Early Central Nervous System Research Articles

The Pathogenesis of Murine Retroviral Infection of the Central Nervous System

Several decades have lapsed since the original description of retroviral infection of the central nervous system (CNS) appeared. With the recent arrival of the autoimmune deficiency syndrome (AIDS) epidemic and the associated human retroviral encephalitis, interest in murine models has been rekindled. In most of the published studies, susceptible mouse strains are infected as neonates with molecularly cloned type-C retroviruses. In most models, a spongiform encephalopathy follows an early CNS endothelial cell infection. The subsequent pathogenesis of this encephalopathy is unknown. In some models neuronal and glial infection is seen, while in others only non-neuroglial elements are infected. This variation can be traced to differences in strains of mice and viruses in addition to differences in assays. The different models offer fertile experimental ground to decipher the role of direct versus indirect neuroglial damage. Reconciliation of these various models where the final neuropathology appears so similar, may be the key to understanding their pathogenesis.

Magnetic Resonance Spectroscopy May Offer Early Look at HIV Disease—Mediated Changes in Brain

PROTON MAGNETIC resonance (MR) spectroscopy may provide a way to study early central nervous system effects of human immunodeficiency virus (HIV) infection. Results of a preliminary study reported at the 78th Scientific Assembly and Annual Meeting of the Radiological Society of North America, held in Chicago, Ill, suggest that MR spectroscopy may be able to detect biochemical changes in brains of HIV-infected individuals who have no symptoms of the acquired immunodeficiency syndrome (AIDS) or evidence of neurocognitive dysfunction. "Proton MR spectroscopy, which can be integrated easily with conventional magnetic resonance imaging devices, provides a means of measuring the levels of various biochemicals in the brain completely noninvasively," says Robert E. Lenkinski, PhD, associate professor of radiology, University of Pennsylvania School of Medicine, Philadelphia, the principal investigator of the study. <h3>Biochemical Fingerprints</h3> In essence, the magnetic resonance spectral patterns obtained are "a collection of fingerprints of the various biochemical compounds present

Early central nervous system changes in human immunodeficiency virus (HIV)-infection.

Early HIV infection of the CNS, as demonstrated by cerebrospinal fluid studies, seems relatively common. However most HIV carriers remain neurologically unimpaired during the incubation period. A few psychometric, radiological, and electrophysiological studies suggest that neurological abnormalities are present at early stages of HIV infection; the findings of these studies are controversial and until recently, they have not been supported by neuropathological data. Early brain changes, including leptomeningitis and vasculitis with myelin pallor and gliosis of the deep white matter are probably secondary to vascular inflammation and opening of the blood-brain barrier. Such conclusions are drawn from the examination of brains of asymptomatic HIV-positive individuals who died from unnatural causes, and of rare cases with acute fatal encephalopathy revealing HIV infection. In addition, early experimental simian immunodeficiency virus infection and feline immunodeficiency virus encephalopathy have demonstrated similar changes to those in man. Although small amounts of viral genome were detected by PCR in a few cases, the early changes in the human brain do not seem to result from a productive HIV infection of the CNS, as seen in HIV encephalitis. The occurrence of a usually asymptomatic and transient immunopathological reaction coinciding with early HIV infection of the nervous system appears to be more likely.

NCAM as a differentiation marker of postmigratory immature neurons in the developing human nervous system

The regional distribution and cellular localization of the neural cell adhesion molecule were investigated in the developing nervous system of human embryos and fetuses, by using immunocytochemistry with antibodies against the human neural cell adhesion molecule. Embryos and fetuses with crown-rump lengths ranging from 15 to 80 mm (corresponding approximately to 6–12 ovulation weeks) were examined. In the telencephalon, immunoreactivity was found in the primordial plexiform layer and in the early cortical plate. During later stages, immunoreactivity was present in the marginal zone, cortical plate, developing subplate zone and radiations of the internal capsule. In the mesencephalon and rhombencephalon, neuronal perikarya were outlined and strong staining was present in fiber bundles. In the spinal cord, strong immunostaining was present in fiber tracts and in dorsal and ventral roots. Immunostaining outlined perikarya of dorsal and ventral gray columns; the neuropil of the developing gray matter was also stained. Contrary to findings in some other species, precursor cells in the proliferating zones, i.e. all cells of ventricular zones and the external granular layer in the developing cerebellum, were not stained. Reactivity, however, was also observed in single mature-looking nerve cell bodies and their processes, which were localized in proliferating zones. All peripheral nervous structures including nerve fibers and peripheral nervous tissue components derived from the neural crest (i.e. sensory and autonomic ganglia) expressed the neural cell adhesion molecule. At the cellular level staining always appeared to be associated with the entire cell membrane of a given neuron including its outgrowing processes. Immunocytochemical staining for neural cell adhesion molecule is an excellent method for the identification of single nerve fibers, nerves and nerve cell bodies in situ in the developing peripheral and early central nervous system. The neural cell adhesion molecule is suggested as a marker of postmigratory immature neurons in the developing human nervous system.

Biology and Violence: From Birth to Adulthood.

This book presents the most comprehensive study to date of the major biological, psychological and environmental predictors of criminal behavior, particularly violence, through a detailed analysis of nearly 1000 low-income black youths from their birth to early adulthood. By examining over 150 variables spanning the lives of these youths, the study concludes that both biological and environmental factors produce strong, and independent, effects on delinquency and adult crime among males and females, who are distinguished from their controls. Powerful influences on violence include behavioral disorders during youth, low school achievement, parents with a low educational level, an absent father, hyperactivity, lead poisoning, left-handedness and mixed dominance, soft neurological signs, and neurological abnormalities. Case study comparisons between the most violent males and females and their controls show that criminals evidence a higher incidence of lead poisoning, disobedience, head injury, and a history of epileptic seizures among themselves or their immediate family members. Violent females are also more likely to have a family member who was incarcerated. The results do not confirm the findings of previous studies indicating direct relationships between violence and early intelligence, mental retardation, socioeconomic status, or early central nervous system dysfunction. The author concludes that both biological and environmental factors, in interaction, cause crime. For example, whereas some factors, such as hyperactivity, can be genetically transmitted across generations, causing a biological predisposition to criminal behavior, hyperactive people, as adults, can in turn, create instability in their families, making their children more prone to criminality, an environmental condition. The author concludes that most factors contributing to criminal and violent behavior can be prevented because they have environmental origins that can be eliminated.

Progressive slowing of reaction time and increasing cerebrospinal fluid concentrations of quinolinic acid in HIV-infected individuals

Neuropsychological functioning and cerebrospinal fluid concentrations of an endogenous neurotoxin, quinolinic acid (QUIN) were evaluated in 52 HIV-positive individuals (71% without constitutional symptoms) and 33 HIV-seronegative controls (including 15 psychiatric patients with adjustment disorders). Although the HIV-positive subjects did not differ from controls on standard neuropsychological tests, simple and choice reactions times (RT) were slow at initial evaluation (P less than 0.01) and became progressively slower at 6-month re-evaluation (P less than 0.05). Cerebrospinal fluid (CSF) QUIN was elevated at initial evaluation and increased during the 6-month interval (P less than 0.05). Moreover, during this 6-month interval, progressive slowing of RT was highly correlated with increasing levels of CSF QUIN (r = 0.85, df = 15, P less than 0.0001) but not with changes in mood, constitutional symptoms, or CD4 cell count. These findings suggest that RT may provide a sensitive behavioral measure of relatively early central nervous system involvement in HIV-infected individuals and that QUIN may play an important role in the pathogenesis of HIV-related neurological dysfunction.

Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases.

We examined 11 brains of human immunodeficiency virus (HIV) seropositive cases who died from unnatural causes (10 intravenous drug abusers who died from heroin overdose and 1 homosexual dead from a gunshot injury); 10 brains of HIV seronegative heroin addicts who died from overdose and 1 seronegative drug abuser who died from gunshot injury served as controls. Complete postmortem examination did not show evidence of acquired immune deficiency syndrome (AIDS) or AIDS related complex. Terminal changes including nerve cell ischemia, edema and diffuse vascular congestion were observed in all cases. Perivascular pigment deposition with macrophages was a constant finding in drug addicts and was probably related to chronic intravenous injection. In contrast, cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis. Granular ependymitis, myelin pallor with reactive astrocytosis and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunocytochemistry was negative for HIV antigens. Our study further supports the view that early central nervous system changes occur in HIV infection.

High‐dose methylprednisolone sodium succinate as a single agent in relapsed childhood acute lymphoblastic leukaemia

Twenty children received methylprednisolone (1 g/m2), daily for 5 to 8 days, as initial single agent therapy for relapsed acute lymphoblastic leukaemia. Bone marrow blasts were reduced to less than 5% in 2 and 5-10% in 3 of 12 patients with bone marrow relapses. In 3/9 with central nervous system relapses the cerebrospinal fluid (CSF) blasts completely cleared and were reduced in 4 others. In two patients with testicular relapses there was shrinkage of tumour and one patient with a navicular bone relapse became pain free. Toxicity was minimal. These results indicate high-dose methylprednisolone is an effective agent, particularly in the treatment of established central nervous system (CNS) disease and could contribute to early CNS directed therapy in acute lymphoblastic leukaemia.

An Experimental Model of Early Central Nervous System Syphilis

Although up to 40% of patients with early syphilis have evidence of central nervous system (CNS) invasion by Treponema pallidum, the pathogenesis of CNS syphilis is not understood. A rabbit model that mimics early CNS involvement in humans was developed and characterized. Mild cerebrospinal fluid pleocytosis was evident 2 weeks after intracisternal inoculation of T. pallidum and peaked at 9 weeks. The VDRL test in cerebrospinal fluid was reactive in 24% of animals, most commonly at 9 weeks after infection. T. pallidum could be isolated from the CNS of animals infected for 4, 6, or 9 weeks but not from animals infected for 12 or 20 weeks. Clinically, 6% of animals developed uveitis, similar to the frequency in patients with secondary syphilis. Thus, this model of meningeal and ocular syphilis seems to be analogous to the early CNS infection in humans and can be used for studies of pathogenesis and treatment.

Early Neurological and Electroencephalographic Changes after Coronary Artery Surgery in Low-risk Patients Younger than 70 Years

Between September 1986 and January 1988 neurological examination and electroencephalography (EEG) was performed before and one week after coronary artery bypass grafting in 66 patients younger than 70 years. Twenty patients were randomized to a bubble oxygenator without an arterial line filter (Group I), 22 patients to a bubble oxygenator with a depth adsorption filter (Group II), and 24 patients to a membrane oxygenator without a filter (Group III). No patient suffered a major stroke but early central nervous system dysfunction occurred after the operation in four patients (20%) in Group I, in four patients (18%) in group II and in two patients (8%) in group III. The difference between group I and III was not statistically significant but a larger number of patients in the groups might alter this. Our prospective study demonstrated a significant incidence of neurologic dysfunction in a low risk patient population undergoing standard coronary artery bypass surgery.

Early invasive CNS aspergillosis

A 46-year-old woman with non-Hodgkin's lymphoma presented with a new onset of seizures. A cranial CT was interpreted as normal. Eight months later, she presented with changed mental status and leg weakness, and a repeat CT scan showed multiple ring-enhancing lesions close to the left frontal sinus, with mass effect. A review of the previous CT scan showed a very small area of sinusitis as well as a small ring-enhancing lesion contiguous to it. A short course of intravenous steroids markedly relieved her symptoms, and a stereotactic biopsy confirmed Aspergillus fumigatus to be the cause of the infection. She was successfully treated with Amphotericin B. Central nervous system (CNS) aspergillosis is a potentially fatal disease. The therapeutic success in this case was related to a high index of suspicion at her second presentation. As the early signs of infection might be subtle and easily missed, patients at high risk for opportunistic infection should be studied carefully when new onset of CNS symptoms occur. Early initiation of therapy should improve the prognosis in such cases.

Tumor necrosis factor in the cerebrospinal fluid of children with central nervous system leukemia

To clarify the role of cytokines in cerebrospinal fluid (CSF) in the pathogenesis of central nervous system (CNS) leukemia, three cytokine activities, interleukin 1 (IL-1)-beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, and their correlations with other laboratory studies of the CSF were analysed in 23 children with acute leukemia. These patients were classified into three groups: group A ( n = 8)—patients with overt CNS leukemia, group B ( n = 5)—patients with CNS leukemia in remission, group C ( n = 10)—patients without CNS disease. IFN-gamma in the CSF was undetectable in these 23 patients. There was no difference in IL-1-beta levels among the three groups. However, TNF-alpha levels were significantly higher in group A than in group B, and higher in group B than in group C. By Kendall's rank sum test, high TNF levels in CSF correlated with high CSF leukemic cell counts and low sugar levels. In two patients with overt CNS leukemia, the TNF level in the CSF decreased gradually with intrathecal chemotherapy. These results indicate that TNF released from stimulated cells in the cerebrospinal space may induce CNS leukemia-related symptoms or alter laboratory parameters measured in the CSF. TNF levels in CSF may also prove useful in diagnosing early CNS involvement in children with acute leukemia.

Aplasia Cutis Congenita and Arteriovenous Fistula

We describe a child with congenital aplasia cutis congenita of the scalp and an occult giant posterior fossa arteriovenous fistula. Previous case reports of central nervous system malformations associated with aplasia cutis congenita are reviewed. The exact incidence of such malformations is unknown. All patients with aplasia cutis congenita should undergo a neurologic evaluation, and their families should be examined for similar lesions. Early central nervous system imaging and other workup may be required, especially if plastic surgery in the head region is being planned.

Borrelia burgdorferi in the Central Nervous System: Experimental and Clinical Evidence for Early Invasion

Intravenous injection into adult Lewis rats of live Borrelia burgdorferi, the spirochetal agent of Lyme disease, was followed by increased permeability of the blood-brain barrier. Permeability was measured by the ratio of 125I-labeled albumin in cerebrospinal fluid to that in blood. Permeability changes were dose-dependent, began 12 h after inoculation, and reversed within 1 week. Only live, intravenously inoculated organisms produced impairment of the blood-brain barrier. A spirochetal strain-dependent effect was noted in that changes were more marked with a recent isolate than with a strain in long-term in vitro culture. Mild pleocytosis and spirochetes were noted in the cerebrospinal fluid of rats with increased blood-brain barrier permeability. This experimental evidence for early central nervous system invasion was pursued in studies of the human disease. Specific B. burgdorferi antigens could be detected in the cerebrospinal fluid of patients with early Lyme disease by use of murine monoclonal antibodies as probes.

The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene.

Krox-20 is a mouse zinc finger gene expressed in a segment-specific manner in the early central nervous system, which makes it a potential developmental control gene. In this report, we show that the Krox-20 protein binds in vitro to two specific DNA sites located upstream from the homeobox containing gene Hox-1.4. The nucleotide sequence recognized by Krox-20 is closely related to the Sp1 target sequence, which is consistent with the similarity existing between the zinc fingers of the two proteins. In co-transfection experiments in cultured cells, Krox-20 dramatically activates transcription from the herpes simplex virus thymidine kinase promoter when an oligomer of its binding site is present in cis close to the promoter. Analysis of mutated binding sites demonstrates that the level of activation by Krox-20 correlates with the affinity of the protein for the mutant sequence. These data indicate that Krox-20 constitutes a sequence-specific DNA-binding transcription factor. Parallel analysis of the expression of Krox-20 and Hox-1.4 in the neural tube by in situ hybridization revealed no overlap, arguing against direct interactions between these two genes. The possible involvement of Krox-20 in the regulation of the transcription of other homeobox genes is discussed in view of their respective patterns of expression.

Infant acute lymphoblastic leukaemia with t(11;19)

Seven cases of infant acute lymphoblastic leukaemia with t(11; 19) (q23; p13) are described. They are characterized by a high white cell count, organomegaly, early central nervous system (CNS) disease, and a poor prognosis. Blasts are usually of an immature early B-cell lineage although monocytoid features are present in some cases. The characteristics of infant acute leukaemia with t(11; 19) are very similar to those found with t(4; 11), and the presence of t(11; 19) may indicate the same poor prognosis.

Cerebrospinal fluid B2-microglobulin levels in meningeal involvement by malignancy

Cerebrospinal fluid (CSF) and serum B2-microglobulin (B2m) levels were measured prospectively in 63 patients with hematological malignancies and 14 patients with solid tumours to evaluate the correlation between elevated levels and malignant infiltration of meninges. Serial CSF B2-m levels were also measured in 18 patients who received prophylactic intrathecal cytotoxic treatment. CSF B2-m levels were significantly higher in patients with central nervous system (CNS) involvement than in those without (p less than 0.001). A CSF B2-m level greater than 1.80 mg/L was closely associated with CNS disease (specificity 96%, sensitivity 76%) and CNS infiltration was also likely when the CSF B2-m level exceeded a simultaneously drawn serum level (specificity 98%, sensitivity 46%). Intrathecal methotrexate prophylaxis resulted in a consistent and significant rise in CSF B2-m levels with an average increase of 96% during a course of intrathecal injections. These results suggest that CSF B2-m levels may not be helpful for predicting early CNS relapse in these patients. However the CSF B2-m level and the corresponding serum B2-m level is a useful adjunct to the cytological diagnosis of CNS involvement by malignancy at presentation. Its value in predicting early CNS relapse and documenting response to CNS treatment requires further clarification.

The development of a simple scaffold of axon tracts in the brain of the embryonic zebrafish, Brachydanio rerio

We have examined neuronal differentiation and the formation of axon tracts in the embryonic forebrain and midbrain of the zebrafish, between 1 and 2 days postfertilisation. Axons were visualised with three techniques; immunocytochemistry (using HNK-1 and antiacetylated tubulin antibodies) and horseradish peroxidase (HRP) labelling in whole-mounted brains, and transmission electron microscopy. Differentiation was monitored by histochemical staining for acetylcholinesterase (AChE). These independent methods demonstrated that a simple grid of tracts and commissures forms the initial axon scaffold of the brain. At 1 day, the olfactory nerve, four commissures, their associated tracts and three other non-commissural tracts are present. By 2 days, these tracts and commissures have all greatly enlarged and, in addition, the optic nerve and tract, and three new commissures and their associated tracts have been added. Small applications of HRP at various sites revealed the origins and projections of some of these earliest axons. Retrogradely labelled cell bodies originated from regions that were also positive for AChE activity. At 1 day, HRP-labelled axons were traced: (1) from the olfactory placode through the olfactory nerve to the dorsal telencephalon; (2) from the telencephalon into the tract of the anterior commissure and also to the postoptic region of the diencephalon; (3) from the hindbrain through the ventral midbrain and diencephalon to the postoptic commissure; (4) from the dorsal diencephalon (in or near the epiphysis) to the tract of the postoptic commissure; (5) from ventral and rostral midbrain through the posterior commissure. Three new projections were demonstrated at 2 days: (1) from the retina through the tract of the postoptic commissure to the tectum; (2) from the telencephalon to the contralateral diencephalon; and (3) from the telencephalon to the ventral flexure. These results show that at 1 day, the zebrafish brain is impressively simple, with a few small, well-separated tracts but by 2 days the brain is already considerably more complex. Most of the additional axons added onto pre-existent tracts rather than pioneered new ones supporting the notion that other axons play a crucial role in the guidance of early central nervous system (CNS) axons.

Decreased Plasma Taurine in Aged Rats

Taurine (TAU) is thought to be a neuromodulator or an inhibitory neurotransmitter in the mammalian brain. In the periphery, TAU is involved in a wide spectrum of physiological functions. One of the most important putative physiological function of TAU is the modulation of cardiovascular activity including blood pressure control. TAU also appears to be important for the development of an organism, especially early central nervous system development. Regional TAU content was measured in brains of adult (6-month) and aged (23- to 26-month) Fischer-344 (F-344) male rats. To assess the putative neurotransmitter role of TAU, release due to potassium depolarization was studied using slices from frontal cortex of F-344 rats. Circulating levels of TAU were also determined in male F-344 rats (6 and 24 months of age) and female Long-Evans rats (LE, 6 and 30 months old). We found no age-related change in TAU stores from the brain regions examined, nor did we find any indication of TAU release due to potassium depolarization in the release paradigm utilized. There was, however, a significant reduction (28 and 42%) in plasma TAU concentration in F-344 and LE rats, respectively. This age-related reduction in plasma TAU may have important consequences both peripherally and centrally with respect to regulation of blood pressure, cardiovascular function, and cardioprotection, as well as possible CNS complications.

Magnetic resonance imaging of the brain in patients with acute monosymptomatic optic neuritis.

Ophthalmologists and neurologists from a catchment area of 1.5 million people were asked to refer all patients with symptoms and signs of optic neuritis (ON) to our neurological department immediately. A total of 68 consecutive patients were extensively screened for known etiologies of ON. Eleven had definite multiple sclerosis (MS); 7 patients could not participate for various reasons. The cerebrum, cerebellum and brainstem of the remaining 50 untreated patients with monosymptomatic ON were MRI scanned at 1.5 T with 2 sequences (slice thickness 4 mm, voxel size 1.2 x 1.2 x 4 mm3): double spin-echo (TR = 1.8 s, TE = 30 and 90 ms, 12 slices axially) and inversion recovery (TR = 2.45 s, TI = 400 ms, TE = 30 ms, 5 slices sagittaly). Magnetic resonance imaging (MRI) was performed within 3-49 (median 16) days from onset of symptoms. MRI demonstrated multiple asymptomatic central nervous system (CNS) lesions in 62% of patients. The appearance, locations and extents of lesions were consistent with demyelination. A scoring system based on number and size of lesions is proposed. Seven of 50 patients developed definite MS during a median follow-up of 11 months; they all had CNS lesions on the first scan. MRI has thus improved the pathophysiological knowledge of idiopathic ON, which from the very onset is a manifestation of MS in at least two thirds of cases. Patients who have early CNS lesions run a much higher risk of later developing clinically definite MS.