Participation of cAMP/PKA-Mediated Signaling Pathways in Functional Activity of Regeneration-Competent Cells in the Nervous Tissue under Conditions of Ethanol-Induced Neurodegeneration.

We studied the involvement of cAMP/PKA signaling in the realization of the growth potential of neural progenitors and secretion of neurotrophic growth factors by glial elements under conditions of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP and PKA in cell cycle progression of the neural progenitor cells and in production of neurotrophins by the cells in nervous tissue under the optimal conditions to vital activity was demonstrated. Ethanol inverted the role of cAMP/PKA signaling pathways in determination of the proliferation-differentiation status of neural stem cells. Selective blockade of adenylate cyclase or PKA in neural stem cells increased the rate of their division against the background of relative decrease in differentiation rate. In addition, cAMP/PKA signaling does not longer participate in neurotrophin production by glial cells in neurodegeneration. These findings suggest that inhibitors of activity/expression of adenylate cyclase and PKA can be considered as possible drugs with regenerative activity for the treatment of nervous system pathologies provoked by alcohol.

Chronic alcohol consumption and its effect on nodes of frontocerebellar and limbic circuitry: comparison of effects in France and the United States.

Alcohol use disorders present a significant public health problem in France and the United States (U.S.), but whether the untoward effect of alcohol on the brain results in similar damage in both countries remains unknown. Accordingly, we conducted a retrospective collaborative investigation between two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) with T1-weighted, structural MRI data collected on a common imaging platform (1.5T, General Electric) on 288 normal controls (NC), 165 uncomplicated alcoholics (ALC), and 26 patients with alcoholic Korsakoff's syndrome (KS) diagnosed at all sites with a common interview instrument. Data from the two countries were pooled, then preprocessed and analyzed together at the U.S. site using atlas-based parcellation. National differences indicated that thalamic volumes were smaller in ALC in France than the U.S. despite similar alcohol consumption levels in both countries. By contrast, volumes of the hippocampus, amygdala, and cerebellar vermis were smaller in KS in the U.S. than France. Estimated amount of alcohol consumed over a lifetime, duration of alcoholism, and length of sobriety were significant predictors of selective regional brain volumes in France and in the U.S. The common analysis of MRI data enabled identification of discrepancies in brain volume deficits in France and the U.S. that may reflect fundamental differences in the consequences of alcoholism on brain structure between the two countries, possibly related to genetic or environmental differences.

Function and dysfunction of prefrontal brain circuitry in alcoholic Korsakoff's syndrome.

The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff's syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking--the types of information and abilities tapped by intelligence tests--remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS.

[Clinical application of neuroimaging to alcohol-related dementia].

Alcohol-related dementia (ARD) is one of the most common dementing disorders in middle-aged people and occurs in heavy drinkers who are estimated to be 10 - 15 % of the adult men in a community. While the concept of ARD is multifactorial and includes all cognitive deficits in alcoholics, the central clinical manifestations are exemplified by Korsakoff's syndrome (KS), a persistent neuropsychiatric syndrome, characterized by amnesia and disorientation that is caused by thiamine deficiency along with excessive alcohol consumption. Antemortem detection of intracranial changes has been made possible by MRI and many studies have revealed that alcoholics have atrophic changes in frontal lobe, cerebellum, medial temporal lobe and hippocampus. However, these brain regions are vulnerable to excessive alcohol and seem to be independent of cognitive deficits in alcoholics. This review shows the regional differences in gray matter volumes between cognitively normal alcoholics and patients with KS. By employing a 3-dimensional MRI method for voxel-based morphometry that enables an automated, unbiased, comprehensive assessment, we demonstrate that parahippocampal/hippocampal atrophy is specific to KS and thalamic atrophy and the third ventricle enlargement are more severe in patients with KS than in cognitively normal alcoholics.

NMDA receptors in frontal cortex and hippocampus of alcohol consumers.

Specific binding of [³H]MK801 to N-methyl-D-aspartate (NMDA) receptors in the frontal cortex and hippocampus (CA1 and gyrus dentatus) was measured by receptor autoradiography in 16 Caucasian chronic alcohol consumers free of clinical manifestations of alcoholism, and compared with 16 Caucasian control subjects. Binding densities were not significantly different between heavy and moderate drinkers, neither between alcohol consumers that were abstinent or non-abstinent before death, nor between ethanol drinkers and controls. Continued alcohol consumption, in the absence of hepatic, neurologic or psychiatric disorders related to alcoholism, does not alter the binding properties of NMDA receptors in the brain areas studied.

Response to ethanol reduced by past thiamine deficiency.

Ethanol-induced intoxication and hypothermia were studied in rats approximately 7 months after severe thiamine deficiency, when treated rats appeared to have recovered their physical health. Previously induced thiamine deficiency without prior ethanol exposure significantly decreased the area under the curve plotted for the concentration of ethanol in blood and also decreased behavioral impairment and hypothermia due to ethanol exposure. Pathophysiologic changes resulting from thiamine deficiency may contribute to both the pharmacodynamic and pharmacokinetic tolerance to ethanol in chronic alcoholics.

Chronic cigarette smoking modulates injury and short-term recovery of the medial temporal lobe in alcoholics.

Memory function is largely mediated by the medial temporal lobe (MTL), and its compromise has been observed in alcohol dependence and chronic cigarette smoking. The effects of heavy alcohol consumption and chronic smoking on hippocampal volumes and MTL metabolites and their recovery during abstinence from alcohol have not been assessed. Male alcoholics in treatment (ALC) [13 smokers (sALC) and 11 non-smokers (nsALC)] underwent quantitative magnetic resonance imaging and short-echo proton magnetic resonance spectroscopic imaging at 1 week and 1 month of sobriety. Outcome measures were compared with 14 age-matched, non-smoking light-drinkers and were related to visuospatial learning and memory. Over 1 month of abstinence, N-acetyl-aspartate, a neuronal marker, and membrane-associated choline-containing metabolites normalized in the MTL of nsALC subjects, but remained low in the MTL of sALC subjects. Metabolite concentration changes in both groups were associated with improvements in visuospatial memory. Hippocampal volumes increased in both groups during abstinence, but increasing volumes correlated with visuospatial memory improvements only in nsALC subjects. In summary, chronic cigarette smoking in alcohol-dependent men appears to have adverse effects on MTL metabolite recovery during short-term sobriety. These data may also have implications for other conditions with established MTL involvement and significant smoking co-morbidity, such as schizophrenia-spectrum and mood disorders.

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.

The neuropathology of amnesia.

Relations between brain damage and memory disturbance are outlined with emphasis on the so-called amnesic syndrome. Following a brief introduction into forms of memory and memory failures, the basic causes of brain damaage (with relevance to amnestic failures) are described. Thereafter, the two best-known forms of brain damage-amnesia relations are reviewed: the consequences of damage to medial temporal lobe structures and to diencephalic regions. For the cases with medial temporal lobe damage, evidence is reported in greater detail for H.M., who has been examined more than any other amnesic patient for more than 30 years now, as a considerable amount of literature has accumulated on his behavior in diverse situations. Other cases with more or less circumscribed damage to medial temporal lobe structures are reviewed so as to outline criteria for or against the hypothesis that there are regions within the medial temporal lobe whose damage might be critical for the amnesic syndrome. Two cases of diencephalic amnesia are summarized in particular (cases of Mair et al., 1979) as they have received extensive neuropsychological and neuropathological investigation. Other cases with, for example, Korsakoff's disease are reviewed, as well as cases with diencephalic, or combined mesencephalic-diencephalic damage without nutritional causes. A third group of patients with massive, but still selective amnesic disturbances are then described: cases of basal forebrain damage, followed by descriptions of Alzheimer's disease which has similarities in the underlying neuropathology. This leads over to cases with more generalized intellectual deteriorations (dementia), which may have developed on the basis of primarily cortical damage or damage principally to basal ganglia structures. After reviewing cases with mainly material-specific memory failures--usually as a consequence of restricted neocortical damage--a separate section follows on patients in whom retrograde amnesia is the prominent symptom. The contribution of animal models of human amnesia is critically reviewed and discrepancies are analyzed between human and animal memory disturbances. This section emphasizes the value of investigating inter-dependencies between brain structures by pointing out that relations between memory disturbances and brain damage may be more complicated than apparent from a simple structure-function assignment. This aspect is further followed up in the conclusions.

What does a comparison of the alcoholic Korsakoff syndrome and thalamic infarction tell us about thalamic amnesia?

In this review, the clinical, neuropsychological, and neuroimaging findings in the alcoholic Korsakoff syndrome and in thalamic amnesia, resulting from focal infarction, are compared. In both disorders, there is controversy over what is the critical site for anterograde amnesia to occur-damage to the anterior thalamus/mammillo-thalamic tract has most commonly been cited, but damage to the medio-dorsal nuclei has also been advocated. Both syndromes show 'core' features of an anterograde amnesic syndrome; but retrograde amnesia is generally much more extensive (going back many years or decades) in the Korsakoff syndrome. Likewise, spontaneous confabulation occurs more commonly in the Korsakoff syndrome, although seen in only a minority of chronic cases. These differences are attributed to the greater prevalence of frontal atrophy and frontal damage in Korsakoff cases.

Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction.

Two brain networks are particularly affected by the harmful effect of chronic and excessive alcohol consumption: the circuit of Papez and the frontocerebellar circuit, in both of which the thalamus plays a key role. Shrinkage of the thalamus is more severe in alcoholics with Korsakoff's syndrome (KS) than in those without neurological complication (AL). In accordance with the gradient effect of thalamic abnormalities between AL and KS, the pattern of brain dysfunction in the Papez's circuit results in anterograde amnesia in KS and only mild-to-moderate episodic memory disorders in AL. On the opposite, dysfunction of the frontocerebellar circuit results in a similar pattern of working memory and executive deficits in the AL and KS. Several hypotheses, mutually compatible, can be drawn to explain that the severe thalamic shrinkage observed in KS has different consequences in the neuropsychological profile associated with the two brain networks.

Brainstem serotonergic neurons in chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

There are several lines of evidence to suggest that serotonergic neurons in the brain are detrimentally affected by chronic alcohol consumption. The present study aims to quantify pathological changes in brainstem regions containing serotonergic neurons in chronic alcoholics compared to age-matched non-alcoholic controls. An antibody specific for tryptophan hydroxylase was used to immunohistochemically demonstrate serotonergic neurons in serial sections of postmortem brainstem. The cases analyzed were divided into four groups on the basis of their clinical and pathological presentation; chronic alcoholics with Wernicke's encephalopathy, chronic alcoholics with additional Korsakoff's psychosis, non-alcoholic controls, and a single chronic alcoholic without neurological complications. There was an overall reduction in the number of serotonergic neurons in all alcoholic cases when compared with controls. All brainstem regions were affected, but the largest neuronal loss was found in areas of the medullary and caudal pontine reticular formation (reduced by 80-90%). Alcoholics with Korsakoff's psychosis did not differ in the amount or extent of pathology from the other alcoholic cases analyzed. The data indicate that significant numbers of serotonergic neurons degenerate in chronic alcoholics. Such a loss is likely to have significant clinical consequences.

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. II. Ageing, Korsakoff's disease, Parkinson's disease, and Alzheimer's disease.

Changes in the dendritic arborisation of Golgi-impregnated basal forebrain neurones with respect to size, shape, orientation, and topology of branching were quantitatively investigated in ageing, Alzheimer's disease (AD), Korsakoff's disease (KD), and Parkinson's disease (PD). A reorganisation of the whole dendritic tree characterized by an increase in both the total dendritic length and the degree of dendritic arborisation as well as by changes in the shape of the dendritic field was found during ageing, in KD, PD, and AD. Dendritic growth under these conditions was related to the extent of cell loss in basal forebrain nuclei. There appeared to be major differences, however, with respect to the overall pattern of dendritic reorganisation between AD on one side and ageing, KD, and PD on the other side. In both ageing and KD, dendritic growth was largely restricted to the terminal dendritic segments, resulting in an increase of the size of the dendritic field (pattern of "extensive growth") In AD, however, dendritic growth mainly resulted in an increase of the dendritic density within the dendritic field without being accompanied by an increase in the size of the volume occupied by the dendritic tree (pattern of "intensive growth"). In AD, aberrant growth processes were frequently observed in the perisomatic area or on distal dendritic segments of basal forebrain neurones of the reticular type. Neurones with aberrant growth profiles were typically located in the direct vicinity of deposits of beta/A4 amyloid. Perisomatic growth profiles were covered by the low-affinity receptor of nerve growth factor p75NGFR. Aberrant growth processes were not present in ageing, KD, and PD. On the basis of the present study, it is concluded that under certain degenerative conditions, reticular basal forebrain neurones undergo a compensatory reorganisation of their dendritic arborisation, a process that has become defective in AD, thereby converting a physiological signal into a cascade of events contributing to the pathology of the disease.

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. III. The basal forebrain compared with other subcortical areas.

The distribution of the reticular neuronal type in the human brain and its involvement in both degeneration and dendritic reorganisation under the conditions of ageing, Korsakoff's disease (KD), Alzheimer's disease (AD), and Parkinson's disease (PD) was comparatively investigated after Golgi impregnation. Reticular neurones are distributed throughout different areas along the brain axis. The cholinergic basal forebrain nuclei, i.e., the basal nucleus of Meynert, the nucleus of the diagonal band, and the medial septal nucleus form the most rostral part of this network of "open nuclei," which is collectively referred to as the "reticular core." Reticular neurones of the following areas were quantitatively investigated by a computer-based three-dimensional analysis: caudate nucleus, globus pallidus, medial septal nucleus, nucleus of the vertical limb of the diagonal band, basal nucleus, medial amygdaloid nucleus, reticular thalamic nucleus, lateral hypothalamic area, subthalamic nucleus, substantia nigra, locus coeruleus, pedunculopontine tegmental nucleus, and raphe magnus nucleus. There are three major findings. First, neurones that were found to be susceptible to degeneration in AD were largely part of the same neuronal populations prone to degeneration during ageing, in KD and PD. Thus, areas could be classified according to their overall degree of vulnerability under the present degenerative conditions as being highly vulnerable (basal forebrain nuclei, caudate nucleus, locus coeruleus), moderately vulnerable (medial amygdaloid nucleus, raphe magnus nucleus, lateral hypothalamic area, substantia nigra, pedunculopontine tegmental nucleus), or marginally vulnerable (globus pallidus, subthalamic nucleus, reticular thalamic nucleus). Second, neuronal populations that are particularly vulnerable to degenerative changes show a high degree of structural plasticity. Third, the degree of this dendritic plasticity is inversely related to the complexity of dendritic arborisation of the neurone. It is concluded that the sparsely ramified reticular type of neurone forms a pool of pluripotent neurones that have retained their plastic capacity throughout life, which makes them vulnerable to a variety of perturbations.

Componential analysis of problem-solving ability: performance of patients with frontal lobe damage and amnesic patients on a new sorting test.

A new sorting task designed to isolate and measure specific components of problem-solving ability was administered to four subject groups: patients with focal frontal lobe lesions, patients with both frontal dysfunction and amnesia (Korsakoff's syndrome), patients with circumscribed (non-Korsakoff) amnesia, and normal control subjects. The patients with circumscribed (non-Korsakoff) amnesia, and normal control subjects. The patients with frontal lobe lesions and patients with Korsakoff's syndrome were impaired on eight of the nine components of the task. The findings run counter to theories of a single or primary impairment in patients with frontal lobe dysfunction. Rather, the results suggest that a wide spectrum of deficits in abstract thinking, cognitive flexibility, and use of knowledge to regulate behavior contributes to the problem-solving impairment of these patients. Although the (non-Korsakoff) amnesic patients performed similarly to normal subjects on most measures, a finer analysis suggested that successful performance on this complex sorting task, in addition to being strongly dependent upon frontal lobe function, is mildly dependent upon memory function.

Magnetic resonance imaging of alcoholic Korsakoff patients.

Eight patients with alcoholic Korsakoff's syndrome were compared to age-matched groups of normal controls and nonamnesic chronic alcoholic patients using magnetic resonance imaging (MRI). Quantitative image-analytic techniques were used to estimate volumes of ventricular and cortical cerebrospinal fluid (CSF), as well as cortical and subcortical grey matter structures. For the nonamnesic alcoholics, these volume analyses revealed large CSF increases with some circumscribed decreases in grey-matter volumes. In contrast, alcoholic Korsakoff patients showed widespread reductions in grey matter volumes in addition to CSF increases, with greatest reductions observed in diencephalic structures. The volume losses that best differentiated the Korsakoff patients from the alcoholic controls included losses in anterior portions of the diencephalon, mesial temporal lobe structures, and the orbitofrontal cortices. These findings suggest that damage to structures other than the mesial thalamic nuclei, such as the hypothalamus and hippocampus, may contribute to the Korsakoff patients' amnesic symptoms.

Build-up and release from proactive interference during chronic ethanol consumption in mice: a behavioral and neuroanatomical study.

Male mice of the BALB/c strain were given a solution of 15% ethanol as their only source of fluid during either 24 or 48 weeks. They were submitted to a sequential alternation (SA) task in a T-maze (6 successive trials). It was found that 48 but not 24 weeks of alcohol administration lead to a deficit as compared to pair-fed or tap-water controls. Whereas experimental mice performed as well as controls on the first 3 choices, they exhibited a gradual decrease in the SA rate on subsequent trials. We suggest that this deficit might result from an exaggerated vulnerability to proactive interference (PI). In order to further test this hypothesis, a second experiment investigated whether a between-trials variation of context of the maze would increase performance. It was found that the SA rate improved as soon as the variation was provided (5th trial). We suggest that the deficit of experimental mice results from an impairment of retrieval processes. A neuroanatomical study was conducted to quantify cell losses resulting from 8, 24 or 48 weeks of ethanol treatment in the mammillary bodies (MM) or the hippocampus (HPC). At the time of appearance of the deficit, MM exhibited a -32% cellular loss, whereas this was only -18% in the HPC. This result emphasises the importance of MM lesion in memory deficits resulting from long-term alcohol consumption.

Korsakoff's psychosis: noradrenergic systems and cognitive impairment.

Recent studies of patients with Korsakoff's amnesia suggest that central noradrenergic (NE) activity is diminished by the brainstem and diencephalic lesions associated with this disease. Similarly, there is a body of evidence that experimental manipulations of central NE activity affect the ability of animals to learn and remember some conditioned behaviors. The relationship between brain NE activity and human amnesia is underscored by evidence of comparable behavioral deficits in animals with NE depleting lesions and in humans with Korsakoff's psychosis. We argue that diminished NE activity impairs cognitive activation and that this limits processes related to attention and to the information processing capacity of patients with Korsakoff's psychosis.

The locus coeruleus and memory: a study of chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

The loss of noradrenergic locus coeruleus neurons has been identified as the possible critical lesion inducing amnesia in alcoholic patients with the Wernicke-Korsakoff syndrome. The present study aims to test this hypothesis by quantifying the number of pigmented locus coeruleus neurons in 4 alcoholics with the Wernicke-Korsakoff syndrome, 5 alcoholics with Wernicke's encephalopathy alone but no amnesia, and 1 alcoholic and 5 age-matched controls with no neurological disorders. Apart from an increased vascularity in the locus coeruleus of alcoholics, no significant differences in the number, morphology or distribution of pigmented locus coeruleus neurons was noted between any of the groups analysed. There was a significant correlation between the number of locus coeruleus neurons and brain weight. These data demonstrate that neither alcohol neurotoxicity nor thiamine deficiency result in a reduction in the number of pigmented cells in the locus coeruleus and refute the hypothesis that locus coeruleus cell loss is critical for the amnesia in the Wernicke-Korsakoff syndrome.

The fine structure of neurofibrillary tangles in a case of atypical presenile dementia.

The neurofibrillary tangles in a case of atypical presenile dementia were studied by electron microscopy. The tangles consisted of 2 types of tubule: one straight, measuring about 15--20 nm in width, the other twisted. Both types of tubule appeared separately in each neuron; however, occasionally twisted tubules seemed to be distributed among the straight tubules. The implications of these findings are briefly discussed.