Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex
The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.
KEY FINDINGS: The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.
BACKGROUND: With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD.
DETAILS: Authors designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. 196 sites were identified that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [RBFOX1], p = 0.04; 4:21788463 [KCNIP4], p < lt; 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [KCNQ5], p = 0.01 and 13:36667102 [DCLK1], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term "vocalization behavior" and "intraspecies interaction between organisms." Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes.
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Source: Zhang, M., Bouland, G. A., Holstege, H., et al. (2023). Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex. Neuro Genetics. 2023; 9(3): e200066. Published: June, 2023. DOI: 10.1212/NXG.0000000000200066.
Bleeding Reversal With Antifibrinolytics or Cryoprecipitate Following Thrombolysis for Acute Ischemic Stroke
While limited by its small sample size, this case series demonstrates significant variability in reversal strategies for thrombolysis-associated bleeding. It also provides additional evidence for the role of antifibrinolytics in this setting.
KEY FINDINGS: While limited by its small sample size, this case series demonstrates significant variability in reversal strategies for thrombolysis-associated bleeding. It also provides additional evidence for the role of antifibrinolytics in this setting.
BACKGROUND: Patients who develop an intracerebral hemorrhage (ICH) following thrombolysis in acute ischemic stroke (AIS) have a mortality rate as high as 50%.
DETAILS: Treatment options include blood products, such as cryoprecipitate, or antifibrinolytics, such as tranexamic acid (TXA) or ε-aminocaproic acid (EACA). Current guidelines recommend cryoprecipitate first-line despite limited data to support one agent over another. In addition, compared to antifibrinolytics, cryoprecipitate is higher in cost and requires thawing before use. This case series seeks to characterize the management of thrombolytic reversal at a single institution as well as provide additional evidence for antifibrinolytics in this setting. Patients were included for a retrospective review if they met the following criteria: presented between January 2011-January 2017, were >18 years of age, were admitted for AIS, received a thrombolytic, and received TXA EACA, or cryoprecipitate. Twelve patients met the inclusion criteria. Ten (83.3%) developed an ICH, one (8.3%) experienced gastrointestinal bleeding, and one (8.3%) had bleeding at the site of knee arthroscopy. Eleven patients received cryoprecipitate (median dose: 10 units), three received TXA (median dose: 1,000 mg), and one patient received EACA (13 g). TXA was administered faster than the first blood product at a mean time of 19 min and 137 min, respectively. Hemorrhagic expansion (N = 8, 66.67%) and inhospital mortality (N = 7, 58.3%) were high.
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Source: Bailey, A. M., Baum, R., Nestor, M .,et al. (2024). Bleeding Reversal With Antifibrinolytics or Cryoprecipitate Following Thrombolysis for Acute Ischemic Stroke: A Case Series. Advanced Emergency Nursing Journal. 2024; 46(2): 101-107. Published: April/June, 2024. DOI: 10.1097/TME.0000000000000512.
Worldwide Incidence of Suicides in Prison
Prison services worldwide, and particularly in Europe, should prioritise suicide prevention. Assessment and management of suicide risk in female individuals living in prison need particular attention due to excess mortality relative to community-based populations.
Summary
A Systematic Review With Meta-Regression Analyses
[Posted 3/Jun/2024]
AUDIENCE: Psychiatry, Ob/gyn
KEY FINDINGS: Prison services worldwide, and particularly in Europe, should prioritise suicide prevention. Assessment and management of suicide risk in female individuals living in prison need particular attention due to excess mortality relative to community-based populations. Interpretation of synthesised data needs to be done with caution due to high heterogeneity between jurisdictions.
BACKGROUND: Suicide is a leading cause of death during imprisonment. This systematic review aimed to synthesise available evidence of prison suicide incidence worldwide.
DETAILS: Authors systematically searched the scientific literature, data repositories, and prison system reports, supplemented by correspondence with prison administrations. Authors included reports on people living in prison but excluded studies in preselected groups (by age or offence type). Absolute numbers and incidence rates of suicide mortality per 100,000 person-years by sex and country were extracted from 2000 to 2021. IQRs were used to describe the suicide incidence in different world regions. Incidence rate ratios comparing suicides of people living in prison with age-standardised general populations were calculated. Authors conducted meta-regression analyses on national-level and prison-level factors to examine heterogeneity. Authors included three scientific studies, 124 official reports, and 11 datasets from email correspondence. Between 2000 and 2021, there were 29,711 reported suicides during 91.2 million person-years of imprisonment in 82 jurisdictions worldwide (sex-specific data available for 13,289 individuals: 12,544 [94.4%] male and 745 [5.6%] female individuals). There were large variations between countries, with most studies reporting suicide rates in the range of 24-89 per 100,000 person-years in both sexes (22-86 in male individuals and 25-107 in female individuals). In meta-regression analyses, Europe (vs other regions), high-income countries (vs low-income and middle-income countries), and countries with lower incarceration rates (vs those with higher incarceration rates) had higher suicide rates. Incidence rate ratios between people who are incarcerated and age-standardised general populations in the same jurisdictions were typically in the range of 1.9-6.0 in male and 10.4-32.4 in female individuals.
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Source: Mundt, A. P., Cifuentes-Gramajo, P. A., Baranyi, G. et al. (2024). Worldwide Incidence of Suicides in Prison: A Systematic Review With Meta-Regression Analyses. The Lancet. 2024; Published: May 29, 2024. DOI: 10.1016/S2215-0366(24)00134-2.
GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia
GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
KEY FINDINGS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia.
DETAILS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen.
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Source: Honkanen E. A., Rönkä J., Pekkonen E., et al. (2024). GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia. Journal of Neurology, Neurosurgery & Psychiatry. 2024; 95(4): 300-308. Published: April, 2024. DOI: 10.1136/jnnp-2023-331668.
Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies
HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
KEY FINDINGS: HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
BACKGROUND: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans.
DETAILS: The study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to TSC2 variants, 5 individuals with focal cortical dysplasia type IIA (FCD IIA) due to genetic variants in MTOR, AKT3, and PIK3CA, and 10 individuals with FCD IIB due to variants in TSC1, MTOR, RHEB, DEPDC5, or NPRL3). Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues (p < 0.0001) compared with those in controls, regardless of genetic cause or variant allele frequency. Elevated HCN4 was not observed in controls or individuals with non-mTOR-related focal epilepsy due to pathogenic variants in ATP1A3, SLC35A2, or FGFR1.
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Source: Coleman, M., Pinaes-Garcia, P., Stephenson, S. E., et al. (2024). Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies. Neuro Genetics. 2024; 10(2). Published: March, 2024. DOI: 10.1212/NXG.0000000000200135.
Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant
This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
KEY FINDINGS: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
BACKGROUND: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.
DETAILS: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.
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Source: Baskar, D., Polavarapu, K., Preethish-kumar, V., et al. (2024). Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant. Neuro Genetics. 2024; 10(1): Published: February, 2024. DOI: 10.1212/NXG.000000000020012.
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