N. Turjanski

Striatal dopaminergic function in restless legs syndrome 18F-dopa and 11C-raclopride PET studies

Objective: To use PET to study striatal dopaminergic function in restless legs syndrome (RLS). Background: RLS is a common disorder experienced by as much as 5% of the population. It has been suggested that this condition is associated with a disturbance of dopaminergic transmission. Methods: The authors measured nigrostriatal terminal dopamine storage with 18F-dopa and striatal D2 receptor binding with 11C-raclopride PET in 13 RLS patients, five of whom were receiving treatment with l-dopa at the time of scanning. RLS results were compared with those of age-matched control subjects. Results: Mean caudate and putamen 18F-dopa uptake were mildly reduced in the RLS patients compared with control subjects, and this reached significance (p = 0.04) in the putamen. Mean D2 binding was reduced in the caudate (p = 0.01) and the putamen (p = 0.008) in RLS patients compared with control subjects. Six of the 13 RLS patients had caudate and putamen D2 binding reduced below the control range. Three other RLS patients showed only reduced putamen D2 binding. There were no significant differences in striatal 18F-dopa uptake or D2 binding between l-dopa–naive and l-dopa–treated RLS patients. Conclusions: These PET findings support the hypothesis of central dopaminergic dysfunction in RLS.

Tremor in Parkinson’s disease and serotonergic dysfunction An 11C-WAY 100635 PET study

Background: The pathophysiologic mechanisms underlying parkinsonian tremor remain unclear. The response to dopaminergic treatment is variable and nondopaminergic mechanisms may play a role in tremor generation. Midbrain raphe 5-HT1A binding provides a functional measure of serotonergic system integrity. With PET, the aim of this study was to examine regional cerebral 11C-WAY 100635 binding to 5-HT1A receptors in patients with PD and to correlate it with severity of tremor. Methods: 11C-WAY 100635 PET was performed on 23 patients with PD and eight age-matched healthy volunteers. Brain 5-HT1A receptor binding was computed using compartmental modeling with a cerebellar reference tissue input function. Results: The authors found mean 27% reduction in the midbrain raphe 5-HT1A binding potential in patients with PD compared to healthy volunteers (p < 0.001). They also showed that Unified Parkinson’s Disease Rating Scale composite tremor scores, but not rigidity or bradykinesia, correlate with 5-HT1A binding in the raphe (p < 0.01). Conclusions: These findings support previous indirect evidence that serotonergic neurotransmission is decreased in PD in vivo. The authors hypothesize that the reduction in raphe 5-HT1A binding represents receptor dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both. An association between 5-HT1A receptor availability in the raphe and severity of parkinsonian tremor was also found.

In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson's disease patients with and without dyskinesias

Dyskinesias are usually seen in Parkinsons disease (PD) patients after several years of L-dopa therapy. Their presence has been attributed to supersensitivity of striatal D1 and D2 receptors. We have used PET to assess striatal D2 receptor binding in untreated PD patients and striatal D1 and D2 binding in L-dopa-treated PD patients. Untreated patients showed a 14% increase in mean D2 receptor binding in the putamen contralateral to the more affected limbs(p < 0.02). Treated patients were segregated into subgroups according to the presence or absence of dyskinesias. There were no differences in mean caudate and putamen D1 and D2 binding between dyskinetic and nondyskinetic patients, matched for duration of clinical disease. Both dyskinetic and nondyskinetic PD subgroups showed a similar 16% reduction of mean caudate D2 binding (p < 0.01) with normal D2 binding in putamen. Mean caudate and putamen D1 binding potentials of both subgroups were reduced by 10% compared with those of controls, though this trend did not reach significance. Putamen D1 binding, however, showed a negative correlation with duration of disease and L-dopa treatment (p < 0.03). These findings suggest that, while exposure of PD patients to L-dopa may be associated with reductions in caudate D2 and caudate and putamen D1 receptor, dyskinesias are unlikely to result from alterations in striatal dopamine receptor binding.

PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome.

Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourettes syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourettes syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourettes syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourettes syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourettes syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourettes syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourettes syndrome and that Tourettes syndrome does not arise from a primary dysfunction of dopaminergic terminals.

Evidence for cortical dysfunction in clinically non-demented patients with Parkinson’s disease: a proton MR spectroscopy study

OBJECTIVES To investigate whether proton magnetic resonance spectroscopy (1H MRS) can detect cortical dysfunction in non-demented patients with Parkinson’s disease, and to correlate changes with cognitive function on formal neuropsychological testing. METHODS Multivoxel1H MRS was performed in 17 patients with levodopa treated idiopathic Parkinson’s disease with out clinical dementia, and 10 age match ed control subjects. Measurements of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine+phosphocreatine (Cr), and Cho/Cr were obtained from right and left temporoparietal cortex and occipital cortex. Fourteen patients with Parkinson’s disease underwent a full battery of neuropsychological testing including performance and verbal subtests of the WAIS-R, Boston naming test, FAS test, and California verbal learning test. RESULTS There were significant temporoparietal cortex reductions in NAA/Cr ratios in right and left averaged spectra of the patients with Parkinson’s disease (p=0.012 after Bonferroni correction) and in spectra contralateral to the worst clinically affected limbs of the patients with Parkinson’s disease compared with controls (p = 0.003 after Bonferroni correction). There was a significant correlation between reduction in NAA/Cr ratios and measures of global cognitive decline, occurring independently of motor impairment (p=0.019). CONCLUSIONS This study suggests that 1H MRS can detect temporoparietal cortical dysfunction in non-demented patients with Parkinson’s disease. Further longitudinal studies are needed to investigate whether these1H MRS changes are predictive of future cognitive impairment in the subset of patients with Parkinson’s disease who go on to develop dementia, or occur as part of the normal Parkinson’s disease process.

A Proton Magnetic Resonance Spectroscopy Study of the Striatum and Cerebral Cortex in Parkinson's Disease

Animal studies have suggested an increased striatal glutamate activity in Parkinsons disease models, although this has not been substantiated in magnetic resonance spectroscopy studies in patients. Our initial aim was to assess glutamate and glutamine levels in the striatum of patients with idiopathic Parkinsons disease, using multivoxel proton magnetic resonance spectroscopy techniques. Since data were collected from other areas of the brain without a priori selection, information on the cortex was also obtained. Twelve healthy volunteers, seven dyskinetic and five non-dyskinetic patients were studied. Peak area ratios of choline-containing compounds (Cho), glutamine and glutamate (Glx) and N-acetyl moieties including N-acetylaspartate (NAx), relative to creatine (Cr) were calculated. Spectra were analysed from the corpus striatum, the occipital cortex and the temporo-parietal cortex. The median Glx/Cr ratio was unaltered in the striatal spectra of Parkinsons disease patients compared to healthy controls. However, the more severely affected patients had significantly reduced NAx/Cr ratios in spectra localised to the temporo-parietal cortex, compared to healthy controls. Furthermore, the entire patient population had significantly reduced Cho/Cr ratios in spectra from the temporo-parietal cortex, compared to the reference population. We found no evidence of increased striatal glutamate in either dyskinetic or non-dyskinetic Parkinsons disease. However, the low NAx/Cr and Cho/Cr ratios in the temporo-parietal cortex may indicate the presence of subclinical cortical dysfunction.

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-fluorodopa (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 Parkinsons 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) l8F-dopa uptake. These Ki values were similar to mean caudate and putamen 9 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.

Increased availability of central benzodiazepine receptors in patients with chronic hepatic encephalopathy and alcohol related cirrhosis

BACKGROUND/AIMS To measure cerebral benzodiazepine receptor binding using 11C-flumazenil positron emission tomography in patients with stable chronic hepatic encephalopathy, who were also characterised by proton magnetic resonance spectroscopy. METHODS Six abstinent patients of mean age 61 years with alcohol related cirrhosis and grade I–II hepatic encephalopathy and 11 matched healthy volunteers were studied. Each patients encephalopathy was defined according to clinical, psychometric, electroencephalographic, and magnetic resonance spectroscopy criteria. Using positron emission tomography, the brain volume of distribution of 11C-flumazenil was obtained; this reflects benzodiazepine receptor availability. Proton magnetic resonance spectra were acquired at 1.5 T using a multivoxel technique; peak area ratios were calculated for choline, glutamine/glutamate, N-acetylaspartate, and creatine resonances. RESULTS The mean volume of distribution of 11C-flumazenil was significantly higher in the cortex, cerebellum, and the basal ganglia in the patients compared with controls (p<0.001). In the patient group, the mean glutamine/glutamate to creatine ratio was significantly increased and the mean choline to creatine ratio was significantly decreased in all brain areas, compared with healthy volunteers. However, the N-acetylaspartate to creatine ratio was unchanged compared with controls. CONCLUSIONS The spectroscopy results reflect the cerebral metabolic derangement associated with hepatic encephalopathy. Stable grade I–II chronic hepatic encephalopathy in alcohol related cirrhosis may be associated with increased cerebral benzodiazepine receptor availability. However, a direct effect of previous chronic exposure to alcohol cannot be excluded.

Parkinson's syndrome after closed head injury : a single case report

A 36 year old man, who sustained a skull fracture in 1984, was unconscious for 24 hours, and developed signs of Parkinson’s syndrome 6 weeks after the injury. When assessed in 1995, neuroimaging disclosed a cerebral infarction due to trauma involving the left caudate and lenticular nucleus. Parkinson’s syndrome was predominantly right sided, slowly progressive, and unresponsive to levodopa therapy. Reaction time tests showed slowness of movement initiation and execution with both hands, particularly the right. Recording of movement related cortical potentials suggested bilateral deficits in movement preparation. Neuropsychological assessment disclosed no evidence of major deficits on tests assessing executive function or working memory, with the exception of selective impairments on the Stroop and on a test of self ordered random number sequences. There was evidence of abulia. The results are discussed in relation to previous literature on basal ganglia lesions and the effects of damage to different points of the frontostriatal circuits.

PET and the investigation of dementia in the parkinsonian patient

Parkinsonism and dementia are present in a number of neurodegenerative conditions. They may be a manifestation of isolated brain stem (Parkinsons disease) or diffuse Lewy body disease (DLBD), or be secondary to combined Lewy body and Alzheimers disease (AD) pathologies. Positron emission tomography (PET) studies show a resting pattern of fronto-temporo-parietal hypometabolism in both, AD and in parkinsonism-dementia (PD-dementia) patients, even when only isolated brain stem Lewy body disease is found at pathology. We have studied three patients fulfilling clinical criteria for diagnosis of DLBD. Their 18F-fluorodeoxyglucose (FDG) PET results showed an AD pattern of fronto-temporo-parietal hypometabolism, though these patients had only mild cognitive dysfunction. Parkinsonism associated with apraxia is observed in corticobasal degeneration (CBD) while impairment of frontal functions, such as planning and sorting, is seen in patients with progressive supranuclear palsy (PSP). PET studies in CBD patients have shown an asymmetric hypometabolism of cortex and thalamus contralateral to the affected limbs, while in PSP patients there is a global metabolic reduction most pronounced in frontal areas and the basal ganglia. These results suggest that metabolic PET studies can help to distinguish PD-dementia, PSP and CBD, but are unable to distinguish PD-dementia from AD. Further studies with post-mortem confirmation are required to establish if DLBD is associated with a distinctive pattern of resting hypometabolism.