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Biomedical subjects

H D Rosas

Publications and source records attributed to H D Rosas.

16 recordsLinked to original sources
PubMed2006

Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG.

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease.

Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion of glutamine repeats in ubiquitously distributed huntingtin protein. Recent studies have shown that mutant huntingtin interferes with the function of widely expressed transcription factors, suggesting that gene expression may be altered in a variety of tissues in HD, including peripheral blood. Affymetrix and Amersham Biosciences oligonucleotide microarrays were used to analyze global gene expression in blood samples of HD patients and matched controls. We identified 322 mRNAs that showed significantly altered expression in HD blood samples, compared with controls (P < 0.0005), on two different microarray platforms. A subset of up-regulated mRNAs selected from this group was able to distinguish controls, presymptomatic individuals carrying the HD mutation, and symptomatic HD patients. In addition, early presymptomatic subjects showed gene expression profiles similar to those of controls, whereas late presymptomatic subjects showed altered expression that resembled that of symptomatic HD patients. These elevated mRNAs were significantly reduced in HD patients involved in a dose-finding study of the histone deacetylase inhibitor sodium phenylbutyrate. Furthermore, expression of the marker genes was significantly up-regulated in postmortem HD caudate, suggesting that alterations in blood mRNAs may reflect disease mechanisms observed in HD brain. In conclusion, we identified changes in blood mRNAs that clearly distinguish HD patients from controls. These alterations in mRNA expression correlate with disease progression and response to experimental treatment. Such markers may provide clues to the state of HD and may be of predictive value in clinical trials.

Adult↗
PubMed2005

Age-related changes in prefrontal white matter measured by diffusion tensor imaging.

Age-related degeneration of brain white matter (WM) has received a great deal of attention, with recent studies demonstrating that such changes are correlated with cognitive decline and increased risk for the development of age-related neurodegenerative disease. Past studies have used magnetic resonance imaging (MRI) to measure the volume of normal and abnormal tissue signal as an index of tissue pathology. More recently, diffusion tensor MRI (DTI) has been employed to obtain regional measures of tissue microstructure, such as fractional anisotropy (FA), providing better spatial resolution and potentially more sensitive metrics of tissue damage than traditional volumetric measures. We used DTI to examine the regional basis of age-related alterations in prefrontal WM. As expected from prior volumetric and DTI studies, prefrontal FA was reduced in older adults (OA) compared to young adults (YA). Although WM volume has been reported to be relatively preserved until late aging, FA was significantly reduced by middle age. Much of prefrontal WM showed reduced FA with increasing age. Ventromedial and deep prefrontal regions showed a somewhat greater reduction compared to other prefrontal areas. Prefrontal WM anisotropy correlated with prefrontal WM volume, but the correlation was significant only when the analysis was limited to participants over age 40. This evidence of widespread and regionally accelerated alterations in prefrontal WM with aging illustrates FA's potential as a microstructural index of volumetric measures.

Adult↗
PubMed2004

Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington's disease.

Transgenic mouse models and other screens are being used to identify potential therapeutic agents for use in clinical trials in Huntington's disease (HD). The development of surrogate markers that can be used in clinical therapeutics is an active area of research. Because HD is relatively uncommon and only a portion of available subjects meet inclusion and exclusion criteria, therapeutic trials are limited by the availability of potential subjects as well as the relative insensitivity of the clinical measures used. Neuroimaging methods offer the potential to provide noninvasive, reproducible, and objective methods not only to better understand the disease process but also to follow in clinical studies to determine if a drug is effective in slowing down disease progression or perhaps even in delaying onset. Following is a review of the literature, which highlights the studies that have been published to date.

Biomarkers↗
PubMed2003

Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis.

BACKGROUND: Most clinical symptoms of Huntington disease (HD) have been attributed to striatal degeneration, but extrastriatal degeneration may play an important role in the clinical symptoms because postmortem studies demonstrate that almost all brain structures atrophy. OBJECTIVE: To fully characterize the morphometric changes that occur in vivo in HD. METHODS: High-resolution 1.5 mm T1-weighted coronal scans were acquired from 18 individuals in early to mid-stages of HD and 18 healthy age-matched controls. Cortical and subcortical gray and white matter were segmented using a semiautomated intensity contour-mapping algorithm. General linear models for correlated data of the volumes of brain regions were used to compare groups, controlling for age, education, handedness, sex, and total brain volumes. RESULTS: Subjects with HD had significant volume reductions in almost all brain structures, including total cerebrum, total white matter, cerebral cortex, caudate, putamen, globus pallidus, amygdala, hippocampus, brainstem, and cerebellum. CONCLUSIONS: Widespread degeneration occurs in early to mid-stages of HD, may explain some of the clinical heterogeneity, and may impact future clinical trials.

Adult↗
PubMed2002

Regional and progressive thinning of the cortical ribbon in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a fatal and progressive neurodegenerative disease that is accompanied by involuntary movements, cognitive dysfunction, and psychiatric symptoms. Although progressive striatal degeneration is known to occur, little is known about how the disease affects the cortex, including which cortical regions are affected, how degeneration proceeds, and the relationship of the cortical degeneration to clinical symptoms. The cortex has been difficult to study in neurodegenerative diseases primarily because of its complex folding patterns and regional variability; however, an understanding of how the cortex is affected by the disease may provide important new insights into it. METHODS: Novel automated surface reconstruction and high-resolution MR images of 11 patients with HD and 13 age-matched subjects were used to obtain cortical thickness measurements. The same analyses were performed on two postmortem brains to validate these methods. RESULTS: Regionally specific heterogeneous thinning of the cortical ribbon was found in subjects with HD. Thinning occurred early, differed among patients in different clinical stages of disease, and appeared to proceed from posterior to anterior cortical regions with disease progression. The sensorimotor region was statistically most affected. Measurements performed on MR images of autopsy brains analyzed similarly were within 0.25 mm of those obtained using traditional neuropathologic methods and were statistically indistinguishable. CONCLUSIONS: The authors propose that the cortex degenerates early in disease and that regionally selective cortical degeneration may explain the heterogeneity of clinical expression in HD. These measures might provide a sensitive prospective surrogate marker for clinical trials of neuroprotective medications.

Adult↗
PubMed2001

Striatal volume loss in HD as measured by MRI and the influence of CAG repeat.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that results from the expansion of a trinucleotide (CAG) repeat on chromosome 4. Progressive degeneration of the striatum is the pathologic hallmark of the disease. Little is known about the regional selectivity of the neurodegeneration and its relationship to the genetic expansion. METHODS: The authors used high-resolution MRI to determine the relationship between the genetic expansion and the degree of striatal degeneration. Morphometric analyses of the striatum from high-resolution MR images from 27 subjects with HD were compared with those of 24 healthy control subjects. RESULTS AND CONCLUSIONS: Striatal volumes were reduced in subjects with HD as compared with control subjects, in agreement with previously published reports. Left-sided volumes were smaller than right-sided volumes in subjects with HD; in healthy subjects, right-sided volumes were smaller. Finally, volume loss was significantly correlated with CAG repeat number. These results have potential implications for the design and assessment of therapeutic agents in the future.

Adult↗
PubMed1999

Riluzole therapy in Huntington's disease (HD).

We conducted a 6-week open-label trial of riluzole (50 mg twice a day) in eight subjects with Huntington's disease. Subjects were evaluated before riluzole treatment, on treatment, and off treatment with the chorea, dystonia, and total functional capacity (TFC) scores from the Unified Huntington's Disease Rating Scale and magnetic resonance spectroscopy measurements of occipital cortex and basal ganglia lactate levels. Adverse events and safety blood and urine tests were assessed throughout the study. All subjects completed the study and riluzole was well tolerated. The age was 45+/-10.2 years (mean +/- standard deviation) and the disease duration was 6.1+/-4.1 years. The chorea rating score improved by 35% on treatment (p = 0.013) and worsened after discontinuation of treatment (p = 0.026). There were no significant treatment effects on the dystonia or TFC scores. The baseline occipital and basal ganglia lactate levels were elevated in all subjects; there was a trend toward lower lactate/creatine ratios during riluzole treatment in the basal ganglia spectra but not in occipital cortex spectra. Additional clinical studies of riluzole for both symptomatic and neuroprotective benefit in Huntington's disease are warranted.

Adult↗
PubMed1999

An integrated strategy for evaluation of metabolic and oxidative defects in neurodegenerative illness using magnetic resonance techniques.

The number of physiologic and metabolic phenomena amenable to analysis using magnetic resonance (MR) techniques is increasing every year. MR techniques can now evaluate tissue parameters relevant to TCA cyclemetabolism, anerobic glycolysis, ATP levels, blood-brain barrier permeability, macrophage infiltration, cytotoxic edema, spreading depression, cerebral blood flow and volume, and neurotransmitter function. The paramagnetic nature of certain oxidation states of iron leads to the ability to map out brain function using deoxyhemoglobin as an endogenous contrast agent, and also allows for mapping of local tissue iron concentrations. In addition to these metabolic parameters, the number of ways to generate anatomic contrast using MR is also expanding; and in addition to conventional anatomic scans, mapping of axonal fiber tracts can also be performed using the anisotropy of water diffusion. A strategy for integration of these multifarious parameters in a comprehensive neurofunctional exam in neurodegenerative illness is outlined in this paper. The goals of the integrated exam, as applied to a given neurodegenerative illness, can be subdivided into three categories: etiology, natural history, and therapeutic end points. The consequences of oxidative stress and/or mitochondrial dysfunction are explored in the context of the various parameters that can be measured using the integrated MR exam.

Animals↗
PubMed1998

Neurocognitive effects of chronic lead intoxication in Andean children.

Lead (Pb) intoxication in children has been associated with neurodevelopmental disabilities which may result in motor and cognitive impairment. We conducted blood lead (PbB) measurements, neurological examinations and cognitive tests on children living in Ecuadorian villages where Pb is used extensively in the glazing of ceramics. Group I consisted of 55 children with a mean PbB level of 48.0 microg/dl (SD: 26.4, range: 9.2-119.1 microg/dl) who received PbB tests and complete neurological examinations. An appreciable number of the children with elevated PbB levels were normal on specific components of the neurological examination. Among the children who showed neurological deficits, higher PbB levels were associated with abnormal tendon reflexes, finger tapping, visual pursuit, size discrimination, draw-a-person, and math calculation skills. Group II consisted of 41 children with a mean PbB level of 47.4 microg/dl (SD: 22.0, range: 6.6-84.7 microg/dl) who were administered Raven's Coloured Progressive Matrices (RCPM) non-verbal reasoning test. Performance on RCPM was abnormal in 22 (53.7%) of 41 children. Children with abnormal RCPM scores had higher PbB levels (t-test: P=0.030). There was a significant inverse correlation between RCPM scores and PbB levels for children ages 9 years and older (r=-0.618, P=0.011). Males had higher mean PbB levels as a function of age than females (t-test: P=0.037), and more males showed neurocognitive deficits. The results demonstrate a range of neurological responses in children with chronically elevated PbB levels from apparent exceptional neuro-physiological tolerance of PbB intoxication, to some fine motor and cognitive deficits.

Ceramics↗
PubMed1998

1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers.

Huntington's disease (HD) is the result of an expanded (CAG) repeat in a gene on chromosome 4. A consequence of the gene defect may be progressive impairment of energy metabolism. We previously showed increased occipital cortex lactate in HD using localized 1H spectroscopy. We have now extended these studies to show an almost threefold elevation in occipital cortex lactate in 31 HD patients as compared with 17 normal control subjects (p < 10(-11)). The spectra in three presymptomatic gene-positive patients were identical to normal control subjects in cortical regions, but three in eight showed elevated lactate in the striatum. Similar to recently reported increases in task-related activation of the striatum in the dominant hemisphere, we found that striatal lactate levels in HD patients were markedly asymmetric (higher on the left side). Markers of neuronal degeneration, decreased N-acetylaspartate (NAA)/creatine and increased choline/creatine levels, were symmetric. Both decreased NAA and increased lactate in the striatum significantly correlated with duration of symptoms. When divided by his or her age, an individual's striatal NAA loss and lactate increase were found to directly correlate with the subject's CAG repeat number, with correlation coefficients of 0.8 and 0.7, respectively. Similar correlations were noted between postmortem cell loss and age versus CAG repeat length. Together, these data provide further evidence for an interaction between neuronal activation and a defect in energy metabolism in HD that may extend to presymptomatic subjects.

Adult↗
PubMed1997

One-year outcome after decompressive surgery for massive nondominant hemispheric infarction.

OBJECTIVE: Massive cerebral infarction is often accompanied by early death secondary to transtentorial herniation. We have tested the hypothesis that decompressive hemicraniectomy for massive nondominant cerebral infarction is lifesaving in a series of 14 patients presenting with right hemispheric infarction and clinical signs of uncal herniation and impending death. We have further analyzed, in prospective follow-up examinations, the levels of physical, psychiatric, and social disabilities in these patients. METHODS: The methods used included retrospective analysis to determine rates of immediate mortality and morbidity after surgical intervention. Prospective follow-up data were obtained to determine the level of recovery in surviving patients after 1 year. Standardized measures of outcome to assess physical, psychiatric, and social recovery included the Barthel Index, Zung Depression Scale, and Reintegration to Normal Living Index. RESULTS: With decompressive hemicraniectomy, we were able to prevent death secondary to transtentorial herniation in all cases; 11 patients experienced long-term survival after the procedure, and three deaths were related to non-neurological causes. We observed that 8 of the 11 surviving patients were at home, were functioning with minimal to moderate assistance, and had Barthel scores greater than 60. The remaining three patients were severely disabled. Seven of the 11 survivors were able to walk at 1 year after undergoing the procedure. Depression and failure to reintegrate socially were experienced by most patients. CONCLUSION: This series confirms the lifesaving nature of hemicraniectomy in patients deteriorating because of cerebral edema after infarction. In patients younger than 50 years, recovery to a state of near-independence is possible.

Activities of Daily Living↗
PubMed1995

Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption.

BACKGROUND: Paraneoplastic neurologic syndromes, although rare, cause significant morbidity and mortality. They are thought to be immunologically mediated, but to date those involving the central nervous system (CNS) have not been particularly responsive to immunologic therapy. The use of the novel immunomodulator, protein A immunoadsorption, was explored to address this question. METHODS: Six patients with neurologic paraneoplastic syndromes were treated with this technique, using the "off line" method. Two hundred fifty ml of plasma was perfused through a column containing protein A covalently attached to a silica matrix. The plasma was then returned to the patient. RESULTS: Five of the patients responded to the therapy, with complete and durable responses in three patients with opsoclonus-myoclonus, objective, though transient, improvement in one patient with paraneoplastic brainstem encephalitis associated with a Merkel cell tumor, and stabilization and partial improvement in one patient with paraneoplastic limbic encephalitis. The patient without response developed a cutaneous vasculitis after the second treatment, and therapy was discontinued. CONCLUSIONS: This therapy appears beneficial for a number of paraneoplastic syndromes, most dramatically in the opsoclonus/myoclonus syndrome.

Adult↗