Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.

Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.

The role of positron emission tomography in the assessment of human neurotransplantation.

Positron emission tomography (PET) using tracers of the dopaminergic system has been used to measure striatal function in a small number of parkinsonian patients undergoing neurotransplantation procedures. Some postoperative scans have shown an unequivocal increase in presynaptic dopaminergic function at the graft site, providing evidence of graft survival independent of clinical assessment. Combined PET and magnetic resonance imaging (MRI) images provide the facility to explore the relationship between graft placement, survival and clinical efficacy.

Localisation in PET images: direct fitting of the intercommissural (AC-PC) line.

A technique is described for estimating the position of the intercommisural line (AC-PC line) directly from landmarks on positron emission tomographic (PET) images, namely the ventral aspects of the anterior and posterior corpus callosum, the thalamus, and occipital pole. The relationship of this estimate to the true AC-PC line, fitted through the centres of the anterior and posterior commissures, showed minimal vertical and angular displacement when measured on magnetic resonance imaging (MRI) scans. Using regression analysis, the ease and reliability of fitting to these points was found to be high. This directly derived AC-PC line estimate was validated in terms of the assumptions used in the method of Fox et al. The ratio of distance between the AC-PC line and a line passing through the base of the inion (GI line) to total brain height was 0.21, as predicted. The technique has been further validated by localizing focal activation of the sensorimotor cortex. The technique is discussed in terms of absolute limits to localization of structures in the brain using noninvasive tomographic techniques in general and PET in particular.

Separating Parkinson's disease from normality. Discriminant function analysis of fluorodopa F 18 positron emission tomography data.

OBJECTIVE: To explore the relationship between normal and parkinsonian fluorodopa F 18 (18F-6-L-fluorodopa [18F-dopa]) uptake data to identify clinically normal subjects who may have preclinical Parkinson's disease. DESIGN: A statistical comparison of striatal fluorodopa F 18 positron emission tomography scan data from patients with Parkinson's disease and normal controls. SETTING: Positron emission tomography unit within a postgraduate teaching hospital. MAIN OUTCOME MEASURES: Discriminant function analysis used to compare the pattern of striatal (left and right caudate and putamen) fluorodopa F 18 uptake in normal subjects and patients with Parkinson's disease. RESULTS: The discriminant score that best separates patients with Parkinson's disease from normal controls is a function of the lowest putamen influx constant minus a function of the caudate influx constant values. Borderline low normal subjects have slightly low fluorodopa F 18 uptake throughout the striatum, whereas patients with early Parkinson's disease have low fluorodopa F 18 uptake in one putamen with preserved uptake in the caudate (for normal subjects, subtracting the caudate influx constants from a function of the lowest putamen value lowers the discriminant score, although it remains positive; for patients, subtracting a larger caudate value from a function of the putamen uptake value leads to a negative score). One control subject had a borderline low discriminant score, compatible with focal nigral pathological changes as expected in preclinical Parkinson's disease. A repeated scan taken 3 years later showed a marked reduction in fluorodopa F 18 uptake, suggesting progressive nigral dysfunction. CONCLUSION: Normal and parkinsonian fluorodopa F 18 uptake data differ both in the overall level of tracer uptake and in its spatial distribution. Subjects whose overall striatal fluorodopa F 18 uptake falls at the borderline of normal and parkinsonian values are likely to be normal if they have uniformly low uptake, but may have early or preclinical Parkinson's disease if uptake into putamen is very much lower than uptake into caudate.

Clinical and positron emission tomographic studies in the 'extrapyramidal syndrome' of dementia of the Alzheimer type.

Extrapyramidal signs, particularly rigidity and tremor, have been reported in a proportion of patients with dementia of the Alzheimer type. To test the hypothesis that these extrapyramidal signs are similar clinically and neurochemically to the extrapyramidal signs of Parkinson's disease, a group of 20 patients satisfying clinical criteria for probable Alzheimer's disease were studied and assessed clinically for the presence of rigidity, tremor, and bradykinesia. In those patients with extrapyramidal signs, qualitative differences were observed between the signs in these patients and in subjects with Parkinson's disease. Fifteen of 20 patients underwent fluoro-18-dopa scans, which showed no significant difference in fluoro-18-dopa uptake into the caudate and putamen between normal subjects and the rigid and nonrigid patients with Alzheimer's disease, in contrast to the marked reduction in fluoro-18-dopa uptake into the putamen that is observed in Parkinson's disease. This provides clinical and in vivo neurochemical support for the hypothesis that extranigral factors may be involved in the pathogenesis of rigidity in Alzheimer's disease.

Comparison of striatal 18F-dopa uptake in adult-onset dystonia-parkinsonism, Parkinson's disease, and dopa-responsive dystonia.

We studied six patients with adult-onset dystonia-parkinsonism (DYS-P) with 18F-6-fluoro-dopa (18F-dopa) positron emission tomography and compared their influx constants (Ki values) with those of six patients with classical childhood-onset dopa-responsive dystonia (DRD), 12 age-matched Parkinson's disease (PD) patients without dystonia, and 21 normal controls. The DYS-P group had significantly reduced mean caudate (67% of normal) and putamen (45% of normal) 18F-dopa uptake. These Ki values were similar to mean caudate and putamen Ki values obtained for the PD group. In contrast, the DRD group showed minor reductions in mean caudate (9%) and putamen (18%) 18F-dopa uptake when compared with normals. The mean caudate:putamen Ki ratio was 1.7 in the DYS-P group and 2.1 in the PD group. In the DRD and normal groups, the caudate:putamen ratios were close to unity. The findings of this study are that adult-onset DYS-P targets the nigrostriatal dopaminergic projections in a pattern similar to PD, with the putamen being more affected. This provides support for the hypothesis that DYS-P may be a phenotypic variant of Lewy body disease. DYS-P seems distinct from childhood-onset DRD, in which striatal 18F-dopa uptake is either normal or only mildly reduced.

Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18F-dopa PET study.

We measured striatal 18F-dopa influx constants (Ki) for 20 patients with isolated, predominantly postural, tremor (eight familial, 12 sporadic) and 11 with predominantly rest tremor. Results were compared with 30 controls and 16 Parkinson's disease (PD) patients. The eight familial essential tremor (ET) patients had normal striatal 18F-dopa uptake. Two of the 12 sporadic postural tremor patients had subnormal putamen 18F-dopa Ki, one (who later became akinetic) falling in the PD range. The mean putamen 18F-dopa uptake of the 11 rest tremor patients was reduced to PD levels (51% of normal). Our findings argue against an association between ET and PD, but support the existence of a "benign" tremulous variant of PD. The presence of low-amplitude rest tremor, cogwheel rigidity, reduced arm swing, and short tremor duration was not a useful predictor of nigral dysfunction in patients with postural tremor. In contrast, patients with predominantly rest tremor, particularly with onset in the leg, consistently showed reduced putamen 18F-dopa uptake.

The effect of entacapone (OR-611) on brain [18F]-6-L-fluorodopa metabolism: implications for levodopa therapy of Parkinson's disease.

We used PET and [18F]-6-L-fluorodopa ([18F]dopa) to measure the effect of a peripheral COMT inhibitor, entacapone, on the extracerebral metabolism and subsequent striatal uptake of [18F]dopa. Four parkinsonian patients and six age-matched normal controls were each scanned twice, once after carbidopa (150 mg) plus placebo and once after carbidopa (150 mg) plus entacapone (400 mg or 800 mg). Without entacapone premedication, by 90 minutes from injection, only 22% of the [18F] signal in plasma represented unmetabolized [18F]dopa (the balance being 3-O-methyl[18F]dopa). After entacapone medication, this fraction increased to 56% of the [18F] signal (p < 0.0001). We did not find any significant differences between the changes observed in patients versus controls or between those subjects who received 400 mg entacapone versus 800 mg in either this or any of the other reported measures. PET image contrast increased in all cases, reflecting an increase in the specific striatal signal ([striatum-occipital]:occipital ratio increased 38% [p < 0.0001]). Entacapone did not alter the rate of striatal uptake and decarboxylation of [18F]dopa as estimated using a graphic approach with metabolite-corrected plasma as input function to calculate the influx constant, Ki(p) (p = NS). This confirms that such an analytic approach adequately corrects for the effect of extracerebral [18F]dopa methylation. In contrast, the influx constant Ki(o) (calculated using occipital counts as the input function) increased 45% after entacapone (p < 0.0001). This demonstrates the sensitivity of this analytic approach to the presence of peripheral 3-O-methyl[18F]dopa and provides an estimate of the percentage increase in brain free [18F]dopa resulting from entacapone premedication.

Guidelines for the management of Parkinson's disease. The Parkinson's Disease Consensus Working Group.

Parkinson's disease is a chronic and disabling illness and there is currently wide variation in its management. This article presents the first UK-specific guidelines for the management of Parkinson's disease and it contains a treatment decision free to aid the physician in deciding when and how to treat patients. We hope this document will prove useful to all those involved in the planning and delivery of care to patients with Parkinson's disease.

The detection of preclinical Parkinson's disease: what is the role of positron emission tomography?

On clinical criteria alone, the diagnosis of early Parkinson's disease can be difficult and, by definition, the prospective recognition of preclinical Parkinson's disease is impossible. Positron emission tomography (PET) using [18F]dopa as tracer has been proposed as a means of identifying patients with preclinical disease. The number of subjects detected to date has been few; most have been identified by serendipity or during the course of family studies. This review examines the significance of a single abnormal scan in an apparently healthy subject in terms of the relationship between normal and abnormal values and the time course of the disease.

Functional magnetic resonance imaging in clinical neurology.

Functional magnetic resonance imaging is a relatively new, noninvasive technique which has a maximum spatial resolution in the range of 1 mm and temporal resolution of 0.1-1 s. The technique is not quantitative but results have proved reliable and reproducible and studies are quick to perform. Already substantial progress has been made in mapping the visual, sensorimotor and auditory systems and promising results achieved in the study of higher cognitive function such as memory and linguistic processing. Clinical applications have been made in epilepsy surgery, the study of schizophrenia, genetic abnormality and cerebral injury.