Citations

Objective Compression of the left renal vein by the superior mesenteric artery, known as nutcracker phenomenon (NCP), can cause retrograde flow and congestion in communicating venous systems. It has recently been speculated that NCP can result in retrograde flow and congestion of the lumbar veins and epidural venous plexus (EVP), thereby affecting the central nervous system. This study describes the novel use of time-resolved magnetic resonance angiography (trMRA) to evaluate for retrograde left second lumbar vein (L2LV) flow and early EVP enhancement in patients with chronic daily headache (CDH) with and without NCP. Methods A retrospective analysis was performed of 31 patients with CDH (27 females and 4 males; median age, 38 years [range, 18–63 years]) who underwent trMRA centered over the L2LV to evaluate the direction of blood flow and presence of early EVP enhancement from May 2020 to March 2022. Descriptive statistics were performed, and anatomic associations were analyzed in patients with and without retrograde L2LV flow and early EVP enhancement. The accuracy of magnetic resonance imaging findings in detecting these flow patterns was also assessed. Results Patients with NCP who demonstrated narrowing of the left renal vein, a positive beak sign (P = 0.052), decreased aortomesenteric distance (P = 0.038), and decreased SMA angle demonstrated increased rates of retrograde L2LV flow and early EVP enhancement. A positive beak sign was 83% specific, and an aortomesenteric distance of ≤6.5 mm was 61% sensitive and 83% specific for identifying retrograde L2LV flow with early regional EVP enhancement in patients with CDH. Conclusions Retrograde L2LV flow with early EVP enhancement in CDH patients can be effectively evaluated using trMRA and was seen with greater propensity in those patients with NCP.

AbstractBackgroundThe syndrome of mild cognitive impairment (MCI) is classified into different subtypes– amnestic MCI (aMCI) and non‐amnestic MCI based on cognitive domains impacted, while different underlying disease etiologies cause the impairments. The Memory Support System (MSS), a memory‐support tool which utilizes a calendar/planner, has been shown to have positive impact on daily functioning in MCI (Chandler et al., 2017). We have previously shown that cognitive impairment severity and personality traits are associated with MSS learning (De Wit et al., 2021; Khayoun et al., 2021). In this study, we hypothesized that 1) participants with single domain aMCI (SD‐aMCI) will have higher MSS learning scores than multi‐domain aMCI (MD‐aMCI), and 2) participants with suspected Alzheimer’s disease (AD) etiology will have lower MSS learning scores than other etiologies.MethodParticipants (mean age = 75.2) underwent daily MSS training between 2017 and 2021 as part of the 10‐day Mayo Clinic HABIT program. The MSS learning success score (LSS) was determined by how far participants progressed in three learning phases of increasing difficulty: Acquisition (0‐2 points), Application (3‐4 points), and Adaptation (5‐6 points; Greenway et al., 2008). Ordinal logistic regression analysis was used to predict MSS learning scores between SD‐aMCI (n = 142) versus MD‐aMCI (n = 119), and AD etiology (n = 213) versus other neurodegenerative etiologies (n = 57). Dementia Rating Scale‐2 scores (Jurica, 2001) were included to control for cognitive severity.ResultCompared to participants with SD‐aMCI, those with MD‐aMCI had 54.1% lower odds of having higher LSS at training end (p = .004), after controlling for cognitive impairment severity. AD versus other etiology’s impact on LSS was nonsignificant.ConclusionParticipants with MD‐aMCI showed poorer MSS learning efficiency than participants with SD‐aMCI. Etiology did not impact MSS learning. Results suggest having more than just memory impairment (e.g., additional language or executive dysfunction) reduces MSS learning, regardless of overall impairment level. Additional MSS training may be needed to facilitate learning for these individuals.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Hexanucleotide G 4 C 2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G 4 C 2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72 450 mice. However, chronic administration of anti-GA antibodies in AAV-(G 4 C 2 ) 149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

Background. The age of a liver transplant (LT) candidate is one of many variables used in the transplant selection process. Most research about the age at transplant has used prespecified age ranges or categories in assessing associations with transplant outcomes. However, there is a lack of knowledge about the age at transplant and survival. This study aimed to examine associations of age at transplant as a continuous variable, in conjunction with other patient and disease-related factors, with patient and graft survival after LT. Methods. We used the Standard Transplant Analysis and Research data to identify LT recipients between January 2002 and June 2018. Cox regression models with a restricted cubic spline term for age examined associations with graft and patient survival after LT. We assessed the interactions of age with recipients’ sex, race/ethnicity, region, indication for transplant, body mass index, model for end-stage liver disease score, diabetes, functional status at transplant, and donor risk index. Results. Age at the time of LT showed a nonlinear association with both graft and patient survival. Each demographic, clinical, transplant-related, and donor-related factor influenced these relationships differently. Conclusions. Our results suggest that some older LT candidates may be better than some younger candidates and that clinicians should not exclusively use age to determine who receives LT.

AbstractLoss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies.We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1–4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures.Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone.Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.

Purpose: The electronic Medical Records and Genomics (eMERGE) Phase III study was undertaken to assess clinical utility of returning medically actionable genomic screening results. We assessed pediatric clinical outcomes following return of pathogenic/likely pathogenic (P/LP) variants in autosomal dominant conditions with available effective interventions. Methods: The two eMERGE III pediatric sites collected outcome data and assessed changes in medical management at 6 and 12 months. Results: We returned P/LP results to 29 participants with outcome data. For 23 of the 29 participants, the P/LP results were previously unknown. Five of the 23 participants were already followed for conditions related to the P/LP variant. Of those receiving novel results and not being followed for the condition related to the P/LP result (n = 18), 14 (77.8%) had a change in healthcare after return of results (RoR). Following RoR, cascade testing of family members occurred for 10 of 23 (43.5%). Conclusions: The most common outcomes post-RoR included imaging/laboratory testing and health behavior recommendations. A change in healthcare was documented in 77.8% of those receiving results by 6 months. Our findings demonstrate how return of genomic screening results impacts healthcare in pediatric populations.

Abstract Background Carotid intraplaque hemorrhage (IPH) is considered a strong marker of histologically defined plaque vulnerability leading to cerebrovascular ischemic events. Cerebral microbleeds (CMBs) represent hemorrhage-prone small vessel disease and they are a common finding on brain MRI in patients with cerebrovascular disease. However, the potential mechanism and the risk for CMBs are not clear. The characteristics of carotid lesions have been considered relevant in the relationship between carotid artery atherosclerosis and the presence of CMBs. The potential association between carotid IPH histologically defined and CMBs has not been investigated yet. Purpose We have previously reported the prevalence of IPH in patients with non-obstructive carotid disease in patients who underwent carotid endarterectomy (CEA). In this study, we aimed to investigate whether the presence and the extent of carotid IPH are related to the existence of CMBs. We hypothesized that patients with carotid IPH would have a higher risk of CMBs. Methods This retrospective study enrolled 101 consecutive patients undergoing CEA with symptomatic (including ischemic stroke, TIA, and amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. Carotid plaque specimens were collected at CEA from all the patients and stained with Movat Pentachrome to identify the presence and the extent (%) of IPH. Neck CTA was obtained to measure the degree of carotid stenosis. Brain MRI was pre-surgically performed and CMBs were studied using T2*-weighted gradient-recalled echo (GRE) or susceptibility-weighted imaging (SWI) sequence. The CMBs were counted and localized. Clinical and biochemical data, comorbidities, and medications were recorded. The association between carotid IPH and CMBs was examined adjusted for other risk factors. Results The presence of carotid IPH was in 57 (56.4%) patients. CMBs were more observed in patients with carotid IPH compared to those without IPH [19 (33.3%) vs 5 (11.4%); p=0.010]. Logistic regression analysis demonstrated an association between the extent of IPH in the carotid atheroma and the presence of CMBs [OR 1.051 (95% CI 1.012–1.090); p=0.009]. Moreover, the carotid IPH extent was associated with the number of CMBs (p=0.004). In patients with CMBs, the median degree of ipsilateral carotid stenosis was 40% (35–65%) and it was 70% (50–80%) in those without CMBs, with a significant difference between the two groups (p=0.049). Conclusions In patients undergoing CEA, the histologically defined presence of carotid IPH and its extent are associated with CMBs on brain MR imaging. CMBs may be a potential mechanism for cerebrovascular events in patients with carotid atherosclerotic IPH and they may be an imaging marker that can distinguish the severity of the carotid artery disease. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Mayo Clinic Foundation