Showing papers in "Annals of Neurology in 1991"

Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.

Abstract: We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.

The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography.

Abstract: We have studied regional cerebral blood flow changes in 6 patients after their recovery from a first hemiplegic stroke. All had a single well-defined hemispheric lesion and at least a brachial monoparesis that subsequently recovered. Each patient had 6 measurements of cerebral blood flow by positron tomography with 2 scans at rest, 2 during movement of fingers of the recovered hand, and 2 during movement of fingers of the normal hand. When the normal fingers were moved, regional cerebral blood flow increased significantly in contralateral primary sensorimotor cortex and in the ipsilateral cerebellar hemisphere. When the fingers of the recovered hand were moved, significant regional cerebral blood flow increases were observed in both contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres. Other regions, namely, insula, inferior parietal, and premotor cortex, were also bilaterally activated with movement of the recovered hand. We have also demonstrated, by using a new technique of image analysis, different functional connections between the thalamic nuclei and specific cortical and cerebellar regions during these movements. Our results suggest that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.

Cerebral hemodynamics in ischemic cerebrovascular disease.

Abstract: During the past decade, technological advances have made it possible to measure regional cerebral hemodynamics in individual patients. Studies performed with these techniques have demonstrated that the degree of carotid stenosis correlates poorly with the hemodynamic status of the ipsilateral cerebral circulation. The primary determinant of cerebral perfusion pressure and blood flow under these circumstances is the adequacy of collateral circulatory pathways. Since collateral circulation varies from patient to patient, there is no critical degree of carotid stenosis that consistently produces hemodynamic compromise of the cerebral circulation. It is, thus, time to abandon the concept of the hemodynamically significant carotid stenosis as it relates to the pathogenesis and treatment of cerebrovascular disease. Measurement of regional cerebral hemodynamics have provided new insight into the pathogenesis of tranisent ischemic attacks and generated some preliminary data on the prognostic and therapeutic importance of chronic reductions in regional cerebral perfusion pressure. Further investigations into the importance of hemodynamic factors in ischemic stroke can now be based on accurate assessment of cerebral (not carotid or vertebrobasilar) hemodynamics in the context of other coexisting epidemiological, clinical, hematological, and angiographic risk factors.

Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status.

Abstract: Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex, concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 38 times above normal in later-stage patients (Walter Reed stages 4 through 6) However, in patients with either clinically overt AIDS dementia complex, aseptic meningitis, opportunistic infections, or neoplasms, CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies, CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier, as measured by the CSF:serum albumin ratio, it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain, the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection

Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study.

Abstract: To identify those factors associated with cerebral hemorrhage among brains with cerebral amyloid angiopathy (CAA), we undertook a comparative postmortem histopathological study of amyloid-containing vessels in the brains of patients with and without hemorrhage. Those without hemorrhage were represented by the following two groups: (1) elderly patients from a large general hospital (n = 66; age range, 75–107 years) and (2) patients with various neuropsychiatric disorders (n = 70; age range, 27–96 years). CAA was found in 45% of thefirst group and in 54% of the second group. The findings in these patients were compared with those in 17 brains in which both CAA and cerebral hemorrhage were present. We found that CAA was more severe in the brains with cerebral hemorrhage than in those without, and that fibrinoid necrosis was seen only in the brains with cerebral hemorrhage (12 of the 17 brains). Microaneurysms occurred only in the presence of severe, rather than moderate or mild, CAA. Serial sections in 2 brains of patients with cerebral hemorrhage showed fibrinoid necrosis, microaneurysms, and vascular rupture in close association with the hemorrhage. In 2 patients, hemorrhage was precipitated by trauma, and in 1, it was secondary to metastatic carcinoma. The features of brains from patients with CAA that are most consistently related to cerebral hemorrhage are (1) a severe degree of CAA and (2) the presence of fibrinoid necrosis, with or without microaneurysms.

Magnetic resonance imaging–based volume studies in temporal lobe epilepsy: Pathological correlations

Abstract: We performed a prospective study correlating magnetic resonance imaging volume measurements of the hippocampal formation with histopathology in 24 patients with intractable partial epilepsy who subsequently underwent an anterior temporal lobectomy for their seizure disorder. Patients with mass lesions verified pathologically were excluded from this study. In 71% of patients, quantitative hippocampal formation atrophy correctly lateralized the temporal lobe of seizure origin; in 29%, the volume study was indeterminant. The severity of the pathological alterations in the hippocampus correlated with the hippocampal formation volume determination. Mesial temporal sclerosis was identified in the surgically excised temporal lobe in 15 patients. The magnetic resonance imaging volume studies indicated hippocampal atrophy in the temporal lobe resected in 14 of the 15 patients. Magnetic resonance imaging-based volume measurements of the hippocampal formation increase the diagnostic yield of magnetic resonance imaging scanning in patients with intractable partial epilepsy related to mesial temporal sclerosis.

Major differences in the dynamics of primary and secondary progressive multiple sclerosis.

Abstract: In patients with primary and secondary progressive multiple sclerosis (MS), major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (18.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials.

Neocortical damage during HIV infection

Abstract: Clinical and pathologicals evidence of subcortical central nervous system (CNS) damage is observed commonly in patients with human immunodeficiency virus (HIV) encephalitis. Whether other CNS regions are also affected has not been well studied. We report neocortical damage in patients with HIV encephalitis. Using quantitative techniques, we demonstrate statistically significant thinning of the neocortex, with a loss of large cortical neurons. Qualitative and quantitative assessments of neocortical neuropil reveal a loss of synaptic density and vacuolation of dendritic processes. Failure to demonstrate an association of these changes with the presence of HIV antigens suggests that neocortical damage may be an indirect effect of HIV infection of the CNS.

Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients.

Abstract: We studied 30 patients with partial epilepsy and a radiological or pathological diagnosis of localized neuronal migration disorders, with a view to surgical treatment. Eight patients had identifiable prenatal etiological factors. The frequency of complex partial, partial motor, and secondarily generalized seizures was approximately 70% each. Drop attacks were present in 27%: Their presence usually correlated with a lesion involving the central region. Partial motor or generalized convulsive status epilepticus occurred in 30%, and was most frequently associated with extensive structural abnormalities involving two or more lobes. A full-scale intelligence quotient of less than 80 was found in 44%. Magnetic resonance imaging (MRI) was superior to computed tomography for identification of the dysplastic cortical lesions. In one third, MRI showed only subcortical abnormalities. It did not allow distinction between true pachygyria, focal cortical dysplasia, or the forme fruste of tuberous sclerosis. The epileptogenic area was usually more extensive than the lesion; it was multilobar in more than 70% of patients. Of 26 surgically treated patients, a histological diagnosis of the type of neuronal migration disorder was possible in 22: 12 had focal cortical dysplasia and 10 the forme fruste of tuberous sclerosis. In the remaining 4, no definite histological diagnosis was made, since the maximally abnormal tissue could not be examined. In the latter, and in the 4 nonoperated patients, the diagnosis of neuronal migration disorder was based on imaging findings. The presence of the forme fruste of tuberous sclerosis correlated with delayed psychomotor development and more extensive epileptogenic areas.

Anti-tumor necrosis factor therapy abrogates autoimmune demyelination.

Abstract: To define a role for the cytokine tumor necrosis factor (TNF) in immune-mediated demyelination, the effect of anti-TNF antibody was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein-(MBP)-sensitized T lymphocytes, an animal model of the human disease multiple sclerosis (MS). In three separate experiments, no mouse sensitized for EAE and then treated with anti-TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease. Examination of CNS tissue from anti-TNF-treated animals showed no pathological changes. CNS tissue from control animals demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti-TNF therapy was inhibitory to encephalitogenic cells, preincubation of MBP-sensitized T lymphocytes with anti-TNF in vitro prior to injection into recipient mice was performed, and resulted in no diminution of their ability to transfer EAE. In addition, spleen cells from anti-TNF-treated mice were capable of serial transfer of EAE, similar to spleen cells from control animals. However, spleen cells from anti-TNF-treated mice did not produce TNF on stimulation with MBP or concanavalin A. This study showed that anti-TNF antibody can inhibit effectively the development of EAE by interfering with the effector, rather than the induction, phase of the disease. Anticytokine therapy may have important applications in the development of new therapeutic strategies for MS.

Frequency and distribution of Alzheimer's disease in Europe: A collaborative study of 1980–1990 prevalence findings

Abstract: We reanalyzed and compared current prevalence estimates of Alzheimer's disease in Europe. Studies characterized as follows qualified for comparison: dementia defined by the Diagnostic and Statistical Manual for Mental Disorders, 3rd edition, or equivalent criteria; Alzheimer's disease diagnosed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association or equivalent criteria; case-finding through direct individual examination; appropriate sample size; and inclusion of institutionalized persons. Of the 23 European surveys of dementia considered, six fulfilled the inclusion criteria. When age and sex were considered, there were no major geographic differences in the prevalence of Alzheimer's disease across Europe. Overall European prevalence (per 100 population) for the age groups 30 to 59, 60 to 69, 70 to 79, and 80 to 89 years was, respectively, 0.02, 0.3, 3.2, and 10.8. Prevalence increased exponentially with advancing age and, in some populations, was consistently higher in women. Prevalence remained stable over 15 years in one study.

Anatomical left-right asymmetry of language-related temporal cortex is different in left- and right-handers

Abstract: Asymmetry of the planum temporale, a language-related intrasylvian area on the superior temporal gyrus, is the most remarkable anatomical left-right asymmetry of the human brain. The in vivo application of magnetic resonance morphometry in 52 healthy volunteers (26 dextrals and 26 sinistrals) revealed that planum temporale asymmetry is correlated with hand dominance. Left-handers had a significantly lesser degree of leftward planum temporale asymmetry than right-handers. Thus, a structural-functional relation exists in cerebral asymmetry. The correlation is likely to reflect language representation. Because familial sinistrality influenced the anatomical pattern in left-handers and planum temporale asymmetry is already present in the newborn, prenatal factors must play an important role in the development of functional laterality.

Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging.

Abstract: The value of magnetic resonance imaging in the detection of hippocampal sclerosis has been controversial. We studied 10 patients aged 22.5 +/- 6.0 years with intractable temporal lobe epilepsy selected because of a history of a prolonged childhood convulsion, which is characteristic of a group of patients in whom hippocampal sclerosis is a constant finding. All 10 patients showed reduction in size of one hippocampus associated with increased signal intensity on T2-weighted magnetic resonance images. These changes were reliably detected on coronal spin-echo images, perpendicular to the long axis of the hippocampus. Appreciation of the normal imaging anatomy of the hippocampus allowed correct interpretation of the relative changes in signal intensities of the hippocampus and adjacent temporal horn on sequential echo images. The side of the abnormal hippocampus on magnetic resonance imaging accorded with the electroencephalographic localization in all 10 patients, and with the lateralization of the early convulsions in all 6 patients where this was known. Temporal lobectomy was performed in all 10 patients. Hippocampal sclerosis was confirmed in the 3 patients in whom hippocampal tissue was available for histological examination. The value of this technique was reinforced by the excellent postoperative results, with 80% being seizure free at a mean follow-up time of 33 +/- 4 months.

Anti-Ri: An antibody associated with paraneoplastic opsoclonus and breast cancer

Abstract: The serum and cerebrospinal fluid (CSF) of 8 women with ataxia, 6 of whom also had eye movement abnormalities believed to be opsoclonus, were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5, adenocarcinoma in an axillary lymph node in 1, and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5,000 to 1:320,000 in serum and from 1:2,000 to 1:16,000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40,000 and CSF titers, from 1:10 to 1:2,000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast, ovarian, or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.

Neuritic pathology and dementia in alzheimer's disease

Abstract: Previous studies of Alzheimer's disease (AD) have correlated the severity of dementia with either the number of senile plaques or neurofibrillary tangles. We used antibodies raised against amyloid beta/A4 protein of senile plaque cores and tau protein as well as thioflavine S and the Campbell-Switzer modification of the Hicks silver method to examine the hippocampal formation and five neocortical regions from 22 nondemented elderly control subjects and 34 demented patients with cerebral senile plaques and neurofibrillary tangles, without complicating disease processes. Ten control subjects (46%) had no beta/A4 protein deposition. Twelve control subjects (54%) had widespread beta/A4 protein deposition but no neocortical neuritic pathology. Of the 34 patients with AD-type changes, 27 (79%) had widespread senile plaques and neurofibrillary tangles, while 7 (21%) had neocortical senile plaques with few neurofibrillary tangles. All demented patients had widespread beta/A4 protein deposition and neocortical tau-immunoreactive, Hicks silver-positive dystrophic neurites. The neurites were found both free in the neuropil as well as surrounding senile plaques. Quantitative analysis showed that dystrophic neurites were significantly increased in patients with AD compared with control subjects and the number of dystrophic neurites and neurofibrillary tangles correlated with the clinical severity of dementia. Widespread cerebral beta/A4 protein deposition may be necessary but by itself is insufficient for the development of dementia in AD.

Mitochondrial oxidative phosphorylation defects in Parkinson's disease

Abstract: Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.

Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment.

Abstract: Twenty-six patients with focal or lateralized neuronal migration disorders and intractable partial epilepsy were treated surgically. Twenty-four had reliable follow-up ranging from 1 to 15 years (mean, 5.0). Pathologically, they fell into two categories: focal cortical dysplasia (12 patients) and forme fruste of tuberous sclerosis (8 patients). In the remaining 4 patients, the material was inadequate for histological analysis. Outcome regarding seizure control was assessed according to a classification most sensitive to variations in frequency of major attacks. Ten (42°) of the 24 patients achieved good or excellent outcome, 6(25°) had a worthwhile decrease in seizure frequency, and 8 (33°) had only discrete improvement. The variable most strongly correlated with surgical outcome was the amount of lesion removed. Seventy-seven percent of patients in whom a complete excision or excision of 50° or more of the lesion was accomplished achieved excellent or good surgical outcome. Conversely, no patient with less than 50° of the lesion removed attained the same result. There was no correlation between other clinical, radiological, or electrographic variables and outcome regarding seizure control. Specifically there was no significant correlation between the amount of excision of the epileptogenic area as judged by scalp electroencephalography and electrocorticography studies, and surgical outcome. In patients with neuronal migration disorders and intractable partial epilepsy, removal of the structural abnormality takes precedence over removal of epileptogenic tissue as the main surgical strategy to achieve seizure control.

Visual dysfunction in Alzheimer's disease: Relation to normal aging

Abstract: In patients with Alzheimer's disease (AD), compared with age-matched and young healthy control subjects, visual deficits in the following functions were observed: color, stereoacuity, contrast sensitivity, and backward masking (homogeneous and pattern). Critical flicker fusion thresholds were normal, relative to age-matched healthy subjects. For color, the majority of the errors were tritanomalous (blue axis). Color and stereoacuity deficits were unrelated to severity of dementia, in accordance with models of vision that describe these functions as modular rather than diffuse for cortical localization. Although contrast sensitivity was depressed throughout the frequency range in AD, more patients were impaired at low than at high spatial frequencies, contrasting with the observed normal aging pattern of high-frequency loss. Healthy elderly subjects showed depressed critical flicker fusion thresholds and reduced contrast sensitivity at high frequencies, relative to the young group; differences between these groups were not found for the other vision tests. A subset of the AD group received detailed neuro-ophthalmological examination, and no abnormalities were found. This finding, taken together with normal thresholds for critical flicker fusion, suggests that the widespread visual dysfunction reported here is more likely to be related to known pathological changes in primary visual and association cortex in AD than to changes in the retina or optic nerve.

Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history.

Abstract: Six patients with early, mild, relapsing-remitting multiple sclerosis were studied with monthly gadolinium-enhanced magnetic resonance imaging scans for 8 to 11 months. Numerous enhancing lesions were observed irrespective of clinical activity. Four of the 6 patients had one or more enhancing lesions present on each examination. The other 2 patients had enhancing lesions noted in 7 and 9 of 11 months. In contrast, only two clinical exacerbations were observed during the study period. Neither the exacerbations nor other changes in symptoms or signs correlated with occurrence of the enhancing lesions. Enhancement generally persisted for less than 1 month. The opening of the blood-brain barrier as reflected by gadolinium enhancement on magnetic resonance imaging may represent ongoing disease activity in patients with mild, relapsing-remitting multiple sclerosis who are clinically stable. The frequency of these lesions appears to be sufficient to use as an outcome measure in clinical trials testing clinical efficacy in patients with early, relapsing-remitting multiple sclerosis.

Hypertension in the elderly is associated with white matter lesions and cognitive decline.

Abstract: Forty-two elderly patients (mean age, 66.2 +/- 5.1 yr) with hypertension, treated for an average of 17.3 years (standard deviation, 10.3), and 42 control subjects (mean age, 66.5 +/- 4.8 yr), matched for age, sex, and level of education, were studied with regard to the detection of lesions in the cerebral white matter with magnetic resonance imaging (MRI), particularly with axial T2-weighted images. The assessment of the MRI scans was blinded. Ten hypertensive patients showed confluent lesions in the white matter, versus only 1 control subject (Chi-square test, p = 0.01). The presence of diffuse lesions of the white matter was related to age but not to the known duration of hypertension, nor to the presence of any other cardiovascular risk factors. Cognitive function was measured in 34 hypertensive patients and in 18 control subjects. Results of the Mini-Mental State Examination, the Stroop color-word test, Trailmaking test, and the visual subtest of the Wechsler Memory Scale were worse in patients with confluent lesions of the white matter; there was no difference in mental functioning between hypertensive patients and control subjects with normal white matter or with only small focal lesions. Our findings suggest that long-standing hypertension in some patients may cause not only strokes but also chronic end-organ damage of the brain in the form of demyelination of the white matter, with cognitive decline.

Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson's disease.

Abstract: We examined the substantia nigra of 8 patients with Parkinson's disease immunohistochemically using antisera against complexes I, II, III, and IV of the mitochondrial electron transport system. In the patients with Parkinson's disease, a fair proportion of the nigral neurons showed reduced staining against the complex I antibody. The proportion of the neurons with reduced staining ranged from 12.7 to 74.1% of the melanized nigral neurons. Although neurons with reduced immunostaining for complex I were also observed in control subjects, the proportion among the nigral neurons was significantly smaller than in parkinsonian patients. Staining for complexes III and IV appeared normal. Staining of substantia nigra for complex II was decreased in 3 parkinsonian patients. These results are consistent with our findings that there is a deletion of gene coding for the four subunits in the mitochondrial DNA located in the striata of parkinsonian patients.

The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys.

Abstract: Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).

Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome.

Abstract: The dopamine hypothesis for Tourette's syndrome proposes that the disorder is pathologically related either to an excessive amount of dopamine or to supersensitive receptors. To evaluate these proposals, pre- and postsynaptic markers of dopamine metabolism were measured in postmortem striatum from three adults with the diagnosis of Tourette's syndrome. Neuronal dopamine uptake carrier sites [( 3H]mazindol binding) were significantly increased in number over control values by 37% in the caudate and by 50% in the putamen. High-pressure liquid chromatographic assays of dopamine and its primary metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid, showed normal findings. D1 and D2 subtypes of dopaminergic receptors [( 3H]SCH 23390 and [3H]spiperone binding, respectively) showed only slight alterations, presumably due to treatment with neuroleptics. The concentration of adenosine 3',5'-monophosphate (cyclic AMP) in putamen was reduced by 23%. Our data support earlier proposals of a dopaminergic abnormality in TS, but suggest that the mechanism involves a significant alteration of uptake sites. We speculate that increases in carrier site binding indicate an enhanced dopamine innervation within the striatum.

Nerve growth factor prevents toxic neuropathy in mice

Abstract: Taxol is a promising new antitumor drug with therapeutic use that is limited by a toxic sensory neuropathy. Taxol is also cytotoxic to dorsal root ganglion neurons in vitro, but this effect is prevented by cotreatment with the trophic protein, nerve growth factor. We sought to develop an animal model and then to determine whether nerve growth factor can prevent taxol neuropathy in vivo. Administration of taxol to mice resulted in a profound sensory neuropathy characterized by decreases in dorsal root ganglion content of the peptide neurotransmitter, substance P, elevated threshold to thermally induced pain, and diminished amplitude of the compound action potential in the caudal nerve. Coadministration of nerve growth factor prevented all of these signs of neurotoxicity. These findings suggest that administration of nerve growth factor may prevent certain toxic sensory neuropathies.

Epileptogenic effect of hypoxia in the immature rodent brain

Abstract: The response to cerebral hypoxia/ischemia may be different in the neonate compared to other age groups. An in vivo model was developed in the rat to determine whether there are age-dependent differences in the effects of hypoxia on electroencephalographic (EEG) activity. EEG recordings were obtained from Long Evans hooded rats deprived of oxygen at five ages: postnatal days 5 to 7, 10 to 12, 15 to 17, 25 to 27, and 50 to 60. Oxygen concentration was varied from 0, 2, 3, and 4% between animals. EEGs were recorded in all animals before, during, and at 1 hour after exposure to the hypoxic condition and at 1 to 7 days afterward in a subset of animals. All animals were deprived of oxygen until the onset of apnea and bradycardia to 20 to 40% of baseline heart rate values. Hypoxia resulted in isoelectric EEG significantly more frequently in the animals deprived of oxygen at postnatal days 25 to 27 and 50 to 60 than in the younger age groups. A highly significant effect was that the animals deprived at postnatal days 5 to 17 revealed a high incidence of epileptiform EEG activity during hypoxia. In contrast, the older animals exhibited only rare isolated EEG spikes before reaching an isoelectric EEG. The severity of hypoxia-induced epileptiform EEG changes was highest in the animals subjected to moderately hypoxic conditions (3% and 4% oxygen) at postnatal days 10 to 12. Furthermore, epileptiform changes persisted for hours to days following prolonged episodes of hypoxia in the younger animals. This study demonstrates a unique response of the immature brain to exhibit epileptiform activity during hypoxia.

Percutaneous electrical stimulation of corticospinal pathways at the level of the pyramidal decussation in humans.

Abstract: Stimulation over the base of the skull can activate descending motor pathways to produce electromyographic (EMG) responses in muscles of the arm and leg. The evoked EMG responses were larger when the muscles were preactivated by a small voluntary contraction compared to when they were completely relaxed. The latency of these responses in preactivated muscles was approximately midway between that produced by electrical stimulation over the motor cortex, and by electrical stimulation over the cervical enlargements. With horizontally spaced electrodes, the latency difference between cortical and brainstem stimulation was 1.8 milliseconds in all muscles tested. The latency difference between cervical and brainstem stimulation was 3.9 milliseconds for the first dorsal interosseous and 2.6 milliseconds for tibialis anterior muscles. These values suggest that brainstem stimulation occurs at the level of the cervicomedullary junction. With vertically spaced electrodes in the midline, stimulation often occurs at a higher level. The EMG responses from brainstem stimulation differed from those following cortical stimulation in two ways: (1) They were simpler in form, and (2) their onset latency was the same in active as it was in relaxed muscles. This suggests that brainstem stimulation evoked a large descending motor volley in comparison with the multiple volleys that cortical stimulation can produce. Collision experiments between cortical and brainstem volleys indicated that the major part of the responses evoked by brainstem stimulation were conducted via the large-diameter component of the corticospinal tract.

Intracerebral hemorrhage: External validation and extension of a model for prediction of 30-day survival

Abstract: We report validation of a previously reported logistic regression model for predicting 30-day survival after supratentorial intracerebral hemorrhage using independent, prospectively collected data. The original model, using initial Glasgow Coma Scale score, hemorrhage size, and pulse pressure, accounted for mortality or survival at 30 days in 92% of patients in the Pilot Stroke Data Bank with a sensitivity of 0.84 and a specificity of 0.96. For external validation, the model was used to predict 30-day status for each patient in the Main Phase Stroke Data Bank for whom complete risk factor information was available. Overall, 90% of patients' outcomes were correctly predicted with a sensitivity of 0.85 and a specificity of 0.92. Two factors not collected in the Pilot Stroke Data Bank, hyperglycemia and intraventricular hemorrhage extension, were assessed to determine if they provided additional predictive information on 30-day mortality. Intraventricular hemorrhage extension contributed significant predictive information in a logistic regression, whereas hyperglycemia did not. The resulting four-factor model with an interaction term (intraventricular hemorrhage extension and Glasgow Coma Scale score) correctly classified the survival status of 94% of patients at 30 days. A more general outcome, death or failure to achieve a "good" Activities of Daily Living Score by one year, was analyzed with respect to the same four factors. The resulting model correctly classified 95% of the patients in the cohort.

MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex.

Abstract: MK-801 and ketamine are noncompetitive N-methyl-D-aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK-801 itself can damage neurons. Here we show that MK-801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72-immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0-mg/kg doses of MK-801 and disappears by 2 weeks. Based on these data, we propose: (1) MK-801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK-801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK-801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults.

Alterations of dopaminergic and noradrenergic innervations in motor cortex in Parkinson's disease.

Abstract: The motor areas of the cerebral cortex contain dense dopaminergic and noradrenergic innervation in humans. We looked for changes of these innervations in cases with Parkinson's disease (PD). The density of fibers immunolabeled with tyrosine hydroxylase or dopamine-beta-hydroxylase was evaluated in the primary motor, premotor, and prefrontal cortical regions in 6 cases with PD and 7 control cases. Reductions of both noradrenergic and dopaminergic cortical innervations were observed, with similar magnitudes of reduction found in the motor and prefrontal regions of the cortex. Depletion of noradrenergic innervation was diffuse, involving all cortical laminae. Depletion of dopaminergic innervation was laminar specific, with the most significant reductions in layers I and II; reductions in layers V and VI were either less marked (prefrontal cortex) or not detectable (primary motor). The results suggest the existence of two separate mesocortical dopaminergic systems in humans, with the one distributing to upper cortical layers being preferentially involved in PD.

A genetic study of idiopathic focal dystonias

Abstract: A genetic study of idiopathic focal dystonias was undertaken by examining 153 first-degree relatives of 40 index patients with torticollis (14 patients), other focal cranial dystonias (16 patients), and writer's cramp (10 patients). Nine relatives with dystonia were identified in 6 families; 8 of these had symptoms such as clumsiness or tremor, but none were aware of any dystonia. A further 4 relatives, now decreased, were affected by history. Overall, 25% of index patients had relatives with dystonia. The results of segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrance as a common cause for focal dystonia. Segregation ratios were not significantly different from those ratios observed in generalized or segmental dystonia in the United Kingdom, and it is possible that a single autosomal dominant gene mutation is responsible for inherited dystonia in the majority of patients irrespective of distribution or severity.