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7 Tesla-field-strength (7 T) Magnetic Resonance Imaging allows the small perforating arteries in the brain to be visualised, and this modality may allow visualisation of the arterial pathology in cerebral small vessel disease. Most studies have used standard Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA). Whether the use of contrast enhancement improves perforating artery visualisation at 7 T remains unclear. In a prospective study, we compared standard ToF MRA with contrast-enhanced (CE) ToF MRA at 7 T for the visualisation of the lenticulostriate arteries (LSAs). Ten patients with symptomatic lacunar stroke were recruited (mean age, SD, 64 ± 9.9 years). Visualisation was assessed using a visual rating scale administered by two independent expert readers and length of the LSAs visible. Visualisation of the LSAs was improved with CE ToF MRA. The mean Visibility and Sharpness Score was higher for CE ToF MRA over standard ToF MRA (2.55 ± 0.64 vs. 1.75 ± 0.68; P = 0.0008). The mean length of LSA visualised was significantly longer with CE ToF MRA compared to standard ToF MRA (24.4 ± 4.5 vs. 21.9 ± 4.0 mm; P = 0.01). CE ToF MRA offers improved visualisation of the LSAs over standard ToF MRA. The addition of contrast may improve the ability to visualise cerebral small vessel disease arterial pathology., BHF Cambridge BHF CRE NIHR Cambridge Biomedical Research Centre

Funder: Medical Research Council, Funder: The Stroke Association, Stroke is a leading cause of disability, and language impairments (aphasia) after stroke are both common and particularly feared. Most stroke survivors with aphasia exhibit anomia (difficulties with naming common objects), but while many therapeutic interventions for anomia have been proposed, treatment effects are typically much larger in some patients than others. Here, we asked whether that variation might be more systematic, and even predictable, than previously thought. 18 patients, each at least 6 months after left hemisphere stroke, engaged in a computerised treatment for their anomia over a 6-week period. Using only: (a) the patients’ initial accuracy when naming (to-be) trained items; (b) the hours of therapy that they devoted to the therapy; and (c) whole-brain lesion location data, derived from structural MRI; we developed Partial Least Squares regression models to predict the patients’ improvements on treated items, and tested them in cross-validation. Somewhat surprisingly, the best model included only lesion location data and the hours of therapy undertaken. In cross-validation, this model significantly out-performed the null model, in which the prediction for each patient was simply the mean treatment effect of the group. This model also made promisingly accurate predictions in absolute terms: the correlation between empirical and predicted treatment response was 0.62 (95% CI 0.27, 0.95). Our results indicate that individuals’ variation in response to anomia treatment are, at least somewhat, systematic and predictable, from the interaction between where and how much lesion damage they have suffered, and the time they devoted to the therapy.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Various methodologies to assess cerebral autoregulation (CA) have been developed, including model - based methods (e.g. autoregulation index, ARI), correlation coefficient - based methods (e.g. mean flow index, Mx), and frequency domain - based methods (e.g. transfer function analysis, TF). Our understanding of relationships among CA indices remains limited, partly due to disagreement of different studies by using real physiological signals, which introduce confounding factors. The influence of exogenous noise on CA parameters needs further investigation. Using a set of artificial cerebral blood flow velocities (CBFV) generated from a well-known CA model, this study aims to cross-validate the relationship among CA indices in a more controlled environment. Real arterial blood pressure (ABP) measurements from 34 traumatic brain injury patients were applied to create artificial CBFVs. Each ABP recording was used to create 10 CBFVs corresponding to 10 CA levels (ARI from 0 to 9). Mx, TF phase, gain and coherence in low frequency (LF) and very low frequency (VLF) were calculated. The influence of exogenous noise was investigated by adding three levels of colored noise to the artificial CBFVs. The result showed a significant negative relationship between Mx and ARI (r = −0.95, p

Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf and TrkB leads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised a de novo missense variant in BDNF and seven rare variants in TrkB identified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons. BDNF/TrkB variant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of function BDNF/TrkB variants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders.

We investigated effects of the ryanodine receptor (RyR) modulator caffeine on Na+ current (INa) activation and inactivation in intact loose-patch clamped murine skeletal muscle fibres subject to a double pulse procedure. INa activation was examined using 10-ms depolarising, V1, steps to varying voltages 0–80 mV positive to resting membrane potential. The dependence of the subsequent, INa inactivation on V1 was examined by superimposed, V2, steps to a fixed depolarising voltage. Current-voltage activation and inactivation curves indicated that adding 0.5 and 2 mM caffeine prior to establishing the patch seal respectively produced decreased (within 1 min) and increased (after ~2 min) peak INa followed by its recovery to pretreatment levels (after ~40 and ~30 min respectively). These changes accompanied negative shifts in the voltage dependence of INa inactivation (within 10 min) and subsequent superimposed positive activation and inactivation shifts, following 0.5 mM caffeine challenge. In contrast, 2 mM caffeine elicited delayed negative shifts in both activation and inactivation. These effects were abrogated if caffeine was added after establishing the patch seal or with RyR block by 10 μM dantrolene. These effects precisely paralleled previous reports of persistently (~10 min) increased cytosolic [Ca2+] with 0.5 mM, and an early peak rapidly succeeded by persistently reduced [Ca2+] likely reflecting gradual RyR inactivation with ≥1.0 mM caffeine. The latter findings suggested inhibitory effects of even resting cytosolic [Ca2+] on INa. They suggest potentially physiologically significant negative feedback regulation of RyR activity on Nav1.4 properties through increased or decreased local cytosolic [Ca2+], Ca2+-calmodulin and FKBP12.

Existing cerebrovascular blood pressure autoregulation metrics have not been translated to clinical care for pediatric cardiac arrest, in part because signal noise causes high index time-variability. We tested whether a wavelet method that uses near-infrared spectroscopy (NIRS) or intracranial pressure (ICP) decreases index variability compared to that of commonly used correlation indices. We also compared whether the methods identify the optimal arterial blood pressure (ABPopt) and lower limit of autoregulation (LLA). 68 piglets were randomized to cardiac arrest or sham procedure with continuous monitoring of cerebral blood flow using laser Doppler, NIRS and ICP. The arterial blood pressure (ABP) was gradually reduced until it dropped to below the LLA. Several autoregulation indices were calculated using correlation and wavelet methods, including the pressure reactivity index (PRx and wPRx), cerebral oximetry index (COx and wCOx), and hemoglobin volume index (HVx and wHVx). Wavelet methodology had less index variability with smaller standard deviations. Both wavelet and correlation methods distinguished functional autoregulation (ABP above LLA) from dysfunctional autoregulation (ABP below the LLA). Both wavelet and correlation methods also identified ABPopt with high agreement. Thus, wavelet methodology using NIRS may offer an accurate vasoreactivity monitoring method with reduced signal noise after pediatric cardiac arrest.

We investigated effects of the ryanodine receptor (RyR) modulator caffeine on Na+ current (INa) activation and inactivation in intact loose-patch clamped murine skeletal muscle fibres subject to a double pulse procedure. INa activation was examined using 10-ms depolarising, V1, steps to varying voltages 0–80 mV positive to resting membrane potential. The dependence of the subsequent, INa inactivation on V1 was examined by superimposed, V2, steps to a fixed depolarising voltage. Current-voltage activation and inactivation curves indicated that adding 0.5 and 2 mM caffeine prior to establishing the patch seal respectively produced decreased (within 1 min) and increased (after ~2 min) peak INa followed by its recovery to pretreatment levels (after ~40 and ~30 min respectively). These changes accompanied negative shifts in the voltage dependence of INa inactivation (within 10 min) and subsequent superimposed positive activation and inactivation shifts, following 0.5 mM caffeine challenge. In contrast, 2 mM caffeine elicited delayed negative shifts in both activation and inactivation. These effects were abrogated if caffeine was added after establishing the patch seal or with RyR block by 10 μM dantrolene. These effects precisely paralleled previous reports of persistently (~10 min) increased cytosolic [Ca2+] with 0.5 mM, and an early peak rapidly succeeded by persistently reduced [Ca2+] likely reflecting gradual RyR inactivation with ≥1.0 mM caffeine. The latter findings suggested inhibitory effects of even resting cytosolic [Ca2+] on INa. They suggest potentially physiologically significant negative feedback regulation of RyR activity on Nav1.4 properties through increased or decreased local cytosolic [Ca2+], Ca2+-calmodulin and FKBP12.