Increased mast cell degranulation within thalamus in early pre-lesion stages of an experimental model of Wernicke's encephalopathy.

A large increase in the number and percentage of degranulating mast cells was observed within thalamus of rats after 6-7 days of thiamine deficiency (TD). No mast cells were detected in the inferior olivary and lateral vestibular nuclei, which are also severely damaged by TD. After 11-12 days of TD, the number of ED2 immunopositive macrophages increased in thalamus. In the brainstem nuclei, an increase in the number of macrophages occurred much earlier in treatment (i.e. day 6). An increase in GFAP-positive astrocytes within thalamus occurred after the changes in mast cells and prior to the increase in macrophages. In brainstem, reactive astrocytes appeared along with the increase in macrophages. These data suggest that mast cell degranulation is a very early response induced by TD, and the resultant release of cytokines and other chemical mediators may play critical roles in both the early vascular damage and eventual tissue destruction within thalamus, but not within brainstem. These results also suggest that macrophages and reactive astrocytes may play more direct roles in the pathogenesis of brainstem lesions.

Excitotoxic cytopathology, progression, and reversibility of thiamine deficiency-induced diencephalic lesions.

The present study examined the cytopathological changes within diencephalon of a rat model of Wernicke's encephalopathy and determined whether administration of thiamine at various intervals after onset of neurological signs can arrest or reverse the cytopathological process. Electron microscopic examination of the brains from animals sacrificed at four progressively severe stages of pyrithiamine-induced thiamine deficiency (PTD) revealed neurocytopathological changes identical to those that have been described in glutamate-induced excitotoxic lesions. These degenerative changes occurred in gelatinosus (Ge) and anteroventral ventrolateral (AVVL) nuclei at an early symptomatic stage and in the ventroposterolateral (VPL), ventroposteromedial (VPM), and ventrolateral (VL) nuclei at slightly later stages of PTD. Light microscopic evaluation of separate groups of PTD rats administered thiamine at each of the same four neurologic stages and allowed to recover for 1 week demonstrated that thiamine treatment is more effective when administered at earlier stages. However, Ge, AVVL, and VPL nuclei sustain severe damage even when thiamine is administered prior to acute neurologic signs. Furthermore, pathologic changes in the mammillary and several midline intralaminar nuclei begin after thiamine administration and reinstitution of thiamine-replete diet to animals in more severe stages of thiamine deficiency. These and other recent findings suggest that excitotoxic and possibly apoptotic mechanisms may mediate neuronal degeneration in the PTD rat model of Wernicke's encephalopathy, and that multiple factors conducive to excitotoxicity may act in concert to produce this syndrome.

Cerebrospinal fluid levels of angiotensin-converting enzyme, acetylcholinesterase, and dopamine metabolites in dementia associated with Alzheimer's disease and Parkinson's disease: a correlative study.

Mean levels of the two hydrolases angiotensin-converting enzyme (ACE) and acetylcholinesterase (AChE), the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and total protein concentration were examined in cerebrospinal fluid (CSF) samples from a group of patients with dementia of the Alzheimer's type, a group of comparably demented patients with Parkinson's disease, and a neurologically healthy elderly control group. Both pathological groups exhibited a significant decrease in the mean levels of ACE activity and DOPAC per milliliter and were distinguishable from one another based on mean CSH HVA levels. Unlike the Parkinson's disease group, whose mean concentration of HVA was lower than, but not significantly different from that of the control group, the mean HVA concentration of the Alzheimer's disease group was significantly elevated. In contrast, comparisons of the mean CSF AChE activity (expressed per milliliter or per milligram of protein) and CSF total protein concentration did not reveal significant differences for any of the groups. Independent of CSF protein concentration, ACE activity per milliliter exhibited a positive correlation with AChE activity per milliliter within the control and Parkinson's disease groups, whereas a statistically significant correlation for these CSF hydrolases was not observed within the Alzheimer's disease group. Thus, the CSF profiles for patients with mild dementias associated with Alzheimer's or Parkinson's disease differed by at least two neurochemical criteria. Based on the levels of ACE activity, DOPAC, and HVA per milliliter of CSF, two discriminant functions were derived and resulted in the correct classification of 71% of all subjects (n = 38) into Alzheimer's disease, Parkinson's disease, and neurologically healthy control groups.

Effects of NBm lesions on T-maze performance and thalamic biochemistry.

Fisher 344 rats underwent bilateral nucleus basalis magnocellularis (NBm) lesioning followed by testing in a delayed nonmatching-to-sample T-maze task. Both lesion and control animals acquired the task although the NBm animals were mildly impaired on acquisition and on trials to criterion. Increasing the delay reduced accuracy of performance equally in both groups. The NBm lesion did not alter the level of several thalamic amino acids. These data indicate that NBm lesioning does not produce a significant impairment in working or reference memory in this task and supports the hypothesis that NBm lesioning impairs attention.

Learning and memory in rape victims with posttraumatic stress disorder.

OBJECTIVE: Studies have shown memory deficits among combat veterans with posttraumatic stress disorder (PTSD); however, high rates of comorbid conditions, including alcoholism, make it difficult to definitively associate these findings with the PTSD diagnosis. In this study the authors examined memory functioning among rape survivors without alcoholism or substance abuse but with PTSD. METHOD: Rape victims with (N = 15) and without (N = 16) PTSD were compared to age- and education-matched nontraumatized comparison subjects (N = 16) on measures of learning and memory. RESULTS: The subjects with PTSD performed significantly worse than the other groups on delayed free recall. The deficits were ameliorated by cueing and recognition testing. CONCLUSIONS: Recall deficits in noncombat PTSD patients strengthen the theory that memory deficits are associated with the PTSD diagnosis. The deficits were mild and were not attributable to comorbid depression, anxiety, or substance abuse.

Serotoninergic system in dementia of the Alzheimer type. Abnormal forms of 5-hydroxytryptophan and serotonin in cerebrospinal fluid.

Serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 14 patients with dementia of the Alzheimer type (DAT) and in nine controls by high-performance liquid chromatography with a novel multisensor coulometric detection system. Concentrations of both 5-HT and 5-HIAA detected by this system were lower than the concentrations obtained using conventional amperometric detection. This difference was caused by coelution of compounds that could be resolved from 5-HT and 5-HIAA by the multisensor coulometric system. One of the coelution compounds, observed in DAT but not in control CSF, behaved like a partially oxidized 5-HT. A compound behaving like partially oxidized 5-HTP was also observed in DAT CSF. Concentrations of 5-HTP, 5-HT, and 5-HIAA were lower in DAT CSF than in a corresponding fraction of control CSF. These results indicate involvement of the serotoninergic system in DAT and might lead to development of a diagnostic test for DAT.

Parkinson's disease. The possible relationship of laterality to dementia and neurochemical findings.

We examined the relationship of disease laterality to neuropsychological and neurochemical features in patients with idiopathic Parkinson's disease (PD). We tested patients with PD, patients with Alzheimer's type of senile dementia, and a control group neuropsychologically, and we determined their CSF levels of homovanillic acid, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindolacetic acid, serotonin, and acetylcholinesterase. The patients with PD were divided into two groups depending on the side of the body with greater disease involvement. Both parkinsonian groups, those more affected on the left (group L) and those more affected on the right (group R), were otherwise similar in all other clinical and historical features. Group L patients showed greater neuropsychological impairments than group R patients. Group L also had significantly higher CSF levels of homovanillic acid and acetylcholinesterase than group R. These findings of neuropsychological and neurochemical differences between groups L and R suggest functional or anatomic asymmetries of dopaminergic systems in the CNS.

Neurochemical pathology in Korsakoff's psychosis: implications for other cognitive disorders.

There seems to be an anatomic correspondence between pathways of monoamine-containing neurons and the brainstem and diencephalic lesions associated with Korsakoff's psychosis. In 25 patients with Korsakoff's disease, we found that CSF levels of metabolites of norepinephrine, dopamine, and serotonin were significantly lower than in controls. Norepinephrine metabolite levels were reduced more consistently and extensively than those of dopamine and serotonin. The 25 patients had circumscribed cognitive deficits, but were not demented. We argue that norepinephrine-containing neurons are selectively damaged in Korsakoff's psychosis and that lesions of brain monoamine-containing neurons cause specific cognitive impairments, not global dementia.

Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies.

We measured the concentrations of the monoamines, their precursors, and their metabolites, and the activity of choline acetyltransferase (ChAT) in basal ganglia and cortical regions of postmortem brains from cases with histologically verified pure Alzheimer's disease (AD), AD with diffusely distributed Lewy bodies (Lewy body variant [LBV]), and normal controls. Dopamine and homovanillic acid (HVA) were severely depleted in basal ganglia of the LBV cases but were not significantly altered in pure AD cases; tyrosine hydroxylase levels in putamen were also significantly reduced in LBV but not AD cases. These reductions in basal ganglia dopamine and HVA suggest that LBV cases have a level of dopamine depletion similar to Parkinson's disease (PD). Additionally, ChAT activity in caudate and norepinephrine concentration in putamen were significantly reduced in the LBV group, which may have contributed to the absence of resting tremor and the milder presentation of parkinsonian features in this group compared with classic PD. In frontal, parietal, and temporal cortex, activity of ChAT in the LBV group was significantly reduced compared with controls and lower than in pure AD.

Somatostatin is increased in the nucleus accumbens in Huntington's disease.

Concentrations of somatostatin-like immunoreactivity (SLI) are elevated in the basal ganglia in Huntington's disease. The present study confirms these findings and, in addition, shows that concentrations of SLI are significantly elevated in the nucleus accumbens (4.04 +/- 0.66 versus 1.69 +/- 0.21 ng/mg protein in controls). This area is relatively spared pathologically and shows little atrophy in Huntington's disease. Since many patients with Huntington's disease are treated with haloperidol, we studied the effects of this drug in rats. There was a dose-dependent reduction of SLI in striatum, parietal cortex, and hippocampus. The elevated concentrations of SLI in the basal ganglia in Huntington's disease, therefore, do not appear to result from haloperidol therapy.

Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism.

We studied a 68-year-old man who died after 13 years of progressive dementia, rigidity, bradykinesia, mild tremor, stooped posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of eyelid opening, anarthria, aphonia, and incontinence. At autopsy, he had generalized brain atrophy with large deposits of iron pigment in the globus pallidus, caudate, and substantia nigra. Axonal spheroids were found in the globus pallidus, substantia nigra, medulla, and spinal cord. The neurochemical analysis of the brain revealed marked loss of dopamine in the nigral-striatal areas, with relative preservation of dopamine in the limbic areas. This is the oldest case of familial Hallervorden-Spatz disease reported and the first with neurochemical analysis of the brain.

Multimodal sensory discrimination deficits in Korsakoff's psychosis.

A consistent impairment in odor identification was observed among a group of 21 amnesic patients, diagnosed as having Korsakoff's psychosis. In a subsequent study of eight Korsakoff and matched alcoholic control subjects, a comparable olfactory deficit was again demonstrated, as well as impairment in color discrimination and auditory perception. No such deficit was observed for a picture identification task designed to control for the non-sensory demands of the olfactory test. Stepwise multiple regression analysis showed a significant correlation between odor identification scores and the concentration of the primary metabolite of norepinephrine in lumbar cerebrospinal fluid. The data demonstrate a consistent coincidence between memory impairment and deficient sensory perception among patients with Korsakoff's psychosis.

Chromogranin A immunoreactivity in human cerebrospinal fluid: properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease.

Although measurement of chromogranin A in the bloodstream is of value in sympathoadrenal investigations, little is systematically known about chromogranin A in cerebrospinal fluid, despite substantial knowledge about its occurrence and distribution in brain. We therefore applied a homologous human chromogranin A radioimmunoassay to cerebrospinal fluid, in order to evaluate the properties and stability of cerebrospinal fluid chomogranin A, as well as its relationship to central noradrenergic neuronal activity, to peripheral (plasma) chromogranin A, and to disease states such as hypertension, renal failure and Parkinsonism. Authentic, physically stable chromogranin A immunoreactivity was found in cerebrospinal fluid (at 37-146 ng/ml; mean, 87.0 +/- 6.0 ng/ml in healthy subjects), and several lines of evidence (including 3.39 +/- 0.27-fold higher chromogranin A in cerebrospinal fluid than in plasma) indicated that it originated from a local central nervous system source, rather than the periphery. Cerebrospinal fluid chromogranin A values were not influenced by administration of effective antihypertensive doses of clonidine or propranolol, and were not related to the cerebrospinal fluid concentrations of norepinephrine, methoxyhydroxyphenylglycol, or dopamine-beta-hydroxylase; thus, cerebrospinal fluid chromogranin A was not closely linked to biochemical or pharmacologic indices of central noradrenergic neuronal activity. Cerebrospinal fluid chromogranin A was not changed (P > 0.1) in essential hypertension (84.2 +/- 14.0 ng/ml) or renal failure (72.2 +/- 13.4 ng/ml), despite a marked (7.1-fold; P < 0.001) increase in plasma chromogranin A in renal failure, and a modest (1.5-fold; P = 0.004) increase in plasma chromogranin A in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid neurotransmitter metabolites in neurologically normal infants and children.

Significant inverse correlations with age were observed for free 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) concentrations in CSF from 75 neurologically normal newborns, infants, and children aged 1 day to 10 years. The concentration of free MHPG decreased rapidly in early neonatal life and was reduced to near adult levels by 8 to 9 months of age. Adult levels of 5-HIAA were observed at about 4 years of age whereas HVA concentrations were still above adult levels at 10 years of age. Data from 0- to 1-month-old premature (28 to 32 weeks of gestation) and full-term (37 weeks of gestation) infants revealed marked changes in HVA and 5-HIAA concentrations which were related to postconceptional rather than postnatal age. This study demonstrates a previously undetected age effect on CSF MHPG concentration during the neonatal period and provides valuable normal data that are necessary for the interpretation of CSF monoamine metabolites in infants and children with hyperphenylalaninemia and other neurologic disease involving monoamine neurotransmitters.

Effects of lesions of thalamic intralaminar and midline nuclei and internal medullary lamina on spatial memory and object discrimination.

Male Sprague-Dawley rats received either radiofrequency lesions of the lateral internal medullary lamina (IML) or ibotenic acid lesions of the lateral intralaminar nuclei (ILN) and midline nuclei (MLN) or sham treatment. Neither lesion group was impaired in the retention of 3 object pair discriminations acquired before surgery nor in the acquisition of a new object pair after surgery. Rats with ILN, but not IML, lesions were impaired in acquiring an initial and 5 subsequent hidden platform locations in a water maze task. These results suggest that damage to both ILN and MLN are needed to produce spatial learning deficits and that extensive damage to the IML or ILN has no detectable effects on retrograde or anterograde memory of object discriminations.

Analysis of aversively conditioned learning and memory in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were trained on tasks motivated by escape from mild footshock. On postmortem examination, the PTD model showed two consistent lesions: a bilaterally symmetrical lesion of the medial thalamus, which was centered on the internal medullary lamina (IML), and a lesion centered on the medial mammillary nuclei. PTD rats with IML lesions were impaired in learning a spatial nonmatching-to-sample (NMTS) task that was mastered without error by controls and PTD animals without IML lesions. These same animals were able to perform as well as controls on discrimination tasks based on either place or visual (light-dark) cues, although they made more errors than controls in reaching criterion in the initial place discrimination problem. These findings are consistent with findings from appetitively motivated tasks that PTD rats with IML lesions have an impaired capacity for working memory but not for reference memory.

Impairment of olfactory, auditory, and spatial serial reversal learning in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were compared with controls for spatial, auditory, and olfactory serial reversal learning (SRL); spatial matching to sample (MTS); auditory go-no-go discrimination; and open-field exploration. PTD rats made more errors reaching criterion for SRL in all modalities but showed normal transfer effects between problems. PTD rats were also impaired in learning the go-no-go and MTS tasks and showed consistent alterations in exploratory activity. It is argued that the PTD rat, like human Korsakoff patients, have impairments of learning and memory (but spared capacity for reference memory) that extend across sensory modalities. Postmortem analyses showed normal indices of cortical cholinergic, noradrenergic, dopaminergic, and serotonergic function and consistent bilateral lesions of the thalamus, which were centered on the internal medullary lamina, and the medial mammillary nucleus.

Independent effects of age and nucleus basalis magnocellularis lesion: maze learning, cortical neurochemistry, and morphometry.

The effects of age and lesion of the cholinergic nucleus basalis magnocellularis (NBm) were assessed behaviorally, morphologically, and biochemically. Groups consisted of rats lesioned 1 month before testing, rats lesioned 13 months before testing, and their respective age-matched controls. Both age and lesion independently induced behavioral deficits in performance on two water maze tasks. The combined effect of these two factors produced behavioral deficits equal to the sum of the individual impairments. NBm lesion produced a 28% decrease in anterior cortical choline acetyltransferase activity and a 20% decrease in synaptophysin immunoreactivity in the neocortex that was stable over a 12-month period. Neither neuritic plaque nor neurofibrillary-tanglelike structures were found in the brains of 18-month-old control rats, nor were they found in NBm-lesioned rats examined 15 months postlesion. There was an age-related decrease in homovanillic acid levels in both control and NBm groups, which suggests a decrease in dopamine turnover. These results show a lack of biochemical and behavioral recovery after NBm lesion and suggest that the effects of age on behavior are independent of NBm-cortical dysfunction.

Memory effect of DL-threo-3,4-dihydroxyphenylserine (DOPS) in human Korsakoff's disease.

A group of amnesic patients with Korsakoff's disease were treated with a single 1 g dose of DL-threo-3,4-dihydroxyphenylserine (DOPS) and placebo (lactose) in a double-blind crossover study. Three hours following administration, patients were given a battery of psychometric tests to determine the effects of the treatment on memory functions. Administration of DOPS had a significant effect on performance on the Memory Passages test but not on any of the other measures of memory. The effect of DOPS on Memory Passages is similar to the response observed following administration of clonidine in Korsakoff patients. Blood pressure and pulse, measured before and every 2 h after treatment, were unaffected by DOPS.

A corticosteroid/dopamine hypothesis for psychotic depression and related states.

In recent years, considerable data have emerged that psychotic (delusional) depression is characterized by pronounced increases in hypothalamic-pituitary-adrenal (HPA) axis activity and positive responses to combined treatment with tricyclic antidepressants and antipsychotic (dopamine-blocking) agents. Recently, a number of observations in several species, including man, point to glucocorticoids' increasing dopamine activity in a variety of tissues and this effect is particularly marked in rat brain mesolimbic dopamine systems. We propose that glucocorticoids' enhancement of dopaminergic activity may explain the development of psychosis/delusions in the context of the depressive episode. Data in support of the hypothesis are presented and the identification of possible enzymatic risk factors are discussed. These interactions also have implications for understanding the biology of corticosteroid-induced psychoses in medical patients and some of the psychiatric complications of Cushing's Disease.