Central Nervous System Atrophy Research Articles

The Deficits of Insulin Signal in Alzheimer's Disease and the Mechanisms of Vanadium Compounds in Curing AD.

Vanadium is a well-known essential trace element, which usually exists in oxidation states in the form of a vanadate cation intracellularly. The pharmacological study of vanadium began with the discovery of its unexpected inhibitory effect on ATPase. Thereafter, its protective effects on β cells and its ability in glucose metabolism regulation were observed from the vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer's disease (AD) is the most common dementia disease in elderly people. However, there are still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which is characterized by senile plaques composed of the amyloid-beta (Aβ) protein in the parenchyma of the brain and the neurofibrillary tangles (NFTs), which are derived from the hyperphosphorylated tau protein in the neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the impaired insulin signaling in the brain. In this review, we summarize the advances in applicating the vanadium compound to AD treatment in experimental research and point out the limitations of the current study using vanadium compounds in AD treatment. We hope this will help future studies in this field.

Neuron-binding antibody responses are associated with Black ethnicity in multiple sclerosis during natalizumab treatment.

Multiple sclerosis is an inflammatory degenerative condition of the central nervous system that may result in debilitating disability. Several studies over the past twenty years suggest that multiple sclerosis manifests with a rapid, more disabling disease course among individuals identifying with Black or Latin American ethnicity relative to those of White ethnicity. However, very little is known about immunologic underpinnings that may contribute to this ethnicity-associated discordant clinical severity. Given the importance of B cells to multiple sclerosis pathophysiology, and prior work showing increased antibody levels in the cerebrospinal fluid of Black-identifying, compared to White-identifying multiple sclerosis patients, we conducted a cohort study to determine B cell subset dynamics according to both self-reported ethnicity and genetic ancestry over time. Further, we determined relationships between ethnicity, ancestry, and neuron-binding IgG levels. We found significant associations between Black ethnicity and elevated frequencies of class-switched B cell subsets, including memory B cells; double negative two B cells; and antibody-secreting cells. The frequencies of these subsets positively correlated with West African genetic ancestry. We also observed significant associations between Black ethnicity and increased IgG binding to neurons. Our data suggests significantly heightened T cell-dependent B cell responses exhibiting increased titres of neuron-binding antibodies among individuals with multiple sclerosis identifying with the Black African diaspora. Factors driving this immunobiology may promote the greater demyelination, central nervous system atrophy and disability more often experienced by Black-, and Latin American-identifying individuals with multiple sclerosis.

Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis.

GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a-/- mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 × 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS-the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.

Effect of Carvacrol on histological analysis and expression of genes involved in an animal model of multiple sclerosis.

The most common non-traumatic neurological disease in young- and middle-aged adults is multiple sclerosis (MS), leading to central nervous system (CNS) atrophy and neurological disorders with loss of myelin and axonal degeneration. Due to the inadequate efficiency of common treatments, some natural products with antioxidant properties such as Carvacrol have been considered. the present study aimed to investigate carvacrol's anti-inflammatory and therapeutic effects on MS symptoms in healthy and experimental autoimmune encephalomyelitis (EAE) induced female Lewis rats. The study was performed in three groups of Lewis rats: control group, EAE model, and EAE treated with carvacrol (carvacrol-treated group). The treatment group received 25mg/kg of carvacrol intraperitoneally daily. Histologic examination and expression analysis of pro-inflammatory genes (Interleukin-1 and 17 (IL-1 and IL-17), Nuclear Factor Kappa B Cells (NF-κB) and Tumor Necrosis Factor-α (TNF-α)), myelin repair, and also regeneration genes (Myelin basic protein (MBP), Oligodendrocyte Transcription Factor 2 (OLIG2) and Platelet-Derived Growth Factor Receptor α (PDGFR-α)) were carried out. Gene studies, Hematoxylin and Eosin (H&E), and Luxol fast blue stain were performed in the lumbar region of the spinal cord. The EAE clinical scores in the carvacrol-treated group were lower than in untreated rats (P<0.001). The expression of two genes, IL-17 and MBP, was confirmed using fluorescence immunohistochemistry (FIHC). A significant decrease was observed in NF-κB and IL-17, and IL-1 gene expression. The MBP and OLIG2 gene expression was increased in the carvacrol-treated group (p<0.001). In EAE, PDGFR-α expression increased about four times. However, carvacrol administration did not affect PDGFR-α and TNF-α gene expression. In this treatment, H&E staining of spinal cord regions showed a significant decrease in inflammatory cell infiltration. Moreover, immunostaining analysis demonstrated a considerable increase in MBP and a reduction in IL-17 secretion. The results showed that carvacrol administration reduces the entry of inflammatory cells into the CNS by stimulating myelination-related processes employing increasing the expression of genes involved in myelin repair and reducing the expression of inflammatory genes. Our findings confirm that carvacrol improves the clinical and pathological symptoms of EAE through its therapeutic and modification properties as a potential adjunctive therapy and needs to be studied more.

Communicating the relevance of neurodegeneration and brain atrophy to multiple sclerosis patients: patient, provider and researcher perspectives.

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial. This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring. The following recommendations were created based on application of patient's and provider's surveys, and various workshops held over a period of 2years: (1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration; (2) the expertise for atrophy measurements should be characterized as evolving; (3) quality patient education materials on these topics should be provided; (4) the need for standardization of MRI exams has to be explained and communicated; (5) providers should discuss background on volumetric changes, including references to normal aging; (6) the limitations of brain volume assessments at an individual-level should be explained; (7) the timing and language used to convey this information should be individualized based on the patient's background and disease status; (8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions; (9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes; (10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and (11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs.

Confounder-adjusted MRI-based predictors of multiple sclerosis disability.

Both aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as "accelerated aging." Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects. Standardized brain MRI and neurological examination were acquired prospectively in 646 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n = 158). MS patients were randomly split into training (n = 277) and validation (n = 131) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales. Confounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperform published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort. GBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.

Neurodegeneration in multiple sclerosis.

Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort.

Background and purposeIn an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short‐term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse‐onset MS.MethodsBrain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing‐remitting [RRMS] and 43 secondary‐progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine‐hole peg test and the timed 25‐foot walk test.ResultsHigher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy.ConclusionThis study demonstrates the capability of short‐term MRI metrics to accurately predict future dynamics of disability progression in a real‐world relapse‐onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care.

Congenital Zika syndrome: A systematic review.

The signs and symptoms of Zika virus infection are usually mild and self-limited. However, the disease has been linked to neurological complications such as Guillain-Barré syndrome and peripheral nerve involvement, and also to abortion and fetal deaths due to vertical transmission, resulting in various congenital malformations in newborns, including microcephaly. This review aimed to describe the o signs and symptoms that characterize the congenital Zika syndrome. A systematic review was performed with a protocol and described according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search strategy yielded 2,048 studies. After the exclusion of duplicates and application of inclusion criteria, 46 studies were included. The main signs and symptoms associated with the congenital Zika syndrome were microcephaly, parenchymal or cerebellar calcifications, ventriculomegaly, central nervous system hypoplasia or atrophy, arthrogryposis, ocular findings in the posterior and anterior segments, abnormal visual function and low birthweight for gestational age. Zika virus infection during pregnancy can cause a series of changes in the growth and development of children, while impacting the healthcare system due to the severity of cases. Our findings outline the disease profile in newborns and infants and may contribute to the development and updating of more specific clinical protocols.

Diffusion tensor imaging of the normal-appearing deep gray matter in primary and secondary progressive multiple sclerosis.

Despite strongly overlapping patterns of clinical and histopathologic findings in primary and secondary progressive multiple sclerosis, differences concerning motor symptoms, central nervous system inflammation, atrophy, and demyelination that cannot be accounted for by lesion load alone remain to be elucidated. To evaluate the normal-appearing deep gray matter in patients with primary and secondary progressive multiple sclerosis, diffusion tensor imaging was used in this study. In 14 multiple sclerosis patients with primary and secondary progressive multiple sclerosis, axial echo-planar single-shot diffusion tensor imaging sequences with 32 diffusion-encoding directions and axial FLAIR sequences were acquired on a 3T system using an eight-channel SENSE head coil. FLAIR hyperintense multiple sclerosis lesions were outlined semi-automatically and normal-appearing deep gray matter was outlined manually (caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus). Fractional anisotropy and mean diffusivity values within the normal-appearing deep gray matter for the two groups were compared. Interhemispheric differences in mean diffusivity values (but not in fractional anisotropy), were significantly higher in primary progressive multiple sclerosis than in secondary progressive multiple sclerosis for the substantia nigra ( P = 0.04) and the putamen ( P = 0.021). Volumes, mean diffusivity, or fractional anisotropy of the remaining normal-appearing deep gray matter did not differ significantly. This study showed a higher interhemispheric difference in the mean diffusivity in the substantia nigra and putamen in patients with primary progressive multiple sclerosis than in those with secondary progressive multiple sclerosis. These changes may represent edema, as well as axonal and myelin loss that can affect the normal-appearing deep gray matter of the two hemispheres differently and may point to differences in the laterality of motor symptoms.

Primary Histiocytic Sarcoma of the Brain in an African Hedgehog (Atelerix albiventris)

A 2.5-year-old African hedgehog (Atelerix albiventris) with signs of progressive paresis/paralysis for approximately 6 months was diagnosed with 'wobbly hedgehog syndrome' (WHS). Post-mortem examination revealed a primary central nervous system (CNS) histiocytic sarcoma (HS) associated with neurodegenerative changes of the CNS and skeletal muscle atrophy. Grossly, a spherical mass infiltrated the left forebrain and was located between the frontal lobe and thalamus in coronal sections. Microscopically, the neoplastic cells had eccentrically located anisokaryotic nuclei and abundant eosinophilic cytoplasm. Immunohistochemically, they were positive for calcium-binding adapter molecule 1, lysozyme, CD68 and vimentin. Ultrastructurally, the neoplastic cells had varying amounts of bundles and whorls of intermediate filaments and scattered lysosomes. This report represents the first documentation of primary CNS HS in this species. Primary CNS HS should be considered as a differential diagnoses for hedgehogs that present with neurological signs of WHS.

Leukodystrophy with Calcifications and Central Nervous System Atrophy: Expansion of the Phenotypic Spectrum Regarding Autosomal Recessive AARS Mutations?

Background/Purpose: In a female patient developmental regression occurred in the second year of life leading to spastic tetraparesis, dysphagia, optic atrophy and epilepsy. Imaging studies showed progressive leukodystrophy, brain and spinal atrophy, cerebral and cerebellar calcifications as well as lactate peak in MR spectroscopy. Electrophysiological studies showed pathologic evoked visual and somato-sensory potentials. Extensive diagnostics did not reveal causes for acquired or known genetic leukodystrophies. Respiratory chain analysis in muscle tissue showed diminished activities for complexes I, II/III and IV.

Immunology of progressive multifocal leukoencephalopathy.

The high prevalence of asymptomatic JC polyomavirus (JCV) infection in the general population indicates coexistence with the human host and efficient immune control in healthy individuals. For unknown reasons, kidney-resident archetypic JCV strains can turn into neurotropic JCV strains which in hereditary or acquired states of immunodeficiency cause opportunistic infection and cytolytic destruction of glial cells or granule cell neurons resulting in progressive multifocal demyelination in the central nervous system (CNS) or cerebellar atrophy, respectively. Immunomodulatory or immunosuppressive therapies with specific monoclonal antibodies including natalizumab, efalizumab, and rituximab have increased the risk of progressive multifocal leukoencephalopathy (PML) among treated patients, highlighting that symptomatic JCV infection of the CNS is associated with disturbances of adaptive immunity affecting B cells, antibodies, and CD4(+) and/or CD8(+) T cells. To date, no specific therapy to overcome PML is available and the only way to eliminate the virus from the CNS is to reconstitute global immune function. However, since the identification of JCV as the causative agent of PML 40years ago, it is still not fully understood which components of the immune system prevent the development of PML and which immune mechanisms are involved in eliminating the virus from the CNS. This review gives an update about adaptive JCV-specific immune responses.

Emerging methods for evaluating the effectiveness of intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis.

Newer outcome-based assessment methods have been developed that complement and improve upon the ability of historical clinical and magnetic resonance imaging (MRI) outcome measures to measure multiple sclerosis (MS) disease activity, patient functionality, treatment efficacy, and the risk of MS disease progression. These newer MS outcome assessments include instruments to evaluate cognitive function and patient quality of life; enhanced measures of disability, such as the Multiple Sclerosis Functional Composite instrument; and newer MRI measures of MS disease activity and neuronal changes, such as permanent T₁ hypointensities and central nervous system atrophy. When utilized in conjunction with standard MS outcome measures, these newer MS outcomes provide a more comprehensive picture of disease status and course and hold promise as tools for use in the development and testing of future MS therapies. The well-established first-line MS therapy intramuscular interferon beta-1a, which has been evaluated using a broad range of assessment methods, was used as a reference MS disease-modifying therapy to provide specific examples of studies utilizing newer evaluation methods. Utilization of evolving disease and assessment measures for patients with MS should improve MS patient diagnosis, treatment decisions, and monitoring of therapy.

Recent Developments in Imaging of Multiple Sclerosis

Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Conventional MRI measures have insufficient sensitivity and specificity to reveal the true degree of pathologic changes occurring in MS. T2-weighted and T1-weighted imaging cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. Nonconventional MRI techniques are now emerging and proving to be more related with the most disabling features of MS. The large variety of MRI metrics presently available are summarized, including measurement of T1-weighted hypointense lesions, central nervous system atrophy, magnetization transfer imaging, myelin water fraction, diffusion tensor imaging, magnetic resonance spectroscopy, and susceptibility-weighted imaging. The most up-to-date MRI techniques and their relationship with central nervous system pathology are described, and a comprehensive overview of the use of MRI in patients with MS is offered. Advanced MRI techniques provide a better understanding of the pathologic processes that most likely are related to disease activity and clinical progression. Such metrics are able to reveal a range of tissue changes that include demyelination, axonal loss, iron deposition, and neurodegeneration and they provide the evidence that important occult pathology is occurring in the normal appearing white and gray matter. Despite these promising results none of these techniques have been adopted in the MRI consensus guidelines for imaging of the brain and spinal cord in patients with MS due to lack of standardization.

Cognition and depression: the effects of fluvoxamine, a sigma‐1 receptor agonist, reconsidered

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression.

MR in the diagnosis and monitoring of multiple sclerosis: An overview

Multiple sclerosis is a chronic, persistent inflammatory–demyelinating disease of the central nervous system that typically presents as an acute clinically isolated syndrome attributable to a monofocal or multifocal demyelinating lesion, which usually affects the optic nerve, spinal cord, or brainstem and cerebellum. Although the diagnosis of multiple sclerosis is still based on clinical findings, magnetic resonance imaging is now integrated in the overall diagnostic scheme of the disease because of its unique sensitivity to demonstrate the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord. Conventional magnetic resonance imaging techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences are highly sensitive in detecting multiple sclerosis plaques and provide a quantitative assessment of inflammatory activity and lesion load. However, there is a persisting mismatch between clinical and magnetic resonance imaging efficacy of approved treatments, which underlies the fact that this technique does not suffice to explain the entire spectrum of the disease process. In recent years, great effort has been dedicated to overcoming these limitations by using non-conventional magnetic resonance-derived metrics that can selectively measure the more destructive aspects of multiple sclerosis pathology and monitor the reparative mechanisms. These metrics, which include unenhanced T1-weighted imaging, measures of central nervous system atrophy, magnetization transfer imaging, proton magnetic resonance spectroscopy, diffusion-weighted imaging, and functional magnetic resonance imaging, provide a better approximation of the pathological substrate of the multiple sclerosis plaques, have increased our understanding of the pathogenesis of the disease, and have proven useful for studying the natural history of multiple sclerosis and monitoring the effects of new treatments. Therefore, magnetic resonance imaging not only plays an essential role in the diagnosis of multiple sclerosis, but can also serve as a true biological marker of the severity of this disease.

Accurate quantification methods to evaluate cervical cord atrophy in multiple sclerosis patients

Automatic accurate measurement techniques are needed to increase reproducibility in the quantification of cervical cord area (CCA) with magnetic resonance (MR) imaging in the assessment of central nervous system (CNS) atrophy in multiple sclerosis (MS) patients. Two segmentation methods were implemented: (1) spatial mean brightness level estimation (SMBLE), and (2) partial-volume modeling (PVM). These were evaluated with the inclusion of spinal cord inclination and/or partial-volume-effect corrections. An averaged manually segmented set was considered as reference. Thirty MR studies were used to compare the different methods. A set of 15 MS patients and 15 control subjects within a two-year longitudinal study were used to evaluate cord atrophy with the best method. Statistical evaluation was made by using an intraclass correlation coefficient and Bland-Altman comparisons. Partial-volume modeling with spinal cord inclination correction and partial-volume spinal-cord contour contribution estimation was the most accurate method. The longitudinal test showed a 4% decrease in CCA in MS patients with no significant reduction in control subjects. The automatic PVM cord-segmentation approach, taking into consideration the spinal-cord inclination and partial-volume treatment, provides reproducibility and increased accuracy in the evaluation of cord atrophy, allowing the monitoring of changes in MS patients.

Clinical–Magnetic Resonance Imaging Correlations in Multiple Sclerosis

Conventional magnetic resonance imaging (MRI) has routinely been used to improve the accuracy of multiple sclerosis (MS) diagnosis and monitoring, detect the effects of disease-modifying therapy, and refine the utility of clinical assessments. However, conventional MRI measures, such as the use of lesion volume and count of gadolinium-enhancing and T2 lesions, have insufficient sensitivity and specificity to reveal the true degree of pathological changes occurring in MS. Newer metrics of MRI analysis, including T1-weighted hypointense lesions (black holes) and central nervous system (CNS) atrophy measures, are able to capture a more global picture of the range of tissue alterations caused by inflammation, demyelination, axonal loss, and neurodegeneration. There is mounting evidence that these MRI measures correlate well with existing and developing neurological impairment and disability. In so doing, these MRI techniques can help elucidate the mechanisms underlying the pathophysiology and natural history of MS. The current understanding is that T1 black holes and CNS atrophy more accurately reflect the neurodegenerative and destructive components of the MS disease process. Therefore, the short and long-term studies that aim to measure the degree and severity of the neurodegenerative MS disease process should incorporate these MRI metrics as part of their standard routine MRI protocols.

Measurement of Brain and Spinal Cord Atrophy by Magnetic Resonance Imaging as a Tool to Monitor Multiple Sclerosis

Evaluation of brain and spinal cord atrophy by magnetic resonance imaging (MRI) has become an increasingly important component of understanding the multiple sclerosis (MS) disease process. These destructive aspects of the disease develop early in the disease course. A growing body of data links brain and spinal cord atrophy to clinical impairment more closely than can be linked with conventional measures of overt lesions. Thus, irreversible tissue damage may be a key factor leading to disease progression. In this review, the authors present the proposed mechanisms leading to central nervous system (CNS) atrophy. They describe the available MRI-based techniques to measure regional and global atrophy of the brain and spinal cord. They compare the rate of atrophy among MS phenotypes and summarize the emerging data linking atrophy to neurological and neuropsychological impairment. Finally, they discuss the effect of disease-modifying immunotherapies on the rate of CNS atrophy in patients with MS. Future research to clarify the etiology and pathophysiology of brain and spinal cord atrophy should provide new targets for therapeutic development.