Aspects Of Central Nervous System Research Articles

Outside-in signaling through the major histocompatibility complex class-I cytoplasmic tail modulates glutamate receptor expression in neurons

The interplay between AMPA-type glutamate receptors (AMPARs) and major histocompatibility complex class I (MHC-I) proteins in regulating synaptic signaling is a crucial aspect of central nervous system (CNS) function. In this study, we investigate the significance of the cytoplasmic tail of MHC-I in synaptic signaling within the CNS and its impact on the modulation of synaptic glutamate receptor expression. Specifically, we focus on the Y321 to F substitution (Y321F) within the conserved cytoplasmic tyrosine YXXΦ motif, known for its dual role in endocytosis and cellular signaling of MHC-I. Our findings reveal that the Y321F substitution influences the expression of AMPAR subunits GluA2/3 and leads to alterations in the phosphorylation of key kinases, including Fyn, Lyn, p38, ERK1/2, JNK1/2/3, and p70 S6 kinase. These data illuminate the crucial role of MHC-I in AMPAR function and present a novel mechanism by which MHC-I integrates extracellular cues to modulate synaptic plasticity in neurons, which ultimately underpins learning and memory.

Visualizing Impairment of the Endothelial and Glial Barriers of the Neurovascular Unit during Experimental Autoimmune Encephalomyelitis In Vivo.

The neurovascular unit (NVU) is composed of microvascular endothelial cells forming the blood-brain barrier (BBB), an endothelial basement membrane with embedded pericytes, and the glia limitans composed by the parenchymal basement membrane and astrocytic end-feed embracing the abluminal aspect of central nervous system (CNS) microvessels. In addition to maintaining CNS homeostasis the NVU controls immune cell trafficking into the CNS. During immunosurveillance of the CNS low numbers of activated lymphocytes can cross the endothelial barrier without causing BBB dysfunction or clinical disease. In contrast, during neuroinflammation such as in multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) a large number of immune cells can cross the BBB and subsequently the glia limitans eventually reaching the CNS parenchyma leading to clinical disease. Immune cell migration into the CNS parenchyma is thus a two-step process that involves a sequential migration across the endothelial and glial barrier of the NVU employing distinct molecular mechanisms. If following their passage across the endothelial barrier, T cells encounter their cognate antigen on perivascular antigen-presenting cells their local reactivation will initiate subsequent mechanisms leading to the focal activation of gelatinases, which will enable the T cells to cross the glial barrier and enter the CNS parenchyma. Thus, assessing both, BBB permeability and MMP activity in spatial correlation to immune cell accumulation in the CNS during EAE allows to specify loss of integrity of the endothelial and glial barriers of the NVU. We here show how to induce EAE in C57BL/6 mice by active immunization and how to subsequently analyze BBB permeability in vivo using a combination of exogenous fluorescent tracers. We further show, how to visualize and localize gelatinase activity in EAE brains by in situ zymogaphy coupled to immunofluorescent stainings of BBB basement membranes and CD45+ invading immune cells.

Astrocyte senescence: Evidence and significance.

Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term “astrosenescence” to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age‐related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age‐associated neurodegenerative disease.

The influence of GDF11 on brain fate and function.

Growth differentiation factor 11 (GDF11) is a transforming growth factor β (TGFβ) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. During development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action. In the aged brain, exogenous, peripherally delivered GDF11 may enhance neurogenesis and angiogenesis, as well as improve neuropathological outcomes. This is in contrast to a predominantly negative influence on neurogenesis in the developing CNS. Seemingly antithetical effects may correspond to the cell types and mechanisms activated by local versus circulating concentrations of GDF11. Yet undefined, distinct mechanisms of action in young and aged brains may also play a role, which could include differential receptor and binding partner interactions. Exogenously increasing circulating GDF11 concentrations may be a viable approach for improving deleterious aspects of brain aging and neuropathology. Caution is warranted, however, since GDF11 appears to negatively influence muscle health and body composition. Nevertheless, an expanding understanding of GDF11 biology suggests that it is an important regulator of CNS formation and fate, and its manipulation may improve aspects of brain health in older organisms.

Guidelines versus ground lines: Tuberculosis of the central nervous system.

This questionnaire-based national survey is aimed at understanding the patterns of practice of various aspects of central nervous system (CNS) tuberculosis (TB) among neurologists. Neurology department of a tertiary medical college. A questionnaire was sent through email to all practicing neurologists in India. The responses were analyzed. Inferential statistics. In all, 144 responses were received (out of the 853 questionnaires sent). The major discrepancies were in the primary antitubercular drug regimen (HRZE + HR), duration for tubercular meningitis (TBM) [12 months] and tuberculoma (12-18 months) to develop, follow-up (varied), linezolid use (varied), proportion of drug-resistant cases (<25%), and not taking histological aids (91%). The cerebrospinal fluid (CSF) TB polymerase chain reaction (PCR) utility (75%), not using CSF adenosine deaminase [ADA] (58%), the strategy to stop antitubercular drugs, and the use of steroids (77%) were according to guidelines. The present survey, for the first time, provides ground-level evidence of various aspects of CNS TB as practiced by neurologists in India. The major diversity was observed in therapeutics such as the choice of antitubercular drugs, its duration, linezolid use beyond the recommended duration, and knowledge of drug resistance. The monitoring aspects of CNS TB also showed variations. The investigational aspects of CNS TB such as using TB PCR, not using CSF ADA, and regular neuroimaging revealed a good clinical practice. Other CSF parameters require uniformity. This survey thus helps to identify areas of future work in CNS TB in India.

Auditory brainstem response in infants with iron deficiency anemia

BackgroundAuditory brainstem response (ABR) in infants with Iron Deficiency Anemia (IDA) helps in understanding the auditory aspects of central nervous system. ObjectivesTo analyse and compare absolute and interpeak latencies of ABR in infants with and without IDA. MethodsABR traces were obtained from 40 anemic ears and 40 non anemic ears, aged 6–24 months. ABR was recorded with 11.1/s clicks at different intensity levels. ResultsAbsolute latencies of all the peaks were prolonged in infants with IDA at 70, 50 and 30 dBnHL except for peak I. Amplitude of peaks I, III and V was not statistically different between the two groups at 70 and 50 dBnHL. Reduced peak amplitude was noted only at 30 dBnHL in infants with IDA which was statistically significant (P < 0.05). Interpeak interval showed no significant difference between anemic and non-anemic infants at 70 dBnHL. Prolonged interpeak latency of peak III-V and I-V was noted at 50 and 30dBnHL. ConclusionFunctional development of auditory system seems to be affected due to iron deficiency. IDA has a long lasting effects on central auditory system when IDA is left untreated This will in turn lead to an alteration in the neuro-functional maturation.

Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury

Evidence is accumulating that repeated mild traumatic brain injury (mTBI) incidents can lead to persistent, long-term debilitating symptoms and in some cases a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy. However, to our knowledge, there are no objective tools to examine to which degree persistent symptoms after mTBI are caused by neuronal injury. To determine whether persistent symptoms after mTBI are associated with brain injury as evaluated by cerebrospinal fluid biochemical markers for axonal damage and other aspects of central nervous system injury. A multicenter cross-sectional study involving professional Swedish ice hockey players who have had repeated mTBI, had postconcussion symptoms for more than 3 months, and fulfilled the criteria for postconcussion syndrome (PCS) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) matched with neurologically healthy control individuals. The participants were enrolled between January 2014 and February 2016. The players were also assessed with Rivermead Post Concussion Symptoms Questionnaire and magnetic resonance imaging. Neurofilament light protein, total tau, glial fibrillary acidic protein, amyloid β, phosphorylated tau, and neurogranin concentrations in cerebrospinal fluid. A total of 31 participants (16 men with PCS; median age, 31 years; range, 22-53 years; and 15 control individuals [11 men and 4 women]; median age, 25 years; range, 21-35 years) were assessed. Of 16 players with PCS, 9 had PCS symptoms for more than 1 year, while the remaining 7 returned to play within a year. Neurofilament light proteins were significantly increased in players with PCS for more than 1 year (median, 410 pg/mL; range, 230-1440 pg/mL) compared with players whose PCS resolved within 1 year (median, 210 pg/mL; range, 140-460 pg/mL) as well as control individuals (median 238 pg/mL, range 128-526 pg/mL; P = .04 and P = .02, respectively). Furthermore, neurofilament light protein concentrations correlated with Rivermead Post Concussion Symptoms Questionnaire scores and lifetime concussion events (ρ = 0.58, P = .02 and ρ = 0.52, P = .04, respectively). Overall, players with PCS had significantly lower cerebrospinal fluid amyloid-β levels compared with control individuals (median, 1094 pg/mL; range, 845-1305 pg/mL; P = .05). Increased cerebrospinal fluid neurofilament light proteins and reduced amyloid β were observed in patients with PCS, suggestive of axonal white matter injury and amyloid deposition. Measurement of these biomarkers may be an objective tool to assess the degree of central nervous system injury in individuals with PCS and to distinguish individuals who are at risk of developing chronic traumatic encephalopathy.

Targeting NO/cGMP Signaling in the CNS for Neurodegeneration and Alzheimer's Disease.

cAMP-response element-binding protein (CREB) plays a central role in various aspects of central nervous system (CNS) function, ranging from the developmental stages to neuronal plasticity and survival in adult brain. Activation of CREB plays a crucial role in learning and memory and is at the convergence of multiple intracellular signaling cascades including CAMKII and MAPK. This review focuses on the important functions of nitric oxide (NO) in activating CREB via the NO receptor, soluble guanylyl cyclase (sGC), and production of the second messenger, cGMP. The involvement of the NO/cGMP signaling pathway in synaptic plasticity suggests several avenues for therapeutic intervention, and targeting early synaptic degeneration could be an attractive approach for the development of novel disease-modifying approaches to treat cognition and memory dysfunction in neurodegenerative diseases.

Wnt Signaling Pathway in Schizophrenia

The Wnt signaling pathway is one of the crucial signaling pathways that regulate many aspects of central nervous system. In this review, we tempt to depict an overall picture of the Wnt signaling with its multitude of roles in schizophrenia. If the Wnt signaling pathway plays a crucial role in the pathogenesis of schizophrenia as we suggest, a better understanding of the Wnt pathway might contribute to developing new and more effective tools for diagnosis and treatment of schizophrenia.

Coupling Hippocampal Neurogenesis to Brain pH through Proneurogenic Small Molecules That Regulate Proton Sensing G Protein-Coupled Receptors

Acidosis, a critical aspect of central nervous system (CNS) pathophysiology and a metabolic corollary of the hypoxic stem cell niche, could be an expedient trigger for hippocampal neurogenesis and brain repair. We recently tracked the function of our isoxazole stem cell-modulator small molecules (Isx) through a chemical biology-target discovery strategy to GPR68, a proton (pH) sensing G protein-coupled receptor with no known function in brain. Isx and GPR68 coregulated neuronal target genes such as Bex1 (brain-enriched X-linked protein-1) in hippocampal neural progenitors (HCN cells), which further amplified GPR68 signaling by producing metabolic acid in response to Isx. To evaluate this proneurogenic small molecule/proton signaling circuit in vivo, we explored GPR68 and BEX1 expression in brain and probed brain function with Isx. We localized proton-sensing GPR68 to radial processes of hippocampal type 1 neural stem cells (NSCs) and, conversely, localized BEX1 to neurons. At the transcriptome level, Isx demonstrated unrivaled proneurogenic activity in primary hippocampal NSC cultures. In vivo, Isx pharmacologically targeted type 1 NSCs, promoting neurogenesis in young mice, depleting the progenitor pool without adversely affecting hippocampal learning and memory function. After traumatic brain injury, cerebral cortical astrocytes abundantly expressed GPR68, suggesting an additional role for proton-GPCR signaling in reactive astrogliosis. Thus, probing a novel proneurogenic synthetic small molecule's mechanism-of-action, candidate target, and pharmacological activity, we identified a new GPR68 regulatory pathway for integrating neural stem and astroglial cell functions with brain pH.

Abdominal migraine reviewed from both central and peripheral aspects

Despite the 2%-5% prevalence of abdominal migraine (AM) during childhood, the precise mechanism remains unknown. In this review, we present recent studies on AM and speculate its mechanism from both peripheral and central nervous system aspects. Although the main symptoms of AM exist at the peripheral level, previous studies have reported possible dysfunction of central nervous system, including photophobia, phonophobia and abnormal visual evoked responses. Recently, a case has been reported with AM combined with "Alice in Wonderland" syndrome with visual and/or bodily distortions, which serves as another piece of evidence of central dysfunction. Another case reported an AM patient having peculiar stereotypical ecchymosis in the legs and buttocks associated with pain attack, which implied possible involvement of peripheral nervous system. Although further investigations and accumulation of AM cases are still needed, we believe that the schema hypothesized here is helpful to plan further experimental approach to clarify the mechanism of this peculiar disease.

The Occupational JP8 Exposure Neuroepidemiology Study (OJENES): Repeated workday exposure and central nervous system functioning among US Air Force personnel

One of the most prevalent workplace chemical exposures historically and currently confronting the global military and civilian workforce is jet propellant (JP) fuel (e.g., JP4, JP5, JP8, jet A1), a complex mixture of numerous hydrocarbon compounds and additives. To date, numerous protective and preventive strategies (e.g., federal exposure limits, workplace procedure protocols, protective gear such as goggles, respirator use, gloves, and coveralls) have been put in place to minimize acutely toxic exposure levels. However, questions remain regarding the effect of repeated exposures at lower (than regulated) levels of JP fuel. The Occupational JP8 Exposure Neuroepidemiology Study (OJENES) was designed to examine the relationships between occupational JP8 exposure over multiple, repeated workdays and specific aspects of central nervous system (CNS) functioning among Air Force (AF) personnel. In this report, we present the OJENES methodology, descriptive findings related to participant characteristics, JP8 exposure levels observed over a work week among higher and lower exposure groups, and neuropsychological task performances at the first study assessment. Results indicated minimal differences between participants in the high and lower exposure groups in terms of descriptive characteristics, other than daily JP8 exposure levels (p<0.001). In addition, neuropsychological task performances for most task measures were not found to be significantly different from reported reference ranges. These findings demonstrated that confounding and misclassification of exposure and outcome status are not major concerns for the study. Therefore, future OJENES analyses targeting the more focused research questions regarding associations between JP8 exposure and CNS functioning are likely to provide valid conclusions, as they will be less influenced by these research biases.

DISC1 in Schizophrenia: Genetic Mouse Models and Human Genomic Imaging

Schizophrenia and related disorders have a major genetic component. Several large-scale studies have uncovered a number of possible candidate genes, but these have yet to be consistently replicated and their underlying biological function remains elusive. One exception is 'Disrupted in schizophrenia 1' (DISC1), a gene locus originally identified in a large Scottish family, showing a heavy burden of major mental illnesses associated with a balanced t(1;11)(q42.1;q14.3) chromosome translocation. Substantial genetic and biological research on DISC1 has been reported in the intervening 10 years: DISC1 is now recognized as a genetic risk factor for a spectrum of psychiatric disorders and DISC1 impacts on many aspects of central nervous system (CNS) function, including neurodevelopment, neurosignaling, and synaptic functioning. Evidence has emerged from genetic studies showing a relationship between DISC1 and quantitative traits, including working memory, cognitive aging, gray matter volume in the prefrontal cortex, and abnormalities in hippocampal structures and function. DISC1 interacts with numerous proteins also involved in neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction, some of which have been reported as independent genetic susceptibility factors for psychiatric morbidity. Here, we focus on the growing literature relating genetic variation in the DISC1 pathway to functional and structural studies of the brain in humans and in the mouse.

Activity-Dependent Expression of Lmx1b Regulates Specification of Serotonergic Neurons Modulating Swimming Behavior

Genetic programs, environmental factors, and electrical activity interact to drive the maturation of the brain. Although the cascade of transcription factors that leads to specification of the serotonergic phenotype has been well characterized, its interactions with electrical activity are not known. Here we show that spontaneous calcium spike activity in the hindbrain of developing Xenopus laevis larvae modulates the specification of serotonergic neurons via regulation of expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2 but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Using global manipulation of activity and targeted alteration of Lmx1b expression, we also demonstrate that changes in the number of serotonergic neurons change larval swimming behavior. The results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior.

Mitochondrial ND5 Gene Variation Associated with Encephalomyopathy and Mitochondrial ATP Consumption

Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A-->G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (Deltapsim) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A-->G mutation; Complex I-linked respiration and Deltapsim were both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F1F0-ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain Deltapsim. This was confirmed by inhibition of glycolysis with 2-deoxy-D-glucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain Deltapsim, representing a potential pathophysiological mechanism in human mitochondrial disease.

Pax6 is required for delta-catenin/neurojugin expression during retinal, cerebellar and cortical development in mice

The transcription factor Pax6 regulates multiple aspects of central nervous system (CNS) development. At the cellular level, the Pax6 mutation was reported to affect homophilic and heterophilic cellular adhesion, neuron polarity and neurite outgrowth. These abnormalities were observed in multiple regions of Pax6-mutant CNS, suggesting a common function for Pax6 in regulating cytoskeletal dynamics. However, target genes mediating Pax6 function in cytoskeletal dynamics remain largely unknown. Using DNA microarrays, we identified delta-catenin ( δ-catenin /neurojugin) as a potential direct target of Pax6 in the CNS. δ-catenin encodes a large cytoskeletal protein that localizes at adherens junction in the CNS and that can modulate neurite outgrowth and N-cadherin turnover. δ-catenin was found to be co-expressed with Pax6 in several regions of the developing CNS. In Pax6 mutant embryos, δ-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in δ-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates δ-catenin expression during CNS development in mice.

Neuropathology: A Reference Text of CNS Pathology

2nd ed, by David Ellison, Seth Love, Leila Chimelli, Brian N. Harding, James Lowe, and Harry V. Vinters, 754 pp, with illus plus index and CD-ROM, Philadelphia, Pa, Mosby, 2004.This is a superb second edition of a book that was first published in 1997 and has since become one of the cornerstones of neuropathology education and practice. As stated by the authors, the aim of the first edition was to provide a reference book that was heavily biased toward the use of color illustrations, yet included much more information than an atlas. The second edition maintains this concept. It contains 47 chapters within 10 sections that cover a wide range of aspects of central nervous system (CNS) pathology and has incorporated new developments in this rapidly growing field with referenced material ending in 2002.As in the first edition, the second edition uses different colors to identify pathogenesis and etiology, clinical aspects, and differential diagnosis and practical advice on diagnosis to help orientate readers to the text. The book contains a wealth of illuminating charts, tables, drawings, and beautiful illustrations of gross and microscopic pathology, with many of the figures new to the second edition. The new edition contains more than twice as many references as its predecessor, and they are now subdivided thematically where appropriate. An accompanying CD-ROM contains more than 2500 images of the text's illustrations and represents an invaluable source of learning and teaching.The first of the 10 sections provides a detailed description of pathologic reactions in the CNS. The second section is devoted to pediatric neuropathology. The book contains chapters that discuss fetal and neonatal hypoxic-ischemic lesions, malformations, hydrocephalus, white matter lesions (leukodystrophies), and neurodegenerative disorders of gray matter in childhood. A chapter of miscellaneous pediatric disorders covers vascular diseases, epilepsy in childhood, and pediatric trauma.Section 3 (vascular disorders) has separate chapters on adult hypoxic and ischemic lesions, vascular disease and infarcts, and hemorrhage. Section 4 covers CNS trauma, and section 5 provides a detailed presentation of infectious diseases of the CNS. There are separate, beautifully illustrated chapters that cover acute and subacute or chronic viral infections, rickettsial and mycoplasma infections, acute bacterial infections and brain abscesses, chronic bacterial infections, fungal diseases, and parasitic infections of the CNS. A section devoted to demyelinating diseases discusses multiple sclerosis, acute \[bu791\]disseminated encephalomyelitis, acute hemorrhagic leukoencephalopathy, and trigeminal neuralgia.Section 7 covers nutritional and metabolic disorders with separate chapters devoted to vitamin deficiencies, systemic metabolic disease, lysosomal and peroxisomal disorders, and mitochondrial encephalopathies. Section 8 discusses toxic CNS injury. In this section, neurodegenerative diseases are presented in chapters on classification and pathogenesis, motor neuron disorders, parkinsonism and akinetic-rigid disorders, ataxic disorders, hyperkinetic movement disorders, dementias, and prion diseases. Thalamic and pallidal degenerations, neuroaxonal dystrophy, and autonomic failure are presented in the last chapter of this section. The 10th section covers CNS neoplasia and paraneoplastic disorders.This second edition will be of great value for pathology, neurology, and neurosurgery residents and should be on the shelf of all practicing pathologists.

Central nervous system atrophy and clinical status in multiple sclerosis.

In this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Cross-sectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies (>/= 5 years) have shown that CNS atrophy is a significant predictor of subsequent long-term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing-remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.

Central Nervous System Atrophy and Clinical Status in Multiple Sclerosis

ABSTRACTIn this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Crosssectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies ([.greaterequal] 5 years) have shown that CNS atrophy is a significant predictor of subsequent long‐term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing‐remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long‐term follow‐up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.

Habituation in fetuses of diabetic mothers.

Fetuses of diabetic mothers exhibit maturational delays in their behaviour and disturbances in behavioural and intellectual functioning in childhood. This suggests an effect of maternal diabetes on the central nervous system of the fetus. The habituation technique enables the functioning of the higher central nervous system to be examined. A normal habituation pattern reflects an intact central nervous system. Previous studies have found abnormalities in the fetal central nervous system are reflected in habituation performance. This paper examined the habituation ability of fetuses of diabetic mothers and of non-diabetic mothers. The fetuses were tested at 28, 32 and 36 weeks of gestation. After 2 min of fetal inactivity a series of vibroacoustic stimuli were presented to the fetus. This continued until no response was observed on five consecutive stimulus presentations. The number of stimulus presentations to habituate at each gestational age was recorded. The results reveal that there was a highly significant main effect of group (F(1,47)=19.65, P<0.001). Fetuses of diabetic pregnancies took longer to habituate. There was a significant effect of gestational age (F(2,94)=44.67, P<0.0001). In both groups the number of trials to habituate decreased with advancing gestation. There was no relationship between random blood glucose levels and habituation performance. The results demonstrate that maternal diabetes affects higher aspects of central nervous system functioning in the fetus.