ABCD1 Research Articles

Net clinical benefit of NOAC in Korean atrial fibrillation patients with low to intermediate stroke risk

Abstract Background The balance of stroke risk reduction and potential hemorrhagic risk associated with anti-thrombotic treatment (ATT) remain unclear in Korean atrial fibrillation (AF) patients with low to intermediate stroke risk, defined as non-gender CHA2DS2-VASc score 0–1. Purpose The net clinical benefit (NCB) analysis of ATT may be helpful to guide stroke prevention strategy in AF patients with non-gender CHA2DS2-VASc score 0–1. Methods This Korean multi-center cohort study retrospectively evaluated the clinical outcomes with single antiplatelet (SAPT), vitamin K antagonist (VKA), and non-vitamin K antagonist oral anticoagulant (NOAC) in non-gender CHA2DS2-VASc score 0–1 and further stratified by biomarker-based ABCD score (Age [≥60 years], B-type natriuretic peptide [BNP] or N-terminal pro-BNP [≥300 pg/ml], Creatinine clearance [<50 ml/min/1.73 m2], and Dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT including thromboembolic and major bleeding events. Results We included 2465 patients (56.2±9.5 years; female, 665 [27.0%]) followed-up for 4.0±2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. In comparison with no treatment, only NOAC demonstrated a positive tendency for stroke prevention (NOAC, NCB 0.47, 95% confidence interval [CI] −0.40 to 2.10; SAPT, NCB −0.31, 95% CI −1.48 to 1.40; and VKA, NCB −1.26, 95% CI −2.97 to 0.67). With detailed risk stratification with ABCD score, NOAC showed a significant NCB for stroke prevention compared with SAPT and VKA (SAPT vs. NOAC, NCB 1.6, 95% CI 0.26–3.50; VKA vs. NOAC, NCB 1.96, 95% CI 0.47–4.16) in patients with ABCD score ≥1. ATT failed to show NCB in patients with truly low stroke risk defined as ABCD score=0. Conclusion Korean AF cohort with low to intermediate stroke risk indicates that, in comparison with no ATT, only ATT with NOAC showed marginal NCB. With further risk stratification by ABCD score, NOAC showed significant advantages over other ATTs (VKA or SAPT) in patients with ABCD ≥1. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Korean Disease Control and Prevention Agency

305 Managing Low and Intermediate Risk Transient Ischemic Attacks in the Time of a Pandemic

Transient Ischemic Attacks (TIA) are both a harbinger of acute ischemic stroke and warrant urgent evaluation and management to reduce stroke risk. Recently, there has been increasing acceptance to evaluate low-risk (ABCD2 score 0-3) patients in an outpatient setting, but there is limited data on management of intermediate (ABCD2 score 4-5) risk patients. We hypothesized that intermediate risk TIA patients being treated according to protocolized medical management and diagnostic testing would have similar clinic follow-up and re- admission rates to low-risk patients.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

When Can an Emergency CTA Be Dispensed with for TIA Patients?

Background: Transient ischemic attacks (TIAs) and minor strokes are often precursors of a major stroke. Therefore, diagnostic work-up of the TIA is essential to reduce the patient’s risk of further ischemic events. Purpose: With the help of this retrospective study, we aim to determine for which TIA patients a CT angiography (CTA) is not immediately necessary in order to reduce radiation exposure and nephrotoxicity. Material and Methods: Clinical and imaging data from patients who presented as an emergency case with a suspected diagnosis of TIA at a teaching hospital between January 2016 and December 2021 were evaluated. The included 1526 patients were divided into two groups—group 1, with major pathologic vascular findings in the CTA, and group 2, with minor vascular pathologies. Results: Out of 1821 patients with suspected TIA on admission, 1526 met the inclusion criteria. In total, 336 (22%) had major vascular pathologies on CTA, and 1190 (78%) were unremarkable. The majority of patients with major vascular pathologies were male and had a history of arterial hypertension, coronary heart disease, myocardial infarction, ischemic stroke, TIA, atherosclerotic peripheral vascular disease, smoking, antiplatelet medication, had a lower duration of TIA symptoms, and had lower ABCD2 scores. Conclusions: We were able to demonstrate a direct correlation between major CTA pathologies and a history of smoking, age, hyperlipidemia, history of peripheral arterial disease, and a history of stroke and TIA. We were able to prove that the ABCD2 score is even reciprocal to CTA pathology. This means that TIA patients without described risk factors do not immediately require a CTA and could be clarified in the course of treatment with ultrasound or MRI.

Rehabilitation of a 17-Year-Old Patient with X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy is an X-linked recessive disease affecting the white matter of the central nervous system along with occasional involvement of the adrenal gland due to mutation of the ABCD1 gene, which leads to accumulation of very-long-chain fatty acid (VLCFA) in the white matter of the brain and adrenal cortex. Diminished vision, speech disturbance, motor weakness, bladder–bowel involvement and adrenal insufficiency can be seen in affected individuals according to phenotype and involved area. In this case, the patient was a 17-year-old male with progressive weakness of all limbs along with the difficulty of speech and vision. Magnetic resonance imaging showed T2 hyperintensity in white matters of temporo-parieto-occipital region, splenium and body of corpus callosum, peritrigonal area, posterior limb of internal capsule and corticospinal tract location of pons and midbrain. His plasma VLCFA was elevated. Along with medical treatment, our rehabilitation team comprising a physiatrist and other supporting members provided rehabilitation management. Although different methods such as dietary modification, bone marrow transplantation and gene therapy have been tried for these types of cases globally, rehabilitation remains the backbone of the management protocol for advanced cases.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention

BackgroundIndividuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. MethodsWe began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. ConclusionThe AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

ABCD2, ABCD2-I, and OTTAWA scores for stroke risk assessment: a direct retrospective comparison

Transient ischemic attack (TIA) is a neurologic emergency characterized by cerebral ischemia eliciting a temporary focal neurological deficit. Many clinical prediction scores have been proposed to assess the risk of stroke after TIA; however, studies on their clinical validity and comparisons among them are scarce. The objective is to compare the accuracy of ABCD2, ABCD2-I, and OTTAWA scores in the prediction of a stroke at 7, 90 days, and 1 year in patients presenting with TIA. Single-centre, retrospective study including patients with TIA admitted to the Emergency Department of our third-level, University Hospital, between 2018 and 2019. Five hundred three patients were included. Thirty-nine (7.7%) had a stroke within 1 year from the TIA: 9 (1.7%) and 24 (4.7%) within 7 and 90 days, respectively. ABCD2, ABCD2-I, and OTTAWA scores were significantly higher in patients who developed a stroke. AUROCs ranged from 0.66 to 0.75, without statistically significant differences at each time-point. Considering the best cut-off of each score, only ABCD2 > 3 showed a sensitivity of 100% only in the prediction of stroke within 7 days. Among clinical items of each score, duration of symptoms, previous TIA, hemiparesis, speech disturbance, gait disturbance, previous cerebral ischemic lesions, and known carotid artery disease were independent predictors of stroke. Clinical scores have moderate prognostic accuracy for stroke after TIA. Considering the independent predictors for stroke, our study indicates the need to continue research and prompts the development of new tools on predictive scores for TIA.

The etiology and clinical features of non-CAH primary adrenal insufficiency in children.

BackgroundThe most common cause of primary adrenal insufficiency (PAI) in children is congenital adrenal hyperplasia; however, other genetic causes occur. There is limited epidemiological and clinical information regarding non-CAH PAI.MethodsData for patients diagnosed from January 2015 to December 2021 at a tertiary hospital in northern China were retrospectively analyzed. We excluded those with CAH, which is the most common pathogenic disease among PAI patients. Next-generation sequencing was used for genetic analysis.ResultsThis retrospective study included 16 children (14 males and 2 females) with PAI. A genetic diagnosis was obtained for 14/16 (87.5%) individuals. Pathogenic variants occurred in 6 genes, including ABCD1 (6/16, 37.5%), NR0B1 (4/16, 25.0%), NR5A1/steroidogenic factor-1 (2/16; 12.5%), AAAS (1/16, 6.25%), and NNT (1/16, 6.25%). No genetic cause of PAI diagnosis was found in 2 girls (2/16, 12.5%).ConclusionsCauses of PAI in children are diverse and predominantly affect males. Most PAI in children is congenital, and ABCD1 gene defects account for the largest proportion of PAI cases. Whole-exome sequencing is a tool for diagnosis. However, diagnoses are unclear in some cases.

ABCD1 Gene Mutations: Mechanisms and Management of Adrenomyeloneuropathy.

Pathogenic variants in the ABCD1 gene on the X chromosome may result in widely heterogenous phenotypes, including adrenomyeloneuropathy (AMN). Affected males typically present in their third or fourth decade of life with progressive lower limb weakness and spasticity, and may develop signs and symptoms of adrenal insufficiency and/or cerebral demyelination. Heterozygous females may be asymptomatic, but may develop a later-onset and more slowly progressive spastic paraparesis. In this review, we describe the clinical presentation of AMN, as well as its diagnosis and management. The role of rehabilitative therapies and options for management of spasticity are highlighted.

High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan

BackgroundAdrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by variants in the ABCD1 gene and can lead to Addison disease, childhood cerebral ALD, or adrenomyeloneuropathy. Presymptomatic hematopoietic stem cell transplantation is the only curative treatment for the disease and requires early detection through newborn screening (NBS) and close follow-up. MethodsAn NBS program for ALD was performed by a two-tiered dried blood spot (DBS) lysophosphatidylcholine C26:0 (C26:0-LPC) concentration analysis. ABCD1 sequencing was eventually added as a third-tier test, and whole exome sequencing was used to confirm the diagnosis of all peroxisomal diseases. Affected newborns were followed-up for adrenal insufficiency and cerebral white matter abnormalities. ResultsWe identified 12 males and 10 females with ABCD1 variants, and 3 patients with Zellweger syndrome from 320,528 newborns. Eight (36.4%) ABCD1 variants identified in the current study were null variants, but there were no hotspots or founder effect. During a median follow-up period of 2.28 years, two (16.7%) male patients with ABCD1 variants developed Addison's disease. Extended family screening revealed one 28-year-old asymptomatic hemizygous father of a null variant (c.678delC). Among the three with Zellweger syndrome, one died at the age of 3 months, one showed developmental delay at the age of 1 year, and one was lost to follow-up. ConclusionScreening for ALD has been added to the NBS program in Taiwan with a high degree of success. The screening algorithm revealed a high proportion of null variants in cases found by NBS in Taiwan, a subset of patients who may have earlier disease onset. We also demonstrate the feasibility of combining the diagnosis of ALD and other peroxisomal disorders into one screening algorithm.

Clinical Features Differ Between Patients With Vertigo Attack Only and Weakness Attack Accompanying Vertigo Before Vertebrobasilar Stroke: A Retrospective Study.

ObjectiveTo determine the different clinical features of patients with vertigo attacks alone and of those with weakness accompanying vertigo attacks before the vertebrobasilar ischemic stroke.MethodsIn this 4-year retrospective study, we manually screened the medical records of 209 patients, hospitalized with vertigo attack as the main complaint who were finally diagnosed with acute vertebrobasilar ischemic stroke. Patients were divided into two groups according to their symptoms: patients who only experienced vertigo attacks prior to the vertebrobasilar stroke (VO group) and patients who had both vertigo and weakness attacks (VW group) prior to the stroke. Clinical parameters, such as infarction site and volume, relative risk factors, ABCD2 score, and medical intervention, were compared between the two groups.ResultsThe prevalence of hypertension was higher in the Vertigo attacks only (VO) group (42.2 vs. 29.0%, p < 0.05). The total cerebral infarction volume in the VO group was larger than the Vertigo and weakness attacks (VW) group (4.44 vs. 2.12 cm3, p < 0.05). Additionally, the cerebellum was more likely to be affected in the VO group. In contrast, patients in the VW group had higher carotid stenosis (14.2 vs. 27.2%, p < 0.05) and ABCD2 score (2.1 ± 1.2 vs. 3.6 ± 1.5, p = 0.02). The percentage of patients with medullary infarctions also increased in the VW group. Vertigo attack events occurred more frequently in the VW group (median 2.4 vs. 4.3, p < 0.04). We also found that the patients in the VW group were more likely to seek medical intervention after vertigo.ConclusionsClinical parameters, such as infarction location, relative risk factors, and ABCD2 score, differed between patients with vertigo symptoms with or without weakness attacks. These findings highlight the different clinical features of patients with vertigo attack only and those with weakness attacks accompanying vertigo prior to vertebrobasilar ischemic stroke.

External validation of ABCD series scores for predicting early stroke events following transient ischemic attack in a large nationwide registry.

In the context of modern guideline-based strategies, new validations of prognostic scores for predicting early stroke risk are needed. We aimed to compare the validity of the ABCD series scores and assess the incremental values of risk components for predicting in-hospital stroke events in patients with transient ischemic attack (TIA). We abstracted data from the Chinese Stroke Center Alliance (CSCA), a nationwide registry with 68,433 TIA patients admitted within 7 days of symptom onset from 1476 hospitals. TIA was defined by time-based criteria according to the World Health Organization (WHO). The discrimination of ABCD, ABCD2, ABCD2-I, and ABCD3 scores for predicting in-hospital stroke events was assessed by the area under the receiver-operating characteristics curves (AUC). The incremental predictive values of added risk predictor were determined by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). A total of 29,286 TIA patients were included, of whom 1466 (5.0%) had in-hospital stroke events. Compared with ABCD2-I score (AUC 0.79, 95% confidence interval [CI] 0.77-0.80), ABCD (AUC 0.58, 95% CI 0.57-0.60), ABCD2 (AUC 0.58, 95% CI 0.56-0.59), and ABCD3 (AUC 0.58, 95% CI 0.56-0.60) had lower predictive utility. An incremental value was observed when adding infarction on DWI (IDI = 0.0597, NRI = 1.1036) into ABCD2 score to be ABCD2-I. The traditional scales utilizing medical history (ABCD, ABCD2, and ABCD3 scores) show fair ability for predicting in-hospital stroke events after TIA, but the ABCD2-I score, which adds infarction on DWI, improves the predictive ability.

Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy.

Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1-/- mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50-54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6-7% after 24 months. In addition, 29-32% of cervical spinal cord astrocytes at 3 weeks and 16-19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33-41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest.

Intracerebral lentiviral ABCD1 gene therapy in an early disease onset ALD mouse model.

X-linked adrenoleukodystrophy (ALD) is a genetic disorder of the ABCD1 gene. We aimed to treat ALD via direct intracerebral injection of lentiviral ABCD1 (LV.ABCD1). Lentiviral vectors (LVs) were injected into the brain of wild type mice to access toxicities and biodistribution. Confocal microscopy illustrated supraphysiological ABCD1 expression surrounding the injection sites, and LVs were also detected in the opposite site of the unilaterally injected brain. In multi-site bilateral injections (4, 6, 8, and 9 sites), LV.ABCD1 transduced most brain regions including the cerebellum. Investigation of neuronal loss, astrogliosis and microglia activation did not detect abnormality. For efficacy evaluation, a novel ALD knockout (KO) mouse model was established by deleting exons 3 to 9 of the ABCD1 gene based on CRISPR/Cas9 gene editing. The KO mice showed behavioral deficit in open-field test (OFT) and reduced locomotor activities in rotarod test at 6 and 7 months of age, respectively. We treated 3-month-old KO mice with bilateral LV.ABCD1 injections into the external capsule and thalamus. ABCD1 expression was detected 15 days later, and the impaired motor ability was gradually alleviated. Our studies established an early onset ALD model and illustrated neurological improvement after LV.ABCD1 intracerebral injection without immunopathological toxicity.

Value of Serum Adiponectin Combined with ABCD2 in Predicting Cerebral Infarction Among Patients with Acute Isolated Vertigo.

IntroductionPatients with acute isolated vertigo have a high risk for developing cerebral infarction (CI). Risk stratification for cerebral infarction in patients with acute isolated vertigo is critical for early treatment and preventative therapy. In the present study, we aim to characterize the diagnostic value of serum adiponectin (APN) combined with ABCD2 scoring in determining cerebral infarction risk.MethodsPatients with acute isolated vertigo admitted to the emergency room were recruited. Diagnosis of cerebral infarction was performed using diffusion-weighted MRI (DWI-MRI) and T2WI and T2Flair imaging. Blood was collected for analysis of APN levels using enzyme-linked immunosorbent assay (ELISA). Multivariate analysis was used to analyze diabetes, hypertension, serum APN, and ABCD2 in association with CI.ResultsCompared to non-CI patients (n = 185), patients with CI (n = 68) demonstrated significantly lower serum APN levels (p < 0.001) and higher ABCD2 score (p < 0.001). A strong negative correlation was found between serum APN levels and ABCD2 scores. Multivariate analysis and ROC analysis suggested that low serum APN and high ABCD2 are strong predictors of CI in patients with acute isolated vertigo. Notably, the combination of APN and ABCD2 had a much stronger predictive sensitivity and specificity.ConclusionOur analysis suggests that the combination of serum APN and ABCD2 analyses offers a significantly improved prediction sensitivity and specificity for CI among patients with acute and isolated vertigo, which supports the potential use of this new marker in clinics.

Multiomics analyses uncover nanoceria triggered oxidative injury and nutrient imbalance in earthworm Eisenia fetida

The toxic stress caused by nanoceria remains vague owing to the limited efforts scrutinizing its molecular mechanisms. Herein, we investigated the impacts of nanoceria on earthworm Eisenia fetida, at the molecular level using the multiomics-based profiling approaches (transcriptomics, metabolomics, and 16 S rRNA sequencing). Nanoceria (50 and 500 mg/kg) significantly increased the contents of malondialdehyde (MDA), Fe, and K in worms, suggesting oxidative injury and nutrient imbalance. This was corroborated by the transcriptomic and metabolomic analyses. Nanoceria decreased the levels of certain genes and metabolites associated with glycerolipid and glycerophospholipid metabolisms, suggesting the production of reactive oxygen species and subsequent oxidative stress. Additionally, the ABCD3 gene belonging to ABC transporter family was upregulated, facilitating Fe uptake by worms. Moreover, the higher contents of MDA, Fe, and K after exposure were tightly associated with the imbalanced intestinal flora. Specifically, a higher relative abundance of Actinobacteriota and a lower relative abundance of Proteobacteria and Patescibacteria were induced. This study, for the first time, revealed that nanoceria at nonlethal levels caused oxidative stress and nutrient imbalance of earthworms from the perspective of genes, metabolites, and gut microbiome perturbations, and also established links between the gut microbiome and the overall physiological responses of the host.

A man with Erb’s disease

A man, currently aged 72, developed a spastic paraparesis without sensory abnormalities progressing to wheel-chair dependence and late urinary incontinence over 14 years. Apart from a history of type 2 diabetes mellitus, he was otherwise well. Extensive blood and CSF investigations including screening for HIV, HTLV1, syphilis, and Lyme disease were normal or negative. There was no evidence of neuropathy or denervation on EMG. MRI showed mild non-specific white matter signal change in both cerebral hemi- spheres. A provisional diagnosis of primary lateral sclerosis (PLS) was revised with the finding of elevated Very Long Chain Fatty Acids (VLCFAs). Genetic testing revealed a novel missense variant c.1771C&gt;Gp. (Arg591Gly) in exon 7 of the ABCD1 gene. Mutation in ABCD1 transporter leads to accumulation of VLCFAs in the peroxisomes and cytosol which is toxic, causing oxidative stress and demyelination in the CNS and PNS. Literature review did not reveal reports of AMN mimicking PLS. Our patient highlights the importance of screening VLCFAs (abnormal in ~99% of men with AMN) in suspected PLS, a diagnosis of exclusion. Diagnosis of ALD/AMN allows genetic counselling, screening for adrenal failure, and access to stem cell therapy for children with asymptomatic cerebral onset ALD.sara.leddy1@nhs.net

Expedited Management of Low-Risk Transient Ischemic Attack Patients: The “Fast-Track” TIA Protocol

ObjectivesTransient ischemic attack (TIA) serves a precursor for an acute ischemic stroke (AIS); however, not all TIA patients harbor the same risk for subsequent AIS. We aimed to investigate expediting outpatient management of low-risk TIA patients (ABCD: Giles and Rothwell, 2007 score ≤ 3) via our “Fast-Track” TIA Protocol (FTTP). Materials and methodsA retrospective analysis was performed on patients who presented to our academic network 04/2020 – 2/2021. Patients who presented with ABCD: Giles and Rothwell, 2007 scores ≤ 3 without large vessel occlusion or flow limiting stenosis were eligible for the FTTP. These patients were discharged on dual antiplatelet therapy and statin and received prescriptions for transthoracic echo, holter monitor, LDL, and A1c along with a scheduled follow-up appointment 30 days from presentation. Results182 consecutive patients were evaluated during this period, 21 (11%) were excluded from analysis due to NIHSS > 0 and/or infarct present on MRI. 35 (22%) patients qualified for FTTP and were directly discharged from the ED. Median ABCD2 score was 2 for the discharge group and 4 for the admitted group. There was a significant difference with respect to age and hypertension. Additionally, the FTTP patient population were more likely to be smokers than the admitted patient population. 3 FTTP patients re-presented to the ED, but none of them suffered a symptomatic stroke. ConclusionsA FTTP demonstrated feasibility and safety with low rates of re-presentation and ischemic stroke. Further research is warranted to determine an optimal patient population that can be safely managed in an outpatient setting.

Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy.

X‐linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β‐oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C‐ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to‐date for ALD. Pioglitazone, an anti‐diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPARγ agonism) and nongenomic (mitochondrial pyruvate carrier—MPC, long‐chain acyl‐CoA synthetase 4—ACSL4, inhibition). However, its use is limited by PPARγ‐driven side effects (e.g. weight gain, edema). PXL065 is a clinical‐stage deuterium‐stabilized (R)‐enantiomer of pioglitazone which lacks PPARγ agonism but retains MPC activity. Here, we show that incubation of ALD patient‐derived cells (both AMN and C‐ALD) and glial cells from Abcd1‐null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1‐null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPARγ agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.

Glycoprotein nonmetastatic melanoma protein B (GNMPB) as a novel biomarker for cerebral adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R2 = 0.3225, p < 0.0001) as well as the gadolinium intensity score (p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p < 0.0001). A positive correlation was shown between CSF GNMPB and another biomarker, chitotriosidase (R2 = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.