Research Spotlight

Kirby, T., Walters, D.C., Shi, X., Turgeon, C., Rinaldo, P., Arning, E., Ashcraft, P., Bottiglieri, T., DiBacco, M., Pearl, P.L., Roullet, J.B. and Gibson, K.M. (2020). “Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency.” Orphanet J Rare Dis 15(1): 261.

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BACKGROUND: Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Samples (mixed sex) included: patients (n = 21 unique samples, 1-39.5 yrs) and parallel controls (n = 9 unique samples, 8.4-34.8 yrs). Archival control data (DBS only; n = 171, 0.5-39.9 yrs) was also included. RESULTS: Metabolites assessed included amino acids (plasma, DBS) and acylcarnitines, creatine, creatinine, and guanidinoacetate (DBS only). Age-related negative correlations for glycine (plasma, DBS) and sarcosine (N-methylglycine, plasma) were detected, accompanied by elevated proline and decreased levels of succinylacetone, argininosuccinate, formaminoglutamate, and creatinine. Significantly low acylcarnitines were detected in patients across all chain lengths (short-, medium- and long-chain). Significant age-dependent positive correlations for selected acylcarnitines (C6-, C12DC(dicarboxylic)-, C16-, C16:1-, C18:1-, C18:2OH-carnitines) were detected in patients and absent in controls. Receiver operating characteristic (ROC) curves for all binary comparisons revealed argininosuccinate and succinylacetone to be the most discriminating biomarkers (area > 0.92). CONCLUSIONS: Age-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA. Our study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism

Kiselica, A.M., Kaser, A.N. and Benge, J.F. (2020). “An Initial Empirical Operationalization of the Earliest Stages of the Alzheimer’s Continuum.” Alzheimer Dis Assoc Disord Sep 21. [Epub ahead of print.].

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PURPOSE: The Alzheimer’s Continuum (AC) includes 2 preclinical stages defined by subjective cognitive complaints, transitional cognitive declines, and neurobehavioral symptoms. Operationalization of these stages is necessary for them to be applied in research. METHODS: Cognitively normal individuals with known amyloid biomarker status were selected from the National Alzheimer’s Coordinating Center Uniform Data Set. Participants and their caregivers provided information on subjective cognitive complaints, neurobehavioral features, and objective cognitive functioning. PATIENTS: The sample included 101 amyloid positive (A+) and 447 amyloid negative (A-) individuals. RESULTS: Rates of subjective cognitive complaints (A+: 34.90%, A-: 29.90%) and neurobehavioral symptoms (A+: 22.40%, A-: 22.40%) did not significantly differ between A+/- individuals. However, the frequency of transitional cognitive decline was significantly higher among A+ (38.00%) than A- participants (24.90%). We explored various empirical definitions for defining the early stages of the AC among A+ participants. Rates of classification into AC stage 1 versus AC stage 2 varied depending on the number of symptoms required: 57.40% versus 42.60% (1 symptom), 28.70% versus 71.30% (2 symptoms), and 6.90% versus 93.10% (all 3 symptoms). CONCLUSION: The presence of 2 of the proposed symptom classes to separate AC stage 2 from stage 1 seems to provide a good empirical balance.

El Ahmadieh, T.Y., Bedros, N.M., Stutzman, S.E., Nyancho, D., Venkatachalam, A.M., MacAllister, M., Ban, V.S., Dahdaleh, N.S., Aiyagari, V., Figueroa, S., White, J.A., Batjer, H., Bagley, C.A., Olson, H.D.M. and Aoun, S.G. (2020). “Automated Pupillometry as a Triage and Assessment Tool in Patients with Traumatic Brain Injury.” World Neurosurg Oct 1;S1878-8750(20)32171-9.

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OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults. Automated Infrared Pupillometry (AIP) has shown promising results in predicting neural damage in aneurysmal subarachnoid hemorrhage and ischemic stroke. We aimed to explore potential uses of AIP in triaging TBI patients. We hypothesized that a brain injury severe enough to require an intervention would show neurological pupillary index (NPI) changes. METHODS: We conducted a prospective pilot study at a Level-1 Trauma Center between November 2019 and February 2020. AIP readings of consecutive patients seen in the emergency department with blunt TBI and abnormal imaging findings on computed tomography were recorded by the assessing Neurosurgery resident. The relationship between NPI and surgical intervention was studied. RESULTS: Thirty-six patients were enrolled, 9 of which received an intervention. NPI was dichotomized into normal (≥3.0) versus abnormal (<3.0) and was predictive of intervention (Fishers exact test; p<0.0001). Six of the nine patients had a GCS ≤8, and imaging signs of increased ICP and underwent craniectomy (n=4) or ICP-monitor placement (n=2) and had an abnormal NPI. Three patients underwent ICP-monitor placement for GCS ≤8 in accordance with TBI guidelines despite minimal imaging findings and had a normal NPI. The GCS of these patients improved within 24-hours requiring ICP-monitor removal. NPI was normal in all patients who did not require intervention. CONCLUSIONS: AIP could potentially be useful in triaging comatose patients after blunt TBI. An NPI ≥3.0 may be reassuring in patients with no signs of mass-effect or increased ICP.

Asrani, S.K., Mellinger, J., Arab, J.P. and Shah, V.H. (2020). “Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action.” Hepatology Sep 28. [Epub ahead of print.].

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Alcohol-associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%-8.6%. In 2017, global prevalence of alcohol-associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol-associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi-faceted and focused on both population and patient-level interventions. Reductions in ALD-related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non-invasive serum and imaging markers, and risk-stratify higher-risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non-healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.

Jabbarzadeh-Tabrizi, S., Boutin, M., Day, T.S., Taroua, M., Schiffmann, R., Auray-Blais, C. and Shen, J.S. (2020). “Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model.” J Lipid Res Aug 31;jlr.RA120000909. [Epub ahead of print.].

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Fabry disease is caused by deficient activity of α-galactosidase A-an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins–and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney and dorsal root ganglion (DRG) were similar in two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared to Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in non-peptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of non-peptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.