Wernicke's encephalopathy: an excitotoxicity hypothesis.

Thiamine deficiency is a recognized cause of Wernicke's encephalopathy (WE), a condition in which small necrotic lesions are found in close proximity to the third and fourth ventricles and the Sylvian aqueduct. Although the neuropathology of WE is well-established, the pathogenic mechanisms that determine the formation and distribution of brain lesions identified with this illness are not understood. It is proposed here that glutamate neurotoxicity causes the brain lesions in WE. Glutamic acid decarboxylase (GAD), an enzyme mainly confined to the central nervous system, protects most regions of the brain from glutamate that accumulates when the activity of alpha-ketoglutarate dehydrogenase, a thiamine-dependent enzyme complex, is reduced. During severe thiamine deficiency, glutamate accumulates in GAD-free peripheral tissues and reaches a concentration in blood at which it passes through circumventricular organs into the cerebral ventricles or contiguous brain and finally diffuses into the extracellular space of proximate diencephalic and brain stem tissues. Extracellular glutamate eventually reaches neurotoxic levels in those tissues and causes the characteristic lesions of WE.

Glutamate: its role in learning, memory, and the aging brain.

L-Glutamate is the most abundant of a group of endogenous amino acids in the mammalian central nervous system which presumably function as excitatory neurotransmitters and under abnormal conditions may behave as neurotoxins. As neurotransmitters, these compounds are thought to play an important role in functions of learning and memory. As neurotoxins, they are believed to be involved in the pathogenesis of a variety of neurodegenerative disorders in which cognition is impaired. Moreover, brain structures which are considered anatomical substrata for learning and memory may be particularly vulnerable to the neurotoxic actions of these excitatory amino acids, especially in the elderly who are also the segment of the population most susceptible to impairments of mnemonic function. This paper is a review of data concerning the role of excitatory amino acids in the processes of learning and memory and in the pathogenesis and treatment of disorders thereof.

Cholinergic function in the aged brain: implications for treatment of memory impairments associated with aging.

The cholinergic hypothesis of impaired memory in Alzheimer's disease has stimulated interest in cholinergic function of the brain in relation to the more common and less serious impairments of memory associated with normal (non-disease) aging. Unlike Alzheimer's disease, it is not clear whether normal aging results in a loss of cholinergic innervation to cerebral cortex and hippocampus, but prevailing evidence suggests that certain aspects of brain cholinergic function are diminished with advancing age. Human and animal data on the effects of aging on cholinergic systems of the brain are reviewed and are discussed in connection with the role these effects may play in the etiology and treatment of the learning and memory impairments associated with aging.

Treatment of age-associated memory impairment with guanfacine.

Alpha2 adrenergic agonists have been shown to improve memory test performance in amnesic humans and aged nonhuman primates. In a group of drugs in this class that were tested for their effects on age-related memory impairments in aged monkeys, guanfacine was the most effective for improving mnemonic function at doses that were without significant side effects. These data prompted studies of guanfacine for its effect on learning and memory in persons with age-associated memory impairment (AAMI), the results of which are now reported. The data suggest that guanfacine may have modest mood-improving effects but had no significant effects on learning and memory in the subjects tested.

Serotonin, memory, and the aging brain.

Serotonin is widely distributed throughout the central nervous system and is implicated in a variety of neural functions such as pain, feeding, sleep, sexual behavior, cardiac regulation and cognition. This paper is concerned with the last of these. Abnormalities of the serotonergic nervous system are well documented in pathologic studies of Alzheimer's disease and there is evidence suggesting that changes in this system occur in association with non-disease aging. Data on the role of serotonin in learning and memory and on the effects of aging on brain serotonin function are reviewed and discussed in relation to pharmacologic treatment strategies for the memory impairments associated with advancing age.

The Korsakoff syndrome: a neurochemical perspective.

Korsakoff's disease is an amnesic syndrome associated with midline diencephalic and brain stem pathology. A number of neurochemical systems course through or near the loci of brain lesions found postmortem in Korsakoff patients, which has stimulated studies to learn whether these systems are implicated in amnesia. Data suggest that the loss of brain catecholamine function contributes to this amnesic syndrome and may also be a factor in the memory impairments associated with normal aging. At present, data are insufficient to determine whether cholinergic systems are disturbed in Korsakoff's patients; however, it is likely that multiple neurochemical abnormalities underlie this disorder.

Age-associated memory impairment: a role for catecholamines.

Age-associated memory impairment (AAMI) is a recently defined clinical state which describes loss of memory function in otherwise healthy persons age 50 and over. This is a relatively modest cognitive impairment thought to be common enough to be a feature of normal aging. There is considerable interest among memory researchers, and in the pharmaceutical industry, to establish the neurochemical basis and develop effective treatment for this condition. As in studies of dementia, much attention is focused on cholinergic function in relation to AAMI, with less emphasis on other neurochemical systems, such as those containing catecholamines. Diminished catecholamine function is implicated in dementing illness of the aged and may also be important in AAMI. This article proposes a role for catecholamines in AAMI and discusses possible treatment strategies.

Long-lasting changes in regional brain amino acids and monoamines in recovered pyrithiamine treated rats.

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine + a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were significantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.

Behavioral impairments, brain lesions and monoaminergic activity in the rat following recovery from a bout of thiamine deficiency.

Learning impairments were measured in rats following recovery from a subacute bout of thiamine deficiency. Behavioral training was carried out in an automated T-maze, beginning with paired run spatial delayed non-matching to sample (PR-1), then light-dark discrimination (LD), light-dark discrimination reversal (LD-R), spatial discrimination (SD), spatial discrimination-reversal (SD-R), and finally retraining on the original paired run task (PR-2). Comparable deficits were observed for PR-1 and PR-2, thus demonstrating long-lasting impairment on delayed non-matching to sample. Experimentals performed as well as controls on LD and LD-R. Two experimental animals were unable to perform above chance on the simple SD task. The remaining 15 experimental animals were equivalent to controls on several measures of SD and SD-R performance (errors to criterion, number of animals reaching criterion, correct responses in last 60 trials) although they were significantly worse than controls on both PR-1 and PR-2. Taken together, these results indicate an impairment of representational memory (PR-1, PR-2) with a spared capacity for dispositional memory (LD, LD-R, SD, SD-R) as defined by Thomas and Spafford (Behav. Neurosci., 1984, 98: 394-404). Histological analyses of left hemispheres revealed a high incidence (94%) of thalamic lesions, specifically within the intralaminar nuclei and ventral parts of the mediodorsal nucleus; and an absence of detectable changes in other structures, including the mammillary bodies, hippocampus, cortex, and locus coeruleus. In the right hemispheres, assays of monoamines and metabolites in 17 brain regions showed significant reduction only for norepinephrine in entorhinal cortex. All animals that were selectively impaired on the paired-run task had both the medial thalamic lesions and reduction in entorhinal norepinephrine.

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.

Monoamines and metabolites in cortex and subcortical structures: normal regional distribution and the effects of thiamine deficiency in the rat.

The present study measured the concentration of monoamines, metabolites and estimates of turnover rate in eighteen separate brain regions from controls and a rat model of Korsakoff's disease induced by a two week bout of pyrithiamine and thiamine deficient diet (PTD). A behaviorally tested control (n = 12) and PTD (n = 17) group, and a non-behaviorally tested PTD group (n = 8) were sacrificed 7 months after recovery from treatment. The brains were dissected into nine cortical areas and nine subcortical regions. In behaviorally tested PTD animals, a significant reduction of NE was observed in entorhinal cortex. Diminished norepinephrine (NE) concentration was also observed in entorhinal, hippocampal, septal and olfactory areas of the non-behaviorally tested PTD group. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased in several brain areas, particularly midbrain-thalamus, striatum, of both groups of recovered PTD animals. These findings are discussed with respect to results and hypotheses presented in our previous study of this animal model. Significant differences in monoamine, metabolite and turnover estimates were also observed among cortical areas of the control animals. Entorhinal cortex contained the highest concentration of NE and 5-hydroxytryptamine (5-HT), while DA was highest in somatosensory cortex. The distribution of 5-HT and 5-HIAA were more homogeneous and displayed a rostral-caudal decline in concentration.

Neurochemical specificity of learning: dopamine and motor learning.

In previous reports of studies of patients with alcoholic Korsakoff's psychosis, data were presented showing significant correlations between neuropsychometric measures of amnesia and the CSF levels of the major brain metabolite of norepinephrine (NE), which was consistently reduced among a large group of experimental subjects. Dopamine (DA) metabolite concentrations in the CSF of this same patient population were also significantly lowered but to a lesser degree and less consistently than the NE metabolite. CSF levels of the DA metabolite did not correlate with any measures of amnesia but did significantly correlate with performance on the Digit-Symbol Substitution Test (DSST) of the Wechsler Adult Intelligence Scale (WAIS), which involves psychomotor skill learning. DSST performance did not correlate with CSF levels of the NE metabolite. These findings led to the hypothesis that the acquisition of motor learning skills is related to brain DA activity. In this study, we tested the hypothesis by correlating the ability of a group of Korsakoff patients to learn two different motor tasks (rotary pursuit and mirror tracing) with the concentrations of CSF metabolites of NE, DA, and serotonin. For both tasks, improvement in performance over three daily testing sessions significantly correlated only with the DA metabolite levels. The data are consistent with the hypothesis of a specific role for DA in motor learning.

Learning impairments after 6-OHDA treatment: a comparison with the effects of thiamine deficiency.

Cortical norepinephrine, dopamine and 3,4-dihydroxyphenylacetic acid were reduced by injection of 6-hydroxydopamine (6-OHDA) jointly into the cisterna magna and the dorsal noradrenergic bundle. On subsequent behavioral testing, deficits were observed for spatial delayed alternation learning, but not for active or passive avoidance. Treatment with clonidine resulted in a significant improvement in spatial delayed alteration for experimental as compared to control animals. Injections of 6-OHDA into the cisterna magna alone had no significant effect on brain chemistry or behavioral measures. These results are similar to previous observations following a bout of thiamine deficiency, in which cortical catecholamines were depleted in animals that had exhibited deficits for spatial delayed alternation learning. We argue that the cortical catecholamine deficits observed in post-thiamine-deficient animals are sufficient to account for the delayed alternation deficits observed in this animal model of Korsakoff's psychosis.

Reduced concentrations of arginine vasopressin and MHPG in lumbar CSF of patients with Korsakoff's psychosis.

The concentrations of arginine vasopressin (AVP), somatostatin (SS), and the primary brain metabolites of norepinephrine (MHPG), serotonin (5-HIAA), and dopamine (HVA) were measured in samples of lumbar CSF obtained from ten amnesics with Korsakoff's psychosis, four patients with a history of Korsakoff's psychosis who had recovered from the amnesic symptoms of this disease, and control subjects. Significant deficits were observed in the amnesic group for AVP and MHPG, but not for the other substances measured. Subjects who had recovered from the amnesic symptoms of Korsakoff's psychosis had increased concentrations of AVP and MHPG, but not of SS or the other monoamine metabolites.

Cognitive enhancement in Korsakoff's psychosis by clonidine: a comparison with L-dopa and ephedrine.

Each of three catecholamine agonist medications (clonidine, L-dopa, and ephedrine) and placebo were administered for 2-week trials to a group of amnesics with Korsakoff's psychosis following a double-blind, counterbalanced design. During the last 3 days of each treatment, patients were given a battery of neuropsychological tests to determine the effects of the drugs on memory and related cognitive processes. Only clonidine had a significant effect on measures of anterograde amnesia, and this response was restricted to the same psychometric measures that improved with clonidine in an earlier study (McEntee and Mair 1980). Each of the medications affected performance on some measures of attention. None of the treatments had any effect on measures of retrograde amnesia or digit-symbol substitution. There appears to be a significant negative correlation between the amnestic effects of clonidine and the concentration of the primary noradrenergic metabolite in lumbar CSF (as measured prior to the initial drug trial).

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.

Thiamine deficiency depletes cortical norepinephrine and impairs learning processes in the rat.

Several lines of evidence indicate that thiamine deficiency causes the Wernicke-Korsakoff syndrome, a human memory disorder. The present study examined behavioral deficits in rats after recovery from a bout of thiamine deficiency. Following behavioral testing, the brains were dissected into regions and assayed biochemically for levels of dopamine, norepinephrine, serotonin and the primary metabolites of these monoamines. Based on previous findings in this laboratory, we predicted that thiamine deficiency not only produces behavioral deficits but loss in catecholamines as well. Impairments were observed for a spatial delayed alternation task that had been learned prior to experimental treatment. In addition, experimental animals were impaired in their ability to acquire two novel tasks, active and passive shock avoidance, after recovery from the acute effects of thiamine deficiency. Comparable deficits were not observed for a number of reflex responses that were measured to assess the general neurological state of the animals. Biochemical analyses revealed that the concentration of norepinephrine was reduced significantly in cortex-hippocampus and olfactory bulb but not in other regions, while dopamine and serotonin levels were not altered in any brain region examined. These data demonstrate that a bout of thiamine deficiency can produce persistent deficits in brain norepinephrine and concomitant decrements in behavioral measures of learning and memory. These results are consistent with our hypothesis and evidence that noradrenergic deficits contribute to the amnesic symptoms of Korsakoff's psychosis.

Monoamine activity correlates with psychometric deficits in Korsakoff's disease.

Korsakoff's psychosis is associated with impairments of memory and perception but not global dementia. We have previously reported diminished concentrations of catecholamine metabolites in the CSF of patients with Korsakoff's psychosis. In this study, we compared CSF monoamine metabolite data with performance on psychometric tests for 26 patients with this disease. We report that patients with more severe neurobehavioral deficits have lower concentrations of monoamine metabolites. Our data also provide evidence that diminished brain noradrenergic and dopaminergic activities are related to impairments on different psychometric tasks.