Cerebral Cortex Of Patients Research Articles

Voxel-wise assessment of progression of regional brain atrophy in relapsing-remitting multiple sclerosis

Objective To perform voxel-wise assessments of regional brain atrophy state and rate in subjects with relapsing–remitting (RR) multiple sclerosis (MS). Background Recently, attention has focused on defining the tissue compartments and regions within which brain atrophy occurs. These regional measures of brain volume changes may help to better define the nature of the pathology underlying MS. In this context, specific regional measures of grey matter (GM) volume changes can be obtained by using the voxel-based morphometry (VBM) approach. Methods Fifty-nine subjects with RR MS underwent conventional MRI at baseline and after a mean follow-up period of 3 years. Cross-sectionally, two VBM analyses (SPM-VBM, based on the Statistical Parametric Mapping software package, and FSL-VBM, based on the FMRIB Software Library tools) were performed to assess cortical GM volumes in RR MS patients compared to 25 age- and sex-matched normal controls (NC). Longitudinally, FSL-VBM and the regional extension of the SIENA method (SIENAr) were both used to assess regional brain atrophy rate in the RR MS patients and its relationship with increases in T 2-weighted white matter (WM) lesion volume over the follow-up period. Results Widespread decrease in cortical GM volume was found in the RR MS patients compared to NC. Both SPM-VBM and FSL-VBM showed similar involvement of cortical regions (frontal, temporal, parietal, occipital lobes and insula), with a close correlation between the numbers of significant voxels obtained with the two different procedures ( r = 0.73, p < 0.001). After 3-year follow-up, both FSL-VBM and SIENAr showed a further significant reduction in GM volume in the lateral frontal and parietal cortices, bilaterally. Regional volume changes also appeared significantly pronounced in correspondence to the increase in T 2-weighted WM lesion volume over the follow-up period. Conclusions By using different methodologies, we showed similar widespread tissue loss in the cerebral cortex of patients with RR MS. This brain tissue loss further progresses over time, particularly in the fronto-parietal cortex and seems to be partially dependent upon the increase of lesion load.

Inhibition of Ca2+‐dependent glutamate release from cerebral cortex synaptosomes of rats with experimental autoimmune encephalomyelitis

Several pathological studies have revealed a prominent involvement of the cerebral cortex in patients with multiple sclerosis (MS). In order to better understand the events that lead to the progressive neuronal dysfunction in MS, herein we explore the contribution of the glutamatergic release in cerebral cortex synaptosomes isolated from rats with experimental autoimmune encephalomyelitis, an animal model reproducing many features of MS. We found that the Ca(2+)-dependent but not the Ca(2+)-independent glutamate release induced by KCl and 4-aminopyridine was significantly decreased during the acute stage of the disease. This inhibited release coincides with the onset of the clinical signs and after 24 h tends to recover the level of the control animals. The results also showed an inhibition of the glutamate release stimulated by ionomycin. When the animals were totally recovered from clinical signs, the neurotransmitter release stimulated by the different inductors was similar to the controls. Examination of the cytosolic Ca(2+) using fura-2-acetoxymethyl ester revealed that the inhibition of glutamate release could not be attributed to a reduction in voltage-dependent Ca(2+) influx. However, this inhibition was concomitant with a lower phosphorylation of synapsin I at P-site1. Our results show that the inhibition observed on the Ca(2+)-dependent neurotransmitter release from cerebral cortex synaptosomes in experimental autoimmune encephalomyelitis is specific and correlates with the beginning of the clinical disease. Moreover, they suggest an alteration in the metabolism of proteins involved in the vesicular glutamate release more than a deregulation in the influx of cytosolic Ca(2+).

Morphometric Changes in the Episodic Memory Network and Tau Pathologic Features Correlate with Memory Performance in Patients with Mild Cognitive Impairment

Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI? Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19). Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein. The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

Cortical demyelination in PML and MS

To characterize pathologic changes in the cerebral cortex of patients with multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). Autopsy brain tissue was obtained from 13 patients with PML, 4 patients with MS, 2 patients with HIV encephalopathy, and 1 subject without neurologic pathology. Immunohistochemistry for myelin proteins, inflammatory cells, and neurofilaments was performed to evaluate the distribution of cortical lesions, their inflammatory activity, and neuritic pathology. Confocal microscopy was applied to examine pathologic changes in neurites in PML cortex. Leukocortical, intracortical, and subpial patterns of cortical demyelination were represented in MS brain tissue. In PML brain tissue intracortical and leukocortical but not subpial lesions were observed. Cortical lesions in PML and MS contained fewer inflammatory cells than demyelinated areas in the white matter. Neuritic pathology in cortical PML lesions was represented by dystrophic and transected neurites. Pathologic modifications in neuritic processes in PML were more evident in highly inflamed white matter than in gray matter areas of demyelination, reminiscent of previous reports of neuritic pathology in MS. JC virus-infected cells were associated with PML white matter, leukocortical and intracortical lesions. Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders.

Reduced brain glutamate in patients with Parkinson's disease

An understanding of the role played by glutamate (Glu) in idiopathic Parkinson's disease (PD) has remained somewhat elusive. Animal models of PD suggest that over-activity of Glu receptors complicates the motor symptoms of PD and that Glu blockade may be a pharmacologic target in PD, whereas patient autopsy studies have proved less convincing for changes in Glu. No previous 1H MRS patient studies have documented changes in glutamate. All but one of these previous studies were performed at 1.5 T. We performed 3 T 1H MRS of the posterior cingulate gyrus in 12 non-demented patients with PD and 12 age-matched, neurologically normal control participants. Glu, N-acetylaspartate (NAA) and choline-containing compounds (Cho) measured in reference to creatine + phosphocreatine (Cr) were determined from single-voxel proton MR spectra measured by PRESS at TE of 80 ms. The results show that the Glu/Cr ratio was reduced in patients with PD compared with controls (t = 2.54; P = 0.019), whereas no differences were observed in NAA/Cr or Cho/Cr ratios. These findings suggest that a reduction in Glu occurs in the cerebral cortex of patients with PD. (1)H MRS at 3 T should be investigated in future studies as a means of tracking the course of metabolic brain changes in association with progression of disease in patients with PD.

Cerebral Acetylcholinesterase Imaging: Development of the Radioprobes

Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [(11)C]MTHA or [(11)C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [(11)C]physostigmine, [(11)C]CP126,998 and 2-[(18)F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[(11)C]methylipiperidin-4-yl acetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [(18)F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.

Increased anisotropy in neonatal meningitis: an indicator of meningeal inflammation

Increased anisotropy in brain abscesses has been shown to be due to adhesion of inflammatory cells and is suggestive of an active inflammatory process. The objective of this study was to determine if similar changes occur in the pia-arachnoid on the surface of the cerebral cortex in patients with pyogenic meningitis, and if these changes regress following antibiotic therapy. Diffusion tensor imaging (DTI) was performed on 14 term neonates (mean age 13 days) with bacterial meningitis and 10 healthy age- and sex-matched controls. Regions of interest (ROIs) were placed on areas including the leptomeninges, the cerebral cortex and adjoining subcortical white matter for quantitation of mean fractional anisotropy (FA) and diffusivity (MD) values. Follow-up MRI was performed in five of the neonates in the patient group after 2 weeks of antibiotic treatment. FA and MD values were compared in patients before and after antibiotic treatment as well as with those in the healthy controls. Significantly higher FA values but no difference in MD values were observed in the patient group as compared to the healthy controls at both time points (before and after antibiotic treatment). Significantly decreased FA values in the frontal, occipital and temporal cortical regions were observed in patients following antibiotic treatment. DTI-derived FA may be of value in the noninvasive assessment of meningeal inflammatory activity and treatment response in neonates.

Cortical spreading depression: an adverse but treatable factor in intensive care?

The aetiology and management of secondary deterioration in patients with acute traumatic or ischaemic brain injury remain serious challenges for clinicians and also for basic neuroscientists. The occurrence of spreading depolarization events and some of their features in the cerebral cortex in patients with traumatic brain injury and aneurysmal subarachnoid haemorrhage, as documented in recent papers, represent a novel pathophysiological mechanism in this setting. The history and definitions of two critically different patterns of depolarization are reviewed on the basis of their physiology and pathophysiology, particularly the responses of the cerebral microcirculation to depolarization as seen in the laboratory. It is now becoming possible to conduct similar assessments in the brain-injured patient. Currently the recorded incidence of depolarization events in patients undergoing craniotomy for traumatic contusions is in the region of 50-60%, rising to 72% following major subarachnoid haemorrhage. Realization of the therapeutic potential of the new findings will depend on clear knowledge of the impact of the different patterns of depolarization on outcome. Meantime, current results call for even stricter attention during clinical management of acute brain injury to secondary factors such as body temperature and plasma glucose.

Cortical and thalamic fMRI responses in partial epilepsy with focal and bilateral synchronous spikes

Objective To determine the blood oxygen level-dependent (BOLD) responses to epileptic discharges in the thalamus and cerebral cortex in patients with partial epilepsy. Methods Among 64 tested patients, 40 had EEG spikes during scanning and were divided in two groups: unilateral or bilateral independent spikes (29 patients) and bilaterally synchronous spikes (11 patients). Each spike topography was analyzed separately, yielding 40 studies in the first group and 17 in the second. Results Forty-five percent of focal spike studies showed significant BOLD responses. Cortical activation (positive BOLD) represented the dominant response and had a better correlation with spike location than cortical deactivation (negative BOLD). In the second group, all patients had significant BOLD responses; they were more widespread compared to the first group, and deactivated areas were as important as activated regions. A thalamic response was seen in 12.5% of studies in the first group and 55% in the second. Conclusions The thalamus is involved in partial epilepsy during interictal discharges. This involvement and also cortical deactivation are more commonly seen with bilateral spikes than focal discharges. Significance These findings show evidence for a role for the thalamus and a more important role for inhibition in secondary bilateral synchrony.

Curvilinear T1 hyperintense lesions representing cortical necrosis after cerebral infarction

Curvilinear T1 hyperintense lesions in the cerebral cortex in patients with subacute infarction were investigated for: (1) the presence or absence of T2* hypointensity and (2) correlations with neuropathologic findings. Thirty-six consecutive patients with subacute to chronic embolic infarction, in whom curvilinear hyperintense lesions in the infarcted cortex were seen on T1-weighted images, underwent echo-planar gradient-echo (GRE-EPI) T2*-weighted imaging. GRE-EPI T2*-weighted imaging revealed no evidence of hemorrhage within the curvilinear T1 hyperintense lesions of the cerebral cortex in all of the patients. In 11 of the 36 patients, focal hypointense lesions were seen in the depth of infarcted gyri on GRE-EPI T2*-weighted images. In the remaining 25 patients, no T2* hypointensities were seen in the infarct zone. Pathological correlation was performed in a patient with middle cerebral artery infarction and curvilinear hyperintense lesions on postmortem T1-weighted images. In the autopsied brain, curvilinear T1 hyperintense lesions corresponded to necrosis of all the cortical layers on histological examination. These data suggest that curvilinear hyperintense lesions in the cerebral cortex on T1-weighted images during the subacute to chronic period of cerebral infarction may not represent hemorrhage.

Stimulation through electrodes implanted near the subthalamic nucleus activates projections to motor areas of cerebral cortex in patients with Parkinson's disease

High-frequency electrical stimulation through electrodes implanted in the subthalamic nucleus (STN) has been shown to reduce significantly the cardinal symptoms of Parkinson's disease (PD). Despite the success of this treatment, the mechanisms of action of stimulation are poorly understood. To elucidate further the mechanisms of action of deep brain stimulation and its effects on cortical activity, we recorded electroencephalographic potentials from 61 scalp-surface electrodes during low-frequency (5-10 Hz) bipolar stimulation in 11 patients with advanced PD (14 implanted electrodes were tested). In all electrodes tested, stimulation through at least one of the four contacts produced a medium-latency waveform with an average onset of 14 +/- 3 ms and peak at 23 +/- 4 ms. This potential typically increased in magnitude across contacts from ventral to dorsal. Within-subject comparisons of median nerve somatosensory evoked potentials demonstrated that the generator of the medium-latency potential was within the primary sensorimotor cortex or lateral premotor cortex ipsilateral to stimulation. The timing and topography of this potential were consistent with indirect activation of the cortex by excitation of pallido-thalamic axons that traverse the dorsal aspect of the STN. The potential evoked by stimulation through the contact used for optimal clinical effect was highly variable across electrodes and frequently different from the medium-latency potential described above, suggesting that the neuronal elements mediating the medium-latency potential were different from those that mediate the clinical effects.

The Structural and Functional Characteristics of the Perifocal Area of the Cerebral Cortex in Acute Brain Injury

The paper shows that the treatment of brain traumatic lesions is a topical problem. Moreover, the complications associated with the development of cerebral recompression play a particular role in the posttraumatic period. The purpose of the present study was to reveal the regularities of reorganization of cyto- and synaptoarchitectonics of different layers of the cerebral cortex in patients with cerebral recompression in the acute period of brain injury. Cerebral cortical biopsy specimens taken in 6 patients from the perifocal area (subdural hematoma and a contusion focus with intracerebral hematoma) were examined. The results were statistically processed, by using a package of the applied programs «StatSoft Statistica 6.0». Based on the findings, the authors suggest that it is necessary to make an early diagnosis and a complex intervention that promotes the improvement of the ultimate results of treatment.

Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor

Deposition of amyloid-β, the fibrillogenic product of the cell surface protein AβPP (amyloid-β protein precursor), occurs in the cerebral cortex of patients with Dementia with Lewy bodies (DLB). Amyloid deposition, basically in the form of senile plaques, occurs not only in the common form (DLBc), which is defined by changes consistent with diffuse Lewy body disease accompanied by Alzheimer's disease (AD), but also in the pure form (DLBp), in which neurofibrillary tangles are absent. The present study analyses the expression of AβPP mRNA isoforms with (AβPP751 and AβPP770) and without (AβPP695) the Kunitz-type serine protease inhibitor (KPI) domain, in the cerebral cortex in DLBc ( n = 4), DLBp ( n = 4), Parkinson's disease (PD, n = 5), AD ( n = 3 stages I–IIA, and n = 4 stage VC of Braak and Braak), amyloid angiopathy (AA, n = 2) and progressive supranuclear palsy (PSP, n = 4) compared with age-matched controls ( n = 6). For this purpose, TaqMan RT-PCR assay was used on frozen post-mortem samples of the frontal cortex (area 8) obtained with short post-mortem delays (8.29 ± 4.57 h) and strict RNA preservation (A 260/280 of 1.78 ± 0.15). A 3.66-fold, 6.67-fold, 4.28-fold and 5.24-fold increases, in the (AβPP751 + AβPP770)/AβPP695 mRNA ratio were found in DLBc, DLBp, AD stage VC and AA, respectively, when compared with controls. No modifications in the ratio were found in PD, AD stage I–IIA and PSP. These findings suggest that alternative splicing of the AβPP mRNA may play a role in βA4 amyloidogenesis in DLBp, DLBc, AD stage VC and Amyloid angiopathy.

Association between schizophrenia and the syntaxin 1A gene

Background Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia. Methods Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. Results In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] χ 2 = 5.898; df = 1; p = .015, family-based association test [FBAT] z = 2.280, p = .023). When the results for the TDT and case-control analyses were combined, the association was stronger ( n = 430; z c = 2.859; p = .004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP. Conclusions The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.

Acetylcholinesterase Imaging: Its Use in Therapy Evaluation and Drug Design

Several cholinesterase (ChE) inhibitors have been labeled with carbon-11 for visualizing binding sites on acetylcholinesterase (AChE) by positron emission tomography (PET). Following intravenous injection of 1,2,3,4-tetrahydro-9-[(11)C]methylaminoacridine or [(11)C]donepezil, however, the radioactivity distribution does not reflect the regional distribution of AChE in the brain of animals, probably because these compounds have high non-specific binding and/or other specific binding sites in vivo in the brain. PET studies with [(11)C]physostigmine and [(11)C]CP-126,998 in the brain of healthy subjects have shown a radioactivity distribution corresponding to the regional distribution of AChE activity measured in postmortem human brains. These radiotracers may be useful for measuring the occupancy of binding sites on AChE by AChE inhibitors, and for investigating the cerebral pharmacokinetics of such therapeutic drugs. An alternative approach to map AChE is the use of acetylcholine analogue substrates. We have developed N-methylpiperidinyl esters labeled with carbon-11 for quantitative measurement of AChE activity. Currently, two N-[(11)C]methylpiperidine esters, N-[(11)C]methylipiperidin-4-ylacetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P or PMP), have been used for clinical studies of Alzheimer's disease and other neurodegenerative diseases. Both [(11)C]MP4A- and [(11)C]MP4P-PET have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with Alzheimer's disease (AD) but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. AChE imaging should prove useful for therapeutic monitoring of the effects of ChE inhibitors, including determination of the appropriate clinical doses of newly developed compounds, and can thus prompt the development of novel drugs targeting AChE.

Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson's disease during subthalamic stimulation

Motor symptoms of Parkinson's disease (PD) are substantially improved by bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN). Altered cerebral blood flow (CBF) in a network of frontal cortical and subcortical structures has been reported in numerous studies of patients undergoing subthalamic stimulation. However, CBF is a controversial indicator of brain activation because measures of blood flow bear a variable relation to measures of brain work and energy metabolism. We hypothesized that STN stimulation would alter the rate of oxygen consumption (CMRO 2) in cerebral cortical areas in proportion to previously reported changes in CBF in patients undergoing stimulation at rest. We used quantitative PET to map CMRO 2 in brain of seven patients with Parkinson's disease, first in a baseline condition with pause of stimulation and medication for a period of 12 h, and again after 4 h of stimulation. Comparison of these two conditions revealed activation of CMRO 2 in the cerebellum, and in specific posterior neocortical regions, most notably in the left lingual gyrus and in the right lateral occipitotemporal gyrus, both of which latter regions are linked to higher-order visual processing. CMRO 2 was unaffected in the frontal cortex. Thus, the present findings do not support the original hypothesis, but suggest that STN stimulation increases energy metabolism in the posterior cerebral cortex, especially in regions involved in perception of movement and the direction of movement to visual cues.

Terminology and classification of the cortical dysplasias.

There have been difficulties in achieving a uniform terminology in the literature regarding issues of classification with respect to focal cortical dysplasias (FCDs) associated with epilepsy. S: To review and refine the current terminology and classification issues of potential clinical relevance to epileptologists, neuroradiologists, and neuropathologists dealing with FCD. A panel discussion of epileptologists, neuropathologists, and neuroradiologists with special expertise in FCD was held. The panel proposed 1) a specific terminology for the different types of abnormal cells encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the different histopathologic abnormalities usually subsumed under the term "microdysgenesis," and suggested that this terminology be abandoned; and 3) a more detailed yet straightforward classification of the various histopathologic features that usually are included under the heterogeneous term of "focal cortical dysplasia." The panel hopes that these proposals will stimulate the debate toward more specific clinical, imaging, histopathologic, and prognostic correlations in patients with FCD associated with epilepsy.

A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and Translocation

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and betaA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.

Magnetic resonance spectroscopy of cerebral cortex is normal in hereditary hyperekplexia due to mutations in the GLRA1 gene.

Excessive startling and stiffness in hereditary hyperekplexia has been attributed to lack of inhibition at either the cortical or brainstem level. Six patients with hereditary hyperekplexia (HH) and a confirmed mutation in the gene encoding the alpha(1) subunit of the glycine receptor (GLRA1) underwent single voxel (1)H magnetic resonance spectroscopy (MRS) of the brainstem and an area of frontal cortex and white matter using a method that allows absolute quantification of metabolites. The results of MRS were within normal limits, although there was a tendency for the neuronal marker N-acetyl aspartate to be reduced in the brainstem of patients compared with that in controls. Thus, we found no evidence to support a deficit in the cerebral cortex in patients with hereditary hyperekplexia due to mutations in the GLRA1 gene.

Increased Density of Neurons Containing NADPH Diaphorase and Nitric Oxide Synthase in the Cerebral Cortex of Patients with HIV-1 Infection and Drug Abuse

To determine whether nitrogen monoxide (nitric oxide; NO) synthase (NOS) and NADPH diaphorase (NDP) co-containing cerebrocortical neurons (NOSN) neurons are affected in patients infected with human immunodeficiency virus type 1 (HIV-1) with and without associated intake of drugs of abuse, we examined the temporal neocortex of 24 individuals: 12 HIV-1 positive (including 3 drug users, 9 non-drug users) and 12 HIV-1 negative (including 6 drug users, and 6 non-drug users). Histochemical labeling for NDP-an enzymatic domain co-expressed in the NOS enzyme-was employed to visualize NOSN. Drug abuse and HIV-1 infection cause independently an increase in NOSN density, but combined they result in up to a 38-fold increase in NOSN density, suggesting that the combination of these factors induces NOS expression powerfully in neurons that normally do not synthesize NDP/NOS. This is associated with an increase in the proportion of NOSN displaying dystrophic changes, indicating that NOSN undergo massive degeneration in association with NOS synthesis induction. The increase in density of NOSN in HIV-1 infected drug abusers may be among the important sources of NO mediating cerebrocortical dysfunction, and the degeneration of NOS-containing local circuit neurons in patients with HIV-1 infection or drug abuse may underlie in part their neuropsychiatric manifestations.