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White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy.

PURPOSE: The purpose of this study was to determine the time course for development of white matter changes induced by high-dose chemotherapy. METHODS: Eight patients with advanced breast cancer were entered into a prospective, longitudinal trial that included examination by MR imaging and proton MR spectroscopy before chemotherapy and through 12 months after treatment with carmustine, cyclophosphamide, and cisplatin, combined with autologous hematopoietic progenitor cell support (AHPCS). RESULTS: Six patients completed induction chemotherapy, at which time all MR imaging studies appeared normal. At 3 months after the conclusion of high-dose chemotherapy and beyond, three of the four patients remaining in the study showed an increasing volume of white matter changes, which appeared to stabilize during the period from 6 months to 1 year. Maximal volumes of abnormal white matter ranged from 73 to 166 cm3. MR spectroscopy showed little or no change in metabolic ratios through the period of observation, although there was a suggestion of small transient treatment-related decreases in the ratio of N-acetyl aspartate (NAA) to creatine. CONCLUSION: White matter changes are common sequelae of treatment with high-dose chemotherapy combined with AHPCS, occurring early in the period following high-dose chemotherapy, with a rapid and progressive accumulation to about 6 months, but not accompanied by persistent neurologic symptoms. The MR spectroscopic analyses suggest a minimal disturbance of the neuronal marker NAA, a finding that may in part explain the good neurologic outcome.

Adult↗

[The role of corticosteroids in analgesic effect caused by stimulation of the periaqueductal gray matter of the midbrain in rats].

The effects of stimulation of periaqueductal gray matter on pain threshold and blood corticosterone level were studied in anesthetized rats. The stimulation resulted in a alteration of analgesia and corticosterone level. Stimuli-induced analgesia was decreased by adrenalectomy. Corticosterone implantation (50 micrograms) in periaqueductal gray matter resulted in the increase of analgesia. Pretreatment with naloxone (1 mg/kg) failed to modify the effect of stimulation of periaqueductal gray matter on analgesia and corticosterone level. Our results indicate the involvement of corticosterone in the analgesia induced the stimulation of periaqueductal gray matter.

Adrenalectomy↗

Sulfate reduction in poorly-drained soils as influenced by organic matter and soil texture.

Investigations of the influence of added organic matter content (rice straw or clover) on the reduction of added sulfate (8 meq/100 g soil) following submergence and incubation of 120 days gave these results: 1. In soils with native organic matter (humus) the rate of sulfate reduction was very low; it slightly increased with increased clay content of the soils. 2. The addition of undecomposed organic matter led to a complete reduction of the added sulfates within 120 days. 3. The varying C/N ratio of the added organic matter appeared to have no influence on the sulfate reduction. 4. As a qualitative indication of the reduction the soil darkened after three weeks of incubation, and an odour of H2S was detected.

Oxidation-Reduction↗

2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion.

Focal microinjection of 2, 3-dihyro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the AMPA/kainate subclass of glutamate receptors, reduces neurological deficits and tissue loss after spinal cord injury. Dose-dependent sparing of white matter is seen at 1 month after injury that is correlated to the dose-related reduction in chronic functional deficits. To determine whether NBQX exerts an acute effect on white matter pathology, female, adult Spague Dawley rats were subjected to a standardized weight drop contusion at T-8 (10 gm x 2.5 cm) and NBQX (15 nmol) or vehicle (VEH) solution focally injected into the injury site 15 min later. At 4 and 24 hr, tissue from the injury epicenter was processed for light and electron microscopy, and the histopathology of ventromedial white matter was compared. The axonal injury index, a quantitative representation of axoplasmic and myelinic pathologies, was significantly lower in the NBQX group at 4 hr (2.7 +/- 0.24, mean +/- SE) and 24 hr (1.4 +/- 0.19) than in VEH controls (3.8 +/- 0.33 and 2.1 +/- 0.20, respectively). Counts of glial cell nuclei indicated a loss of at least 60% at 4 and 24 hr after injury in the VEH group compared with uninjured controls. NBQX treatment reduced this glial loss by half. Immunohistochemistry revealed that the spared glia were primarily oligodendrocytes. Thus, the chronic effects of NBQX in reducing white matter loss after spinal cord injury appear to be attributable to the reduction of acute pathology and may be mediated through the protection of glia, particularly oligodendrocytes.

Animals↗

Age-dependent changes in magnetization transfer contrast of white matter in the pediatric brain.

BACKGROUND AND PURPOSE: It is unknown to what extent magnetization transfer contrast (MTC) in white matter of the brain changes during myelination. The goal of this study was to measure the age-dependent changes of MTC in different regions of the pediatric brain and to evaluate their relation to T2 relaxation times. METHODS: Seventy children aged 1 week to 80 months without evidence of organic brain disease underwent MR imaging of the brain. A double-echo spin-echo (SE) sequence and an SE sequence with and without an off-resonance pulse were performed in the axial orientation. Using paired images, we calculated MTC ratios in 13 predefined regions of the brain and compared them with the T2 relaxation times measured in the same areas. Regression analysis was performed for both parameters to evaluate age dependency. RESULTS: MTC in white matter increased during myelination from a range of 13% to 19% to a range of 34% to 37%. At the same time, T2 relaxation times decreased from a range of 115 to 160 milliseconds to a range of 60 to 70 milliseconds after myelination. For both MTC and T2 relaxation times, age dependency could be expressed by a monoexponential function. CONCLUSION: A strong positive correlation exists between MTC ratios and the degree of myelination in the pediatric brain, and an inverse correlation exists between MTC and T2 relaxation times. Fast proton relaxation within macromolecules in the myelinated white matter and subsequent MT may be the most important reason for the decreasing T2 relaxation time of white matter during brain myelination.

Aging↗

Characterisation of PM(10), PM(2.5) and benzene soluble organic fraction of particulate matter in an urban area of Kolkata, India.

In this study, the relationship between inhalable particulate (PM(10)), fine particulate (PM(2.5)), coarse particles (PM(2.5 - 10)) and meteorological parameters such as temperature, relative humidity, solar radiation, wind speed were statistically analyzed and modelled for urban area of Kolkata during winter months of 2003-2004. Ambient air quality was monitored with a sampling frequency of twenty-four hours at three monitoring sites located near traffic intersections and in an industrial area. The monitoring sites were located 3-5 m above ground near highly trafficked and congested areas. The 24 h average PM(10) and PM(2.5) samples were collected using Thermo-Andersen high volume samplers and exposed filter papers were extracted and analysed for benzene soluble organic fraction. The ratios between PM(2.5) and PM(10) were found to be in the range of 0.6 to 0.92 and the highest ratio was found in the most polluted urban site. Statistical analysis has shown a strong positive correlation between PM(10) and PM(2.5) and inverse correlation was observed between particulate matter (PM(10) and PM(2.5)) and wind speed. Statistical analysis of air quality data shows that PM(10) and PM(2.5) are showing poor correlation with temperature, relative humidity and solar radiation. Regression equations for PM(10) and PM(2.5) and meteorological parameters were developed. The organic fraction of particulate matter soluble in benzene is an indication of poly aromatic hydrocarbon (PAH) concentration present in particulate matter. The relationship between the benzene soluble organic fraction (BSOF) of inhalable particulate (PM(10)) and fine particulate (PM(2.5)) were analysed for urban area of Kolkata. Significant positive correlation was observed between benzene soluble organic fraction of PM(10) (BSM10) and benzene soluble organic fraction of PM(2.5) (BSM2.5). Regression equations for BSM10 and BSM2.5 were developed.

Air↗

Particulate matter concentration and air quality affected by windblown dust in the Columbia plateau.

The USEPA has proposed to regulate PM(coarse) (particulate matter 2.5 to 10 microm in diameter). Exceedance of the proposed National Ambient Air Quality Standard (NAAQS) for PM(coarse) is expected within the Columbia Plateau of the Pacific Northwest United States based on the high frequency of dust storms and the large contribution of crustal material to fugitive dust in the region. The objective of this study was to explore the implication of the proposed NAAQS for PM(coarse) on air quality. Concurrent observations of both PM10 (particulate matter </=10 microm in diameter) and PM(fine) (particulate matter </=2.5 microm in diameter) were made at Kennewick, WA from 1999 through 2005. Daily PM(coarse) concentration was determined as the difference between PM10 and PM(fine) concentrations. The number of exceedances of the proposed USEPA NAAQS for PM(coarse) was determined for various levels of the standard (the proposed daily level is 70 microg m(-3)). Over the 7 yr of this study, the PM10 standard was exceeded on 16 d with PM(fine) constituting 4 to 7% of PM10. The proposed PM(coarse) standard would have been exceeded on 35 d and represents a 120% increase in the number of exceedances over the current PM10 standard. Changing the level of the proposed PM(coarse) standard to that of the current PM10 standard (150 microg m(-3)) would result in a 20% decrease in the number of exceedances of the PM standard. The results of this study suggest that the proposed NAAQS for PM(fine) and PM(coarse) will be exceeded more frequently than the current PM(fine) and PM10 standard in a region subject to seasonal dust storms.

Air Pollutants↗

[Primary research on indoor air concentration of particulate matter in residential house and its relationship with ambient pollution level].

OBJECTIVE: To investigate the indoor air concentration of particulate matter in residential house and its relationship with ambient pollution level. METHODS: Indoor and outdoor air level of PM2.5 and PM10 were monitored in 10 residential houses in downtown area. RESULTS: In the non-heating period, the indoor air level of PM2.5 and PM10 were 27.0 - 272.9 microg/m3 and 42.9 - 309.6 microg/m3, respectively. In the heating period, PM2.5 and PM10 were 20.7 - 251.4 microg/m3 and 34.0 - 283.9 microg/m3, respectively. There were good correlation between the indoor air concentrations of PM2.5 and PM10. The relationships between the indoor and outdoor air concentrations of PM2.5 and PM10, however, were not clear. CONCLUSION: Our results showed that there were serious indoor air pollution of particulate matter in residential house. Further research will be needed to clarify the characteristics of indoor air particulate matter pollution and its influence on resident.

Air Pollutants↗

Developmental changes of glial fibrillary acidic protein in cerebral white matter.

Developmental changes were observed in the glial fibrillary acidic protein (GFAP)--positive glia of cerebral white matter (including myelination glia) in the frontal lobes of 38 normal cases. With age, GFAP-positive processes gradually became larger and their location shifted from preponderantly in the deep white matter to mostly in the superficial white matter. This shift in pattern of GFAP-positive glia may be related to the parallel changes in perinatal brains in the localization of leukomalacic lesions. However, the shift is a normal developmental phenomenon on which such lesions are superimposed.

Aging↗

Cognitive and neurologic findings in subjects with diffuse white matter lucencies on computed tomographic scan (leuko-araiosis).

As part of a prospective clinicopathologic study, a cohort of 105 "normal" elderly volunteers was investigated with computed tomographic scans, psychometric testing (Extended Scale for Dementia [ESD]) and neurologic examination. Computed tomographic scans were evaluated for the presence or absence of white matter lucencies, termed leuko-araiosis. These are defined as patchy or diffuse areas of decreased attenuation involving only white matter and with no change in adjacent ventricles or sulci. The nine controls with leuko-araiosis had lower scores on the ESD than the 96 controls without leuko-araiosis (mean ESD with leuko-araiosis, 227.1 +/- 14; without leuko-araiosis, 237.1 +/- 8), and the difference remains significant even after adjusting for the possible confounding effects of age, sex, education, and infarct detected on computed tomography. Significant differences were also found comparing subjects with leuko-araiosis and those without in respect to abnormal gait, limb power, plantar response, and the rooting and palmomental reflexes. Leuko-araiosis may represent a marker for early dementia. The pathophysiology of this finding remains uncertain. Our results suggest that white matter abnormalities play a role in the development of intellectual impairment in the elderly.

Aged↗

Brain white-matter changes in the elderly prone to falling.

Falls and impaired gait are a major source of morbidity in the elderly. Why some elderly become prone to falling is often unclear. We analyzed the gait, equilibrium, and brain computed tomography results of 40 elderly subjects without evidence of neurologic disease known to be associated with falls. Twenty of these subjects were prone to falling and the remaining 20 were nonfalling controls. These two groups were comparable in terms of age and sex (mean age, 83.3 years [SE, 1.7 years]). The group of fallers had significantly worse gait and equilibrium scores and a greater degree of white-matter hypodensity on computed tomography. White-matter hypodensity correlated with impaired gait and equilibrium scores but not with impaired performance on cognitive testing. This study reveals the association of white-matter disease with gait and balance impairment leading to falls in the elderly.

Accidental Falls↗

Magnetic resonance imaging white matter lesions and cognitive impairment in hypertensive individuals.

To search for a morphologic basis of cognitive impairment possibly associated with essential hypertension, we studied 35 otherwise asymptomatic hypertensive individuals (mean age, 38.7 years; range, 22 to 49 years) and 20 normotensive control subjects (mean age, 37.9 years; range, 26 to 49 years) using neuropsychologic tests and magnetic resonance imaging. Irrespective of drug treatment, hypertensive individuals performed significantly worse than did control subjects when assessed for verbal memory and total learning and memory capacity, while there were no differences in test results of visual memory, attention, vigilance, and reaction time. The hypertensive individuals also described themselves as less active but ranked similar on five other mood subscales. Punctate high-signal intensities of the white matter were found almost twice as often in the hypertensive group (38%) as in the control group (20%). There was no difference in test performance between hypertensive individuals with and those without white matter lesions, however. Our results confirm the presence of subtle neuropsychologic deficits and indicate a higher frequency of white matter signal abnormalities in essential hypertension, as shown on magnetic resonance imaging, but do not indicate a correlation of these findings with each other.

Adult↗

Clinical correlates of white-matter changes on magnetic resonance imaging scans of the brain.

We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.

Aged↗

Magnetic resonance imaging signal hyperintensities in the deep and subcortical white matter. A comparative study between stroke patients and normal volunteers.

Mixed population studies suggest a relationship between deep and subcortical white matter hyperintensities on magnetic resonance imaging and cerebrovascular disease. To further clarify this issue we compared the prevalence and extent of such signal abnormalities between a group of 133 consecutive stroke patients (mean age, 54.7 +/- 16.7 years) and 101 normal volunteers (mean age, 54.7 +/- 13.1 years). Diabetes and cardiac disease were significantly more common in patients than in normal subjects. Prevalence rates of clinically silent lesions were 44% and 47.5%, respectively. Beginning confluent and confluent foci were seen in 19.5% of patients, but in only 7.5% of normal subjects. Significant univariate correlations were found for the presence and extent of lesions with age, diabetes, cardiac disease, severity of extracranial carotid arteriosclerosis, and arterial hypertension, but not with the diagnosis of stroke or the type of brain infarction. Multivariate regression analysis established age and diabetes mellitus as the only independent predictors of white matter damage. We conclude that more extensive white matter abnormalities in stroke patients stem from their higher rate of cerebrovascular risk factors but are unrelated to the occurrence of ischemic attacks per se.

Adolescent↗

Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging.

Magnetic resonance imaging was used to determine the volumes of brain, subcortical gray matter nuclei, and the ventricular and sulcal cerebrospinal fluid in 27 healthy men. Subjects were divided into young (less than 35 years, n = 10) and old (greater than 60 years, n = 17) groups. Volumes were normalized as percent intracranial volume. Older subjects had significantly less brain mass and significantly larger ventricular and peripheral cerebrospinal fluid volumes than the younger men. The caudate and lenticular nuclei were significantly smaller in older than younger men. This significant difference remained when their volumes were expressed as a ratio of cerebral brain matter volume. This cross-sectional study demonstrates age-related atrophy and concurrent dilation of cerebrospinal fluid spaces in healthy subjects. Of brain regions affected, the caudate and lenticular nuclei are significantly more affected by healthy aging than is cerebral brain matter; this may account for some of the motor abnormalities in aging.

Adult↗

T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study.

CONTEXT: While gray matter T2 hypointensity in multiple sclerosis (MS) has been associated with physical disability and clinical course, previous studies have relied on visual magnetic resonance imaging (MRI) assessments. OBJECTIVE: To quantitatively determine if T2 hypointensity is associated with conventional MRI and clinical findings in MS. DESIGN: Case-control study. SETTING: University-affiliated community-based hospital. SUBJECTS: Sixty patients with MS and 50 controls. MAIN OUTCOME MEASURES: T2 intensities of the substantia nigra, red nucleus, thalamus, putamen, globus pallidus, and caudate; third ventricular width; total brain T1 (hypointense) and T2 (hyperintense) lesion volumes; Expanded Disability Status Scale (physical disability) score; and disease course. RESULTS: Deep gray matter T2 hypointensity was present in patients with MS in all structures (P<.005) except for the substantia nigra. T2 hypointensity was associated with third ventricle enlargement and higher T2 but not T1 plaque load. The regression model predicting third ventricle width included caudate T2 hypointensity (P =.006). The model predicting T2 lesion load included globus pallidus T2 hypointensity (P =.001). Caudate T2 hypointensity was the only variable associated with disability score in regression modeling (P =.03). All T2 hypointensities differentiated the secondary progressive from the relapsing-remitting clinical courses. The final model (P<.001) predicting clinical course retained T2 hypointensity of the thalamus, caudate, and putamen but not MRI plaques or atrophy. CONCLUSIONS: Gray matter T2 hypointensity in MS is associated with brain atrophy and is a stronger predictor of disability and clinical course than are conventional MRI findings. While longitudinal studies are warranted, these results suggest that pathologic iron deposition is a surrogate marker of the destructive disease process.

Adult↗

Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.

BACKGROUND: X-linked hereditary demyelinating neuropathies (Charcot-Marie-Tooth Disease [CMTX]) caused by mutations in the connexin 32 (Cx32) gene account for approximately 10% to 20% of all hereditary demyelinating neuropathies. Mild subclinical central nervous system (CNS) involvement has been previously described, and CMTX patients with transient white matter lesions allied to CNS symptoms have very recently been described. This is of potential interest, as Cx32 is widely expressed in both peripheral nerve and the brain. PATIENTS: We describe a family with hereditary demyelinating neuropathy and transient CNS symptoms. For this study, family members underwent genotyping and detailed clinical, electrophysiological, and magnetic resonance imaging examination. RESULTS: We present a CMTX family with a novel mutation in the Cx32 gene. Affected family members show, in addition to the classic polyneuropathy, transient and reversible white matter lesions on magnetic resonance imaging scans, correlating similarly transient CNS symptoms. CONCLUSION: Patients with CMTX can present with transient CNS symptoms and marked white matter lesions on magnetic resonance imaging scans.

Adult↗

White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease.

BACKGROUND: White matter lesions (WMLs) are prevalent in nondemented aging and in Alzheimer disease (AD). Their relationship with cognition in the earliest stages of AD is unknown. OBJECTIVE: To assess the relationship between WMLs and cognition in nondemented aging and in early-stage AD. DESIGN: Cross-sectional study. SETTING: Alzheimer Disease Research Center, St Louis, MO. PARTICIPANTS: Participants were nondemented (n = 88) or had very mild (n = 48) or mild (n = 20) AD. MAIN OUTCOME MEASURES: Regression coefficients for deep WMLs and periventricular WMLs (PVWMLs) as predictors of cognition, after controlling for age, educational achievement, brain atrophy, and infarctlike lesions. RESULTS: White matter lesions were present in nondemented aging and in early-stage AD, with no group differences in deep WML burden and a modest PVWML burden increase in the AD group. The prevalence of infarctlike lesions was equivalent between groups. Age and hypertension were related to deep WML burden and PVWML burden. Deep WML burden and PVWML burden were associated with reduced global cognition in AD but not in nondemented aging. A PVWML x AD status interaction for global cognition suggests that the relationship between PVWMLs and cognition is modified by AD. In AD, global cognitive reductions were related to impairments in visual memory, processing speed, and executive function. CONCLUSIONS: White matter lesions are prevalent in nondemented aging and in early-stage AD, and their presence influences cognitive impairment in the earliest stages of AD. Individuals with early-stage AD may be more vulnerable to the cognitive effect of WMLs than nondemented aging individuals with similar WML burden.

Age of Onset↗