Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy

Zanigni, Stefano; Terlizzi, Rossana; Tonon, Caterina; Testa, Claudia; Manners, David Neil; Capellari, Sabina; Gallassi, Roberto; Poda, Roberto; Gramegna, Laura Ludovica; Calandra-Buonaura, Giovanna; Sambati, Luisa; Cortelli, Pietro; Lodi, Raffaele

doi:10.1016/j.brainresbull.2015.07.002

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…Autosomal-dominant leukodystrophy (ADLD) is an extremely rare, fatal, and late onset progressive neurological disorder which affects the white matter of the central nervous system (CNS) usually, in the IV or V decade [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

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Section: Introductionmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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“…These findings, together with clinical symptoms of myelopathy with autonomic dysfunction, are sufficiently specific to enable the diagnosis, which can be confirmed by genetic analysis. 15,16 There are no previous studies measuring glucose metabolism in LMNB1-related ADLD. There is no significant pathology in the cerebral cortex, while in the cerebellum the number of Purkinje cells is reduced and the number of Bergmann astroglial cells slightly increased.…”

Section: Lmnb1-related Autosomal Dominant Leukodystrophy (Adld) Is Anmentioning

confidence: 99%

“…Further, metabolite levels in the parenchyma have been found to be normal when quantified using creatine as an internal reference. 15,16 There are no previous studies measuring glucose metabolism in LMNB1-related ADLD.…”

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confidence: 99%

Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy

et al. 2018

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“…Compared with the onset of clinical symptoms, MRI findings have been observed about a decade earlier (Finnsson et al, 2015). On conventional MRI, ADLDs are characterized by diffuse and symmetrical lesions in WM and cerebellar peduncles, accompanied by the less-effected periventricular region, optic radiations, and U-fibers (Melberg et al, 2006; Brunetti et al, 2014; Corlobe et al, 2015; Finnsson et al, 2015; Zanigni et al, 2015). Several reports have indicated previously that bilateral abnormal signals in corticospinal tracts, internal capsule, corpus callosum, lemniscus medialis, corticonuclear tracts, and cerebellar peduncles have been observed (Melberg et al, 2006; Finnsson et al, 2013; Potic et al, 2013; Corlobe et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Several reports have indicated previously that bilateral abnormal signals in corticospinal tracts, internal capsule, corpus callosum, lemniscus medialis, corticonuclear tracts, and cerebellar peduncles have been observed (Melberg et al, 2006; Finnsson et al, 2013; Potic et al, 2013; Corlobe et al, 2015). Recent studies evidenced decreased brain WM metabolism and pathological sediments of lactate in lateral ventricle CSF in using single-voxel proton-MR Spectroscopy (1H-MRS) (Finnsson et al, 2013, 2019; Zanigni et al, 2015). Furthermore, ADLD is a progressive and fatal disease, and affected people usually survive for 10–20 years after the onset of symptoms (Giorgio et al, 2013; Finnsson et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy Presenting as Movement Disorder: A Case Report and Review of the Literature

Zhang

Bai

et al. 2019

Front. Neurosci.

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Adult-onset autosomal dominant leukodystrophy (ADLD) is a lately described rare form of leukodystrophy with only one family report from China. As the only disease associated with increased lamina B1 encoded by LMNB1, ADLDs have different clinical presentations, ranging from autonomic to pyramidal tract and cerebellar ataxia. Here, we report a case of ADLD that presented with positional tremor as the initial symptom. T2-weighted brain MRI showed brain atrophy and diffuse high signal intensity of the cerebral white matter and the brain stem. The precise diagnosis was made by identification of the mutated gene. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as tremor in China.

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Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy

Cited by 15 publications

References 42 publications

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy

LMNB1-Related Adult-Onset Autosomal Dominant Leukodystrophy Presenting as Movement Disorder: A Case Report and Review of the Literature

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