse events (irAEs) occur in up to 50% of patients and also affect the peripheral nervous system. The exact pathomechanism is unclear; however, an autoimmune process is implicated. Thus, the clinical evaluation of irAEs in the peripheral nervous system is still demanding. We retrospectively analyzed nerve ultrasound (NU) data of polyneuropathies (PNPs) secondary to checkpoint inhibitors. Materials and Methods: NU data of patients with PNP symptoms secondary to ICI therapy were retrospectively analyzed using the Ultrasound Pattern Sum Score (UPSS) as a quantitative marker. Our findings were compared with a propensity score match analysis (1:1 ratio) to NU findings in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and chemotherapy-associated PNP patients. Results: In total, 10 patients were included (4 female, mean age 66 ± 10.5, IQR 60-77), where NU was performed in 80%. The UPSS obtained ranged from 0 to 5 (mean 2 ± 1.6, IQR 1-2.5). The morphological changes seen in the NUs resembled sonographic changes seen in chemotherapy-associated PNP (n = 10, mean UPSS 1 ± 1, IQR 0-2) with little to no nerve swelling. In contrast, CIDP patients had a significantly higher UPSS (n = 10, mean UPSS 11 ± 4, IQR 8-13, p < 0.0001). Conclusions: Although an autoimmune process is hypothesized to cause peripheral neurological irAEs, NU showed no increased swelling as seen in CIDP. The nerve swelling observed was mild and comparable to ultrasound findings seen in chemotherapy-associated PNP.

Intravenous thrombolysis in acute ischemic stroke after antagonization of unfractionated heparin with protamine: case series and systematic review of literature.

Background and aims: Intravenous thrombolysis (IVT) is standard of care for disabling acute ischemic stroke (AIS) within a time window of ⩽ 4.5 h. Some AIS patients cannot be treated with IVT due to limiting contraindications, including heparin usage in an anticoagulating dose within the past 24 h or an elevated activated prothrombin time (aPTT) > 15 s. Protamine is a potent antidote to unfractionated heparin. Objectives: The objective of this study was to investigate the safety and efficacy of IVT in AIS patients after antagonization of unfractionated heparin with protamine. Methods: Patients from our stroke center (between January 2015 and September 2021) treated with IVT after heparin antagonization with protamine were analyzed. National Institutes of Health Stroke Scale (NIHSS) was used for stroke severity and modified Rankin Scale (mRS) for outcome assessment. Substantial neurological improvement was defined as the difference between admission and discharge NIHSS of ⩾8 or discharge NIHSS of ⩽1. Good outcome at follow-up after 3 months was defined as mRS 0-2. Safety data were obtained for mortality, symptomatic intracerebral hemorrhage (sICH), and for adverse events due to protamine. Second, a systematic review was performed searching PubMed and Scopus for studies and case reviews presenting AIS patients treated with IVT after heparin antagonization with protamine. The search was limited from January 1, 2011 to September 29, 2021. Furthermore, we conducted a propensity score matching comparing protamine-treated patients to a control IVT group without protamine (ratio 2:1, match tolerance 0.2). Results: A total of 16 patients, 5 treated in our hospital and 11 from literature, [65.2 ± 13.1 years, 37.5% female, median premorbid mRS (pmRS) 1 (IQR 1, 4)] treated with IVT after heparin antagonization using protamine were included and compared to 31 IVT patients [76.2 ± 10.9 years, 45% female, median pmRS 1 (IQR 0, 2)]. Substantial neurological improvement was evident in 68.8% of protamine-treated patients versus 38.7% of control patients (p = 0.028). Good clinical outcome at follow-up was observed in 56.3% versus 58.1% of patients (p = 0.576). No adverse events due to protamine were reported, one patient suffered sICH after secondary endovascular thrombectomy of large vessel occlusion. Mortality was 6.3% versus 22.6% (p = 0.236). Conclusion: IVT after heparin antagonization with protamine seems to be safe and, prospectively, may extend the number of AIS patients who can benefit from reperfusion treatment using IVT. Further prospective registry trials would be helpful to further investigate the clinical applicability of heparin antagonization.

Targeted parallel DNA sequencing detects circulating tumor-associated variants of the mitochondrial and nuclear genomes in patients with neuroblastoma.

BACKGROUND: The utility for liquid biopsy of tumor-associated circulating single-nucleotide variants, as opposed to mutations, of the mitochondrial (mt) and nuclear genomes in neuroblastoma (NB) is unknown. PROCEDURE: Variants of the mt and nuclear genomes from tumor, blood cells, and consecutive plasma samples of five patients with metastatic NB that relapsed or progressed were analyzed. Targeted parallel sequencing results of the mt genome, and of the coding region of 139 nuclear genes and 22 miRNAs implicated in NB, were correlated with clinical imaging and laboratory data. RESULTS: All tumors harbored multiple somatic mt and nuclear single nucleotide variants with low allelic frequency, most of them not detected in the circulation. In one patient a tumor-associated mt somatic variant was detected in the plasma before and during progressive disease. In a second patient a circulating nuclear tumor-associated DNA variant heralded clinical relapse. In all patients somatic mt and nuclear variants not evident in the tumor biopsy at time of diagnosis were found circulating at varying timepoints. This suggests either tumor heterogeneity, evolution of tumor variants or a confounding contribution of normal tissues to somatic variants in patient plasma. The number and allelic frequency of the circulating variants did not reflect the clinical course of the tumors. Mutational signatures of mt and nuclear somatic variants differed. They varied between patients and were detected in the circulation without mirroring the patients' course. CONCLUSIONS: In this limited cohort of NB patients clinically informative tumor-associated mt and nuclear circulating variants were detected by targeted parallel sequencing in a minority of patients.

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting.

PURPOSE: The recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET. MATERIALS AND METHODS: A total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aß42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses. RESULTS: Seven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis. CONCLUSION: Our results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

Fear conditioning and stimulus generalization in association with age in children and adolescents.

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8-17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS-) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS-): four generalization stimuli depicting gradual morphs from CS+ to CS- in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS-, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

Computed Tomography-Based Tumor Heterogeneity Analysis Reveals Differences in a Cohort with Advanced Pancreatic Carcinoma under Palliative Chemotherapy.

PURPOSE: Imaging in pancreatic cancer is a challenge, especially regarding therapy response evaluation. Tumor size, attenuation, and perfusion are widely used as parameters for computed tomography (CT) examinations, but are often limited due to blurry tumor borders and missing qualitative parameters. To improve monitoring of therapy response, we tested a new CT-based approach of tumor heterogeneity feature analysis. METHODS: A total of 13 patients with pancreatic adenocarcinoma undergoing abdominal CT according to standard as baseline imaging with clinical follow-up and imaging (median time span 64 days) under systematic therapy (FOLFIRINOX/gemcitabine) were retrospectively analyzed. Progression was defined as new lesions and local tumor spread. Tumor heterogeneity analysis was performed using mintLesion®. Seven different image features referring to image heterogeneity were analyzed. Statistical analysis was performed with Spearman's rank correlation and Mann-Whitney U test. RESULTS: During follow-up, tumor volume did not significantly change between our groups with overall progression (local and systemic) and progression-free patients (p = 0.661). Mean positivity of pixel values were significantly higher in patients without progression compared to patients with progression (p = 0.030). There was a significant negative correlation between changes in kurtosis and time to local tumor spread (p = 0.008) or systemic progression (p = 0.017). CONCLUSIONS: Results suggest that analysis of tumor heterogeneity might provide valuable information from routine-acquired images regarding therapy response evaluation. This might help adjusting therapy regimes and could be easily integrated in clinical workflows. Furthermore, this procedure might possibly predict therapy response and, hence could lead the way to find a potential marker for progression-free survival.

Comparison of MRI-based and PET-based image pre-processing for quantification of 11C-PBB3 uptake in human brain.

PURPOSE: Quantification of tau load using 11C-PBB3-PET has the potential to improve diagnosis of neurodegenerative diseases. Although MRI-based pre-processing is used as a reference method, not all patients have MRI. The feasibility of a PET-based pre-processing for the quantification of 11C-PBB3 tracer was evaluated and compared with the MRI-based method. MATERIALS AND METHODS: Fourteen patients with decreased recent memory were examined with 11C-PBB3-PET and MRI. The PET scans were visually assessed and rated as either PBB3(+) or PBB3(-). The image processing based on the PET-based method was validated against the MRI-based approach. The regional uptakes were quantified using the Mesial-temporal/Temporoparietal/Rest of neocortex (MeTeR) regions. SUVR values were calculated by normalizing to the cerebellar reference region to compare both methods within the patient groups. RESULTS: Significant correlations were observed between the SUVRs of the MRI-based and the PET-based methods in the MeTeR regions (rMe=0.91; rTe=0.98; rR=0.96; p<0.0001). However, the Bland-Altman plot showed a significant bias between both methods in the subcortical Me region (bias: -0.041; 95% CI: -0.061 to -0.024; p=0.003). As in the MRI-based method, the 11C-PBB3 uptake obtained with the PET-based method was higher for the PBB3(+) group in each of the cortical regions and for the whole brain than for the PBB3(-) group (PET-basedGlobal: 1.11 vs. 0.96; Cliff's Delta (d)=0.68; p=0.04; MRI-basedGlobal: 1.11 vs. 0.97; d=0.70; p=0.03). To differentiate between positive and negative scans, Youden's index estimated the best cut-off of 0.99 from the ROC curve with good accuracy (AUC: 0.88±0.10; 95% CI: 0.67-1.00) and the same sensitivity (83%) and specificity (88%) for both methods. CONCLUSION: The PET-based pre-processing method developed to quantify the tau burden with 11C-PBB3 provided comparable SUVR values and effect sizes as the MRI-based reference method. Furthermore, both methods have a comparable discrimination accuracy between PBB3(+) and PBB3(-) groups as assessed by visual rating. Therefore, the presented PET-based method can be used for clinical diagnosis if no MRI image is available.

Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents.

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LALA genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.

Anxiety risk SNPs on chromosome 2 modulate arousal in children in a fear generalization paradigm.

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8-12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal.

Quantitative DWI predicts event-free survival in children with neuroblastic tumours: preliminary findings from a retrospective cohort study.

BACKGROUND: Quantitative diffusion-weighted imaging (DWI) probes into tissue microstructure in solid tumours. In this retrospective ethically approved study, we investigated DWI as a potential non-invasive predictor of tumour dignity and prognosis in paediatric patients with neuroblastic tumours. METHODS: Nineteen consecutive patients with neuroblastoma (NB, n = 15), ganglioneuroblastoma (GNB, n = 1) and ganglioneuroma (GN, n = 3) underwent 3-T magnetic resonance imaging at first diagnosis and after 3-month follow-up, following a protocol including DWI (b = 50 and 800 s/mm2) in addition to standard sequences. All DWI scans were analysed for tumour volume assessment and apparent diffusion coefficient (ADC) calculation. Correlation with tumour pathology and risk factors (bone-marrow metastases, MYCN-amplification and 1p-deletion), therapeutic regime (observation versus chemotherapy) and clinical follow-up was evaluated. RESULTS: At baseline, mean ADC in NB was lower than in GNB/GN (0.76 vs. 1.47 × 10-3 mm2/s, p = 0.003). An ADC cutoff ≤ 1.05 identified malignant disease with 100.0% sensitivity (95% confidence interval [CI] 29.2-100.0%) and 93.8% specificity (95% CI 69.8-99.8%). Initial ADC was < 0.80 in all NB patients with eventual tumour relapse. During follow-up, tumour ADC values increased in the observation group (NB/GN) without relapse (p = 0.043). In eventually relapsing tumours, ADC values at follow-up tended to decrease further despite reduction in tumour volume. CONCLUSIONS: ADC values at first presentation differed significantly between malignant and benign neuroblastic tumours. Low baseline ADC was predictive of tumour progression and relapse in NB patients. With therapy, increasing ADC values appeared to predict relapse-free survival, while a decreasing ADC during therapy was an indicator of poor prognosis.

Prognostic value of [18F]FDG-PET/CT in multiple myeloma patients before and after allogeneic hematopoietic cell transplantation.

PURPOSE: Despite improved treatment options, multiple myeloma (MM) remains an incurable disease. The aim of this study was to investigate the prognostic value of positron emission tomography/computed tomography (PET/CT) using 18F-2'-deoxy-2'-fluorodeoxyglucose ([18F]FDG) in MM patients shortly before and ~100 days after allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: In this retrospective analysis, we evaluated [18F]FDG-PET/CT-scans of 45 heavily pre-treated MM patients before and 27 patients after scheduled allo-HCT. All scans were qualitatively and semi-quantitatively assessed for the presence of active disease. Serological response was recorded according to International Myeloma Working Group (IMWG) criteria. Progression-free (PFS) and overall survival (OS) were correlated with different PET/CT-derived parameters, such as presence, number and maximum standardized uptake value (SUVmax) of focal myeloma lesions. The impact of extramedullary disease on patient outcome was also assessed. RESULTS: PET/CT negativity -prior to or following allo-HCT- was a favorable prognostic factor for progression-free and overall survival (both, PFS and OS: pre-HSCT p < 0.001, post-HCT p < 0.005). High FDG-uptake (SUVmax > 6.5) revealed a significantly shortened survival compared to patients with a lower SUVmax (<6.5) (OS, 5.0 ± 1.1 m vs. not reached - longest 122.0 m; p < 0.001). Moreover, our data prove that a higher number (>3) of focal lesions (pre-HCT: both PFS and OS: p < 0.001; post-HCT PFS: p < 0.001, OS: p = 0.139) as well as the presence of extramedullary disease serve as adverse prognostic factors prior to and after allo-HCT. At response assessment after allo-HCT, [18F]FDG-PET/CT had a complementary value in prognostication in addition to IMWG criteria alone. CONCLUSION: [18F]FDG-PET/CT before and shortly after allogeneic HCT is a powerful predictor for progression-free and overall survival in MM patients.