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Neuroprotection and neuroregeneration

roles for the white matter

Baldassarro, Vito Antonio1; Stanzani, Agnese2; Giardino, Luciana1,3; Calzà, Laura3,4,5,*; Lorenzini, Luca1

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doi: 10.4103/1673-5374.335834
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Neurodegenerative diseases and central nervous system (CNS) lesions due to trauma or vascular accidents are significant health concerns. The Global Burden of Diseases study estimated that in 2017, the total number of disability-adjusted life years attributable to neurological disorders was 21 million in the EU, and 41.1 million in the WHO European region. The total number of deaths was 1.1 million in the EU and 1.97 million in the WHO European region, with neurological disorders as the third leading cause after cardiovascular disease and cancer (Deuschl et al., 2020).

Great effort has been made to develop incisive therapeutic tools to cure or to slow the clinical course of neurological diseases and lesions, and to understand the mechanisms leading to the related functional impairment. Most of this effort has been focused on neurons as the main cell of the gray matter (GM) and on related neuroprotective strategies. However, many failures in related clinical trials have severely hindered research (Dhir et al., 2020).

Over the last few decades, two events have contributed to turning researchers’ attention to the white matter (WM), both as a component of CNS disease pathology and as a potential therapeutic target.

The first event was the discovery of a new cell type, the oligodendrocyte precursor cell (OPC), in the mature CNS in the late 1980s (Dawson et al., 2003). OPCs are the precursors of oligodendrocytes, responsible for myelin development during embryogenesis, turnover, and repair in the mature CNS, being the number of oligodendrocytes depending on the OPCs number. These precursors are generated during development to allow myelination, but a pool of undifferentiated precursors remains all over the mature CNS. These quiescent unipotent stem cells can be activated again by different stimuli, which are present in the inflammatory microenvironment to trigger the proliferation, migration, and differentiation (Nishiyama et al., 2021). These cells can repair myelin and re-myelinate axons, thus indirectly contributing to neuroprotection. Remyelination is currently the only known self-repair ability of the CNS, potentially providing full anatomical and functional neuroregeneration.

The second event was the introduction of imaging techniques to visualize and measure WM in clinical settings (Wozniak and Lim, 2006). WM accounts for a large percentage of CNS volume, ranging from 20% in the cerebral cortex (Mota et al., 2019) to 80% in the spinal cord (Henmar et al., 2020). It is formed by the axons and their myelin sheaths and consists of a multilamellar membrane structure. This structure is created by the spiral wrapping and subsequent compaction of the oligodendrocyte plasma membrane and facilitates the efficient transmission of electrical signals in neural pathways (Simons and Nave, 2016). Diffusion tensor imaging (DTI) can detect WM alterations invisible to conventional imaging techniques (Lubetzki et al., 2020), and has permitted the visualization of WM alterations in WM diseases such as multiple sclerosis (MS), in CNS lesions such as spinal cord injury (SCI), and neurodegenerative pathologies such as Alzheimer’s disease (AD) (Tae et al., 2018).

Starting from the assumption that remyelination is crucial for the prevention of neurodegeneration, and that spontaneous myelin repair is commonly observed in the mature CNS, this review aims to discuss the potential of the WM and OPCs as targets for neuroprotective therapies in lesions and chronic neurodegenerative diseases of the CNS. We consider three different diseases: MS, as an example of WM primary pathology; SCI as an example of CNS lesion; and AD as an example of chronic progressive neurodegenerative disease.

Search Strategy and Selection Criteria

All years were chosen in the search, but giving more importance to the publications of the last 5 years. These searches were performed between June and September 2021. Studies cited in this review were searched on the NCBI PubMed database using the following keywords: thyroid hormone AND oligodendrocyte precursor cells; white matter imaging; myelin repair; remyelination; oligodendrocyte precursor cells AND remyelination block; thyroid hormone metabolism; multiple sclerosis AND white matter; spinal cord injury AND white matter; traumatic brain injury AND white matter; Alzheimer’s diseases AND white matter. Articles related to central nervous system pathologies but without a specific focus on white matter were excluded.

Oligodendrocyte Precursor Cells, Developmental Myelination and the Role of Thyroid Hormone: a Brief Summary

Myelination is a process whereby oligodendrocytes wrap their plasma membrane around the axons, insulating it and ensuring proper propagation of the axon potential from the neuron cell body to the presynaptic nerve ending. During embryonic development, oligodendrocytes derive from OPCs, which are generated from neural stem cells, multipotent cells of the neural tube, which are also the common precursor of neurons and astrocytes. The OPC population is generated in three temporally different waves, spatially organized in a ventral-dorsal direction. In rodents, the first wave arises in the ventral ventricular zone from the medial ganglionic eminence and the anterior entopeduncular area (at embryonic day (E) 12.5) soon after neural tube closure. At E15.5, a second wave originates from the lateral and caudal ganglionic eminences, followed by a third wave from the dorsal subventricular zone at birth (E21/P0). OPCs originating from the first ventral wave appear to have a backup function, replaced postnatally almost in their entirety unless the following two waves are perturbed (van Tilborg et al., 2018; Kuhn et al., 2019). In the spinal cord, a ventral wave of OPC production in the promotor neuron domain (E12.5) is followed by a production of cells in the dorsal precursor domains (E15.5). Contrary to that which occurs in the encephalon, the second wave of OPC generation produces only 20% of the population (van Tilborg et al., 2018). OPCs proliferate and migrate, populating the entire developing CNS and triggering the differentiation/maturation into mature oligodendrocytes, finally wrapping the axon to form the myelin sheets.

This cell population is regulated by hormones. Like most of the cells in adult mammalian organisms, OPCs depend on thyroid hormones (THs) to maintain metabolic pathways and regulate the expression of target genes. The thyroid status of a cell is not only dependent on proper thyroid gland function, but also on a complex biochemical process occurring at the TH target cells. The thyroid gland synthesizes thyroxine (T4) through the uptake of both iodine, which acts as a pro-hormone, and triiodothyronine (T3), the active form, at a ratio of 80 (T4) to 20 (T3) %. THs are distributed throughout the blood and cerebrospinal fluid by four types of TH distributor albumin, transthyretin, thyroxine-binding globulin, and a number of lipoproteins (Pagnin et al., 2021). The main TH distributor responsible for the delivery of THs to tissues is transthyretin, a homo-tetrameric protein produced mainly by liver and choroid plexus epithelial cells, which moves T4 from the blood into the cerebrospinal fluid and the brain parenchyma (Alshehri et al., 2020).

The THs then cross the plasma membrane via specific transporter proteins such as MCT8, a ubiquitous transporter. In the CNS, MCT8 is expressed in adult tissues and during development by glial cells, neurons, and along the blood-brain barrier, the latter being the main route of TH entry into the CNS. Both T3 and T4, as well as the inactive metabolite rT3, bind to MCT8 with high affinity.

The T4/T3 plasma ratio is reversed at a cellular level, where deiodinase (Dio) enzymes remove iodine atoms from a specific position, converting T4 to T3 (Dio2), and T3 to T2 (Dio1, Dio3) or T4 to rT3 (Dio3) (Calzà et al., 2015, 2018; Luongo et al., 2019). T3 exerts its genomic action through TH receptors (TRs; TRα and TRβ), a class of nuclear receptors, which regulate the expression of target genes, including myelin protein-encoding genes, in combination with other nuclear receptors such as RXRγ (Baldassarro et al., 2019, 2021a). T3, T4, T2, and rT3 also have non-genomic, rapid-onset actions, at mitochondria, cytoskeleton, and metabolism levels (Davis et al., 2016). Some of these non-genomic pathways are mediated by specific integrins located in the plasma membrane (mainly αvβ3), involving ERK1/2, MAPK or PI3K-AKT, enabling the trafficking of TRs into the nucleus and mediating gene expression regulation and post-translational protein synthesis (Pagnin et al., 2021).

CNS development and particularly myelination is strictly dependent on THs, which derive from maternal blood prior to the functional maturation of the fetal thyroid gland between 3 and 13 gestational weeks. Maternal/fetal TH production then overlaps during the second half of gestation, with postnatal myelination being fully regulated by newborn TH production (Pagnin et al., 2021). Inadequate TH levels during prenatal development lead to irreversible physical and mental retardation, resulting in a severe condition known as “cretinism”, where myelinating abnormalities and WM lesions are preeminent (Stenzel and Huttner, 2013). Maternal subclinical hypothyroidism, due to factors such as prenatal exposure to thyroid-disrupting chemicals, a large class of environmental pollutants, which alter thyroid gland physiology, TH plasma transportation, intracellular balance, and TR availability (Mughal et al., 2018), is also associated with poor neurological and intellectual development (Liu et al., 2018; Zhang et al., 2021). Finally, the key role of intracellular TH concentration in brain development is illustrated by the Allan-Herndon-Dudley syndrome, in which mutations on the SLC16A2 gene lead to the production of pathological and dysfunctional variants of the MCT8 protein (Pagnin et al., 2021).

THs are the essential driver of OPCs differentiation. T3 acts via genomic and non-genomic mechanisms to drive the OPC out of the cell cycle and to activate the differentiation (Lee and Petratos, 2016), being the intracellular level of T3 the key determinant of proliferation/differentiation switch (Pagnin et al., 2021). While the association between low TH, elevated TSH and rT3 levels and poor neurodevelopmental outcomes in prematurity, intrauterine growth restriction, and neonatal hypoxia (Pereira and Procianoy, 2001) have been thoroughly established in both clinical practice and preclinical research, the diagnostic and therapeutic aspects of these outcomes are still controversial (Eerdekens et al., 2019). TH treatments have been proposed and tested for these perinatal injuries to favor WM maturation, with contrasting results.

Following the action of T3 at the cell cycle level, many other soluble and contact factors deriving from axons, astrocytes, microglia, vasculature, and extracellular matrix tightly regulate OPC biology till proper myelin sheath formation (Baydyuk et al., 2020) (Figure 1). These signals act via transcriptional and translational regulation, epigenetic controls including miRNA, histone modifications, and DNA methylation (Tiane et al., 2019), and the arrangement of the actin cytoskeleton (Bercury and Macklin, 2015). Astrocytes act on OPCs through the secretion of different growth factors, including platelet-derived growth factor (PDGF), fibroblast growth factor, and leukemia inhibitory factor, and the interleukin (IL)-6, promoting the proliferation and survival of OPCs. They also secrete endothelin-1 and extracellular matrix (ECM) components, regulating migration and differentiation. Fibronectin stimulates migration/proliferation and the potentiation of PDGF-A action by integrin signals (αvβ1 and αvβ3), and both fibronectin and laminin promote the extension of the oligodendrocyte processes. Growth factors are also secreted by endothelial cells and pericytes, used by OPCs as a scaffold for migration. Finally, while microglial cells do not appear to be essential for adult OPC survival and differentiation, in response to noxious stimuli induce maturation or cell death, depending on their state of activation (Baydyuk et al., 2020).

OPCs and mature oligodendrocytes also express neurotransmitter receptors. Neuronal activity can therefore regulate OPC migration, proliferation, differentiation, and myelination, and the main neurotransmitters involved in this process appear to be glutamate and GABA. Glutamate acts as a chemoattractant, accelerating integrin-mediated motility through AMPA receptors. Depending on the differentiation state of the OPC, glutamate may act also as a maturation inducer. The GABAA receptor reduces OPC proliferation, while GABAB enhances it [reviewed by Baydyuk et al. (2020)]. Actually, OPCs are electrically sensitive, form synapses with neurons, support blood-brain barrier integrity, and mediate neuroinflammation (Akay et al., 2021).

Seeing Is Believing: White Matter Imaging

The development of new imaging techniques has finally allowed researchers to assess the impact of WM alterations in adult human CNS lesions and chronic neurodegenerative diseases. Conventional MRI permits the evaluation of cerebral macrostructure in many pathological situations and is widely used to monitor longitudinal white matter changes, disease progression, and the effects of treatment. But more innovative techniques, such as diffusion MRI, show the geometry and integrity of the underlying microstructure and quantify the severity of tissue damage, specifically decreased myelin content and axonal integrity (Bailey et al., 2014). DTI is an MRI-based technique, which uses anisotropic diffusion to visualize and estimate the organization of the WM in neuronal tissue (Fiani et al., 2020). It can be used in association with fiber tractography, a 3D reconstruction technique to assess neural tracts using DTI data, and permits clinicians to detect disease features such as inflammation, edema, demyelination, and hemorrhage (Zaninovich et al., 2019). Other new imaging techniques in addition to DTI appear to offer better sensitivity in detecting demyelination/remyelination. These include the relaxation along a fictitious field MRI technique, which displays a distinct pattern of changes in the remyelination phases when used in combination with DTI and magnetization transfer (MT), reflecting not only the myelin content but also the architecture of myelin sheets, as well the presence of gliosis (Holikova et al., 2021). The relaxation along a fictitious field 4 technique has demonstrated its efficacy, and sometimes its superiority over DTI in a rat model of demyelination (Lehto et al., 2017), especially in MS models where it appears to be a sensitive method for the detection of subtle abnormalities, not only in normal-appearing WM but also in the deep gray matter in multiple sclerosis (Filip et al., 2020). These advanced quantitative MRI techniques have not yet been integrated into clinical practice, where more conventional MRI scans remain the modalities of choice for monitoring clinical disease progression (Filip et al., 2020). Finally, the application of 9T MRI to WM analysis has allowed in vivo analysis of distinct WM fiber tracts in experimental animals (Schaeffer et al., 2017).

Overall, MRI-based myelin imaging methods show a good reproducibility and correlation with histology, as also confirmed by imaging in animal models, thus offering a powerful instrument for monitoring remyelination-enhancing therapies (van der Weijden et al., 2021). Their application in animal models also allows robust end-point identification in a translational perspective. For example, it is possible to monitor the progression of WM injury in SCI in rats by DTI, by assessing myelination status and evaluating when WM-directed therapies may be appropriate and how these should be used (Wu et al., 2020). DTI technology in SCI in monkeys has permitted the longitudinal monitoring of lesion evolution, separating axon degeneration and demyelination into different sensory and motor tracts to compare spinal cord anatomy with behavioral assessments, and the evaluation of secondary degeneration, not only at the lesion site but also in remote segments above and below the injury (Mishra et al., 2020). Prior to DTI, the tissue adjacent to the injury site was presumed to be healthy if conventional MRI suggested normal anatomy, while preclinical studies using DTI have indicated that this perilesional area may harbor evolving pathology (Herrera et al., 2008).

Myelin Repair in Adulthood: Oligodendrocyte Precursor Cell Differentiation Impairment, Inflammation, and Thyroid Hormone Tissue Metabolism

When myelination is complete after birth, some OPCs remain quiescent, forming the adult pool of precursors present in the GM and WM of the mature CNS. OPCs are the most abundant proliferative population in the adult CNS, representing 5–8% of all cells, and can be recognized by the expression of membrane markers such as NG2 and PDGF. OPCs are not a homogeneous population – those in the WM are more responsive to PDGF-A and are morphologically and genetically more mature than the precursors in the GM (Kuhn et al., 2019).

The OPCs in GM are also less mature, less responsive to astrocyte signals, and less sensitive to interferon γ and tumor necrosis factor α detrimental effects. Thus, probably due to these intrinsic differences, it has been described that remyelination in GM is more fast and efficient than in WM (Lentferink et al., 2018).

OPC density throughout the entire CNS is kept under tightly regulated homeostatic control, with OPCs which have undergone apoptosis or differentiation being rapidly replaced. Newly generated OPCs derive from the resident pool by asymmetric division, a mechanism, which permits maintenance of the quiescent pool and production of the differentiating cells. New OPCs can be also generated by the neural stem/progenitor population in the mature CNS, such as those of the subventricular zone. Physiological OPC turnover decreases with age due to the gradual lengthening of the cell cycle, accumulation of intracellular cell cycle inhibitors, or the decrease of growth factor availability (Akay et al., 2021).

OPCs and the WM are highly vulnerable to various types of damage, both during development and adulthood. In fact, OPCs and oligodendrocytes are vulnerable to all agents which are toxic for neurons, such as oxygen/glucose deprivation, inflammatory cytokines, and glutamate (Baldassarro et al., 2017, 2020). Severe WM damage is a common occurrence in neonates exposed to perinatal hypoxia/ischemia, which contributes to the consequent severe neurocognitive deficit (Shao et al., 2021a). DTI studies have demonstrated associations between WM integrity and cognition measures during adolescence in children suffering neonatal hypoxia-ischemia, showing for example that reduced information processing speed is mediated in part by the reduced integrity of major WM tracts (Gosar et al., 2020).

In the meantime, OPCs can be activated in the case of WM injury, can fully differentiate in mature oligodendrocytes, thus providing an anatomical and functional myelin repair. As the initial step of this process, the OPCs are activated to migrate to the lesion site and proliferate. Inflammation is a fundamental trigger to induce remyelination, and the balance between proliferation and differentiation induction is maintained by a series of factors. The soluble factors mainly secreted by the immune system and astrocytes, for example, such as growth factors (fibroblast growth factor 2, EGF, and PDGF), cytokines, and chemokines, are fundamental for initiating the process by inducing OPC proliferation (Armada-Moreira et al., 2015) (Figure 1).

Figure 1:
Influence of different factors on OPC differentiation.Schematic representation of thyroid hormone tissue metabolism and the main extrinsic factors regulating OPC proliferation, migration, differentiation, and oligodendrocyte maturation. Dio2: Deiodinase 2; Dio3: deiodinase 3; ECM: extracellular matrix; EGF: epidermal growth factor; ET-1: endothelin-1; FGF2: fibroblast growth factor 2; IL-1β: interleukin-1 beta; IL-6: interleukin-6; LIF: leukemia inhibitory factor; MCT8: monocarboxylate transporter 8; OATP1C1: organic anion transporter family member 1C1; OL: oligodendrocyte; OPC: oligodendrocyte precursor cell; PDGF: platelet-derive growth factor; rT3: reverse triiodothyronine; RXRγ: retinoid X receptor gamma; T2: 3,5-diiodothyronine; T3: triiodothyronine; T4: thyroxine; TNFα: tumor necrosis factor alpha; TRs: thyroid hormone receptors; VEGF: vascular endothelial growth factor.Under certain conditions, however, and for reasons still poorly understood, the OPCs fail to differentiate fully into myelinating oligodendrocytes, and myelin damage exposes the nude axons to the inflammatory microenvironment and degeneration. This OPC differentiation block is a key event in pathologies with WM damage as a primary or secondary event. Inflammation plays a key role in the demyelination/remyelination balance, sometimes acting as a two-faced Janus which stimulates OPC proliferation but blocks differentiation, depending partly on the intensity of the inflammation itself (Spaas et al., 2021). A variety of molecules are involved in this complex process, but tissue inflammation is a common denominator in conditions such as MS and SCI, due to the action of inflammatory cytokines as transforming growth factor-β1, tumor necrosis factor α, IL-1β, IL-6, IL-17, and interferon γ (Baldassarro et al., 2020; Spaas et al., 2021).

The pathological mechanisms leading to myelin damage may act directly on the oligodendrocyte cell, or solely on myelin sheaths preserving the cell body (Bradl and Lassmann, 2010), with the OPC being induced to differentiate and form new myelin in both cases. It has been observed that partially injured oligodendrocytes are capable of participating in myelin repair in some animals, including humans (Duncan et al., 2018).

As already discussed, the tissue and intracellular concentration of THs are key components of the proper OPC differentiation machinery. The strict relationship between TH and the WM in adulthood as well as during development is confirmed by the abnormalities in various fiber tracts (Singh et al., 2014), and a significant reduction in the WM volume in cortical and cerebellar areas has been observed in adult hypothyroid patients and measured using diffusion tensor tractography (Singh et al., 2013). Hyperthyroidism also has an impact on adult WM structure, where microstructural alterations in the WM have been observed, in keeping with the results of preclinical studies (Aslan et al., 2020). A large body of literature indicates that inflammation modifies TH intracellular uptake; the intracellular conversion of the inactive T4 to the active T3; TR availability and binding, and T3 inactivation (D’Intino et al., 2011). An impairment of Dio2 and an increase in Dio3 activities are the main alterations, inducing a reduced tissue availability of T3 (Fernández et al., 2016). This leads to a severe impairment of the molecular machinery of TH cellular targets, including OPC differentiation, in a condition known as “non-thyroidal illness syndrome” or “euthyroid sick syndrome”, in which circulating TH concentration does not reflect the TH tissue and intracellular concentration (Fliers and Boelen, 2020).

Given the importance of restoring a proper OPC differentiation capacity during the remyelination, a number of drugs have been proposed to enhance remyelination, some of which act by stimulating OPC differentiation. Examples include IRX4204 ( identifier: NCT02438215) and bexarotene (EudraCT number: 2014-003145-99), both RXRγ agonists; the antipsychotic drug quetiapine fumarate ( identifier: NCT02087631); the LINGO-1 antagonist opicinumab ( identifier: NCT01864148; NCT03222973); the cytochromeP450 inhibitor clemastine ( identifier: NCT02040298), and thyroid hormone ( identifier: NCT02760056) (Balestri et al., 2021).

Various pathologies cause an alteration in this complex molecular machinery, leading to an OPC/oligodendrocyte deficiency and consequent WM damage. In the following paragraphs, OPC/oligodendrocyte alterations in example diseases are illustrated and discussed for the impact on neurodegeneration, and the proof-of-concept related to TH replacement therapies are discussed as an example of WM-directed neuroprotective therapies.

Multiple sclerosis

As the most widespread and most thoroughly researched inflammatory demyelinating disease in humans, MS has been the “pivot” condition for investigating WM imaging and OPC biology. While conventional MRI techniques are routinely used to visualize lesion load, advanced MRI allows the exploration of changes in tissue composition (Cercignani and Bouyagoub, 2018). DTI has been widely used to examine the WM, GM, optic nerve, and spinal cord of MS patients at different stages of the disease, contributing to a better understanding of the different pathophysiological substrates of the disease, and the complexity of its clinical evolution (Filippi et al., 2016), as well as for treatment monitoring. Magnetic resonance spectroscopy can show axonal damage even in normal-appearing white matter, thus supporting the view that WM lesions ultimately lead to neuron degeneration. Cortical gray matter atrophy has in fact been demonstrated in MS, where cortical lesions responsible for cognitive disability are more common in secondary progressive MS, where OPCs are not activated than in the relapsing-remitting form, where OPCs can repair myelin damage (Pflugshaupt et al., 2016).

In the most common clinical variant (relapsing-remitting), the clinical onset of the disease and the acute symptomatic phase are characterized by what is known as “active lesions” in the WM, massively infiltrated by peripheral immune cells and macrophages. Subsequently, the plaque microenvironment evolves to include a myriad of inflammatory cytokines, which lead to astrocyte and microglia activation, demyelination, and axonal damage (Psenicka et al., 2021). During this phase, and in this variant of the disease, OPCs proliferate and differentiate into mature oligodendrocytes, fully repairing the WM damage and restoring anatomical and functional integrity. However, this process progressively fails due to repeated relapses and OPC pool exhaustion or aging, while in the chronic progressive form it fails to begin at all. In vivo and in vitro models have permitted researchers to identify the role of OPCs in remyelination failure, showing that the exit of the OPC from the cell cycle is blocked by inflammatory cytokines, thus preventing terminal differentiation (Psenicka et al., 2021). The OPC differentiation block has also been identified in human MS tissue samples (Kuhlmann et al., 2008).

The re-establishment of an appropriate intracellular environment, namely the TH level, is recognized as a pre-requisite for orchestrating the machinery which drives the OPCs out of the cell cycle toward terminal differentiation (Lee and Petratos, 2016). A number of preclinical studies have explored the administration of TH, TH analogs, or TR ligands to overcome inflammation-induced remyelination impairment in many inflammatory demyelinating experimental diseases. The pilot condition in these studies was experimental allergic encephalomyelitis, the most widely used animal model for MS, in which we demonstrated that exogenous TH administration improves remyelination and neuroprotection by partially correcting tissue hypothyroidism (Fernandez et al., 2004; Dell’Acqua et al., 2012). Several independent labs have confirmed these results in many different animal models of demyelinating diseases (reviewed in (Calzà et al., 2018), and a clinical trial (NCT02760056) was finally established (Wooliscroft et al., 2020).

MS offers a seminal example of the major role of WM, not only for proper axonal function but also for axonal protection from damage due to the inflammatory microenvironment. If myelin is not properly repaired, retrograde degeneration leads to neuron death, a mechanism, which makes MS the reference disease for the development of neuroprotective strategies based on OPC/oligodendrocyte and WM integrity (Psenicka et al., 2021).

Spinal cord and traumatic brain injury

Quantitative MRI for WM study was subsequently extended to other conditions, including SCI and traumatic brain injury. Both of these conditions are characterized by a primary lesion, triggered by the injury, followed by a phase known as “secondary degeneration” and by stabilization after several months. SCI is a seminal condition for myelinated neural tract analysis, including both axons and respective myelin sheaths. MRI has permitted researchers to map not only the extent of the primary damage but also its extension rostrocaudally, as well as the rearrangements in brain connectivity following lesion (Seif et al., 2019). Brain DTI analysis has shown myelin decrease and progressive structural changes along the neuroaxis following trauma in acute and chronic SCI patients (Ziegler et al., 2018), showing unexpected correlations between brain volume and neurological deficits (Ziegler et al., 2018), as well as volume changes in the brain related to the atrophy of myelinated axons and their cell bodies within the gray matter of sensory and motor cortices (Seif et al., 2019).

Extensive oligodendrocyte and OPC cell death occurs during the first two weeks following injury in the epicenter as well as regions distal to the lesion (Hassannejad et al., 2019). Extensive OPC proliferation subsequently occurs over time and within the first two weeks post-injury, producing oligodendrocytes responsible for the de novo ensheathment of a maximum of 30% of myelinated spinal axons at the injury epicenter 3 months after SCI (Assinck et al., 2017).

TH treatment has been also proposed to overcome the inflammation-induced OPC differentiation block in SCI. Several different biomaterial-assisted local delivery systems have been proposed, thus avoiding the risk of hyperthyroidism connected with systemic delivery. Hydrogel-based drug (Shultz et al., 2017) and polymeric scaffold local delivery systems also containing anti-inflammatory drugs at doses comparable to safe human doses promoted new mature oligodendrocyte formation and myelination in rat SCI, also improving locomotor functional outcomes (Bighinati et al., 2020).

Alzheimer’s disease

AD is characterized by a long biological history, one which precedes clinical onset by decades, progressively evolving until the classical pathological landmarks (intraneuronal fibrillary tangles and extracellular amyloid plaques) appear, and every stage of the AD process is characterized by WM alterations (Shao et al., 2021b). Volumetric MRI measures are a current standard as outcome measures in clinical trials assessing disease-modifying therapies in AD (Anderson et al., 2012): DTI has indicated a decreased fractional anisotropy value in mild cognitive impairment patients when applied to WM study, and WM diffusivity changes were associated with the progression of AD (Lo Buono et al., 2020). A dysconnectivity between the entorhinal cortex and hippocampus in patients with mild cognitive impairment and AD has also been observed by diffusion kurtosis imaging, alterations suggesting that AD pathology may propagate stepwise along WM pathways in a condition known as “disconnection syndrome”, and that the clinical expression of AD may be supported by the selective vulnerability of pyramidal neuron subtypes and the consequent loss of cortico-cortical connections (Kamagata et al., 2020).

Concomitant with the increase in β-amyloid plaques, the cerebral matter of AD patients shows a significant decrease in the myelin proteins (myelin basic protein, proteolipid protein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase), indicative of WM degeneration. In vitro studies have also demonstrated the apoptosis of undifferentiated OPCs and differentiated mouse oligodendrocytes following exposure to amyloid peptide β1–42 (Tognatta and Miller, 2016). An age-related decrease in myelin basic protein immunostaining and OPC density, together with a decline in the number of OPC replications, has also been described in 3xTg AD mice (Vanzulli et al., 2020).

AD pathology also includes neuroinflammation, and it has been suggested that AD-associated inflammation enhances OPC susceptibility to the oxidative stress associated with the hostile AD microenvironment (Bandyopadhyay, 2021). Interestingly, an association between thyroid function and AD has also emerged, and it has been suggested that low CNS TH levels may predispose to AD via increasing APP expression, and consequently to Aβ peptide and β-amyloid levels (Figueroa et al., 2021).

Notably, OPC dysfunctions have also been described in other neurodegenerative and psychiatric diseases, like Parkinson’s and Huntington’s diseases, schizophrenia, and major depressive disorders (Clayton and Tesar, 2021). In amyotrophic lateral sclerosis, although motoneuron degeneration is responsible for the clinical phenotype, the accumulation of pathological proteins (superoxide dismutase 1, TAR DNA binding protein 43) in oligodendrocytes, myelin alterations, and defective OPC maturation have been reported (Raffaele et al., 2021). Finally, molecular deficits linked to energy metabolism and solute transport in oligodendrocytes as well as in neurons contribute to the pathogenesis of cortical lesions in Creutzfeldt-Jakob disease (Andres Benito et al., 2018).

Concluding Remarks

While neuroprotection is a recognized target in many forms of neurological damage and chronic neurodegenerative diseases, most of the clinical trials on neuroprotection in MS, the reference WM disease, either failed, were interrupted, or provided inconclusive results (Huntemann et al., 2021). We believe that three points must be considered for successful clinical translation of preclinical data supporting therapies for myelin repair in adulthood.

The first point relates to the in vitro step of the drug discovery pipelines, which should consider regional OPC heterogeneity and specific pathophysiology. Most chemical entities in in vitro screening programs are based on primary cortical fetal OPCs: these cells are not exposed to in vitro conditions, which mimic the inflammatory microenvironment, making them unsuited to determining whether potential drugs can effectively overcome the OPC differentiation block related to inflammation (Manousi et al., 2021). These cells are also unfit for studies related to adult OPC pathologies, which differ from those affecting fetal OPCs (Windrem et al., 2004). The use of primary cortical OPCs also ignores the lineage induction phase, however, this critical step can be investigated by deriving OPCs from neural stem cells (Baldassarro et al., 2021b), and taking into consideration regional heterogeneity (Hayashi and Suzuki, 2019).

The second point relates to clinical study design, which should include WM monitoring in primary neurodegenerative diseases also.

The third point regards the longitudinal evolution of the pathologies since both CNS lesions and chronic degenerative diseases are evolving conditions. The study of the potential role of pharmacological approaches to improve myelin restoration requires stringent clinical trial design, adopting the appropriate time windows for treatments, as suggested by preclinical studies.

Author contributions:Manuscript writing: VAB, LC, LL; data search and collection: VAB, AS, LG, LC, LL; supervision: LC. All authors approved the final version of the manuscript.

Conflicts of interest:There are no conflicts of interest.

C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y.

1. Akay LA, Effenberger AH, Tsai LH 2021 Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function Genes Dev 35 180–198
2. Alshehri B, Pagnin M, Lee JY, Petratos S, Richardson SJ 2020 The role of transthyretin in oligodendrocyte development Sci Reports 2020 101 10 1–19
    3. Anderson VM, Schott JM, Bartlett JW, Leung KK, Miller DH, Fox NC 2012 Gray matter atrophy rate as a marker of disease progression in AD Neurobiol Aging 33 1194–1202
    4. Andres Benito P, Dominguez Gonzalez M, Ferrer I 2018 Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease Prion 12 216–225
    5. Armada-Moreira A, Ribeiro FF, Sebastião AM, Xapelli S 2015 Neuroinflammatory modulators of oligodendrogenesis Neuroimmunol Neuroinflammation 2 263–273
      6. Aslan K, Gunbey HP, Cortcu S, Ozyurt O, Avci U, Incesu L 2020 Diffusion tensor imaging in hyperthyroidism: assessment of microstructural white matter abnormality with a tract-based spatial statistical analysis Acta Radiol 61 1677–1683
      7. Assinck P, Duncan GJ, Plemel JR, Lee MJ, Stratton JA, Manesh SB, Liu J, Ramer LM, Kang SH, Bergles DE, Biernaskie J, Tetzlaff W 2017 Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury J Neurosci 37 8635-8654
      8. Bailey M, Hafler DA, Pelletier D 2014 Multiple sclerosis and acute disseminated encephalomyelitis: immunology encyclopedia of the neurological sciences Aminoff MJ, Daroff RB 144–147 New York Academic Press Inc
        9. Baldassarro VA, Marchesini A, Giardino L, Calzà L 2017 PARP activity and inhibition in fetal and adult oligodendrocyte precursor cells: Effect on cell survival and differentiation Stem Cell Res 22 54–60
          10. Baldassarro VA, Krężel W, Fernández M, Schuhbaur B, Giardino L, Calzà L 2019 The role of nuclear receptors in the differentiation of oligodendrocyte precursor cells derived from fetal and adult neural stem cells Stem Cell Res 37 101443
            11. Baldassarro VA, Marchesini A, Giardino L, Calzà L 2020 Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells-derived oligodendrocyte precursor cells Glia 68 898–917
            12. Baldassarro VA, Flagelli A, Sannia M, Calzà L 2021a Nuclear receptors and differentiation of oligodendrocyte precursor cells Vitam Horm 116 389–407
            13. Baldassarro VA, Giardino L, Calzà L 2021b Oligodendrocytes in a dish for the drug discovery pipeline: the risk of oversimplification Neural Regen Res 16 291–293
              14. Balestri S, Giovane A Del, Sposato C, Ferrarelli M, Ragnini-wilson A 2021 The current challenges for drug discovery in CNS remyelination Int J Mol Sci 22 1–30
                15. Bandyopadhyay S 2021 Role of neuron and glia in Alzheimer's disease and associated vascular dysfunction Front Aging Neurosci 13 653334
                  16. Baydyuk M, Morrison VE, Gross PS, Huang JK 2020 Extrinsic factors driving oligodendrocyte lineage cell progression in CNS development and injury Neurochem Res 45 630–642
                  17. Bercury KK, Macklin WB 2015 Dynamics and mechanisms of CNS myelination Dev Cell 32 447–458
                  18. Bighinati A, Focarete ML, Gualandi C, Pannella M, Giuliani A, Beggiato S, Ferraro L, Lorenzini L, Giardino L, Calzà L 2020 Improved functional recovery in rat spinal cord injury induced by a drug combination administered with an implantable polymeric delivery system J Neurotrauma 37 1708–1719
                  19. Bradl M, Lassmann H 2010 Oligodendrocytes: biology and pathology Acta Neuropathol 119 37–53
                  20. Calzà L, Baldassarro VA, Fernandez M, Giuliani A, Lorenzini L, Giardino L 2018 Thyroid hormone and the white matter of the central nervous system: from development to repair Vitam Horm 106 253–281
                  21. Calzà L, Fernández M, Giardino L 2015 Role of the thyroid system in myelination and neural connectivity Compr Physiol 5 1405–1421
                  22. Cercignani M, Bouyagoub S 2018 Brain microstructure by multi-modal MRI: is the whole greater than the sum of its parts? Neuroimage 182 117–127
                  23. Clayton BLL, Tesar PJ 2021 Oligodendrocyte progenitor cell fate and function in development and disease Curr Opin Cell Biol 73 35–40
                  24. D'Intino G, Lorenzini L, Fernandez M, Taglioni A, Perretta G, Del Vecchio G, Villoslada P, Giardino L, Calzà L 2011 Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism J Neuroendocrinol 23 778–790
                    25. Davis PJ, Goglia F, Leonard JL 2016 Nongenomic actions of thyroid hormone Nat Rev Endocrinol 12 111–121
                    26. Dawson MRL, Polito A, Levine JM, Reynolds R 2003 NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS Mol Cell Neurosci 24 476–488
                    27. Dell'Acqua ML, Lorenzini L, D'Intino G, Sivilia S, Pasqualetti P, Panetta V, Paradisi M, Filippi MM, Baiguera C, Pizzi M, Giardino L, Rossini PM, Calzà L 2012 Functional and molecular evidence of myelin- and neuroprotection by thyroid hormone administration in experimental allergic encephalomyelitis Neuropathol Appl Neurobiol 38 454–470
                    28. Deuschl G, Beghi E, Fazekas F, Varga T, Christoforidi KA, Sipido E, Bassetti CL, Vos T, Feigin VL 2020 The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017 Lancet Public Heal 5 e551–e567
                      29. Dhir N, Medhi B, Prakash A, Goyal MK, Modi M, Mohindra S 2020 Pre-clinical to clinical translational failures and current status of clinical trials in stroke therapy: a brief review Curr Neuropharmacol 18 596–612
                      30. Duncan ID, Radcliff AB, Heidari M, Kidd G, August BK, Wierenga LA 2018 The adult oligodendrocyte can participate in remyelination Proc Natl Acad Sci U S A 115 E11807–E11816
                      31. Eerdekens A, Langouche L, Van den Berghe G, Verhaeghe J, Naulaers G, Vanhole C 2019 Review shows that thyroid hormone substitution could benefit transient hypothyroxinaemia of prematurity but treatment strategies need to be clarified Acta Paediatr Int J Paediatr 108 792–805
                      32. Fernandez M, Pirondi S, Manservigi M, Giardino L, Calzà L 2004 Thyroid hormone participates in the regulation of neural stem cells and oligodendrocyte precursor cells in the central nervous system of adult rat Eur J Neurosci 20 2059–2070
                      33. Fernández M, Baldassarro VA, Sivilia S, Giardino L, Calzà L 2016 Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: direct impact on OPCs differentiation failure Glia 64 1573–1589
                        34. Fiani B, Noblett C, Nanney J, Doan T, Pennington E, Jarrah R, Sarno E, Nikolaidis D 2020 Diffusion tensor imaging of the spinal cord status post trauma Surg Neurol Int 11 276
                        35. Figueroa PBS, Ferreira AFF, Britto LR, Doussoulin AP, Torrão A da S 2021 Association between thyroid function and Alzheimer's disease: a systematic review Metab Brain Dis 36 1523–1543
                        36. Filip P, Svatkova A, Carpenter AF, Eberly LE, Nestrasil I, Nissi MJ, Michaeli S, Mangia S 2020 Rotating frame MRI relaxations as markers of diffuse white matter abnormalities in multiple sclerosis NeuroImage Clin 26 102234
                          37. Filippi M, Rocca MA, Ciccarelli O, De Stefano N, Evangelou N, Kappos L, Rovira A, Sastre-Garriga J, Tintorè M, Frederiksen JL, Gasperini C, Palace J, Reich DS, Banwell B, Montalban X, Barkhof F 2016 MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines Lancet Neurol 15 292–303
                          38. Fliers E, Boelen A 2020 An update on non-thyroidal illness syndrome J Endocrinol Invest 44 1597–1607
                          39. Gosar D, Tretnjak V, Bregant T, Neubauer D, Derganc M 2020 Reduced white-matter integrity and lower speed of information processing in adolescents with mild and moderate neonatal hypoxic-ischaemic encephalopathy Eur J Paediatr Neurol 28 205–213
                          40. Hassannejad Z, Shakouri-Motlagh A, Mokhatab M, Zadegan SA, Sharif-Alhoseini M, Shokraneh F, Rahimi-Movaghar V 2019 Oligodendrogliogenesis and axon remyelination after traumatic spinal cord injuries in animal studies: a systematic review Neuroscience 402 37–50
                          41. Hayashi C, Suzuki N 2019 Heterogeneity of oligodendrocytes and their precursor cells Adv Exp Med Biol 1190 53–62
                          42. Henmar S, Simonsen EB, Berg RW 2020 What are the gray and white matter volumes of the human spinal cord? J Neurophysiol 124 1792–1797
                          43. Herrera JJ, Chacko T, Narayana PA 2008 Histological correlation of diffusion tensor imaging metrics in experimental spinal cord injury J Neurosci Res 86 443–447
                          44. Holikova K, Laakso H, Salo R, Shatillo A, Nurmi A, Bares M, Vanicek J, Michaeli S, Mangia S, Sierra A, Gröhn O 2021 RAFF-4, magnetization, transfer and diffusion tensor MRI of lysophosphatidylcholine induced demyelination and remyelination in rats Front Neurosci 15 625167
                          45. Huntemann N, Rolfes L, Pawlitzki M, Ruck T, Pfeuffer S, Wiendl H, Meuth SG 2021 Failed interrupted or inconclusive trials on neuroprotective and neuroregenerative treatment strategies in multiple sclerosis: update 2015–2020 Drugs 81 1031–1063
                          46. Kamagata K, Andica C, Hatano T, Ogawa T, Takeshige-Amano H, Ogaki K, Akashi T, Hagiwara A, Fujita S, Aoki S 2020 Advanced diffusion magnetic resonance imaging in patients with Alzheimer's and Parkinson's diseases Neural Regen Res 15 1590–1600
                            47. Kuhlmann T, Miron V, Cuo Q, Wegner C, Antel J, Bruck W 2008 Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis Brain 131 1749–1758
                            48. Kuhn S, Gritti L, Crooks D, Dombrowski Y 2019 Oligodendrocytes in development, myelin generation and beyond Cells 8 1424
                            49. Lee JY, Petratos S 2016 Thyroid hormone signaling in oligodendrocytes: from extracellular transport to intracellular signal Mol Neurobiol 53 6568–6583
                            50. Lehto LJ, Albors AA, Sierra A, Tolppanen L, Eberly LE, Mangia S, Nurmi A, Michaeli S, Gröhn O 2017 Lysophosphatidyl choline induced demyelination in rat probed by relaxation along a fictitious field in high rank rotating frame Front Neurosci 11 433
                            51. Lentferink DH, Jongsma JM, Werkman I, Baron W 2018 Grey matter OPCs are less mature and less sensitive to IFNγthan white matter OPCs: consequences for remyelination Sci Rep 8 1–15
                              52. Liu Y, Chen H, Jing C, Li F 2018 The association between maternal subclinical hypothyroidism and growth, development, and childhood intelligence: a meta-analysis JCRPE J Clin Res Pediatr Endocrinol 10 153–161
                                53. Lo Buono V, Palmeri R, Corallo F, Allone C, Pria D, Bramanti P, Marino S 2020 Diffusion tensor imaging of white matter degeneration in early stage of Alzheimer's disease: a review Int J Neurosci 130 243–250
                                54. Lubetzki C, Zalc B, Williams A, Stadelmann C, Stankoff B 2020 Remyelination in multiple sclerosis: from basic science to clinical translation Lancet Neurol 19 678–688
                                55. Luongo C, Dentice M, Salvatore D 2019 Deiodinases and their intricate role in thyroid hormone homeostasis Nat Rev Endocrinol 15 479–488
                                56. Manousi A, Göttle P, Reiche L, Cui QL, Healy LM, Akkermann R, Gruchot J, Schira-Heinen J, Antel JP, Hartung HP, Küry P 2021 Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence EBioMedicine 65 103276
                                  57. Mishra A, Wang F, Chen LM, Gore JC 2020 Longitudinal changes in DTI parameters of specific spinal white matter tracts correlate with behavior following spinal cord injury in monkeys Sci Rep 10 17316
                                  58. Mota B, Dos Santos SE, Ventura-Antunes L, Jardim-Messeder D, Neves K, Kazu RS, Noctor S, Lambert K, Bertelsen MF, Manger PR, Sherwood CC, Kaas JH, Herculano-Houzel S 2019 White matter volume and white/gray matter ratio in mammalian species as a consequence of the universal scaling of cortical folding Proc Natl Acad Sci U S A 116 15253–15261
                                  59. Mughal BB, Fini JB, Demeneix BA 2018 Thyroid-disrupting chemicals and brain development: an update Endocr Connect 7 R160–186
                                    60. Nishiyama A, Shimizu T, Sherafat A, Richardson WD 2021 Life-long oligodendrocyte development and plasticity Semin Cell Dev Biol 116 25–37
                                    61. Pagnin M, Kondos-Devcic D, Chincarini G, Cumberland A, Richardson SJ, Tolcos M 2021 Role of thyroid hormones in normal and abnormal central nervous system myelination in humans and rodents Front Neuroendocrinol 61 100901
                                    62. Pereira DN, Procianoy RS 2001 Effect of perinatal asphyxia on thyroid hormones J Pediatr (Rio J) 77 175–178
                                    63. Pflugshaupt T, Geisseler O, Nyffeler T, Linnebank M 2016 Cognitive impairment in multiple sclerosis: clinical manifestation, neuroimaging correlates, and treatment Semin Neurol 36 203–211
                                    64. Psenicka MW, Smith BC, Tinkey RA, Williams JL 2021 Connecting neuroinflammation and neurodegeneration in multiple sclerosis: are oligodendrocyte precursor cells a nexus of disease? Front Cell Neurosci 15 654284
                                      65. Raffaele S, Boccazzi M, Fumagalli M 2021 Oligodendrocyte dysfunction in amyotrophic lateral sclerosis: mechanisms and therapeutic perspectives Cells 10 1–32
                                        66. Schaeffer DJ, Adam R, Gilbert KM, Gati JS, Li AX, Menon RS, Everling S 2017 Diffusion-weighted tractography in the common marmoset monkey at 9.4t J Neurophysiol 118 1344–1354
                                        67. Seif M, Gandini Wheeler-Kingshott CA, Cohen-Adad J, Flanders AE, Freund P 2019 Guidelines for the conduct of clinical trials in spinal cord injury: neuroimaging biomarkers Spinal Cord 57 717–728
                                        68. Shao R, Sun D, Hu Y, Cui D 2021a White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia J Neurosci Res 99 991–1008
                                        69. Shao W, He X, Li X, Tao W, Zhang J, Zhang S, Wang L, Qiao Y, Wang Y, Zhang Z, Peng D 2021b Disrupted white matter networks from subjective memory impairment to amnestic mild cognitive impairment Curr Alzheimer Res 18 35–44
                                        70. Shultz RB, Wang Z, Nong J, Zhang Z, Zhong Y 2017 Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury J Neural Eng 14 036014
                                          71. Simons M, Nave KA 2016 Oligodendrocytes: myelination and axonal support Cold Spring Harb Perspect Biol 8 a020479
                                            72. Singh S, Modi S, Bagga D, Kaur P, Shankar LR, Khushu S 2013 Voxel-based morphometric analysis in hypothyroidism using diffeomorphic anatomic registration via an exponentiated lie algebra algorithm approach J Neuroendocrinol 25 229–234
                                            73. Singh S, Trivedi R, Singh K, Kumar P, Shankar LR, Khushu S 2014 Diffusion tensor tractography in hypothyroidism and its correlation with memory function J Neuroendocrinol 26 825–833
                                            74. Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson DM, Moya PR, Piccart E, Hellings N, Eijnde BO, Derave W, Schreiber R, Vanmierlo T 2021 Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders Cell Mol Life Sci 78 4615–4637
                                            75. Stenzel D, Huttner WB 2013 Role of maternal thyroid hormones in the developing neocortex and during human evolution Front Neuroanat 7 19
                                              76. Tae WS, Ham BJ, Pyun SB, Kang SH, Kim BJ 2018 Current clinical applications of diffusion-tensor imaging in neurological disorders J Clin Neurol 14 129–140
                                                77. Tiane A, Schepers M, Rombaut B, Hupperts R, Prickaerts J, Hellings N, van den Hove D, Vanmierlo T 2019 From OPC to oligodendrocyte: an epigenetic journey Cells 8 1236
                                                  78. Tognatta R, Miller RH 2016 Contribution of the oligodendrocyte lineage to CNS repair and neurodegenerative pathologies Neuropharmacology 110 539–547
                                                  79. van der Weijden CWJ, García DV, Borra RJH, Thurner P, Meilof JF, van Laar PJ, Dierckx RAJO, Gutmann IW, de Vries EFJ 2021 Myelin quantification with MRI: a systematic review of accuracy and reproducibility Neuroimage 226 117561
                                                  80. van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ, Rowitch DH, Nijboer CH 2018 Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury Glia 66 221–238
                                                  81. Vanzulli I, Papanikolaou M, De-La-Rocha IC, Pieropan F, Rivera AD, Gomez-Nicola D, Verkhratsky A, Rodríguez JJ, Butt AM 2020 Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease Neurobiol Aging 94 130–139
                                                  82. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G, Roy NS, Goldman SA 2004 Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain Nat Med 10 93–97
                                                  83. Wooliscroft L, Altowaijri G, Hildebrand A, Samuels M, Oken B, Bourdette D, Cameron M 2020 Phase I randomized trial of liothyronine for remyelination in multiple sclerosis: A dose-ranging study with assessment of reliability of visual outcomes Mult Scler Relat Disord 41 102015
                                                  84. Wozniak JR, Lim KO 2006 Advances in white matter imaging: a review of in vivo magnetic resonance methodologies and their applicability to the study of development and aging Neurosci Biobehav Rev 30 762–774
                                                  85. Wu TL, Byun NE, Wang F, Mishra A, Janve VA, Chen LM, Gore JC 2020 Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging NMR Biomed 33 e4216
                                                  86. Zaninovich OA, Avila MJ, Kay M, Becker JL, Hurlbert RJ, Martirosyan NL 2019 The role of diffusion tensor imaging in the diagnosis, prognosis, and assessment of recovery and treatment of spinal cord injury: a systematic review Neurosurg Focus 46 E7
                                                  87. Zhang F, Lin X, Liu A, Chen J, Shan Z, Teng W, Yu X 2021 Maternal subclinical hypothyroidism in rats impairs spatial learning and memory in offspring by disrupting balance of the TrkA/p75NTR signal pathway Mol Neurobiol 58 4237–4250
                                                  88. Ziegler G, Grabher P, Thompson A, Altmann D, Hupp M, Ashburner J, Friston K, Weiskopf N, Curt A, Freund P 2018 Progressive neurodegeneration following spinal cord injury: Implications for clinical trials Neurology 90 e1257–1266

                                                  Alzheimer’s disease; multiple sclerosis; oligodendrocyte precursor cells; spinal cord injury; thyroid hormone; traumatic brain injury; white matter; white matter imaging

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