Development of the basal hypothalamus through anisotropic growth

The adult hypothalamus is subdivided into distinct domains: pre‐optic, anterior, tuberal and mammillary. Each domain harbours an array of neurones that act together to regulate homeostasis. The embryonic origins and the development of hypothalamic neurones, however, remain enigmatic. Here, we summarise recent studies in model organisms that challenge current views of hypothalamic development, which traditionally have attempted to map adult domains to correspondingly located embryonic domains. Instead, new studies indicate that hypothalamic neurones arise from progenitor cells that undergo anisotropic growth, expanding to a greater extent than other progenitors, and grow in different dimensions. We describe in particular how a multipotent Shh^/Fgf10‐expressing progenitor population gives rise to progenitors throughout the basal hypothalamus that grow anisotropically and sequentially: first, a subset displaced rostrally give rise to anterior‐ventral/tuberal neuronal progenitors; then a subset displaced caudally give rise to mammillary neuronal progenitors; and, finally, a subset(s) displaced ventrally give rise to tuberal infundibular glial progenitors. As this occurs, stable populations of Shh^+ive and Fgf10^+ive progenitors form. We describe current understanding of the mechanisms that induce Shh^+ive/Fgf10^+ive progenitors and begin to direct their differentiation to anterior‐ventral/tuberal neuronal progenitors, mammillary neuronal progenitors and tuberal infundibular progenitors. Taken together, these studies suggest a new model for hypothalamic development that we term the “anisotropic growth model”. We discuss the implications of the model for understanding the origins of adult hypothalamic neurones.     

In vivo development of dendritic orientation in wild-type and mislocalized retinal ganglion cells

Background

The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated.

Results

Using a combination of genetic fate-mapping and loss-of-function analyses, we examined the contribution and function of Sonic hedgehog (Shh)-expressing and Shh-responsive (Nkx2-1 ⁺ and Gli1 ⁺) neurons in the medial amygdala. Specifically, we found that Shh- and Nkx2-1-lineage cells contribute differentially to the dorsal and ventral subdivisions of the postnatal medial amygdala. These Shh- and Nkx2-1-lineage neurons express overlapping and non-overlapping inhibitory neuronal markers, such as Calbindin, FoxP2, nNOS and Somatostatin, revealing diverse fate contributions in discrete medial amygdala nuclear subdivisions. Electrophysiological analysis of the Shh-derived neurons additionally reveals an important functional diversity within this lineage in the medial amygdala. Moreover, inducible Gli1 ^CreER(T2) temporal fate mapping shows that early-generated progenitors that respond to Shh signaling also contribute to medial amygdala neuronal diversity. Lastly, analysis of Nkx2-1 mutant mice demonstrates a genetic requirement for Nkx2-1 in inhibitory neuronal specification in the medial amygdala distinct from the requirement for Nkx2-1 in cerebral cortical development.

Conclusions

Taken together, these data reveal a differential contribution of Shh-expressing and Shh-responding cells to medial amygdala neuronal diversity as well as the function of Nkx2-1 in the development of this important limbic system structure.     

Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei

Background

The ventral midbrain contains a diverse array of neurons, including dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and neurons of the red nucleus (RN). Dopaminergic and RN neurons have been shown to arise from ventral mesencephalic precursors that express Sonic Hedgehog (Shh). However, Shh expression, which is initially confined to the mesencephalic ventral midline, expands laterally and is then downregulated in the ventral midline. In contrast, expression of the Hedgehog target gene Gli1 initiates in the ventral midline prior to Shh expression, but after the onset of Shh expression it is expressed in precursors lateral to Shh-positive cells. Given these dynamic gene expression patterns, Shh and Gli1 expression could delineate different progenitor populations at distinct embryonic time points.

Results

We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express Shh (Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from Shh- and Gli1-expressing progenitors located outside of the ventral midline give rise to astrocytes.

Conclusions

We define a ventral midbrain precursor map based on the timing of Gli1 and Shh expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions.     

Septal contributions to olfactory bulb interneuron diversity in the embryonic mouse telencephalon: role of the homeobox gene <Emphasis Type="Italic">Gsx2</Emphasis>

Background

Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified.

Methods

In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2 ^Cre/+ mice.

Results

Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin⁺ (CR⁺) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons. Moreover, Gsx2 conditional mutants (cKOs), with septum but not dLGE recombination, showed impaired generation of CR⁺ interneurons within the OB GL. These Gsx2 cKOs exhibited reduced proliferation within the septal subventricular zone (SVZ), which correlated well with the reduced number of CR⁺ interneurons observed.

Conclusions

Our findings indicate that the septum and LGE contribute differently to OB interneuron diversity. While the dLGE provides a wide range of OB interneuron subtypes, the septum is more restricted in its contribution to the CR⁺ subtype. Gsx2 is required in septal progenitors for the correct expansion of SVZ progenitors specified toward the CR⁺ subtype. Finally, the septum has been suggested to be the exclusive source of CR⁺ interneurons in postnatal studies. Our results here demonstrate that dLGE progenitors in the embryo also contribute to this OB neuronal subtype.

     

Topographical organization of projections from the subiculum to the hypothalamus in the rat

The projections from the subiculum to the hypothalamus were comprehensively examined in the rat by using the anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde cholera toxin B subunit (CTb) methods. Tracing of efferents with PHA-L indicated that the medial preoptic region received projection fibers from the temporal two-thirds of the subiculum, whereas the anterior, tuberal, and mammillary regions received those from the full longitudinal extent of the subiculum. The subicular projections to the anterior and tuberal hypothalamic regions were also found to be organized in a topographical manner such that the temporal-to-septal axis of origin in the subiculum determined a ventromedial-to-dorsolateral axis of termination in the medial zone of the hypothalamus: Massive labeled fibers from the temporalmost part of the subiculum terminated in the subparaventricular zone and its caudal continuum around the dorsal and medial aspects of the ventromedial nucleus, and those from progressively more septal parts terminated in progressively more dorsolateral parts of the medial zone. In addition, the temporal-to-septal axis of origin in the subiculum tended to determine a medial-to-lateral axis of termination in the preoptic region as well as a ventral-to-dorsal axis of termination in the mammillary region. Furthermore, the temporal-to-septal axis of origin in the septal two-thirds of the subiculum corresponded to a ventrolateral-to-dorsomedial axis of termination in the medial mammillary nucleus. The topographical projections from the subiculum to the medial zone of the hypothalamus were confirmed by CTb experiments, representatively in the subicular projections to the anterior hypothalamic region. These results suggest that different populations of neurons existing along the longitudinal axis of the subiculum may exert their influences on the execution of different hypothalamic functions.     

Lacking of palladin leads to multiple cellular events changes which contribute to NTD

Background

The actin cytoskeleton-associated protein palladin plays an important role in cell motility, morphogenesis and adhesion. In mice, Palladin deficient embryos are lethal before embryonic day (E) 15.5, and exhibit severe cranial neural tube and body wall closure defects. However, the mechanism how palladin regulates the process of cranial neural tube closure (NTC) remains unknown.

Methods

In this paper, we use gene knockout mouse to elucidate the function of palladin in the regulation of NTC process.

Results

We initially focuse on the expression pattern of palladin and found that in embryonic brain, palladin is predominantly expressed in the neural folds at E9.5. We further check the major cellular events in the neural epithelium that may contribute to NTC during the early embryogenesis. Palladin deficiency leads to a disturbance of cytoskeleton in the neural tube and the cultured neural progenitors. Furthermore, increased cell proliferation, decreased cell differentiation and diminished apical cell apoptosis of neural epithelium are found in palladin deficient embryos. Cell cycle of neural progenitors in Palladin ^-/- embryos is much shorter than that in wt ones. Cell adhesion shows a reduction in Palladin ^-/- neural tubes.

Conclusions

Palladin is expressed with proper spatio-temporal pattern in the neural folds. It plays a crucial role in regulating mouse cranial NTC by modulating cytoskeleton, proliferation, differentiation, apoptosis, and adhesion of neural epithelium. Our findings facilitate further study of the function of palladin and the underlying molecular mechanism involved in NTC.

     

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway

Membrane-bound solute carriers (SLCs) are essential as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC family comprise about 400 transporters, and we have identified two new putative family members, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). They cluster phylogenetically with SLCs of MFS type, and both proteins are conserved in chordates, while MFSD1 is also found in fruit fly. Based on homology modelling, we predict 12 transmembrane regions, a common feature for MFS transporters. The genes are expressed in abundance in mice, with specific protein staining along the plasma membrane in neurons. Depriving mouse embryonic primary cortex cells of amino acids resulted in upregulation of Mfsd1, whereas Mfsd3 is unaltered. Furthermore, in vivo, Mfsd1 and Mfsd3 are downregulated in anterior brain sections in mice subjected to starvation, while upregulated specifically in brainstem. Mfsd3 is also attenuated in cerebellum after starvation. In mice raised on high-fat diet, Mfsd1 was specifically downregulated in brainstem and hypothalamus, while Mfsd3 was reduced consistently throughout the brain.     

Correlation of occupational stress with depression,anxiety, and sleep in Korean dentists: cross-sectional study

Background

This study aimed to investigate the degree of occupational stress and the clinical mental state of dentists. In addition, we investigated the correlation of occupational stress with depression, anxiety, and sleep among dentists in Korea.

Methods

A cross-sectional survey on 231 dentists was conducted using the Doctor Job Stress Scale, Center for Epidemiologic Studies Depression Scale (CES-D), State-Trait Anxiety Index (STAI), and Pittsburgh Sleep Quality Index (PSQI). Correlation of occupational stress with mental health was investigated by adjusted multiple regression analysis.

Results

The scores of CES-D, STAI, and PSQI revealed a significant correlation with the Doctor Job Stress Scale (t?=?3.93, P?<?0.0001; t?=?4.05, P?<?0.0001; t?=?4.18, P?<?0.0001, respectively). In particular, patient factors and clinical responsibility/judgment factors were significantly associated with depression (t?=?2.80, P?=?0.0056; t?=?4.93, P?<?0.0001, respectively), anxiety (t?=?2.35, P?=?0.0195; t?=?5.11, P?<?0.0001, respectively), and sleep (t?=?3.78, P?=?0.0002; t?=?4.30, P?<?0.0001, respectively), whereas work factors were not associated with any mental health state.

Conclusions

This study confirms that dentists as professions experience more severe mental states. For successful mental health care among dentists, stress management focusing on interpersonal relationship with patients and responsibility as an expert rather than the intensity of work should be considered.

     

Transcranial Doppler Monitoring of Intracranial Pressure Plateau Waves

Background

Transcranial Doppler (TCD) has been used to estimate ICP noninvasively (nICP); however, its accuracy varies depending on different types of intracranial hypertension. Given the high specificity of TCD to detect cerebrovascular events, this study aimed to compare four TCD-based nICP methods during plateau waves of ICP.

Methods

A total of 36 plateau waves were identified in 27 patients (traumatic brain injury) with TCD, ICP, and ABP simultaneous recordings. The nICP methods were based on: (1) interaction between flow velocity (FV) and ABP using a “black-box” mathematical model (nICP_BB); (2) diastolic FV (nICP_FV _d ); (3) critical closing pressure (nICP_CrCP), and (4) pulsatility index (nICP_PI). Analyses focused on relative changes in time domain between ICP and noninvasive estimators during plateau waves and the magnitude of changes (? between baseline and plateau) in real ICP and its estimators. A ROC analysis for an ICP threshold of 35 mmHg was performed.

Results

In time domain, nICP_PI, nICP_BB, and nICP_CrCP presented similar correlations: 0.80 ± 0.24, 0.78 ± 0.15, and 0.78 ± 0.30, respectively. nICP_FV _d presented a weaker correlation (R = 0.62 ± 0.46). Correlations between ?ICP and ?nICP were better represented by nICP_CrCP and BB, R = 0.48, 0.44 (p < 0.05), respectively. nICP_FV _d and PI presented nonsignificant ? correlations. ROC analysis showed moderate to good areas under the curve for all methods: nICP_BB, 0.82; nICP_FV _d , 0.77; nICP_CrCP, 0.79; and nICP_PI, 0.81.

Conclusions

Changes of ICP in time domain during plateau waves were replicated by nICP methods with strong correlations. In addition, the methods presented high performance for detection of intracranial hypertension. However, absolute accuracy for noninvasive ICP assessment using TCD is still low and requires further improvement.

     

Social networks and symptomatic and functional outcomes in schizophrenia: a systematic review and meta-analysis

Purpose

To conduct a systematic review and meta-analysis to examine the strength of associations between social network size and clinical and functional outcomes in schizophrenia.

Method

Studies were identified from a systematic search of electronic databases (EMBASE, Medline, PsycINFO, and Web of Science) from January 1970 to June 2016. Eligible studies included peer-reviewed English language articles that examined associations between a quantitative measure of network size and symptomatic and/or functional outcome in schizophrenia-spectrum diagnoses.

Results

Our search yielded 16 studies with 1,929 participants. Meta-analyses using random effects models to calculate pooled effect sizes (Hedge’s g) found that smaller social network size was moderately associated with more severe overall psychiatric symptoms (N?=?5, n?=?467, g?=???0.53, 95% confidence interval (CI)?=???0.875, ??0.184, p?=?0.003) and negative symptoms (N?=?8, n?=?577, g?=???0.75, 95% CI?=???0.997, ??0.512, p?=?0.000). Statistical heterogeneity was observed I²?=?63.04%; I²?=?35.75%,) which could not be explained by low-quality network measures or sample heterogeneity in sensitivity analyses. There was no effect for positive symptoms (N?=?7, n?=?405, g?=???0.19, 95% CI?=?0.494, 0.110, p?=?0.213) or social functioning (N?=?3, n?=?209, g?=?0.36, 95% CI?=???0.078, 0.801, p?=?0.107). Narrative synthesis suggested that larger network size was associated with improved global functioning, but findings for affective symptoms and quality of life were mixed.

Conclusion

Psychosocial interventions which support individuals to build and maintain social networks may improve outcomes in schizophrenia. The review findings are cross-sectional and thus causal direction cannot be inferred. Further research is required to examine temporal associations between network characteristics and outcomes in schizophrenia and to test theoretical models relating to explanatory or mediating mechanisms.

     

GBA-Associated Parkinson’s Disease and Other Synucleinopathies

Purpose of Review

GBA mutations are the most common known genetic cause of Parkinson’s disease (PD). Its biological pathway may be important in idiopathic PD, since activity of the enzyme encoded by GBA, glucocerebrosidase, is reduced even among PD patients without GBA mutations. This article describes the structure and function of GBA, reviews recent literature on the clinical phenotype of GBA PD, and suggests future directions for research, counseling, and treatment.

Recent Findings

Several longitudinal studies have shown that GBA PD has faster motor and cognitive progression than idiopathic PD and that this effect is dose dependent. New evidence suggests that GBA mutations may be important in multiple system atrophy. Further, new interventional studies focusing on GBA PD are described. These studies may increase the interest of PD patients and caregivers in genetic counseling.

Summary

GBA mutation status may help clinicians estimate PD progression, though mechanisms underlying GBA and synucleinopathy require further understanding.

     

Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia

Introduction

We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD).

Methods

Presymptomatic MAPT (n?=?15) and GRN mutation carriers (n?=?31), and healthy controls (n?=?39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression.

Results

MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p?<?0.05). Cognitive decline in ScreeLing phonology (p?=?0.046) and letter fluency (p?=?0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p?=?0.025) for an underlying MAPT mutation.

Discussion

Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD.

     

Interaction between cytochrome P450 2A6 and Catechol-<Emphasis Type="Italic">O</Emphasis>-Methyltransferase genes and their association with smoking risk in young men

Background

Although some effects of gene–gene interactions on nicotine–dopamine metabolism for smoking behavior have been reported, polymorphisms of cytochrome P450 (CYP) 2A6 and catechol-O-methyltransferase (COMT) have not been studied together to determine their effects on smokers. The aim of this study was to investigate the effects of the interaction between the CYP 2A6 and COMT genes on smoking behavior in young Taiwanese men.

Results

A self-report questionnaire regarding smoking status was administered to 500 young men. Polymorphisms of the CYP 2A6 and COMT genes as well as urinary nicotine and urinary cotinine levels were determined. The odds ratio for starting smoking was significantly lower in subjects carrying a CYP2A6 low activity/variant COMT rs4680 genotype than in those possessing a CYP2A6 wild-type/variant COMT rs4680 genotype (0.44, 95% confidence interval = 0.19–0.98, P = 0.043). Comparisons of Fagerstrom Test for Nicotine Dependence (FTND), Physiological Cigarette Dependence Scale (PCDS), and Cigarette Withdrawal symptoms (CWS-21) among the smokers with different CYP2A6/COMT polymorphisms were not significantly different. The adjusted urinary nicotine concentrations were not significantly different between the two groups carrying different genotypes. The adjusted urinary cotinine level was significantly different between the COMT rs4680 wild-type group and COMT rs4680 variant group [92.46 ng/μL vs. 118.24 ng/μL (median value), P = 0.041] and between the COMT rs4680 wild-type/COMT rs165599 variant group and COMT rs4680 variant/COMT rs165599 variant group (97.10 ng/μL vs. 122.18 ng/μL, P = 0.022).

Conclusions

These findings suggest that a single nucleotide polymorphism (rs4680) of the COMT gene and the interaction between the CYP 2A6 and COMT genes affect smoking status in young Taiwanese men.

     

Radiographic and microsurgical characteristics of proximal (A1) segment aneurysms of the anterior cerebral artery

Background

Proximal A1 segment aneurysms of the anterior cerebral artery (ACA) radiologically resemble internal carotid artery bifurcation (ICBIF) aneurysms because of their anatomical proximity. However, proximal A1 aneurysms exhibit distinguishing features, relative to ICBIF aneurysms. We report our experience of managing proximal A1 aneurysms, then compare them to ICBIF aneurysms.

Methods

Among 2191 aneurysms treated between 2000 and 2016 in a single institution, we retrospectively reviewed 100 cases categorized as ICBIF or A1 aneurysms. We included aneurysms originating from the ICBIF and ACA, proximal to the anterior communicating artery (A1 segment) and divided them into two groups: proximal A1 (n?=?32) and ICBIF (n?=?50). If any portion of the aneurysm involved the ICBIF, it was classified as ICBIF. Aneurysms wholly located in the A1 segment were classified as proximal A1. Patient factors and angiographic factors were evaluated and compared.

Results

The proximal A1 group exhibited differences in aneurysm size (p?=?0.013), posterior aneurysm direction (p?=?0.001), and A1 perforators as incorporating vessels (p?=?0.001). The proximal A1 group tended to rupture more frequently when the aneurysm was smaller (p?=?0.046). One case of morbidity occurred in the proximal A1 group.

Conclusion

Compared to ICBIF aneurysms, proximal A1 aneurysms were smaller and directed posteriorly, with incorporating perforators. Because of these characteristics, it may be difficult to perform clipping with 360° view in microsurgical field. Therefore, when planning to treat proximal A1 aneurysms, different treatment strategies may be necessary, relative to those used for ICBIF aneurysms.

     

Emerging Monogenic Complex Hyperkinetic Disorders

Purpose of Review

Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.

Recent Findings

Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,.

Summary

Thanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.

     

<Emphasis Type="Italic">ABCC8</Emphasis> Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

Objective

Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE.

Methods

DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy.

Results

Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004).

Conclusions

This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.