Decreased striatal monoaminergic terminals in multiple system atrophy detected with positron emission tomography.

We examined the density of striatal presynaptic monoaminergic terminals, using a ligand for the type 2 vesicular monoamine transporter, (+)-[11C]dihydrotetrabenazine, with positron emission tomography in 7 normal control subjects, 8 multiple system atrophy (MSA) patients with predominantly parkinsonian features (MSA-P), 8 MSA patients with principally cerebellar dysfunction (MSA-C), and 6 sporadic olivopontocerebellar atrophy (sOPCA) patients. The findings were correlated with the results of neurological evaluations and magnetic resonance imaging studies. Specific binding was significantly reduced in the putamen of all patient groups in the order MSA-P < MSA-C < sOPCA, compared with controls. Mean blood-to-brain ligand transport (K1) was significantly decreased in the putamen of all patient groups and in the cerebellar hemispheres of MSA-C and sOPCA but not MSA-P groups, compared with controls. Significant negative correlations were found between striatal binding and the intensity of parkinsonian features and between cerebellar K1 and the intensity of cerebellar dysfunction. The results suggest fundamental differences between MSA-P and MSA-C groups reflecting differential severity of degeneration of nigrostriatal and cerebellar systems in these two forms of MSA. The findings also show that some sOPCA patients have subclinical nigrostriatal dysfunction and are at risk of developing MSA with disease progression.

Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]dihydrotetrabenazine and positron emission tomography.

We used (+)[11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter, with positron emission tomography to study striatal monoaminergic presynaptic terminals in 7 male severe chronic alcoholic subjects without Wernicke-Korsakoff disease compared with 7 male normal controls of similar ages. We found reduced specific binding in the caudate nucleus and putamen in the alcoholic group, and the difference reached significance in the putamen. Specific binding was not decreased in the thalamus, which was examined as a reference structure. We also detected deficits in blood-to-brain transfer rate, K1, in the same regions of the alcoholic group, with a significant difference in the putamen. K1 was unchanged in the thalamus. The finding of reduced striatal VMAT2 in severe chronic alcoholic patients suggests that nigrostriatal monoaminergic terminals are reduced, with or without loss of neurons from the substantia nigra. The findings suggest that the damaging effects of severe chronic alcoholism on the central nervous system are more extensive than previously considered.

The significance of family history status in relation to neuropsychological test performance and cerebral glucose metabolism studied with positron emission tomography in older alcoholic patients.

Patients with severe chronic alcoholism have decreased rates of glucose metabolism in the medial frontal lobe and correlated abnormalities of neuropsychological functioning. The potential influence of family history of alcoholism has not been examined in these patients. In a retrospective study, we used neuropsychological tests and neuroimaging employing [18F]fluorodeoxyglucose with positron emission tomography to study 48 older subjects who had histories of severe, chronic alcohol dependence. These patients were divided into two groups: 27 with a first-degree relative with chronic alcoholism and 21 patients without first-degree relative with chronic alcoholism. No differences were found between groups on either neuropsychological or neuroimaging tests. These results suggest that a family history of alcoholism does not moderate the damaging effects of severe chronic alcoholism on the functioning of the medial frontal lobe.

Effects of abstinence and relapse upon neuropsychological function and cerebral glucose metabolism in severe chronic alcoholism.

Prolonged excessive consumption of alcohol has been associated with a variety of cognitive disorders accompanied by neuropathological and neurochemical abnormalities of the brain, particularly in the frontal lobes. Studies with positron emission tomography (PET) have shown decreased local cerebral metabolic rates for glucose (lCMRglc) in frontal regions, with correlated abnormalities on neuropsychological tests sensitive to executive functioning. This investigation was designed as a pilot study to examine the effects of abstinence and relapse in patients with severe chronic alcoholism studied longitudinally with PET and with neuropsychological evaluation to assess both general and executive functioning. Six patients, including 4 who remained relatively abstinent and 2 who relapsed following their initial evaluation, were studied twice, with inter-evaluation intervals ranging from 10 to 32 months. The patients who remained abstinent or who had minimal alcohol use showed partial recovery of lCMRglc in two of three divisions of the frontal lobes and improvement on neuropsychological tests of general cognitive and executive functioning, whereas the patients who relapsed had further declines in these areas. These results, although based upon a relatively small number of subjects, provide preliminary support for at least partial recovery of metabolic and cognitive functioning in individual patients who abstain from alcohol.

Impaired upper limb coordination in alcoholic cerebellar degeneration.

BACKGROUND: Alcoholic cerebellar degeneration (ACD) is a disorder resulting from severe chronic alcoholism and malnutrition and is characterized by cognitive disturbances, ataxia of gait, and truncal instability, with generally preserved coordination of the upper extremities. OBJECTIVES: To determine whether cognitive deficits in patients with ACD are the same as those seen in patients with severe chronic alcoholism without ACD and to determine whether upper limb motor coordination is different in the 2 groups. DESIGN: We examined cognitive function and upper limb coordination in 56 patients with severe chronic alcoholism, 13 with ACD and 43 without ACD, who had comparable levels of total alcohol intake. Neuropsychological and motor function was measured using an expanded Halstead-Reitan Neuropsychological Test Battery, including the Tactual Performance Test and Grooved Pegboard Test. RESULTS: Neither group had impaired coordination of upper limb function on clinical neurological examination. Both groups had impaired performance on neuropsychological tests involving executive function, but the patients with ACD had greater impairment of upper limb coordination than the patients without ACD as measured by the Tactual Performance Test and Grooved Pegboard Test. CONCLUSIONS: The findings suggest that these 2 groups have similar cognitive deficits but that upper extremity motor functions are more significantly impaired in the ACD group and that quantitative tasks of motor function reveal these impairments.

Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atrophy demonstrated with positron emission tomography.

We used [11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (VMAT2), with positron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.11). Mean blood-to-brain [11C]dihydrotetrabenazine transport (K1) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K1 was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal VMAT2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease.

Effects of disulfiram on positron emission tomography and neuropsychological studies in severe chronic alcoholism.

Disulfiram is an aldehyde dehydrogenase inhibitor that is widely used as an adjunctive agent in the treatment of patients with severe chronic alcoholism. Recent positron emission tomography (PET) studies of local cerebral metabolic rates for glucose (ICMRglc) and benzodiazepine receptor binding in alcoholic patients have shown regional cerebral abnormalities; however, some of the patients were studied while receiving disulfiram, which could influence the biochemical processes under investigation. In a retrospective investigation, we examined the influence of disulfiram administration on the results of PET studies of ICMRglc and benzodiazepine receptor binding and neuropsychological tests of cognition and executive function in patients with severe chronic alcoholism. [18F]Fluorodeoxyglucose was used to measure ICMRglc in 48 male patients, including 11 receiving and 37 not receiving disulfiram in therapeutic doses. [11C]Flumazenil was used to measure benzodiazepine receptor binding in 17 male patients, including 3 receiving and 14 not receiving disulfiram. All patients studied with FMZ were also examined with fluorodeoxyglucose. PET studies of ICMRglc revealed significantly decreased global values in the patients receiving disulfiram compared with those not receiving disulfiram. PET studies of benzodiazepine receptor binding revealed decreased flumazenil influx and distribution volume in patients receiving disulfiram. The neuropsychological tests demonstrated no differences between the two groups of subjects. The findings suggest that disulfiram may influence the results of PET studies of glucose metabolism and benzodiazepine receptor binding.

Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics.

Positron emission tomography was used with [11C]flumazenil (FMZ) and [18F]fluorodeoxyglucose to study GABA type A/benzodiazepine (GA-BA-A/BDZ) receptors and cerebral metabolic rates for glucose (1CMRg1c) in 17 male patients with severe chronic alcoholism (ALC), 8 with (ACD) and 9 without alcoholic cerebellar degeneration (non-ACD). In comparison with male normal controls of similar ages, the ALC group had significantly reduced FMZ ligand influx (K1), FMZ distribution volume (DV), and 1CMRg1c bilaterally in the medial frontal lobes, including superior frontal gyrus and rostral cingulate gyrus; the ACD group had significant reductions of K1, DV, and 1CMRg1c bilaterally in the same distribution, and also in the superior cerebellar vermis; and the non-ACD group had significant reductions of K1, DV, and 1CMRg1c bilaterally in the same regions of the frontal lobes but not in the superior cerebellar vermis. When compared with the non-ACD group, the ACD group had significant reductions of K1, and DV bilaterally in the superior cerebellar vermis. The results suggest that severe chronic alcoholism damages neurons containing GA-BA-A/BDZ receptors in the superior medial aspects of the frontal lobes, and in patients with clinical signs of ACD, neurons containing GABA-A/BDZ receptors in the superior cerebellar vermis.