Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neurology
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22957
Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria
Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.
PMCID:6522063
PMID: 30615115
ISSN: 1460-2083
CID: 4310212
A benchmark for the size of the QM system required for accurate hybrid QM/MM calculations on the metal site of the protein copper, zinc superoxide dismutase
The protein superoxide dismutase 1 (SOD1) is a copper and zinc-binding protein that has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The Zn(II) binding to SOD1 is critical for the stability of the protein, and has been by itself implicated in ALS pathogenesis. Hence, the quantum mechanical (QM) study of the Zn(II)-site of SOD1 is relevant for understanding ALS. The hybrid QM-molecular mechanics (QM/MM) approach commonly employed for the QM study of proteins is highly dependent on the size of the sub-system treated quantum-mechanically. The size of the QM system also determines the computational feasibility of a given method. In the present work, we compare optimized geometries for the metal site and Zn(II) dissociation energies obtained with a QM/MM methodology employing different sizes for the QM sub-system. We find that geometries converge rapidly to RMSDs of around 0.3Â Ã…, and fails to converge further, while a QM system of 480 atoms was required for converging the Zn(II) interaction energy of SOD1 to within 5Â kcal*mol-1, and a 611-atoms QM system for a 1Â kcal*mol-1 convergence with respect to our reference, 1280 QM-atoms system. Graphical Abstract The size of the QM system is critical for both the accuracy and the computational cost of a QM/MM calculation. We have identified a optimum balance for the study of the active site of the coppper, zinc superoxide dismutase.
PMID: 31154525
ISSN: 0948-5023
CID: 5263532
Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults
In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.
PMID: 31262718
ISSN: 1950-6945
CID: 3967962
Short Takes [Editorial]
PMID: 30898415
ISSN: 1873-5150
CID: 3776232
Dispersion in Scores on the Richmond Agitation and Sedation Scale as a Measure of Delirium in Patients with Subdural Hematomas
BACKGROUND:Delirium is a frequent complication of critical illness, but its diagnosis is more difficult in brain-injured patients due to language impairment and disorders of consciousness. We conducted a prospective cohort study to determine whether Richmond Agitation and Sedation Scale (RASS) scores could be used to reliably diagnose delirium in the setting of brain injury. We also examined clinical factors associated with delirium in patients with subdural hematomas (SDH) and assessed its impact on functional outcome at discharge. METHODS:We prospectively enrolled 55 patients with the primary diagnosis of SDH admitted to the neurological intensive care unit (ICU) and screened them for delirium with the Confusion Assessment Method-ICU (CAM-ICU). As our primary outcome, we examined whether the standard deviation of RASS scores (RASS dispersion) could be used to diagnose delirium. We also looked at trends in RASS scores as a way to distinguish different causes of delirium. Then, using logistic regression, we identified factors associated with delirium in patients with SDH and quantified the impact of delirium on the modified Rankin Scale at discharge. RESULTS:Delirium as defined by the CAM-ICU was present in 35% (N = 19) of patients. RASS dispersion correlated well with the CAM-ICU (AUC of the ROC was 0.84). Analyzing the temporal trend of changes in the RASS was helpful in identifying new brain injuries as the underlying etiology of CAM-ICU positivity. Age, APACHE II scores on admission, baseline functional impairment, midline shift on initial imaging, and infections were associated with an increased risk of delirium. Delirium was associated with a worse functional outcome. CONCLUSIONS:RASS dispersion correlates highly with CAM-ICU positivity, and monitoring trends in RASS scores can identify delirium caused by new brain injuries. Delirium as defined by the CAM-ICU is common in patients with SDH and portends worse outcomes.
PMID: 30506177
ISSN: 1556-0961
CID: 3876182
Memory, Subjective Memory and Motor Functioning in Non-Demented Elders With and Without Parkinson's Disease
Parkinson's Disease (PD) is a progressive neurological condition characterized by motor and non-motor symptoms impacting life quality. The main aim of the current study was to investigate the effect of PD on objective (i.e., working memory and semantic memory) and subjective memory (i.e., self-reported seriousness of forgetting, mnemonic usage and actual memory efficiency) controlling for the effect of depressive symptomatology. The relationship of working memory performance to gait and mobility indices was also examined, as well as the factors predicting subjective memory were explored. Fifty-four community-dwelling adults (mean age = 72.3 years, SD = 8.8) were recruited in Sardinia, an Italian island located in the Mediterranean Sea. Specifically, 27 non-demented adults with mild, early-stage PD were matched for years of education, age, and gender with a sample of healthy individuals. Participants completed a test battery assessing objective memory, subjective memory, and depressive symptoms, and an instrumental analysis of gait and functional mobility was performed. Participants with PD had poorer objective memory across all indices measured and displayed a restricted set of gait and posture impairments. Working memory performance was selectively related to gait and posture measures. Moreover, participants with PD had lower trust in their memory efficiency relative to the past than the control healthy group. Finally, 22% of the variance in seriousness of the consequences of forgetting was predicted by education and general cognitive efficiency. Overall, the present findings confirm the presence of changes in both objective and subjective memory in PD, independent from depressive symptoms.
PMCID:7871757
PMID: 33574963
ISSN: 1841-0413
CID: 5353372
A catalog of genetic loci associated with kidney function from analyses of a million individuals
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
PMID: 31152163
ISSN: 1546-1718
CID: 3936112
Should there be less emphasis on levodopa-induced dyskinesia in Parkinson's disease?
PMID: 30983023
ISSN: 1531-8257
CID: 4095882
Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
PMID: 30739198
ISSN: 1432-0533
CID: 3691682
Mental health symptoms and disorders in elite athletes: a systematic review on cultural influencers and barriers to athletes seeking treatment
OBJECTIVE:To summarise the literature on the barriers to athletes seeking mental health treatment and cultural influencers of mental health in elite athletes. DESIGN/METHODS:Systematic review DATA SOURCES: PubMed, Cochrane, Scopus, SportDiscus (Ebsco), and PsycINFO (ProQuest) up to November 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES/UNASSIGNED:Qualitative and quantitative original studies of elite athletes (those who competed at the professional, Olympic, or collegiate/university levels), published in any language. RESULTS:Stigma, low mental health literacy, negative past experiences with mental health treatment-seeking, busy schedules, and hypermasculinity are barriers to elite athletes seeking mental health treatment. Cultural influencers of mental health in elite athletes include: (1) the lack of acceptance of women as athletes; (2) lower acceptability of mental health symptoms and disorders among non-white athletes; (3) non-disclosure of religious beliefs; and (4) higher dependence on economic benefits. Coaches have an important role in supporting elite athletes in obtaining treatment for mental illness. Brief anti-stigma interventions in elite athletes decrease stigma and improve literary about mental health. CONCLUSION/CONCLUSIONS:There is a need for various actors to provide more effective strategies to overcome the stigma that surrounds mental illness, increase mental health literacy in the athlete/coach community, and address athlete-specific barriers to seeking treatment for mental illness. In this systematic review, we identified strategies that, if implemented, can overcome the cultural factors that may otherwise limit athletes seeking treatment. Coaches are critical for promoting a culture within elite athletes' environments that encourages athletes to seek treatment.
PMID: 31092400
ISSN: 1473-0480
CID: 4174012
