Corticospinal Tract Degeneration Research Articles

Spinogenesis in spinal cord motor neurons following pharmacological lesions to the rat motor cortex

IntroductionMotor function is impaired in multiple neurological diseases associated with corticospinal tract degeneration. Motor impairment has been linked to plastic changes at both the presynaptic and postsynaptic levels. However, there is no evidence of changes in information transmission from the cortex to spinal motor neurons. MethodsWe used kainic acid to induce stereotactic lesions to the primary motor cortex of female adult rats. Fifteen days later, we evaluated motor function with the Basso, Beattie, Bresnahan (BBB) scale and the rotarod and determined the density of thin, stubby, and mushroom spines of motor neurons from a thoracolumbar segment of the spinal cord. Spinophilin, synaptophysin, and β III tubulin expression was also measured. ResultsPharmacological lesions resulted in poor motor performance. Spine density and the proportion of thin and stubby spines were greater. We also observed increased expression of the 3 proteins analysed. ConclusionThe clinical symptoms of neurological damage secondary to Wallerian degeneration of the corticospinal tract are associated with spontaneous, compensatory plastic changes at the synaptic level. Based on these findings, spontaneous plasticity is a factor to consider when designing more efficient strategies in the early phase of rehabilitation.

Cerebrovascular pathology presenting as corticobasal syndrome: An autopsy case series of “vascular CBS”

BackgroundThe corticobasal syndrome (CBS) is heterogeneous in terms of postmortem neuropathology. While it has been previously studied with antemortem neuroimaging, clinicopathologic features of corticobasal syndrome associated with cerebrovascular pathology (vascular CBS) have yet to be reported. MethodsTo identify vascular CBS, we searched the database of the CurePSP Brain Bank for patients with a clinical diagnosis of CBS who failed to meet neuropathologic criteria for corticobasal degeneration (CBD) or other neurodegenerative disease processes, but who had significant cerebrovascular pathology. Hemibrains were assessed macroscopically and processed for histological assessment. Medical records were reviewed to characterize clinical features of vascular CBS. ResultsOf 217 patients with an antemortem diagnosis of CBS, we identified three patients with vascular CBS. Multiple infarcts in the watershed regions (frontal lobe and motor cortex), periventricular white matter, thalamus, and basal ganglia were observed in two patients. One patient had no cortical infarcts, but had multiple white matter infarcts and corticospinal tract degeneration. All were clinically thought to have CBS based on progressive asymmetric motor symptoms, including rigidity and apraxia, as well as cognitive impairment. Antemortem imaging studies showed findings of chronic cerebrovascular disease, with infarcts or white matter pathology. ConclusionsThis autopsy study of vascular CBS shows that, while rare, cerebrovascular pathology involving the frontal lobe, white matter tracts, basal ganglia, thalamus, and corticospinal tract can underlie clinical features suggestive of CBS. When neuroimaging suggests an alternative explanation, including chronic infarcts in critical regions, caution is merited in considering CBD as the underlying pathology.

Are Cognitive Changes in Hereditary Spastic Paraplegias Restricted to Complicated Forms?

Background: Little is known about the cognitive profile of Hereditary Spastic Paraplegias (HSP), where most scientific attention has been given to motor features related to corticospinal tract degeneration.Objectives: We aimed to perform a broad characterization of the cognitive functions of patients with pure and complicated HSP as well as to determine the frequency of abnormal cognitive performances in the studied subtypes.Methods: A two-center cross-sectional case-control study was performed. All individuals underwent cognitive assessment through screening tests (Mini Mental State Examination—MEEM and Montreal Cognitive Assessment—MOCA) and tests to assess specific cognitive functions (Verbal fluency with phonological restriction—FAS; Verbal categorical fluency—FAS-cat and Rey's Verbal Auditory Learning Test -RAVLT).Results: Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study. SPG4 patients had worse performances in MOCA, FAS, FAS-cat, and RAVLT when compared to controls. Most SPG4 patients presented cognitive changes not compatible with dementia, performing poorly in memory, attention and executive functions. SPG5 patients scored lower in executive functions and memory, and SPG7 patients performed poorly on memory tasks. All evaluated cognitive functions were markedly altered in CTX and SPG11 patients.Conclusions: Cognitive abnormalities are frequent in HSP, being more severe in complicated forms. However, cognitive impairments of pure HSPs might impact patients' lives, decreasing families' socioeconomic status and contributing to the overall disease burden.

The Spinal Transcriptome after Cortical Stroke: In Search of Molecular Factors Regulating Spontaneous Recovery in the Spinal Cord.

In response to cortical stroke and unilateral corticospinal tract degeneration, compensatory sprouting of spared corticospinal fibers is associated with recovery of skilled movement in rodents. To date, little is known about the molecular mechanisms orchestrating this spontaneous rewiring. In this study, we provide insights into the molecular changes in the spinal cord tissue after large ischemic cortical injury in adult female mice, with a focus on factors that might influence the reinnervation process by contralesional corticospinal neurons. We mapped the area of cervical gray matter reinnervation by sprouting contralesional corticospinal axons after unilateral photothrombotic stroke of the motor cortex in mice using anterograde tracing. The mRNA profile of this reinnervation area was analyzed using whole-genome sequencing to identify differentially expressed genes at selected time points during the recovery process. Bioinformatic analysis revealed two phases of processes: early after stroke (4–7 d post-injury), the spinal transcriptome is characterized by inflammatory processes, including phagocytic processes as well as complement cascade activation. Microglia are specifically activated in the denervated corticospinal projection fields in this early phase. In a later phase (28–42 d post-injury), biological processes include tissue repair pathways with upregulated genes related to neurite outgrowth. Thus, the stroke-denervated spinal gray matter, in particular its intermediate laminae, represents a growth-promoting environment for sprouting corticospinal fibers originating from the contralesional motor cortex. This dataset provides a solid starting point for future studies addressing key elements of the post-stroke recovery process, with the goal to improve neuroregenerative treatment options for stroke patients.SIGNIFICANCE STATEMENT We show that the molecular changes in the spinal cord target tissue of the stroke-affected corticospinal tract are mainly defined by two phases: an early inflammatory phase during which microglia are specifically activated in the target area of reinnervating corticospinal motor neurons; and a late phase during which growth-promoting factors are upregulated which can influence the sprouting response, arborization, and synapse formation. By defining for the first time the endogenous molecular machinery in the stroke-denervated cervical spinal gray matter with a focus on promotors of axon growth through the growth-inhibitory adult CNS, this study will serve as a basis to address novel neuroregenerative treatment options for chronic stroke patients.

Brain MRI shows white matter sparing in Kennedy's disease and slow-progressing lower motor neuron disease.

The extent of central nervous system involvement in Kennedy's disease (KD) relative to other motor neuron disease (MND) phenotypes still needs to be clarified. In this study, we investigated cortical and white matter (WM) MRI alterations in 25 patients with KD, compared with 24 healthy subjects, 25 patients with sporadic amyotrophic lateral sclerosis (ALS), and 35 cases with lower motor neuron-predominant disease (LMND). LMND patients were clinically differentiated into 24 fast and 11 slow progressors. Whole-brain cortical thickness, WM tract-based spatial statistics and corticospinal tract (CST) tractography analyses were performed. No significant difference in terms of cortical thickness was found between groups. ALS patients showed widespread decreased fractional anisotropy and increased mean (MD) and radial diffusivity (radD) in the CST, corpus callosum and fronto-temporal extra-motor tracts, compared with healthy controls and other patient groups. CST tractography showed significant alterations of DT MRI metrics in ALS and LMND-fast patients whereas KD and LMND-slow patients were comparable with healthy controls. Our study demonstrated the absence of WM abnormalities in patients with KD and LMND-slow, in contrast with diffuse WM damage in ALS and focal CST degeneration in LMND-fast, supporting the use of DT MRI measures as powerful tools to differentiate fast- and slow-progressing MND syndromes, including KD.

Amyotrophic Lateral Sclerosis: The Most Common And Lethal Form Of Motor Neuron Disease-a Case Report From Middle East

A neurodegenerative disorder which is fatal, rapidly progressive and has no effective treatment till date is amyotrophic lateral sclerosis. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. It is a devastating disease leading to death within 3-5 years in most cases. The diagnosis of AML is difficult to made in spite of acknowledgment for 140 years. It is diagnosed by clinical presentation which is a combination of upper and lower motor neuron signs and electro diagnostic studies which gives information about diffuse motor axonal injury. This neurodegenerative disorder results in degeneration of corticospinal tracts and anterior horn cells and involving motor neurons of the cerebral cortex, brainstem, and spinal cord. There are a variable signs and symptoms of this disease, so the diagnosis is very important for the management and better outcome of the patients. Cause of death in these patients is usually respiratory failure

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

Wallerian degeneration of corticospinal tract following stroke – indicator of worse prognosis

Wallerian degeneration of corticospinal tract following stroke – indicator of worse prognosis

Corticospinal tract degeneration in ALS unmasked in T1-weighted images using texture analysis.

The purpose of this study was to investigate whether textures computed from T1-weighted (T1W) images of the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS) are associated with degenerative changes evaluated by diffusion tensor imaging (DTI). Nineteen patients with ALS and 14 controls were prospectively recruited and underwent T1W and diffusion-weighted magnetic resonance imaging. Three-dimensional texture maps were computed from T1W images and correlated with the DTI metrics within the CST. Significantly correlated textures were selected and compared within the CST for group differences between patients and controls using voxel-wise analysis. Textures were correlated with the patients' clinical upper motor neuron (UMN) signs and their diagnostic accuracy was evaluated. Voxel-wise analysis of textures and their diagnostic performance were then assessed in an independent cohort with 26 patients and 13 controls. Results showed that textures autocorrelation, energy, and inverse difference normalized significantly correlated with DTI metrics (p < .05) and these textures were selected for further analyses. The textures demonstrated significant voxel-wise differences between patients and controls in the centrum semiovale and the posterior limb of the internal capsule bilaterally (p < .05). Autocorrelation and energy significantly correlated with UMN burden in patients (p < .05) and classified patients and controls with 97% accuracy (100% sensitivity, 92.9% specificity). In the independent cohort, the selected textures demonstrated similar regional differences between patients and controls and classified participants with 94.9% accuracy. These results provide evidence that T1-based textures are associated with degenerative changes in the CST.

Neurite orientation and dispersion density imaging (NODDI) detects cortical and corticospinal tract degeneration in ALS

BackgroundCorticospinal tract (CST) degeneration and cortical atrophy are consistent features of amyotrophic lateral sclerosis (ALS). We hypothesised that neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion...

StartReact during gait initiation reveals differential control of muscle activation and inhibition in patients with corticospinal degeneration

Corticospinal lesions cause impairments in voluntary motor control. Recent findings suggest that some degree of voluntary control may be taken over by a compensatory pathway involving the reticulospinal tract. In humans, evidence for this notion mainly comes from StartReact studies. StartReact is the acceleration of reaction times by a startling acoustic stimulus (SAS) simultaneously presented with the imperative stimulus. As previous StartReact studies mainly focused on isolated single-joint movements, the question remains whether the reticulospinal tract can also be utilized for controlling whole-body movements. To investigate reticulospinal control, we applied the StartReact paradigm during gait initiation in 12 healthy controls and 12 patients with ‘pure’ hereditary spastic paraplegia (HSP; i.e., retrograde axonal degeneration of corticospinal tract). Participants performed three consecutive steps in response to an imperative visual stimulus. In 25% of 16 trials a SAS was applied. We determined reaction times of muscle (de)activation, anticipatory postural adjustments (APA) and steps. Without SAS, we observed an overall delay in HSP patients compared to controls. Administration of the SAS accelerated tibialis anterior and rectus femoris onsets in both groups, but more so in HSP patients, resulting in (near-)normal latencies. Soleus offsets were accelerated in controls, but not in HSP patients. The SAS also accelerated APA and step reaction times in both groups, yet these did not normalize in the HSP patients. The reticulospinal tract is able to play a compensatory role in voluntary control of whole-body movements, but seems to lack the capacity to inhibit task-inappropriate muscle activity in patients with corticospinal lesions.

Espinogénesis en motoneuronas de la médula espinal tras la lesión farmacológica de la corteza motora de ratas

IntroductionMotor function is impaired in multiple neurological diseases associated with corticospinal tract degeneration. Motor impairment has been linked to plastic changes at both the presynaptic and postsynaptic levels. However, there is no evidence of changes in information transmission from the cortex to spinal motor neurons. MethodsWe used kainic acid to induce stereotactic lesions to the primary motor cortex of female adult rats. Fifteen days later, we evaluated motor function with the BBB scale and the rotarod and determined the density of thin, stubby, and mushroom spines of motor neurons from a thoracolumbar segment of the spinal cord. Spinophilin, synaptophysin, and β iii-tubulin expression was also measured. ResultsPharmacological lesions resulted in poor motor performance. Spine density and the proportion of thin and stubby spines were greater. We also observed increased expression of the 3 proteins analysed. ConclusionThe clinical symptoms of neurological damage secondary to Wallerian degeneration of the corticospinal tract are associated with spontaneous, compensatory plastic changes at the synaptic level. Based on these findings, spontaneous plasticity is a factor to consider when designing more efficient strategies in the early phase of rehabilitation.

Chapter 2 - HIV neuropathology

Primary human immunodeficiency virus (HIV) neuropathologies can affect all levels of the neuraxis and occur in all stages of natural history disease. Some, like HIV encephalitis, HIV myelitis, and diffuse infiltrative lymphocytosis of peripheral nerve, reflect productive infection of the nervous system; others, like vacuolar myelopathy, distal symmetric polyneuropathy, and central and peripheral nervous system demyelination, are not clearly related to regional viral replication, and reflect more complex cascades of dysregulated host immunity and metabolic dysfunction. In pediatric patients, the spectrum of neuropathology is altered by the impacts of HIV on a developing nervous system, with microcephaly, abundant brain mineralization, and corticospinal tract degeneration as examples of this unique interaction. With efficacious therapies, CD8 T-cell encephalitis is emerging as a significant entity; often this is clinically recognized as immune reconstitution inflammatory syndrome, but has also been described in the context of viral escape and treatment interruption. The relationship of HIV neuropathology to clinical symptoms is sometimes straightforward, and sometimes mysterious, as individuals can manifest significant deficits in the absence of discrete lesions. However, at all stages of the natural history disease, neuroinflammation is abundant, and critical to the generation of clinical abnormality. Neuropathologic and neurobiologic investigations will be central to understanding HIV nervous system disorders in the era of efficacious therapies.

Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal-frontal scalp regions (in γ-band) and between bilateral regions over motor areas (in θ-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging.

Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence

ObjectiveClinical data suggest early involvement of the corticospinal tract (CST) in spinocerebellar ataxia type 2 (SCA2). Here we tested if early CST degeneration can be detected in prodromal SCA2 mutation carriers by electrophysiological markers of CST integrity. MethodsCST integrity was tested in 15 prodromal SCA2 mutation carriers, 19 SCA2 patients and 25 age-matched healthy controls, using corticomuscular (EEG-EMG) and intermuscular (EMG-EMG) coherence measures in upper and lower limb muscles. ResultsSignificant reductions of EEG-EMG and EMG-EMG coherences were observed in the SCA2 patients, and to a similar extent in the prodromal SCA2 mutation carriers. In prodromal SCA2, EEG-EMG and EMG-EMG coherences correlated with the predicted time to ataxia onset. ConclusionsFindings indicate early CST neurodegeneration in SCA2. EEG-EMG and EMG-EMG coherence may serve as biomarkers of early CST neurodegeneration in prodromal SCA2 mutation carriers. SignificanceFindings are important for developing preclinical disease markers in the context of currently emerging disease-modifying therapies of neurodegenerative disorders.

Neuroimaging patterns along the ALS-FTD spectrum: a multiparametric imaging study

Frontotemporal dementia is associated with considerable clinical, genetic and pathological heterogeneity. The objective of this study is to characterise the imaging signatures of the main FTD phenotypes along the ALS-FTD spectrum. A total of 100 participants underwent comprehensive multimodal neuroimaging, genetic testing and neuropsychological evaluation. Seven patients with behavioural variant FTD (bvFTD), 11 patients with non-fluent-variant primary progressive aphasia (nfvPPA), two patients with sematic-variant primary progressive aphasia(svPPA), 10 patients with amyotrophic lateral sclerosis and FTD carrying the C9orf72 hexanucleotide repeat (C9 + ALS-FTD), 10 patients with ALS-FTD without hexanucleotide repeats (C9-ALS-FTD), 20 ALS patients without behavioural or cognitive deficits (ALSnci) and 40 healthy controls (HC) were included in a prospective quantitative neuroimaging study. Phenotype-specific spatial patterns of pathology were identified along the ALS-FTD spectrum, highlighting a strikingly focal distribution of disease burden as opposed to global atrophy. Significant motor cortex and corticospinal tract degeneration was identified in both bvFTD and nfvPPA patients. C9-ALS-FTD patients exhibited widespread extramotor pathology and significant precentral gyrus atrophy compared to ALSnci patients. ROI analyses confirmed focal grey matter alterations in Broca’s and Wernicke’s area in language variant FTD cohorts. Our findings confirm that the clinical manifestations of FTD are underpinned by phenotype-specific patterns of white and grey matter degeneration.

Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis

A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department. Levels of NFL. The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS. This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1− and Abcd1−/Abcd2−/− mice) and X-ALD patient’s fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1−/Abcd2−/− mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic plasticity and to induce long-term functional recovery. The observed therapeutic effect of neural precursor cells seems to underlie their capacity to upregulate the glial glutamate transporter on astrocytes through the vascular endothelial growth factor inducing favorable changes in the electrical and molecular stroke microenvironment. Cell-based approaches able to influence plasticity seem particularly suited to favor poststroke recovery.

Immunoablation and Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: The Ultimate Test for the Autoimmune Pathogenesis Hypothesis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a progressive death of motor neurons for which there is no cure or effective treatment. The cause of ALS and the specific mechanisms of neuronal death remain unknown. However, considerable evidence supports the existence of autoimmune mechanisms contributing to pathogenesis in ALS, including biochemical, morphological, pharmacological, and physiological studies performed in animal models, cell culture, or with ex vivo preparations (1–6). Typical hallmarks of autoimmunity, such as circulating immune complexes, higher frequency of a particular histocompatibility type, or association with other autoimmune diseases, have also been reported (7, 8). An important marker of autoimmunity is the degree of T-lymphocytic infiltration in the anterior horn of the spinal cord from ALS patients (9, 10). Using monoclonal antibodies against T-cells, B-cells, and macrophages, almost 80% of the specimens show a cellular mononuclear infiltration. The cellular composition of the spinal cord inflammation consists of subsets of suppressor or cytotoxic T-cells and macrophages in the anterior and lateral corticospinal tracts and anterior horns (10). T-helper cells are also observed in proximity to corticospinal tract degeneration (11). Hence, inflammation in ALS spinal cord and brain appears to be primarily due to T-cells and macrophages (12), and aberrant macrophage activity is believed by many investigators to contribute to the pathology underlying ALS. This may explain the recent promising results of an ALS phase 2 clinical trial of NP001, a regulator of inflammatory macrophage activity (13). Although the predefined endpoints in this study did not reach statistical significance, administration of NP001 was associated with cessation in disease progression in 27% of patients, approximately 2.5 times greater than the percentage in patients on placebo. Two major plasma markers of inflammation, interleukin-18 (IL-18) and lipopolysaccharide (LPS), differentiated NP001 responders from non-responders, suggesting that the subgroup of patients with greater baseline biomarkers of neuroinflammation experienced the most benefit (13). Additional evidence pointing toward pathologic involvement of autoimmune processes has been the finding that immunoglobulins from ALS patients have been shown to cause apoptosis of motor neurons in primary spinal cord cultures (14) and that passive transfer of immunoglobulins to mice caused abnormalities at motor end-plates and degeneration of motor neurons (4, 15). These findings suggest that antibodies can contribute to disease pathogenesis. Increased levels of interleukins IL-17 and IL-23 have also been found in serum and cerebrospinal fluid of ALS patients (16). This increment is thought to be a sign of T-helper 17 (Th17) activation, a subset of T-cells suggested to be crucial in destructive autoimmunity. Astrocytes have also been shown to participate in the pathogenesis of ALS by producing a microenvironment toxic to motor neurons through increased neuroinflammation, oxidative damage, and glutamate excitotoxicity (17, 18). Overactivated astroglia produce high levels of protein S100B and other proinflammatory factors, which exacerbate neuroinflammation. The extracellular effects of S100B vary, depending on the concentration attained; at nanomolar concentrations, S100B is trophic to neurons, but at micromolar concentrations, S100B causes neuronal apoptosis (19, 20). Many of the effects of S100B on neurons are transduced by the receptor for advanced glycation end-products (RAGE), which participates in the pathophysiology of brain inflammatory disorders by regulating several inflammation-related events, including activation and migration of microglia and neutrophils to inflammatory sites (19–21). Extravasation of S100B into the systemic circulation can also trigger a pathologic autoimmune reaction with circulating antibodies that may re-enter the CNS to initiate an autoimmune response (22). Hence, S100B can be viewed as an astrocytic endokine that can act as an immunoregulator to participate in inflammation and autoimmunity. Additional support for the autoimmune pathogenesis hypothesis is the finding that ALS has recently been included in the spectrum of neurologic manifestations associated with voltage-gated potassium channel (VGKC) autoimmunity (23–25).