Biomedical subjects

S Y Ma

Publications and source records attributed to S Y Ma.

At least 19 recordsLinked to original sources

PubMed2000

Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease.

Recent studies indicate that there is a marked reduction in trkA-containing nucleus basalis neurons in end-stage Alzheimer's disease (AD). We used unbiased stereological counting procedures to determine whether these changes extend to individuals with mild cognitive impairment (MCI) without dementia from a cohort of people enrolled in the Religious Orders Study. Thirty people (average age 84.7 years) came to autopsy. All individuals were cognitively tested within 12 months of death (average MMSE 24.2). Clinically, 9 had no cognitive impairment (NCI), 12 were categorized with MCI, and 9 had probable AD The average number of trkA-immunoreactive neurons in persons with NCI was 196, 632 +/- 12,093 (n = 9), for those with MCI it was 106,110 +/- 14,565, and for those with AD it was 86,978 +/- 12,141. Multiple comparisons showed that both those with MCI and those with AD had significant loss in the number of trkA-containing neurons compared to those with NCI (46% decrease for MCI, 56% for AD). An analysis of variance revealed that the total number of neurons containing trkA immunoreactivity was related to diagnostic classification (P < 0.001), with a significant reduction in AD and MCI compared to NCI but without a significant difference between MCI and AD. Cell density was similarly related to diagnostic classification (P < 0.001). There was a significant correlation with the Boston Naming Test and with a global score measure of cognitive function. The number of trkA-immunoreactive neurons was not correlated with MMSE, age at death, education, apolipoprotein E allele status, gender, or Braak score. These data indicate that alterations in the number of nucleus basalis neurons containing trkA immunoreactivity occurs early and are not accelerated from the transition from MCI to mild AD.

Aged↗

PubMed2000

Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.

Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons.

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3- to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons.

Animals↗

PubMed2000

Pramipexole attenuates the dopaminergic cell loss induced by intraventricular 6-hydroxydopamine.

The D3 preferring dopamine agonist pramipexole has been shown to attenuate the cell loss induced by levodopa in vitro. Pramipexole was herein evaluated in the 6-hydroxydopamine lesion model to determine its in vivo effect. Rats were treated with pramipexole or saline before and after an intracerebroventricular 6-hydroxydopamine injection. In the preliminary study, 6-hydroxydopamine produced a 68% reduction in striatal dopamine and a 62% loss in tyrosine hydroxylase immunoreactive (THir) cell counts in the substantia nigra. Pramipexole treated animals exhibited a 29% and a 27% reduction in striatal dopamine and THir cell counts, respectively. THir cell counts and striatal dopamine were significantly correlated. In the stereological study, 6-hydroxydopamine reduced THir cell counts by 47% in saline treated animals and 26% in pramipexole treated animals. These data demonstrate that pramipexole attenuates the biochemical and THir cell changes normally produced by 6-hydroxydopamine consistent with its neuroprotective actions in vitro.

Animals↗

PubMed2000

Reduction in TrkA-immunoreactive neurons is not associated with an overexpression of galaninergic fibers within the nucleus basalis in Down's syndrome.

Down's syndrome (DS) individuals develop neuropathological features similar to Alzheimer's disease (AD), including degeneration of cholinergic basal forebrain (CBF) neurons. In AD a reduction in CBF/trkA-containing neurons has been suggested to trigger a hyperexpression of galaninergic fibers within the nucleus basalis subfield of the basal forebrain. The present study examined the interrelationship between reductions in CBF/trkA-containing neurons and the overexpression of galaninergic fibers within the nucleus basalis in DS. Within the nucleus basalis stereologic evaluation revealed a 46% reduction in the number of trkA-immunopositive neurons, whereas optical density measurements displayed a nonsignificant 18% reduction in neuronal trkA immunoreactivity in DS as compared with age-matched controls. Western blot analysis also showed a significant reduction in cortical trkA protein levels in DS. A semiquantitative examination of galaninergic fibers in the nucleus basalis revealed only a modest hypertrophy of galaninergic fibers within the nucleus basalis in DS. The present findings indicate a significant reduction in trkA within the nucleus basalis and cortex with only a moderate hypertrophy of galaninergic fibers in DS. These observations suggest that DS may not be an exact genetic model for investigation of changes in the AD basal forebrain.

Aged↗

PubMed1999

Dopamine transporter-immunoreactive neurons decrease with age in the human substantia nigra.

Unbiased disector stereologic cell counting was applied to sections from the human substantia nigra that were immunostained by using a monoclonal antibody against the dopamine transporter (DAT). This antibody was found to penetrate the full thickness of the stained section. Quantification of the number of DAT immunostained neurons was performed in human cases stratified into three age groups, young (ages 0-49 years), middle aged (ages 50-69 years), and aged (ages 70-85 years). The number of DAT-immunoreactive nigral neurons was normalized for each case by constructing a ratio of the number of DAT-containing neurons to total number of neuromelanin-containing cells in each subject's sample. Three types of DAT nigral neurons were seen: type 1, intensely stained; type 2, lightly stained; and type 3, DAT-immunonegative neuromelanin-containing perikarya. By 50 years of age, the number of type 1 neurons decreased significantly (P < 0.0001), whereas the number of type 2 neurons increased with age (P < 0.0001). Type 3 neurons also increased with age (P < 0.01), although less robustly than type 2 neurons. Type 1 neurons decreased by 11.2% per decade, and the total number of nigral neurons (types 1-3) decreased by 6.7% per decade. Relative to the young group, there were 75% and 88% reductions in type 1 neurons in the middle-aged and aged groups, respectively. This contrasts with the 35% and 41% reductions in total number of neuromelanin-containing neurons seen in middle-aged and aged groups, respectively. The young group had significantly more type 1 neurons and fewer type 2 neurons compared with middle-aged and aged participants. Post-hoc analyses indicated that the young group had significantly fewer type 3 neurons compared with middle-aged and aged participants. These findings demonstrate an age-related reduction in the number of substantia nigra DAT-immunoreactive neurons. Therefore, insight into the mechanisms regulating the rate of DAT synthesis may aid in our understanding of the decline of DATs with aging and its functional significance.

Adolescent↗

PubMed1999

Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease.

As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.

Aged↗

PubMed1999

Lentiviral gene transfer to the nonhuman primate brain.

Lentiviral vectors infect quiescent cells and allow for the delivery of genes to discrete brain regions. The present study assessed whether stable lentiviral gene transduction can be achieved in the monkey nigrostriatal system. Three young adult Rhesus monkeys received injections of a lentiviral vector encoding for the marker gene beta galatosidase (beta Gal). On one side of the brain, each monkey received multiple lentivirus injections into the caudate and putamen. On the opposite side, each animal received a single injection aimed at the substantia nigra. The first two monkeys were sacrificed 1 month postinjection, while the third monkey was sacrificed 3 months postinjection. Robust incorporation of the beta Gal gene was seen in the striatum of all three monkeys. Stereological counts revealed that 930,218; 1,192,359; and 1,501,217 cells in the striatum were beta Gal positive in monkeys 1 (n = 2) and 3 (n = 1) months later, respectively. Only the third monkey had an injection placed directly into the substantia nigra and 187,308 beta Gal-positive cells were identified in this animal. The injections induced only minor perivascular cuffing and there was no apparent inflammatory response resulting from the lentivirus injections. Double label experiments revealed that between 80 and 87% of the beta Gal-positive cells were neurons. These data indicate that robust transduction of striatal and nigral cells can occur in the nonhuman primate brain for up to 3 months. Studies are now ongoing testing the ability of lentivirus encoding for dopaminergic trophic factors to augment the nigrostriatal system in nonhuman primate models of Parkinson's disease.

Animals↗

PubMed1999

Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing.

This study used the dissector method to evaluate pigmented nigral neuronal loss in the substantia nigra pars compacta with age. Dissector counts can be used to estimate the absolute and accurate total neurone numbers. In addition, the area and diameter of the neuronal cell body was estimated by using a computerized morphometric analysis in a single section of the substantia nigra pars compacta. Brain samples from 26 people with an age range from 17 to 90 years were studied. A significant decrease in the total number of pigmented neurones (r=-0.83, P<0.001) and their density (r=-0.83, P<0.001) with age was found in the substantia nigra pars compacta. The number of pigmented neurones counted from a single section also showed an age-dependent decline (r=-0.76, P<0.001). According to the regression equations, the total number of pigmented neurones estimated by dissector counts decreased by 9.8% per decade and the neuronal density decreased by 7.4% per decade. The area of the neuronal cell body decreased by 3.2% per decade. This latter change corresponds to an approximate 4.4% decrease per decade in neuronal volume. These findings show that both the number of pigmented neurones and their size in the substantia nigra pars compacta decreases with age. However, the reductions in the total number of pigmented neurones are more dramatic than the reduction in neurone size with ageing.

Adolescent↗

PubMed1998

Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys.

Although the role of dopamine dysfunction is well established in Parkinson's disease, the effect of nigrostriatal degeneration on motor performance during normal aging is less well understood. In this study, aged rhesus monkeys (25-27 years old) displayed significant impairments relative to young (3-5 years old) cohorts in motor function as assessed on a fine motor task and home cage activity. Additionally, the clinical motor function of aged monkeys was impaired relative to young monkeys as assessed on a clinical rating scale. Unbiased stereologic measurements of the substantia nigra revealed a significant age-related loss of tyrosine hydroxylase-immunoreactive (TH-ir; 50.3%) and dopamine transporter-immunoreactive (DAT-ir; 33.2%) nigral neurons. The monkeys performance on the fine motor task and on the clinical rating scale was correlated with TH-ir neuronal counts. The number of DAT-ir nigral neurons was correlated with activity and clinical rating scale scores. Our results suggest that age-related motor impairments in nonhuman primates are associated with spontaneous decreases in TH-ir and DAT-ir nigral cells. The correlation of motor deficits with the loss of TH-ir and DAT-ir nigral neurons suggests that aged nonhuman primates may provide a useful model for mimicking changes seen in human aging and early Parkinson's disease.

Aging↗

PubMed1997

Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts.

Previous studies based on single sections have suggested a significant correlation between pigmented neuronal loss in the substantia nigra (SN) and clinical features in Parkinson's disease (PD). However, disector (DS) counts-unbiased and accurate stereological estimates have not been available. To evaluate total neuron numbers in the pars compacta of the substantia nigra (SNpc) in relation to clinical features, we estimated the neuron counts in the SNpc by the DS method in brain samples from 12 controls and 12 PD patients. The total number of pigmented neurons in the whole SNpc was significantly reduced in PD patients (to 45% of the control mean, P < 0.001). The density of pigmented neurons (neuron/mm3) was reduced to 51% of the average control value (P < 0.001). No significant difference was seen in the volume (mm3) of the SNpc between PD patients and controls. Furthermore, the total number of pigmented neurons in the SNpc showed a significant negative correlation with the duration of disease (r = -0.86, P < 0.001) and with the stage of disease (r = -0.58, P < 0.05) in PD patients. Using an unbiased neuron counting method, these relationships, for the first time, demonstrate that the more severe pigmented neuronal loss in the SNpc is associated with the longer duration and the more severe stage of disease in PD patients.

Case-Control Studies↗

PubMed1996

A quantitative morphometrical study of neuron degeneration in the substantia nigra in Parkinson's disease.

We studied the pigmented neurons of the substantia nigra (SN) from 8 controls and 20 patients with Parkinson's disease (PD) using a computerized morphometric methodology. On the basis of neuronal topography, several anatomic regions were outlined in the SN. In these subregions the area, perimeter, diameter of the cell bodies and cell numbers were measured and were counted in the controls and PD patients. The measurements were made at the level of the exit of the third cranial nerve from the brain stem. In PD patients, when the whole SN was considered, the mean area, mean perimeter and diameter of the pigmented cell bodies were significantly reduced by 35%, 20% and 21% respectively from the control mean values. Regionally, the pigmented neuron area in the medial ventral part (VM), medial dorsal part (DM), lateral ventral part (VL), lateral dorsal part (DL) and pars lateralis part (PL) showed a significant reduction of 33-41% as compared to controls. In these subregions, a significant decrease in PD patients from the control mean values was seen both in the pigmented neuron perimeter, by 19-26%, and the diameter by 19-25%. This decrease in cell size suggests that, in PD patients, the remaining pigmented neurons in the SN are in a process of degeneration and atrophy. In PD patients the number of pigmented neurons in the whole SN decreased about 76% from control values. Evaluation of the influence of cell size on the apparent quantity of cells in sections indicates, however, that in PD patients the impact of true loss of pigmented neurons is far more dramatic than the impact of their decrease in size.

Aged↗

PubMed1995

Destructive encephalopathy in incontinentia pigmenti: a case report.

We report a 2-day-old neonate with incontinentia pigmenti combined with destructive encephalopathy. Generalized seizures developed soon after birth; characteristic papulovesicles and hyperpigmented linear streaks appeared several days later. The brain CT scan showed multiple low density areas with cortical atrophy and ventricular enlargement. Histopathological examination favored the diagnosis of incontinentia pigmenti. Although a series of microbiological examinations failed to identify any infectious agent, the patient was still treated vigorously with anticonvulsants, systemic antibiotics, and acyclovir from the beginning of hospitalization. However, the seizures persisted, and the patient died 26 days after birth. Our report suggests that incontinentia pigmenti with encephalopathy may have a fatal prognosis.

Anticonvulsants↗

PubMed1995

Cell counts in the substantia nigra: a comparison of single section counts and disector counts in patients with Parkinson's disease and in controls.

The disector (DS) is a method by which it is possible to estimate the density of cells in a volume of tissue, and when associated with Cavalieri's principle, the total number of cells of a neural nucleus. Since the introduction of this method, there has been some uncertainty about the value of cell counts estimated using single section (SS). To compare these two methods, we counted the pigmented neurons in the pars compacta of the substantia nigra (SNpc) in seven normal controls and in four patients with Parkinson's disease (PD), using both single histological sections and the DS. The calculations were performed at two different levels of the substantia nigra. Level I was cut through the colliculus superior and caudal red nucleus, and level II showed the exit of the third cranial nerve in all cases. As methods, the two counts were in close agreement (Pearson's correlation coefficient at levels I and II were r = 0.97 and r = 1.00, respectively, P < 0.001). The correspondence was different in the controls and in the parkinsonian patients, however, as can be judged from the slopes of the average regression lines (0.20 for controls, 0.31 for parkinsonian patients). It is nevertheless evident that once the regression line has been defined. DS counts can be estimated from SS counts when the pigmented neuron numbers are counted in the SNpc. The results suggest that comparisons of pigmented neuron counts made from SS are relevant if the cutting level of the section is well defined, and if section thickness is kept constant.

Adult↗

PubMed1995

Single section and disector counts in evaluating neuronal loss from the substantia nigra in patients with Parkinson's disease.

In order to investigate the correlation between single section (SS) and disector (DS) counts for estimating the pigmented neurons in the pars compacta of the substantia nigra (SNpc), 12 patients with Parkinson's disease (PD) and seven controls were studied. The SS counts were obtained at the level of the exit of the third cranial nerve in the SNpc. The DS counts were made from the whole volume of the SNpc. There was a significant correlation between SS and DS counts (r = 0.94, P < 0.001), suggesting that the methods closely agree. Comparison of SS and DS counts in controls and PD patients showed that the pigmented neurons in PD were decreased by 75% (P < 0.001) and 55% (P < 0.001) in the SS and DS counts, respectively. This study suggests that loss of pigmented neurons from the SNpc in PD can be estimated by either method.

Aged↗

PubMed1990

[Studies on the resolution of racemic gossypol. IV. Use of threo (-) or (+)-1-(p-nitrophenyl)-1,3-dihydroxypropylamine-2 as the resolving agent].

Threo (-) or (+)-1-(p-nitrophenyl)-1,3-dihydroxypropylamine-2 was found to be a useful resolving agent for racemic gossypol. The optical and chemical stability of the condensate of enantiomeric gossypols with the titled amine and the great difference in the Rf values on TLC and the solubilities in various solvents between the two diastereoisomeric condensates facilitate the separation. Therefore, the pure isomers can be easily obtained by means of chromatography or crystallization.

Chloramphenicol↗

PubMed1989

Tissue and age specific expression of the myc proto-oncogene family throughout the life span of the C57BL/6J mouse strain.

The expression of the proto-oncogene myc family (c, L and N) in terms of steady-state mRNA levels was determined in seven different normal non-cancerous tissues throughout the life span (seven different ages) of the C57BL/6J male mouse strain. C-myc oncogene expression was highest in prenatal and newborn ages and then decreased to its lowest levels at about 6 months of age. With further increase of age, a progressive pattern of increase in expression of c-myc was found in brain, liver, skin, and small intestine. However, for kidney, spleen and heart, little or no significant change was evident. Significant differential expression of c-myc was found in most tissues in animals of the same age, with highest expression consistently being found in spleen and liver at all ages. For the N-myc and L-myc oncogenes, expression was also highest in prenatal and newborn tissue as compared to the 6-month young adult, but little or no further change was found at older ages. However, substantial tissue-dependent differences in expression were also found, and no expression at all was detected at any age for N-myc in liver and for L-myc in heart, small intestine and liver. Taken together, these results indicate that the expression of the proto-oncogenes c-, L- and N-myc is dependent not only on tissue and embryonic development, as previously shown by other workers, but also on age past the young adult stage of life span. The age-dependent increase in expression of c-myc oncogene found in normal-appearing non-cancerous tissues is of particular interest as possibly reflecting tissue alterations related to both the aging process and the age-dependent increase in cancer incidence.

Age Factors↗

PubMed1989

[Diagnosis of intraocular foreign body by computed tomography].

To evaluate the computed tomography in diagnosis of foreign bodies in the eye or close to the scleral wall, it was used with routine orbital radiography for comparison. The Simens Somatom DR3 CT Scanner with a 512 x 512 matrix was used in 50 random cases, and 45 cases were confirmed by surgery. The results indicated that the positive rate of CT in detecting intraocular foreign bodies was 98% (49/50), vs 90% (45/50) for radiography. The smallest metallic intraocular foreign body detected by CT was 0.4 x 0.25 mm and a cupric foreign body of 0.2 x 0.1 mm escaped detection. The error rate of CT in detecting single foreign body in the ocular wall was 1/30, while that of radiography was 10/30. Intraocular multiple foreign bodies could be demonstrated by multiple laminae of CT, and non-metallic foreign bodies could also be differentiated.

Adolescent↗