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1.
Early Hum Dev ; 122: 8-14, 2018 07.
Article in English | MEDLINE | ID: mdl-29803998

ABSTRACT

BACKGROUND: Neonates with hypoxic-ischemic encephalopathy (HIE) and seizures have poorer outcome for undetermined reasons. AIMS: Our aim was to determine if brain imaging was more abnormal in neonates with HIE and electrographically confirmed seizures and whether this was impacted by seizure burden. STUDY DESIGN: Single center retrospective review. SUBJECTS: Forty-eight term neonates with HIE (with and without seizures) underwent MRI brain scans before age 14 days between the years 2008 and 2013. OUTCOME MEASURES: Images were rated using a MRI injury score and fractional anisotropy (FA) values were extracted from diffusion tensor imaging (DTI). RESULTS: The seizure group (n = 25) had significantly more injury within white matter, basal ganglia, posterior limb of internal capsule, and watershed areas compared to the group without seizures (n = 23). The severity of injury in all measured areas increased with increasing seizure severity. The seizure group also had lower FA values in posterior limb of the internal capsule and the splenium of corpus callosum. CONCLUSIONS: Neonates with HIE and seizures had more brain injury that occurred in areas typically affected by HIE and was greater with higher seizure burden. Seizures may be a marker of more severe brain injury or seizures themselves may amplify brain damage from HIE.


Subject(s)
Diffusion Tensor Imaging , Hypoxia-Ischemia, Brain/diagnostic imaging , Infant, Newborn, Diseases/diagnostic imaging , Magnetic Resonance Imaging , Seizures/diagnostic imaging , Female , Humans , Hypoxia-Ischemia, Brain/complications , Infant, Newborn , Male , Seizures/complications
3.
Neurology ; 79(1): e1-4, 2012 Jul 03.
Article in English | MEDLINE | ID: mdl-22753451

ABSTRACT

Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is an uncommon outcome of prolonged focal status epilepticus in childhood. The prolonged focal motor seizure usually occurs during the course of a febrile illness and is followed by hemiplegia ipsilateral to the side of convulsions. This is accompanied by radiologic evidence of acute cytotoxic edema in the affected hemisphere followed by chronic atrophy. Intractable epilepsy may develop at a time remote from the initial presentation. The clinical features of HHE syndrome were first described more than 5 decades ago but its pathophysiology remains poorly understood and the long-term cognitive outcomes are unclear. Early recognition of the syndrome may help provide patients and families with an accurate prognosis regarding the subsequent development of epilepsy.


Subject(s)
Hemiplegia/diagnosis , Seizures/diagnosis , Status Epilepticus/diagnosis , Child , Diagnosis, Differential , Hemiplegia/complications , Humans , Infant , Male , Seizures/complications , Status Epilepticus/complications , Syndrome
4.
Brain Res ; 1433: 85-97, 2012 Jan 18.
Article in English | MEDLINE | ID: mdl-22177775

ABSTRACT

This fMRI study investigated the development of language lateralization in left- and righthanded children between 5 and 18 years of age. Twenty-seven left-handed children (17 boys, 10 girls) and 54 age- and gender-matched right-handed children were included. We used functional MRI at 3T and a verb generation task to measure hemispheric language dominance based on either frontal or temporo-parietal regions of interest (ROIs) defined for the entire group and applied on an individual basis. Based on the frontal ROI, in the left-handed group, 23 participants (85%) demonstrated left-hemispheric language lateralization, 3 (11%) demonstrated symmetric activation, and 1 (4%) demonstrated right-hemispheric lateralization. In contrast, 50 (93%) of the right-handed children showed left-hemispheric lateralization and 3 (6%) demonstrated a symmetric activation pattern, while one (2%) demonstrated a right-hemispheric lateralization. The corresponding values for the temporo-parietal ROI for the left-handed children were 18 (67%) left-dominant, 6 (22%) symmetric, 3 (11%) right-dominant and for the right-handed children 49 (91%), 4 (7%), 1 (2%), respectively. Left-hemispheric language lateralization increased with age in both groups but somewhat different lateralization trajectories were observed in girls when compared to boys. The incidence of atypical language lateralization in left-handed children in this study was similar to that reported in adults. We also found similar rates of increase in left-hemispheric language lateralization with age between groups (i.e., independent of handedness) indicating the presence of similar mechanisms for language lateralization in left- and right-handed children.


Subject(s)
Functional Laterality/physiology , Language , Psychomotor Performance/physiology , Acoustic Stimulation/methods , Adolescent , Age Factors , Child , Child, Preschool , Female , Humans , Magnetic Resonance Imaging , Male
5.
Am J Intellect Dev Disabil ; 116(5): 344-59, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21905803

ABSTRACT

The authors used functional magnetic resonance imaging (fMRI) to investigate neural activation during a semantic-classification/object-recognition task in 13 persons with Down syndrome and 12 typically developing control participants (age range  =  12-26 years). A comparison between groups suggested atypical patterns of brain activation for the individuals with Down syndrome. Correlation analyses between an index of visual spatial ability and brain activation depicted a positive relationship between (a) this index and brain activation in regions of the occipital and parietal lobes for the typically developing individuals and (b) the middle and dorsal frontal gyri in the individuals with Down syndrome. These findings supported the authors' hypothesis that persons with Down syndrome demonstrate atypical neural activation compared with typically developing individuals matched for chronological age.


Subject(s)
Brain/physiopathology , Down Syndrome/physiopathology , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Pattern Recognition, Visual/physiology , Semantics , Verbal Learning/physiology , Adolescent , Adult , Aptitude/physiology , Brain Mapping , Child , Dominance, Cerebral/physiology , Down Syndrome/diagnosis , Down Syndrome/psychology , Female , Humans , Male , Psychomotor Performance/physiology , Reaction Time/physiology , Reference Values , Young Adult
6.
J Child Neurol ; 26(2): 223-7, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20833799

ABSTRACT

Deletions of chromosome 17p13.3 result in neuronal migration defects such as isolated lissencephaly sequence and Miller-Dieker syndrome. LIS1 is the deleted gene within this region and is thought to directly cause isolated lissencephaly sequence and contribute to Miller-Dieker syndrome. Two additional genes (14-3-3ε and CRK) on the telomeric end of chromosome 17p reportedly contribute to the severe phenotype of Miller-Dieker syndrome. We report 2 patients with deletions of chromosome 17p13.3 involving the genes 14-3-3ε and CRK but not LIS1 with previously unreported, identical phenotypes of macrocephaly, small stature, dysmorphic features, generalized epilepsy, developmental delay, and nonspecific white matter changes. The findings in this report suggest that patients who have deletions of 14-3-3ε and/or CRK should be monitored closely for the development of seizures.


Subject(s)
14-3-3 Proteins/genetics , Chromosome Deletion , Chromosomes, Human, Pair 17 , Developmental Disabilities/genetics , Epilepsy, Generalized/genetics , Megalencephaly/genetics , Proto-Oncogene Proteins c-crk/genetics , Brain/abnormalities , Child, Preschool , Cytogenetics , Electroencephalography , Female , Humans , Syndrome
8.
Brain Res Bull ; 79(5): 322-32, 2009 Jun 30.
Article in English | MEDLINE | ID: mdl-19480991

ABSTRACT

Age-related differences in the regional recruitment of prefrontal cortex (PFC) during cognitive tasks suggests that aging is associated with functional reorganization. Cholinergic enhancement with physostigmine reduces activity in the PFC regions selectively recruited during working memory (WM) and increases activity in visual processing areas, suggesting that augmenting cholinergic function reduces task effort by improving the visual representation of WM stimuli. Here, we investigated how cholinergic enhancement influenced PFC and visual cortical activity in young and older subjects as WM difficulty was altered. Regional cerebral blood flow (rCBF) was measured using H(2)(15)O-PET in 10 young and 10 older volunteers during a parametrically varied face WM task, following an i.v. infusion of saline and physostigmine. Reaction time decreased during physostigmine relative to placebo in both groups. Prefrontal brain regions selectively recruited in each age group that responded differentially to task demands during placebo, had no significant activity during physostigmine. Medial visual processing areas showed task-selective increases in activity during drug in both groups, while lateral regions showed decreased activity in young and increased activity in older participants at longer task delays. These results are consistent with our previous findings, showing that the modulatory role of the cholinergic system persists during aging, and that the effects of cholinergic enhancement are functionally specific rather than anatomically specific. Moreover, the use of the parametric design allowed us to uncover group specific effects in lateral visual processing areas where increasing cholinergic function produced opposite effects on neural activity in the two age groups.


Subject(s)
Acetylcholine/metabolism , Aging , Brain/physiology , Memory, Short-Term/physiology , Pattern Recognition, Visual/physiology , Acetylcholine/antagonists & inhibitors , Adult , Aged , Analysis of Variance , Brain/diagnostic imaging , Brain/drug effects , Brain Mapping , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Cholinesterase Inhibitors/administration & dosage , Female , Humans , Linear Models , Male , Memory, Short-Term/drug effects , Pattern Recognition, Visual/drug effects , Photic Stimulation , Physostigmine/administration & dosage , Positron-Emission Tomography , Reaction Time/drug effects
9.
Brain Lang ; 106(3): 184-94, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18762059

ABSTRACT

OBJECTIVE: Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. METHODS: Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. RESULTS: Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. INTERPRETATION: This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.


Subject(s)
Cerebral Cortex/physiopathology , Dominance, Cerebral/physiology , Functional Laterality/physiology , Infarction, Middle Cerebral Artery/physiopathology , Language , Adolescent , Cerebral Cortex/pathology , Child , Cognition/physiology , Female , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Gyrus Cinguli/pathology , Gyrus Cinguli/physiopathology , Humans , Image Processing, Computer-Assisted , Infarction, Middle Cerebral Artery/pathology , Magnetic Resonance Imaging/methods , Male , Neuropsychological Tests , Statistics as Topic , Task Performance and Analysis , Temporal Lobe/pathology , Temporal Lobe/physiopathology , Time Factors , Verbal Behavior/physiology , Visual Cortex/pathology , Visual Cortex/physiopathology
10.
J Cogn Neurosci ; 20(7): 1342-53, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18284346

ABSTRACT

Previously, we demonstrated that enhancing cholinergic activity during a working memory (WM) task improves performance and reduces blood flow in the right anterior middle/superior frontal cortex, an area known to be important for WM. The purpose of this study was to evaluate the interaction between WM task demands and cholinergic enhancement on neural responses in the prefrontal cortex. Regional cerebral blood flow (rCBF) was measured using H(2)(15)O and positron emission tomography, as 10 young healthy volunteers performed a parametrically varied match-to-sample WM for faces task. For each item, a picture of a face was presented, followed by a delay (1, 6, 11, or 16 sec), then by the presentation of two faces. Subjects were instructed to identify which face they previously had seen. For control items, nonsense pictures were presented in the same spatial and temporal manner. All conditions were performed during an intravenous infusion of saline and physostigmine (1 mg/hr). Subjects were blind to the substance being infused. Reaction time increased significantly with WM delay, and physostigmine decreased reaction time across delay conditions. Significant task-related rCBF increases during saline infusion were seen in superior frontal, middle frontal, and inferior frontal regions, and the response magnitudes in the regions increased systematically with task difficulty. In all of these prefrontal regions, physostigmine administration significantly reduced rCBF during task, particularly at longer task delays, so that no correlation between task delay and rCBF was observed. In the ventral visual cortex, physostigmine increased rCBF at longer task delays in medial regions, and decreased rCBF over delay conditions in lateral cortical areas. These results indicate that, during cholinergic potentiation, brain activity in prefrontal regions is not modulated by increases in WM task demands, and lends further support to the hypothesis that cholinergic modulation enhances visual processing, making the task easier to perform, and thus, compensate for the need to recruit prefrontal cortical regions as task demands increase.


Subject(s)
Acetylcholine/metabolism , Brain Mapping , Cerebrovascular Circulation/physiology , Memory, Short-Term/physiology , Prefrontal Cortex/physiology , Adult , Cerebrovascular Circulation/drug effects , Cholinesterase Inhibitors/pharmacology , Female , Humans , Male , Memory, Short-Term/drug effects , Neuropsychological Tests , Pattern Recognition, Visual/drug effects , Pattern Recognition, Visual/physiology , Photic Stimulation/methods , Physostigmine/pharmacology , Positron-Emission Tomography/methods , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/drug effects , Reaction Time/drug effects , Time Factors
11.
Brain Lang ; 105(2): 99-111, 2008 May.
Article in English | MEDLINE | ID: mdl-17905426

ABSTRACT

OBJECTIVE: Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. METHODS: Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. RESULTS: Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. INTERPRETATION: This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.


Subject(s)
Cerebral Cortex/physiopathology , Functional Laterality/physiology , Infarction, Middle Cerebral Artery/physiopathology , Language , Semantics , Acoustic Stimulation/methods , Adolescent , Case-Control Studies , Cerebral Cortex/pathology , Child , Female , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Gyrus Cinguli/pathology , Gyrus Cinguli/physiopathology , Humans , Infarction, Middle Cerebral Artery/pathology , Language Tests/statistics & numerical data , Magnetic Resonance Imaging/methods , Male , Neuropsychological Tests/statistics & numerical data , Psychomotor Performance/physiology , Temporal Lobe/pathology , Temporal Lobe/physiopathology , Verbal Behavior/physiology , Visual Cortex/pathology , Visual Cortex/physiology
12.
Pediatr Neurol ; 37(6): 398-403, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18021919

ABSTRACT

Endogenous coenzyme Q10 is an essential cofactor in the mitochondrial respiratory chain, a potent antioxidant, and a potential biomarker for systemic oxidative status. Evidence of oxidative stress was reported in individuals with trisomy 21. In this study, 14 children with trisomy 21 had significantly increased (P < 0.0001) plasma ubiquinone-10 (the oxidized component of coenzyme Q10) compared with 12 age- and sex-matched healthy children (historical controls). Also, the mean ratio of ubiquinol-10 (the biochemically reduced component):total coenzyme Q10 was significantly decreased (P < 0.0001). After 3 months of ubiquinol-10 supplementation (10 mg/kg/day) to 10 patients with trisomy 21, the mean ubiquinol-10:total coenzyme Q10 ratio increased significantly (P < 0.0001) above baseline values, and 80% of individual ratios were within normal range. No significant or unexpected adverse effects were reported by participants. To our knowledge, this is the first study to indicate that the pro-oxidant state in plasma of children with trisomy 21, as assessed by ubiquinol-10:total coenzyme Q10 ratio, may be normalized with ubiquinol-10 supplementation. Further studies are needed to determine whether correction of this oxidant imbalance improves clinical outcomes of children with trisomy 21.


Subject(s)
Down Syndrome/diet therapy , Down Syndrome/physiopathology , Oxidation-Reduction/drug effects , Ubiquinone/analogs & derivatives , Vitamins/therapeutic use , Adolescent , Case-Control Studies , Child , Coenzymes/blood , Coenzymes/therapeutic use , Female , Follow-Up Studies , Humans , Male , Statistics, Nonparametric , Ubiquinone/blood , Ubiquinone/therapeutic use , Vitamins/blood
13.
Pediatr Neurol ; 35(1): 30-7, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16814082

ABSTRACT

Controlled studies of coenzyme Q(10) dosing and tolerance have been reported in adults, but not in pediatric patients. This study compares low- and high-dose coenzyme Q(10) (LiQ-NOL syrup) absorption and tolerance in children with Down syndrome. After a 1-month low-dose (1.0 mg/kg/day) run-in period, all participants received high-dose coenzyme Q(10) (10.0 mg/kg/day) for two additional months (in randomized sequence as one daily dose or split into two daily doses). Chemistry profiles and complete blood counts were determined just before and at the study completion. Plasma coenzyme Q(10) concentrations were determined initially and at each study visit. Parents reported adverse events and study drug evaluations using standardized forms. Most of the 16 children who completed this study tolerated high-dose coenzyme Q(10) well. Uncooperative behavior resulted in premature withdrawal of two participants, and may have been treatment-related. Pre- and posttreatment laboratory test changes were considered to be clinically nonsignificant. Study results indicate that high-dose coenzyme Q(10) (10 mg/kg/day) is well-absorbed and well-tolerated by most children with Down syndrome, and appears to provide plasma concentrations which are comparable to previous adult studies administering much higher coenzyme Q(10) dosages.


Subject(s)
Down Syndrome/blood , Down Syndrome/drug therapy , Ubiquinone/analogs & derivatives , Absorption/drug effects , Absorption/physiology , Behavioral Symptoms/blood , Behavioral Symptoms/chemically induced , Chemistry, Pharmaceutical , Child , Child, Preschool , Coenzymes , Dose-Response Relationship, Drug , Female , Humans , Infant , Male , Ubiquinone/administration & dosage , Ubiquinone/adverse effects , Ubiquinone/blood
14.
Am J Psychiatry ; 162(11): 2061-70, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16263845

ABSTRACT

OBJECTIVE: Age-associated cholinergic dysfunction may contribute to the cognitive decline observed during aging, including a decline in working memory. The current study was designed to determine how healthy aging influences the neural response to working memory before and during pharmacological potentiation of the cholinergic system. METHOD: In 13 young and 13 older healthy volunteers, regional cerebral blood flow (rCBF) was measured by using [15O]H2O and positron emission tomography across 10 scans that alternated between a working-memory-for-faces task and rest. In all subjects, the first two scans were obtained during intravenous saline infusion. Seven young and eight older subjects then received intravenous infusion of physostigmine, a cholinesterase inhibitor, and the remaining six young and five older subjects continued to receive saline. RESULTS: In the placebo condition, task-specific rCBF increases in prefrontal regions were observed in the right middle and inferior frontal cortices in young subjects and in more anterior and ventral prefrontal regions in older individuals. Physostigmine during the working memory task significantly improved performance in both age groups. The right prefrontal regions that were selectively recruited in each age group during the placebo condition showed significantly lower rCBF during physostigmine administration. CONCLUSIONS: Cholinergic enhancement does not affect structurally defined cortical regions but rather modulates neural activity in functionally defined regions, that is, in task-related prefrontal cortical areas that are selectively and distinctively recruited in young and older subjects.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Memory/physiology , Physostigmine/pharmacology , Positron-Emission Tomography , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Psychomotor Performance/drug effects , Adult , Age Factors , Aged , Brain/blood supply , Brain/diagnostic imaging , Brain Mapping , Female , Humans , Infusions, Intravenous , Male , Memory/drug effects , Middle Aged , Oxygen Radioisotopes , Prefrontal Cortex/diagnostic imaging , Psychomotor Performance/physiology , Reaction Time/drug effects , Reaction Time/physiology , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , Water
15.
Neuroreport ; 15(17): 2575-8, 2004 Dec 03.
Article in English | MEDLINE | ID: mdl-15570155

ABSTRACT

To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9-18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Broca's, middle frontal, Wernicke's, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.


Subject(s)
Aging/physiology , Brain Mapping , Brain/blood supply , Brain/physiology , Magnetic Resonance Imaging , Adolescent , Brain/anatomy & histology , Child , Child, Preschool , Female , Functional Laterality/physiology , Humans , Image Processing, Computer-Assisted/methods , Male , Neuropsychological Tests , Oxygen/blood , Psychomotor Performance/physiology , Verbal Behavior/physiology
16.
Ann Neurol ; 56(6): 808-14, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15562430

ABSTRACT

Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.


Subject(s)
Down Syndrome/blood , Gene Expression Profiling/methods , Neurofibromatosis 1/blood , Repressor Proteins/blood , Cluster Analysis , Down Syndrome/genetics , Gene Expression Regulation/physiology , Humans , Neurofibromatosis 1/genetics , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins
17.
Arch Neurol ; 61(11): 1721-4, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15534183

ABSTRACT

BACKGROUND: Markers of human brain dopamine metabolism are reported to decline with age. However, the cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA), a major dopamine metabolite, is reported to not change or to increase in elderly individuals. OBJECTIVE: To estimate the rate of delivery of HVA from the brain to CSF, taking into account the HVA concentration gradient in the spinal subarachnoid space and CSF flow. METHODS: Homovanillic acid concentrations were measured in 5 serial 6-mL aliquots of CSF removed from the L3-4 or L4-5 interspaces of 7 healthy young (mean +/- SD age, 28.7 +/- 4.6 years) subjects and 7 healthy elderly (mean +/- SD age, 77.1 +/- 6.3 years) subjects. Cisterna magna HVA concentrations were estimated from the slopes of the HVA concentrations along the spinal subarachnoid space. The products of cisternal HVA concentrations and published values for CSF flow were used to estimate lower limits for brain delivery of HVA to CSF, according to the Fick principle. RESULTS: The mean +/- SD HVA concentration in the initial lumbar CSF sample in the young subjects, 116 +/- 66 pmol/mL, did not differ significantly from 140 +/- 86 pmol/mL in the elderly subjects. Estimated cisternal HVA concentrations equaled 704 and 640 pmol/mL, respectively, in the young and elderly subjects. Multiplying these concentrations by CSF flow rates of 591 and 294 mL/d, respectively, gave lower limits for rates of delivery of HVA from the brain to CSF. These rates equaled 416 and 175 nmol/d, respectively. CONCLUSION: A 50% decline in the lower limit for the rate of HVA delivery from the brain to CSF in elderly individuals is consistent with other evidence that brain dopaminergic neurotransmission declines with age.


Subject(s)
Aging/physiology , Homovanillic Acid/cerebrospinal fluid , Receptors, Dopamine/physiology , Adult , Aged , Aged, 80 and over , Blood-Brain Barrier , Brain Chemistry , Female , Homovanillic Acid/pharmacokinetics , Humans , Male
18.
Brain Res Bull ; 63(2): 147-54, 2004 Mar 15.
Article in English | MEDLINE | ID: mdl-15130704

ABSTRACT

Studies using positron emission tomography (PET) have reported that global and regional values for cerebral blood flow and metabolic rates for glucose (CMRglc and rCMRglc) decline with age in humans. We wished to determine if such decreases could have reflected a partial volume effect (PVE) of cerebral atrophy in the elderly, rather than "intrinsic" reductions per gram brain. We used PET to compare rCMRglc, before and after correcting for the PVE, between 13 healthy older men (aged: 55-82 years) and 11 healthy young men (aged: 22-34 years). PET was performed with 18F-fluoro-2-deoxy-d-glucose while the subjects were in the "resting" state (eyes covered and ears plugged with cotton). The PET scans were normalized to a common brain volume after superimposing them on the subjects' tissue segmented magnetic resonance scans. Analysis showed that rCMRglc in the absence of a PVE correction was significantly less in the older group in insular, frontal, superior temporal cortical, and thalamic regions. Statistical significant differences in rCMRglc, however, were absent after the PVE correction. Thus, statistically significant age reductions in regional brain glucose metabolism, corrected for brain atrophy, are not detectable in healthy normotensive men scanned while in the resting state.


Subject(s)
Aging/metabolism , Blood Pressure/physiology , Brain/metabolism , Glucose/metabolism , Adult , Aged , Aged, 80 and over , Aging/pathology , Atrophy/metabolism , Atrophy/pathology , Brain/pathology , Humans , Male , Middle Aged , Neuropsychological Tests/statistics & numerical data , Tomography, Emission-Computed/methods
19.
Am J Psychiatry ; 160(10): 1870-8, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14514503

ABSTRACT

OBJECTIVE: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures. METHOD: Hippocampus and corpus callosum measures were obtained from volumetric T(1)-weighted MRI scans of 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age=41.8 years, 14 women). RESULTS: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group. CONCLUSIONS: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.


Subject(s)
Cognition , Corpus Callosum/pathology , Down Syndrome/pathology , Hippocampus/pathology , Magnetic Resonance Imaging , Adult , Age Factors , Down Syndrome/psychology , Female , Humans , Linear Models , Male , Mental Status Schedule , Middle Aged , Neuropsychological Tests
20.
Neurobiol Aging ; 23(3): 389-96, 2002.
Article in English | MEDLINE | ID: mdl-11959401

ABSTRACT

Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF). Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity. In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis. IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord. Compared to respective age-matched normal subjects, CSF IMPase activity was unaltered in DS, DAT and MID. However, in normal volunteers there was a significant positive correlation between age and CSF IMPase activity. Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/enzymology , Down Syndrome/cerebrospinal fluid , Down Syndrome/enzymology , Phosphoric Monoester Hydrolases/cerebrospinal fluid , Acetylcholinesterase/cerebrospinal fluid , Adult , Age Factors , Aged , Aged, 80 and over , Analysis of Variance , Butyrylcholinesterase/cerebrospinal fluid , Enzyme Activation , Female , Humans , Male , Middle Aged , Observer Variation , Prospective Studies , Regression Analysis , Spinal Puncture/statistics & numerical data , Time Factors
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