Brain最新文献

Functional neuroimaging has provided several new tools for improving both the diagnosis and prognosis in patients with DoC. These tools are now being used to detect residual and covert awareness in behaviourally non-responsive patients with an acquired severe brain injury and predict which patients are likely to recover. Despite endorsement of advanced imaging by multiple clinical bodies, widespread implementation of imaging techniques such as functional MRI (fMRI), electroencephalography (EEG), and positron emission tomography (PET) in both acute and prolonged disorders of consciousness patients has been hindered by perceived costs, technological barriers, and lack of expertise needed to acquire, interpret, and implement these methods. In this review we provide a comprehensive overview of neuroimaging in DoC, the different technical approaches employed (i.e. fMRI, EEG, PET), the imaging paradigms used (active, passive, resting state) and the types of inferences that have been made about residual cortical function based on those paradigms (e.g., perception, awareness, communication). Next, we outline how these barriers might be overcome, discuss which select patients stand to benefit the most from these neuroimaging techniques, and consider when during their clinical trajectory imaging tests are likely to be most useful. Moreover, we make recommendations that will help clinicians decide which advanced imaging technologies and protocols are likely to be most appropriate in any particular clinical case. Finally, we describe how these techniques can be implemented in routine clinical care to augment current clinical tools and outline future directions for the field as a whole.

Tuberous sclerosis complex (TSC) is a phenotypically heterogeneous autosomal dominant epilepsy, neuropsychiatric, and tumoral predisposition disease, occurring due to germline variants in the TSC1 or TSC2 genes. Despite an improving understanding of the varied phenotypes TSC may present with, there remains an incomplete understanding of the disease trajectory and genotype-phenotype relationship in this disorder. We sought to examine whether an unbiased clustering approach could uncover subgroups of disease trajectories in TSC and enhance understanding of genotype-phenotype correlation. In this observational, prospective, multicentre natural history cohort of patients with confirmed diagnosis of TSC (TSC Alliance Natural History Database), data collected from 2006 - 2022 was used to identify groups of co-occurring phenotypes. This was a multicentre study involving 18 TSC clinical network centres in the US. 947 individuals were included, all of whom had a clinical diagnosis of tuberous sclerosis complex. Each patient was required to have complete characterization of 29 phenotype features associated with TSC. The primary outcomes were consensus clusters of clinical features defining subgroups of patients with TSC and their association with genotype. 947 individuals (50% male) across the TSC Alliance Natural History Database were included in this study, and 29 clinical features were used to define clusters of phenotypes to define disease trajectories. Four reproducible and distinct disease subgroups were identified: angiomyolipoma-predominant TSC (cluster 1), TSC with infantile spasms (cluster 2), neuropsychiatric TSC (cluster 3), and a milder phenotype of TSC (cluster 4). Variants in the rho domain of hamartin and the TSC1 binding domain of tuberin preferentially associated with cluster 1, with increased likelihood of angiomyolipomas, dermatologic findings, and subependymal giant cell astrocytoma. Four distinct disease subgroups exist in TSC and differentially associate with variant location, informing deep genotype-phenotype correlation in TSC with potential impact in personalizing disease surveillance, treatment, and clinical trial endpoint choice. Additional prospective data are needed to confirm these findings.

Rhabdomyolysis is an acute failure of cellular homeostasis resulting in muscle breakdown, triggered by trauma, infection, drugs, or strenuous exercise. Recurrent rhabdomyolysis is often associated with genetic and metabolic defects of skeletal muscle. The sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by the ATP2A2 gene, is an intracellular pump located in the sarcoplasmic and endoplasmic reticulum that is essential for maintaining intracellular calcium (Ca2+) homeostasis and is highly expressed in slow-twitch muscle. Heterozygous loss-of-function variants in ATP2A2 have previously been associated with dominant skin diseases, but not with rhabdomyolysis. In this study, we report a rare novel heterozygous missense variant in the ATP2A2 gene (c.1583G>A, p.R528Q) identified in 14 affected individuals from three unrelated families with recurrent rhabdomyolysis. Muscle biopsy revealed mild myopathic changes with fiber type uniformity, core-like structures, and Z-band streaming, but normal levels of SERCA2 protein. Ca2+ imaging showed that SR/ER Ca2+ reuptake mediated by SERCA2 was significantly slower in myotubes derived from patient fibroblasts carrying the c.1583G>A variant. We hypothesize that the ATP2A2 variant impairs SERCA2a function in slow-twitch muscle, disrupting SR Ca²⁺ reuptake and causing cytosolic Ca²⁺ overload following a trigger, leading to recurrent rhabdomyolysis. Morphant zebrafish embryos with atp2a2a knockdown showed morphological and functional muscle abnormalities with a reduction in body length and trunk muscle area associated with a reduction in locomotor activity in zebrafish larvae. Coinjection of wild-type human SERCA2a mRNA, but not variant SERCA2a mRNA, resulted in complete rescue of the phenotype. This study reveals a novel association between a heterozygous ATP2A2 variant and autosomal dominant recurrent rhabdomyolysis. Both in vitro and in vivo studies provide evidence that the variant alters SERCA2 function causing abnormal intracellular Ca2+ homeostasis in skeletal muscle, resulting in rhabdomyolysis. The work not only increases understanding of autosomal dominant rhabdomyolysis but also provides a diagnostic conclusion for three generations of affected individuals across the three families.

The blood-brain barrier (BBB) is a specialized vascular structure that protects the brain microenvironment from toxins and pathogens in the blood. At the same time, the BBB presents a significant challenge for drug development, as it restricts the entry of most therapeutics into the brain. In this review, we first examine recent findings on the molecular and cellular architecture of the BBB, emphasizing the diverse mechanisms that facilitate the transport and exchange of molecules between the blood and the brain. We discuss current knowledge on the heterogeneity of the BBB along the arteriovenous axis and across different brain regions. Then, we explore the molecular and functional changes in the BBB that occur during normal aging, neurodegeneration, and acute brain injuries and how prolonged BBB impairment affects transport mechanisms and disease progression. Additionally, we discuss novel developments in drug delivery strategies to transport small molecules, biologicals or cellular therapeutics across the BBB. Finally, we examine therapeutic opportunities to restore the BBB and discuss future directions in the field.