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Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

ABSTRACT: Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association with markers of cerebral disease. The allele frequency of APOE4 was not significantly different from that of the general population at 17%. Young males with cALD that were APOE4 carriers had similar CSF protein and chitotriosidase activity to that of non-carriers. In contrast, APOE4 carriers had an increased burden of cerebral disease involvement as determined by MRI severity score (10.5 vs 7.0 points, p?=?0.01), higher gadolinium intensity score (2.0 vs 1.3 points, p?=?0.007), inferior neurologic function (neurologic function score 2.4 vs 1.0, p?=?0.001), and elevated CSF MMP2 levels compared to that of non-carriers (13168 vs 9472?pg/mL, p?=?0.01). These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease.

SUBMITTER: Orchard PJ

PROVIDER: S-EPMC6536544 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

Orchard Paul J PJ Markowski Todd W TW Higgins LeeAnn L Raymond Gerald V GV Nascene David R DR Miller Weston P WP Pierpont Elizabeth I EI Lund Troy C TC

Scientific reports 20190527 1

Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association ...[more]

PMID: 31133696

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Project description:BACKGROUND:In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS:We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS:A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS:Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

Project description:Cerebral adrenoleukodystrophy (ALD) is a rare neuroinflammatory disorder characterized by progressive demyelination. Mutations within the ABCD1 gene result in very long-chain fatty acid (VLCFA) accumulation within the peroxisome, particularly in the brain. While this VLCFA accumulation is known to be the driving cause of the disease, oxidative stress can be a contributing factor. For patients with early cerebral disease, allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care, and this can be supported by antioxidants. To evaluate the involvement of fatty acid oxidation in the disease, F2-isoprostanes (F2-IsoPs), F2-dihomo-isoprostanes (F2-dihomo-IsoPs) and F4-neuroprostanes (F4-NeuroPs)-which are oxygenated metabolites of arachidonic (ARA), adrenic (AdA) and docosahexaenoic (DHA) acids, respectively-in plasma samples from ALD subjects (n = 20)-with various phenotypes of the disease-were measured. Three ALD groups were classified according to patients with: (1) confirmed diagnosis of ALD but without cerebral disease; (2) cerebral disease in early period post-HSCT (<100 days post-HSCT) and on intravenous N-acetyl-L-cysteine (NAC) treatment; (3) cerebral disease in late period post-HSCT (beyond 100 days post-HSCT) and off NAC therapy. In our observation, when compared to healthy subjects (n = 29), in ALD (i), F2-IsoPs levels were significantly (p < 0.01) increased in all patients, with the single exception of the early ALD and on NAC subjects; (ii) significant elevated (p < 0.0001) amounts of F2-dihomo-IsoPs were detected, with the exception of patients with a lack of cerebral disease; (iii), a significant increase (p < 0.003) in F4-NeuroP plasma levels was detected in all ALD patients. Moreover, F2-IsoPs plasma levels were significantly higher (p = 0.038) in early ALD in comparison to late ALD stage, and F4-NeuroPs were significantly lower (p = 0.012) in ALD subjects with a lack of cerebral disease in comparison to the late disease stage. Remarkably, plasma amounts of all investigated isoprostanoids were shown to discriminate ALD patients vs. healthy subjects. Altogether, isoprostanoids are relevant to the phenotype of X-ALD and may be helpful in predicting the presence of cerebral disease and establishing the risk of progression.

Project description:BackgroundApolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD), and the ε4 allele (APOE4) may interact with lifestyle factors that relate to brain structural changes, underlying the increased risk of AD. However, the exact role of APOE4 in mediating interactions between the peripheral circulatory system and the central nervous system, and how it may link to brain and cognitive aging requires further elucidation. In this analysis, we investigated the association between APOE4 carrier status and multimodal biomarkers (diet, blood markers, clinical diagnosis, brain structure, and cognition) in the context of gene-environment interactions.MethodsParticipants were older adults from a longitudinal observational study, the Boston Puerto Rican Health Study (BPRHS), who self-identified as of Puerto Rican descent. Demographics, APOE genotype, diet, blood, and clinical data were collected at baseline and at approximately 12th year, with the addition of multimodal brain magnetic resonance imaging (MRI) (T1-weighted and diffusion) and cognitive testing acquired at 12-year. Measures were compared between APOE4 carriers and non-carriers, and associations between multimodal variables were examined using correlation and multivariate network analyses within each group.ResultsA total of 156 BPRHS participants (mean age at imaging = 68 years, 77% female, mean follow-up 12.7 years) with complete multimodal data were included in the current analysis. APOE4 carriers (n = 43) showed reduced medial temporal lobe (MTL) white matter (WM) microstructural integrity and lower mini-mental state examination (MMSE) score than non-carriers (n = 113). This pattern was consistent with an independent sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) of n = 283 non-Hispanic White adults without dementia (mean age = 75, 40% female). Within BPRHS, carriers showed distinct connectivity patterns between multimodal biomarkers, characterized by stronger direct network connections between baseline diet/blood markers with 12-year blood/clinical measures, and between blood markers (especially lipids and cytokines) and WM. Cardiovascular burden (i.e., hypertension and diabetes status) was associated with WM integrity for both carriers and non-carriers.ConclusionAPOE4 carrier status affects interactions between dietary factors, multimodal blood biomarkers, and MTL WM integrity across ~12 years of follow-up, which may reflect increased peripheral-central systems crosstalk following blood-brain barrier breakdown in carriers.

Dataset Information

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

Publications

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

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