Elevated cerebrospinal fluid tau protein levels in Wernicke's encephalopathy.

OBJECTIVE: Limited neuronal cell loss is seen in the neuropathology of Wernicke's encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer's disease (AD) as a disease control. METHODS: CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau(181)) and amyloid beta-protein ending at amino acid 42 (A beta 42) in CSF were also determined for comparison between acute WE with AD. RESULTS: Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau(181) and A beta 42 differed between acute WE and AD. CONCLUSIONS: Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE.

Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias.

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.

Cerebrospinal fluid tau protein levels in demented and nondemented alcoholics.

The tau protein levels in cerebrospinal fluid (CSF-tau) were examined in 27 patients with alcohol dependence (20 demented and 7 nondemented), 36 age and dementia severity-matched patients with Alzheimer's disease (AD), and 23 age-matched normal control subjects. The CSF-tau levels in the demented alcoholic group (alcohol-induced organic brain disorders, 25.4 +/- 10.2 pg/ml) was significantly lower (p < 0.0001) than that in the AD group (96.1 +/- 53.3 pg/ml), but not significantly different from that in the nondemented alcoholics (18.1 +/- 10.2 pg/ml) or the controls (19.2 +/- 12.9 pg/ml). Using a 44.9 pg/ml as a cut-off value (mean + 2 SD of the normal control group), only one patient with alcohol-induced organic brain disorders exceeded the value, whereas 3 of 36 of the AD group showed CSF-tau levels less than this level. These findings suggest that alcohol-induced organic brain disorders are a group of dementias that are characterized by normal CSF-tau levels, and that the CSF examination for tau in combination with other clinical findings may help in differentiating alcohol-induced organic brain disorders from AD.

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.

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.

Effective pharmacotherapy of alcoholic amnestic disorder with fluvoxamine. Preliminary findings.

Ten patients with alcoholic chronic organic brain disease were categorized as having alcohol amnestic disorder, or Korsakoff's psychosis (n = 6), dementia associated with alcoholism (n = 3), or compensated alcoholic liver disease (n = 1). All patients had severe deficits in memory for recently acquired information (episodic memory). Patients with alcohol dementia also showed global intellectual decline, including decreased performance on measures of semantic (knowledge) memory and reduction in levels of cerebrospinal fluid somatostatin. In a 4-week double-blind crossover design, the serotonin-uptake blocker fluvoxamine maleate (100 to 200 mg/d) was found to improve episodic memory in only the patients with alcohol amnestic disorder. These improvements in memory were significantly correlated with reductions in levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory failure in patients with alcohol amnestic disorder.

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.

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.

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.

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.

Central nervous system catecholamine metabolism in Korsakoff's psychosis.

We attempted to replicate previous reports of impaired central noradrenergic activity in patients with Korsakoff's psychosis. No differences were demonstrated in lumbar cerebrospinal fluid concentrations of norepinephrine or its major metabolite, 3-methoxy-4-hydroxyphenyl glycol (MHPG), or in the contribution of plasma to cerebrospinal fluid free MHPG in 6 patients with clinically well characterized Korsakoff's psychosis and 8 age-matched healthy, normal volunteers. Likewise, cerebrospinal fluid concentrations of the major metabolites of dopamine (homovanillic acid) and serotonin (5-hydroxyindoleacetic acid) were the same in patients and controls.

Memory impairment in Korsakoff's psychosis: a correlation with brain noradrenergic activity.

The concentration of the primary brain metabolite of norepinephrine is diminished in the lumbar spinal fluid of patients with Korsakoff's syndrome. The extent of its reduction is significantly correlated with measures of memory impairment for individual patients. These data suggest that the memory disorder of Korsakoff's syndrome may result from damage to ascending noradrenergic pathways by the diencephalic and brainstem lesions associated with this disease.