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BACKGROUND AND OBJECTIVES: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DISCUSSION: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.
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Adrenoleucodistrofia , Cuerpo Calloso , Imagen de Difusión Tensora , Sustancia Blanca , Humanos , Masculino , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/complicaciones , Niño , Estudios Retrospectivos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Adolescente , Tractos Piramidales/diagnóstico por imagen , Tractos Piramidales/patología , Preescolar , Trasplante de Células Madre Hematopoyéticas , Pruebas Neuropsicológicas , Estudios de Cohortes , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Leukodystrophies, a group of rare demyelinating disorders, mainly affect the CNS. Clinical presentation of different types of leukodystrophies can be nonspecific, and thus, imaging techniques like MRI can be used for a more definitive diagnosis. These diseases are characterized as cerebral lesions with characteristic demyelinating patterns which can be used as differentiating tools. In this review, we talk about these MRI study findings for each leukodystrophy, associated genetics, blood work that can help in differentiation, emerging diagnostics, and a follow-up imaging strategy. The leukodystrophies discussed in this paper include X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe's disease, Pelizaeus-Merzbacher disease, Alexander's disease, Canavan disease, and Aicardi-Goutières Syndrome.
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Adrenoleucodistrofia , Leucodistrofia de Células Globoides , Leucodistrofia Metacromática , Enfermedades Neurodegenerativas , Enfermedad de Pelizaeus-Merzbacher , Humanos , Leucodistrofia Metacromática/diagnóstico por imagen , Leucodistrofia Metacromática/patología , Leucodistrofia de Células Globoides/diagnóstico por imagen , Leucodistrofia de Células Globoides/patología , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genéticaRESUMEN
In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast injection and magnetic resonance imaging (MRI) acquisition to avoid false-negative results. We acquired axial two-dimensional (2D) and three-dimensional (3D) T1-weighted gradient-echo every 6 min from 0 to 36 min after contrast administration (gadobutrol 0.1 mmol/kg) in an ALD patient with enlarging white matter lesions and progressive neuropsychological symptoms, using a 3-T magnet. The image signal over time was qualitatively assessed and measured in two regions of interest. On 3D sequences, no definite CE was appreciated, whereas on 2D sequences, CE was noticed after 6 min and definitely evident after 12 min, when 73% of the maximum signal intensity was measured. In ALD subjects, contrast-enhanced 2D T1-weighted gradient-echo sequences acquired at least 10 min after contrast injection may be considered to reduce false negative results.Relevance statementOur report is the first attempt to find an optimal delay between contrast administration and T1-weighted acquisition in cALD patients in order to correctly detect disease activity and avoid false negative results.Key points⢠The optimal time between contrast injection and image acquisition for MRI of adrenoleukodystrophy is unknown.⢠Contrast enhancement predicts adrenoleukodystrophy progression and could help patient's selection for the therapy.⢠We acquired two post-contrast T1-GRE-2D/3D sequences several times to find the best injection-time.⢠T1-weighted 2D GRE resulted more sensitive than T1-weighted 3D GRE even after long intervals from injection.⢠A delay of about 10 min may minimize false negatives.
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Adrenoleucodistrofia , Medios de Contraste , Humanos , Adrenoleucodistrofia/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVE: Adult cerebral X-linked adrenoleukodystrophy (ACALD) with initial frontal lobe involvement is a rare genetic disease that is easily misdiagnosed and underdiagnosed. We sought to improve the early identification of such diseases. METHODS: We present three cases of adult X-linked adrenoleukodystrophy (ALD) with initial frontal lobe involvement and identify an additional 13 cases from the database. The clinical and imaging characteristics of the overall sixteen cases were analyzed. RESULTS: The average age of onset was 37 years, with 15 male and 1 female patient. A total of 12 patients (75%) developed a decline in cerebral executive and cognitive functions. Brain trauma is the possible trigger for the onset of ALD in five patients (31%). An elevated level of very-long-chain fatty acids (VLCFA) was observed in all 15 patients on whom a plasma VLCFA was performed.10 patients with gene tests showed different mutation sites in the ABCD1 gene. Brain MRI of six patients (46%) were characterized by frontal lobe "butterfly wings"-like lesions with peripheral rim enhancement. Four patients underwent brain biopsies (patients 1, 3, 15, and 13), and five patients (31%) were initially misdiagnosed (patients 1, 2, 3, 11, and 15). Nine of the patients with follow-up records experienced poor prognoses, and five of them, unfortunately, died (56%). CONCLUSION: ACALD patients with anterior patterns tend to be misdiagnosed. The early clinical manifestation is a decline in cerebral executive and cognitive function. Brain trauma may be a trigger for this pattern. Brain MRI findings are characterized by frontal lobe "butterfly wing"-like lesions with peripheral rim enhancement. The determination of the VLCFA levels and the genetic detection of the causative mutations are required to confirm the diagnosis.
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Adrenoleucodistrofia , Lesiones Traumáticas del Encéfalo , Animales , Humanos , Masculino , Adulto , Femenino , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genética , Transportadoras de Casetes de Unión a ATP , Mutación , Lóbulo Frontal/diagnóstico por imagenRESUMEN
Background and Objectives: X-linked adrenoleukodystrophy (X-ALD) occurs due to the mutation in the ABCD1-gene. Our study was to correlate the clinical, radiological, and biochemical features in a cohort of X-ALD patients. Methods: We retrospectively analyzed 48 (M: F: 47:1) biochemically confirmed cases of X-ALD, classified them as cerebral ALD (childhood, adolescent, and adult), adrenomyeloneuropathy, Addisonian only. The Magnetic Resonance Imaging (MRI) of the radiological patterns was classified based on Loes classification. Results: The various clinical phenotypes were childhood cerebral X-ALD (58.3%), adolescent cerebral X-ALD (14.6%), adult-cerebral X-ALD (20.8%), Addisonian variant (4.2%), and adrenomyeloneuropathy (AMN) (2.1%). The imaging features were posterior white matter (Pattern-1) observed in 33 (68.75%) patients, cerebellar white matter (Pattern-4) noted in 5 subjects, anterior white matter (Pattern-2) observed in 3 patients, combined parieto-occipital and frontal white matter (Pattern-5) observed in 3 patients, isolated projection fiber (Pattern-3) observed in 1 patient. Rare features of the involvement of optic tract, anterior and lateral columns of cervicodorsal cord, bilateral central tegmental tracts, basal ganglia, and tigroid appearance were observed. Interpretation: This is a comprehensive clinical, biochemical, and imaging analysis with follow-up information of one of the largest series of X-ALD patients. The knowledge regarding the clinical features, typical and atypical imaging patterns is of vital importance for early diagnosis and treatment.
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Adrenoleucodistrofia , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genética , Hospitales , Humanos , Imagen por Resonancia Magnética/métodos , Fenotipo , Estudios RetrospectivosRESUMEN
PURPOSE: To compare conventional T1 TSE with MPRAGE for enhancement detection in cerebral adrenoleukodystrophy (CALD). MATERIALS AND METHODS: Contrast-enhanced T1 TSE and MPRAGE sequences of 34 CALD patients demonstrating enhancement were evaluated. Contrast ratios were calculated by drawing ROIs to the most enhancing part of demyelination and normal-appearing deep white matter on both T1 TSE and MPRAGE. A comparison was performed between ratios using paired T test. RESULTS: Mean age of 34 included male children was 8 (5-11 years). There was no statistically significant difference between T1 TSE and MPRAGE ratios. However, in 4 out of 34 examinations, minimal contrast enhancement was noted only in T1 TSE sequence. CONCLUSION: Our data indicate that both T1 TSE and MPRAGE sequences are valuable in determining contrast enhancement in CALD. Although there is not a statistically significant difference between the two techniques, T1 TSE sequence appears to be more sensitive for low degree of enhancement.
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Adrenoleucodistrofia , Sustancia Blanca , Niño , Humanos , Masculino , Adulto , Adrenoleucodistrofia/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVE: The objective of this study is to describe the typical and atypical clinical and neuroimaging features of ALD in Chinese patients, which will help early diagnosis and intervention to improve prognosis of ALD. METHODS: Forty-one patients in the Leukoencephalopathy Clinic of Neurology Department, Peking Union Medical College Hospital were enrolled. Detailed clinical manifestations and MRI features were analyzed. The relationship between phenotype and genotype as well as biochemical analysis was observed. RESULTS: The patients were classified according to phenotype and onset age, including 14 childhood cerebral ALD (CCALD), 8 adolescent cerebral ALD (adoCALD), 3 adult cerebral ALD (ACALD), 14 adrenomyeloneuropathy (AMN), and 2 ALD in women. AMN was the main presentation in adults. Visual impairment was usual onset symptom in CCALD and cognitive decline and psychiatric symptoms were found in adoCALD and ACALD. Typical MRI feature of CALD was symmetrical peri-ventricular "butterfly wings" like lesions in frontal and/or occipital lobe with peripheral DWI hyperintensities and Gd enhancement. Corpus callosum and internal capsule were always involved. Unilateral lesions were also possible. Cerebral AMN presented with centrum semiovale diffuse involvement. Spinocerebellar variant was a special subtype of AMN with obvious cerebellar and brainstem lesions. No relationships between phenotype and genotype as well as biochemical VLCFAs analysis were found. CONCLUSIONS: We emphasize that corpus callosum and internal capsule are always involved in ALD. A unilateral lesion is also possible. Neuroimaging of cerebral AMN is different from typical CALD with more centrum semiovale involvement. We support spinocerebellar variant was a rare subtype of AMN.
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Adrenoleucodistrofia , Adolescente , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genética , Animales , Niño , China , Femenino , Genotipo , Humanos , Neuroimagen , FenotipoRESUMEN
Adrenoleukodystrophy is a rare X-linked hereditary disease that results in accumulation of very-long-chain fatty acids in all body tissues, thus causing demyelination of the white matter. Magnetic resonance imaging (MRI) is a reliable radiological modality to demonstrate the extension of brain lesions and severity of the disease. In the classic form, the parieto-occipital white matter is affected. Besides, atypical MRI findings such as primary frontal lobe involvement are rarely described. We report a case of adrenoleukodystrophy presenting with rare MRI findings such as bilateral symmetric frontal lobe white matter changes suggesting anterior predominance.
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Adrenoleucodistrofia , Adrenoleucodistrofia/diagnóstico por imagen , Humanos , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disease due to a mutation in the ABCD1 gene that leads to the accumulation of very-long-chain fatty acids in tissues. OBJECTIVE: To describe one patient with severe childhood cerebral X-ALD and to analyze his diagnostic process and the rapeutic possibilities. CLINICAL CASE: 7-year-old male child, with a six-month history of decreased visual acuity, learning difficulties due to lack of attention, reading and writing impairment, and social isolation. On physical examination, he presented bilateral decrease in visual acuity, hypoprosexia, hyperpigmented lesions on the hands, and gait abnormality. Brain MRI showed bilateral white mat ter signal alteration in parieto-occipital regions, with 12 points on the Loes' scale. He also presented adrenal insufficiency, meeting clinical criteria for X-ALD. Very-long-chain fatty acid was elevated, confirming the diagnosis. Three months later, the patient progressed to vision loss and inability to walk. MRI was repeated showing 15 points in the Loes' scale due to extensive structural involvement of the central nervous system, with rapidly progressive deterioration. Therefore, he was not consi dered a candidate for bone marrow transplantation. CONCLUSION: This case of X-ALD was of severe childhood cerebral presentation, with rapid progression. The clinical evaluation and classification of radiological findings according to the Loes' scale should guide the choice of management.
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Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/diagnóstico por imagen , Niño , Ácidos Grasos/sangre , Humanos , Imagen por Resonancia Magnética , Masculino , MutaciónRESUMEN
BACKGROUND AND PURPOSE: Cerebral adrenoleukodystrophy is a devastating neurological disorder caused by mutations in the ABCD1 gene. Our aim was to model and compare the growth of early cerebral lesions from longitudinal MRIs obtained in presymptomatic patients with progressive and arrested cerebral adrenoleukodystrophy using quantitative MR imaging-based lesion volumetry. MATERIALS AND METHODS: We retrospectively quantified and modeled the longitudinal growth of early cerebral lesions from 174 MRIs obtained from 36 presymptomatic male patients with cerebral adrenoleukodystrophy. Lesions were manually segmented using subject-specific lesion-intensity thresholding. Volumes were calculated and plotted across time. Lesion velocity and acceleration were calculated between sequentially paired and triplet MRIs, respectively. Linear mixed-effects models were used to assess differences in growth parameters between progressive and arrested phenotypes. RESULTS: The median patient age was 7.4 years (range, 3.9-37.0 years). Early-stage cerebral disease progression was inversely correlated with age (ρ = -0.6631, P < .001), early lesions can grow while appearing radiographically stable, lesions undergo sustained acceleration in progressive cerebral adrenoleukodystrophy (ß = 0.10 mL/month2 [95% CI, 0.05-0.14 mL/month2], P < .001), and growth trajectories diverge between phenotypes in the presymptomatic time period. CONCLUSIONS: Measuring the volumetric changes in newly developing cerebral lesions across time can distinguish cerebral adrenoleukodystrophy phenotypes before symptom onset. When factored into the overall clinical presentation of a patient with a new brain lesion, quantitative MR imaging-based lesion volumetry may aid in the accurate prediction of patients eligible for therapy.
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Adrenoleucodistrofia , Adolescente , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genética , Adulto , Niño , Preescolar , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.
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Adrenoleucodistrofia/cirugía , Enfermedades Desmielinizantes/etiología , Lóbulo Frontal/patología , Trasplante de Células Madre Hematopoyéticas , Trastornos Mentales/etiología , Sustancia Blanca/patología , Adolescente , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/diagnóstico por imagen , Niño , Preescolar , Enfermedades Desmielinizantes/diagnóstico por imagen , Emociones , Lóbulo Frontal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/diagnóstico por imagen , Pruebas Neuropsicológicas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagenRESUMEN
X-linked adrenoleukodsytrophy (ALD) is a genetic neuro-metabolic disorder, causing a slowly progressive myelopathy in adult male and female patients. New disease modifying therapies for myelopathy are under development. This calls for new (imaging) markers able to measure disease severity and progression in clinical trials. In this prospective cohort study, we measured cerebral metabolite levels with Magnetic Resonance Spectroscopy (MRS), and evaluated their potential as biomarkers for disease severity and neurodegeneration in ALD. We used a comprehensive protocol of 3T Magnetic Resonance Spectroscopic Imaging (MRSI) and 7T Single Voxel Spectroscopy (SVS) in a large cohort of adult ALD males without cerebral demyelination. One hundred seven baseline scans - 59 obtained in ALD patients (42 3T MRSI and 17 7T SVS) and 48 obtained in healthy male controls (32 3T MRSI and 16 7T SVS) - and 82 one and two-year follow-up scans (66 3T MRSI and 16 7T SVS) of ALD patients were included. Both protocols showed significantly lower concentration ratios of N-acetylaspartate/creatine (tNAA/tCr) and Glx (glutamine + glutamate)/tCr in the grey and white matter of patients, compared to controls. A novel finding is the higher level of inositol (Ins)/tCr and choline containing compounds (tCho)/tCr in ALD patients without cerebral demyelination. Furthermore, tNAA/tCr correlated strongly with clinical measures of severity of myelopathy. There was no detectable change in metabolite ratios after one-year or two-year follow-up. Our results imply that cerebral metabolite levels - and more specifically the tNAA/tCr ratio - measured with MRS, have potential value as (imaging) biomarkers in ALD.
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Adrenoleucodistrofia , Adrenoleucodistrofia/diagnóstico por imagen , Adulto , Ácido Aspártico , Biomarcadores , Encéfalo/diagnóstico por imagen , Colina , Creatina , Femenino , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Estudios ProspectivosRESUMEN
OBJECTIVE: X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder characterized by progressive demyelination ranging from mild myelopathic forms (adrenomyeloneuropathy [AMN]) to severe cerebral variants (adult cerebral adrenoleukodystrophy [ACALD]). The aim of this study was to compare cognitive function in adult-onset X-ALD phenotypes. METHODS: Cognitive function in various domains (intelligence, attention, memory, executive function, and processing speed) was assessed in 172 adults (117 with AMN, 30 with arrested ACALD, and 25 with acute ACALD) using comprehensive neuropsychological batteries. Phenotype differences were examined by analyses of variance. RESULTS: X-ALD phenotypes significantly differed in nonverbal intelligence, sustained attention, verbal encoding, nonverbal recognition, and processing speed (ps < 0.050). No group differences emerged regarding verbal intelligence, verbal retrieval and recognition, and executive function (ps > 0.050). Specifically, patients with acute ACALD showed severe cognitive deficits compared to AMN and normal data, with largest effects on processing speed. Contrary, cognition was overall intact in patients with AMN, independent of sex and corticospinal tract involvement, and those with arrested ACALD showed mild cognitive dysfunction, particularly in verbal encoding and processing speed. INTERPRETATION: Cerebral demyelination in patients with X-ALD causes white matter dementia, mainly characterized by an extreme slowdown in processing speed associated with deficits in attention and learning. Most patients with AMN show intact cognitive function. Future prospective, longitudinal studies with more sensitive imaging techniques are required to clarify whether early mild cognitive dysfunction found in some patients with AMN may be associated with subtle myelin abnormalities that do not yet appear as white matter lesions on cerebral MRI (cMRI) but have the potential to serve as early predictors of later cerebral progression. ANN NEUROL 2021;90:266-273.
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Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/psicología , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/psicología , Cognición/fisiología , Fenotipo , Adolescente , Adrenoleucodistrofia/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/epidemiología , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques-including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging-used in ALD and their role in clinical practice and research opportunities for the future.
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Adrenoleucodistrofia , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/terapia , Adulto , Biomarcadores , Niño , Imagen de Difusión Tensora , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , MasculinoRESUMEN
In 2009, cerebral adrenoleukodystrophy (c-ALD) became the first brain disease to be treated with lentiviral (LV)-based hematopoietic stem cell gene therapy with the ABCD1 gene in four boys (P1-P4) who had demyelinating lesions expected to be lethal in the short term and no bone marrow donor. We report the clinical and magnetic resonance imaging (MRI) follow-up over a mean of 8.8 years posttransplant. In parallel, vector genome copies, expression of transgenic ALD protein (ALDP), and viral integration sites were determined in peripheral blood cells. Prior to transplant, the four patients had a normal or near normal neurocognitive status but gadolinium-enhanced demyelination in various brain regions. Gadolinium diffusion disappeared during the first year posttransplant. P3 kept a near normal status until 8.3 years of follow-up, but P1, P2, and P4 showed major cognitive degradation around 9, 28, and 60 months posttransplant. Neurological status and demyelination stabilized until last evaluation in P2, but deteriorated in both P1 at 10 years and P4 at 3 years posttransplant. The proportion of myeloid and lymphoid cells expressing transgenic ALDP decreased by half within 5 years then stabilized around 5% to 10%. Integration site analysis revealed a durable polyclonal distribution of genetically corrected hematopoietic cells. No adverse effects were observed. The long-term arrest of demyelination at MRI and persistence of transduced hematopoietic progenitors support that LV gene therapy may be a safe and durable treatment of c-ALD. However, the neurological degradation observed in three out of four patients mitigates the benefit of this therapy, calling for an earlier intervention, more potent vectors, and additional therapeutic strategies.
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Adrenoleucodistrofia , Trasplante de Células Madre Hematopoyéticas , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/terapia , Estudios de Seguimiento , Terapia Genética , Células Madre Hematopoyéticas , Humanos , MasculinoRESUMEN
OBJECTIVE: To prospectively determine the value of optical coherence tomography (OCT) as a surrogate outcome measure for the progression of myelopathy in males with adrenoleukodystrophy. METHODS: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness were measured at baseline, 1- and 2-year follow-up in patients and age-matched controls. We assessed the severity of myelopathy with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go. Linear mixed model analysis was used to compare changes in retinal layer thickness of patients to controls. In addition, we correlated changes in retinal layer thickness with changes in clinical parameters. RESULTS: Longitudinal data were available for 28 patients and 29 controls. Peripapillary RNFL (pRNFL) thickness decreased significantly in patients compared to controls (-1.75µm, p = 0.001), whereas change in macular GCL and RNFL was not different between groups. Analysis of the symptomatic subgroup showed that, apart from a similar decrease in pRNFL thickness, GCL thickness decreased significantly (-0.55 µm, p = 0.014). There were moderately strong correlations between changes in retinal layer thickness and changes in clinical parameters of severity of myelopathy. INTERPRETATION: This prospective study demonstrates the potential of OCT-measured retinal neurodegeneration as a surrogate outcome measure for the progression of myelopathy in adrenoleukodystrophy. As differences were small, our findings need to be confirmed with longer follow-up and/or in a larger patient sample.
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Adrenoleucodistrofia/diagnóstico por imagen , Progresión de la Enfermedad , Neuronas Retinianas/patología , Enfermedades de la Médula Espinal/diagnóstico por imagen , Tomografía de Coherencia Óptica , Adolescente , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/patología , Adulto , Anciano , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Células Ganglionares de la Retina/patología , Índice de Severidad de la Enfermedad , Enfermedades de la Médula Espinal/etiología , Enfermedades de la Médula Espinal/patología , Adulto JovenRESUMEN
OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes. METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences. RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size. CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.
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Adrenoleucodistrofia , Adrenoleucodistrofia/diagnóstico por imagen , Adulto , Biomarcadores , Encéfalo/diagnóstico por imagen , Estudios Transversales , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Médula EspinalAsunto(s)
Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/diagnóstico por imagen , Progresión de la Enfermedad , Paresia/diagnóstico por imagen , Paresia/etiología , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Adrenoleucodistrofia/genética , Preescolar , Humanos , Masculino , Paresia/genéticaRESUMEN
BACKGROUND: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. METHODS: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. RESULTS: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8-48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula. CONCLUSIONS: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.