Mehran Ghaemi

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult‐onset parkinsonism of pseudo‐dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18‐fluorodopa (FDOPA) and 11C‐raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson‘s disease. Similar to findings in the sporadic Parkinson’s disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C‐raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinsons disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinsons disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects. Ann Neurol 2001;49:367–376

Tissue at risk of infarction rescued by early reperfusion : A positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute Stroke

Thrombolytic therapy of acute ischemic stroke can be successful only as long as there is penumbral tissue perfused at rates between the thresholds of normal function and irreversible structural damage, respectively. To determine the proportion of tissue at risk of infarction, cerebral perfusion was studied in 12 patients with acute ischemic stroke who underwent treatment with systemic recombinant tissue plasminogen activator (0.9 mg/kg body weight according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms, using [15O]-H2O positron emission tomography (PET) before or during, and repeatedly after thrombolysis. The size of the regions of critically hypoperfused gray matter were identified on the initial PET scans, and changes of perfusion in those areas were related to the clinical course (followed by the National Institutes of Health stroke scale) and to the volume of infarcted gray matter demarcated on magnetic resonance imaging 3 weeks after the stroke. Whereas the initial clinical score was unrelated to the size of the ischemic area, after 3 weeks there was a strong correlation between clinical deficit and volume size of infarcted gray matter (Spearmans rho, 0.96; P < 0.001). All patients with a severely hypoperfused (< 12 mL/100 g/min) gray matter region measuring less than 15 mL on first PET showed full morphologic and clinical recovery (n = 5), whereas those with ischemic areas larger than 20 mL developed infarction and experienced persistent neurologic deficits of varying degree. Infarct sizes, however, were smaller than expected from previous correlative PET and morphologic studies of patients with acute stroke: only 22.7% of the gray matter initially perfused at rates below the conventional threshold of critical ischemia became necrotic. Actually, the percentage of initially ischemic voxels that became reperfused at almost normal levels clearly predicted the degree of clinical improvement achieved within 3 weeks. These sequential blood flow PET studies demonstrate that critically hypoperfused tissue can be preserved by early reperfusion, perhaps related to thrombolytic therapy. The results correspond with experimental findings demonstrating the prevention of large infarcts by early reperfusion to misery perfused but viable tissue.

Plasticity of language networks in patients with brain tumors: a positron emission tomography activation study.

We investigated plasticity of language networks exposed to slowly evolving brain damage. Single subject O‐15‐water language activation positron emission tomography studies were analyzed in 61 right‐handed patients with brain tumors of the left hemisphere, and 12 normal controls. In controls, activations were found in left Brodmanns Area (BA)44 and BA45, superior posterior temporal gyrus bilaterally, and right cerebellum. Patients additionally activated left BA46, BA47, anterior insula, and left cerebellum. Superior temporal activation was less frequent, and activations in areas other than posterior temporal gyrus were found bilaterally. Frontolateral activations within the nondominant hemisphere were only seen in patients (63%) with frontal or posterior temporal lesions. Laterality indices of frontolateral cortex showed reversed language dominance in 18% of patients. Laterality indices of the cerebellum were negatively correlated with language performance. Two compensatory mechanisms in patients with slowly evolving brain lesions are described: An intrahemispheric mechanism with recruitment of left frontolateral regions other than classic language areas; and an interhemispheric compensatory mechanism with frontolateral activation in the nondominant hemisphere. The latter one was only found in patients with frontal or posterior temporal lesions, thus supporting the hypothesis that right frontolateral activations are a disinhibition phenomenon.

Differentiating multiple system atrophy from Parkinson’s disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging

Objectives: The differential diagnosis between typical idiopathic Parkinson’s disease (PD) and the striatonigral variant of multiple system atrophy (MSA-P) is often difficult because of the presence of signs and symptoms common to both forms of parkinsonism, particularly at symptom onset. This study investigated striatal and midbrain findings in MSA-P and PD patients in comparison with normal controls with the use of positron emission tomography (PET) and three dimensional magnetic resonance imaging (3D MRI) based volumetry to increase the differential diagnostic accuracy between both disease entities. Methods: Nine patients with MSA-P, 24 patients with PD, and seven healthy controls were studied by MRI and PET with 6-[18F]-fluoro-L-dopa (FDOPA), [18F]fluoro-deoxyglucose (FDG), and 11-C-Raclopride (RACLO). Striatal and extrastriatal volumes of interest (VOI) were calculated on the basis of the individual MRI data. The PET data were transferred to the VOI datasets and subsequently analysed. Results: MSA-P differed significantly from PD patients in terms of decreased putaminal volume, glucose metabolism, and postsynaptic D2 receptor density. The striatal FDOPA uptake was equally impaired in both conditions. Neither MRI volumetry nor PET imaging of the midbrain region further contributed to the differential diagnosis between PD and MSA-P. Conclusions: The extent and spatial distribution of functional and morphological changes in the striatum permit the differentiation of MSA-P from PD. Both, multi-tracer PET and 3D MRI based volumetry, may be considered equivalent in the assessment of different striatal abnormality in both disease entities. In contrast, MRI and PET imaging of the midbrain does not provide a further gain in diagnostic accuracy.

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: Evidence from a FDG-PET study in advanced Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinsons disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in nonmotor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.

Permanent Cortical Damage Detected by Flumazenil Positron Emission Tomography in Acute Stroke

BACKGROUND AND PURPOSE Therapy of acute ischemic stroke can only be effective as long as neurons are viable and tissue is not infarcted. Since gamma-aminobutyric acid receptors are abundant in the cortex and sensitive to ischemic damage, specific radioligands to their subunits, the central benzodiazepine receptors (BZR), may be useful as indicators of neuronal integrity and as markers of irreversible damage. To test this hypothesis we studied the binding of the BZR ligand [11C]flumazenil (FMZ) early after ischemic stroke in comparison to the extent of final infarcts and hypometabolic cortical areas. METHODS In 10 patients cerebral blood flow, cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction (OEF), and FMZ binding were studied by positron emission tomography 3.5 to 16 hours after onset of their first hemispheric stroke. Early changes in flow, oxygen metabolism, and FMZ binding were compared with permanent disturbances in glucose metabolism, and the size of the final infarcts was determined on MRI or CT 12 to 22 days after the stroke. RESULTS In all patients except one cerebral blood flow was disturbed, with marked decreases in eight and a hyperperfusion in one patient corresponding to the location of neurological deficits. In these areas CMRO2 was also reduced but to a variable degree, inducing highly variable OEF. Areas with markedly decreased CMRO2 (<60 micromol/100 g per minute) corresponded to regions with decreased FMZ binding (<4.0 times the mean value in the white matter). In all patients the final cortical infarcts were visible on the early FMZ images. Infarcts could be discriminated from noninfarcted cortex by decreased FMZ binding despite a wide range of OEF. In finally hypometabolic cortex FMZ binding was initially decreased or normal, with OEF covering a wide range; this suggested neuronal loss and/or deactivation as the cause of metabolic disturbance. Additionally, a highly significant correlation was found between FMZ distribution within the first 2 minutes after injection and regional cerebral blood flow. CONCLUSIONS These results demonstrate that permanently and irreversibly damaged cortex can be detected by reduced FMZ binding early after stroke. Since FMZ distribution additionally images regional cerebral perfusion, BZR radioligands have a potential as clinically useful tracers in patients with acute ischemic stroke. The evidence of tissue damage furnished by these tracers might be of relevance for the selection of individual therapeutic strategies.

Monosymptomatic resting tremor and Parkinson's disease: A multitracer positron emission tomographic study

We sought to elucidate the relationship between monosymptomatic resting tremor (mRT) and Parkinsons disease (PD). We studied eight mRT patients (mean Hoehn and Yahr [H&Y], 1.1 ± 0.4), eight patients with PD (mean H&Y, 1.5 ± 0.8), who showed all three classic parkinsonian symptoms, and seven age‐matched healthy subjects. Subjects underwent cerebral magnetic resonance imaging (MRI) and multitracer positron emission tomography (PET) with 6‐[18F]fluoro‐L‐dopa (F‐dopa), [18F]fluorodeoxyglucose (FDG), and [11C]raclopride (RACLO). PD and mRT patients did not show significant differences in F‐dopa‐, RACLO‐, or FDG‐PET scans. In F‐dopa‐ and RACLO‐PET, significant differences between the pooled patient data and control subjects were found for the following regions: anterior and posterior putamen ipsilateral and contralateral to the more affected body side, and ipsilateral and contralateral putaminal gradients of the Ki values. Furthermore, we found a difference for the normalized glucose values of the whole cerebellum between the control group (0.94 ± 0.06) and PD patients (1.01 ± 0.04; P < 0.05) but not for the mRT group (0.97 ± 0.03). Our findings indicate that monosymptomatic resting tremor represents a phenotype of Parkinsons disease, with a nearly identical striatal dopaminergic deficit and postsynaptic D2‐receptor upregulation in both patient groups. We suggest that the cerebellar metabolic hyperactivity in PD is closer related to akinesia and rigidity rather than to tremor.

Alterations of neuropsychological function and cerebral glucose metabolism after cardiac surgery are not related only to intraoperative microembolic events.

BACKGROUND AND PURPOSE High-intensity transient signals (HITS) during cardiac surgery are capable of causing encephalopathy and cognitive deficits. This study was undertaken to determine whether intraoperative HITS cause alterations of neuropsychological function (NPF) and/or cerebral glucose metabolism (CMRGlc), even in a low-risk patient group, and whether induced changes are interrelated. METHODS Eighteen patients without signs of cerebrovascular disease underwent elective coronary artery bypass grafting (CABG), and two of these additionally underwent valve replacement in normothermia. Intraoperatively, HITS were recorded by means of transcranial Doppler ultrasonography (TCD). Perioperatively, NPF and CMRGlc were assessed using a standardized complex test battery and positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose (FDG-PET), respectively. RESULTS Intraoperatively, the number of HITS ranged from 90 to 1710 per patient and hemisphere, more on the right side than on the left (P<.05). HITS occurred primarily during cardiopulmonary bypass (71.3%) and, to a lesser extent, during aortic manipulation (22.2%). Changes in global and regional CMRGlc between first (one day preoperatively) and second (8 to 12 days postoperatively) FDG-PET scans were mild. No correlations were found between the number of HITS, age of patient, duration of cardiac ischemia or cardiopulmonary bypass and the changes in CMRGlc. In patients with recorded HITS and a postoperative decrease of regional CMRGlc (n=11), the maximal decrease of rCMR Glc in each hemisphere below the individual global change of CMRGlc correlated with the number of HITS (r= -0.46, P<.05). Limitations in NPF occurred 8 to 12 days postoperatively, resolved within 3 months, and were not found to be correlated to the absolute number of HITS or changes in CMRGlc. CONCLUSIONS HITS during cardiac surgery can cause alterations of both NPF and CMRGlc, even in a low-risk patient group. However, the number of HITS and changes in NPF and CMRGlc are not necessarily interrelated, which indicates that (1) the location of brain damage related to HITS is more important for the development of NPF than is the absolute number of HITS, and (2) factors in addition to HITS might contribute to surgery-related brain damage.

Crossed cerebellar diaschisis in acute human stroke: a PET study of serial changes and response to supratentorial reperfusion

Crossed cerebellar diaschisis (CCD) is well described in the chronic phase of stroke, but few data describe acute CCD and its serial changes after reperfusion. Using positron emission tomography (PET), we studied acute CCD with respect to supratentorial perfusion and outcome measures. In 19 acute stroke patients receiving intravenous thrombolysis (<3 h), 15O-water PET assessed CCD and supratentorial hypoperfusion volume before thrombolysis, 3, 24 h and 14 days later. Infarct volume at day 14 and NIHSS score at 3 months were assessed. Supratentorial hypoperfusion decreased from 25 cm3 (median) before thrombolysis to 0.1 cm3 at day 14. Baseline CCD was 13.4% and decreased continuously to 6.1% after 14 days. The NIHSS score decreased from 11 to 4 pts after 3 months. Infarct volume was 1.1 cm3. Crossed cerebellar diaschisis correlated to the hypoperfusion volume within the first 24 h after stroke, but not later. Hypoperfusion correlated to outcome measures at the early stage only. In contrast, CCD correlated to outcome values at all four measurements. Reperfusion with recovery of CCD was seen in patients with small infarcts and good clinical outcome and vice versa. Our data suggest that (i) CCD occurs as early as 3 h after stroke and might be reversible; (ii) acute CCD is closely related to the volume of supratentorial hypoperfusion. At later time points, however, CCD is disconnected from supratentorial perfusion but strongly associated to outcome measures; (iii) CCD is not susceptible to nonnutritional reperfusion and adds valuable information to interpret supratentorial reperfusion patterns.

[18F]fluorodopa uptake in the upper brainstem measured with positron emission tomography correlates with decreased REM sleep duration in early Parkinson's disease

Sleep disturbances are common in patients with Parkinsons disease (PD). Previous studies have shown alterations of polysomnographic sleep parameters in PD, such as overall diminution of slow-wave and REM sleep duration, absence of muscle atonia during REM and increased occurrence of periodic leg movements during sleep. The pathogenesis of sleep dysregulation in PD is unknown. The aim of this study was to determine relations of abnormal polysomnographic sleep parameters and the dopaminergic function of the striatum and the upper brainstem measured with the use of positron emission and magnetic resonance tomography in 10 early-stage PD patients with a history of sleep disturbances. Our data demonstrated a significant inverse correlation of absolute and percentage REM sleep duration with the mesopontine [18F]6-fluorodopa (FDOPA) uptake in PD patients. Therefore, the results point to a REM inhibiting effect of increased monaminergic transmission within the upper brainstem in early-stage PD. This finding emphasises the pathophysiological significance of a disturbed neurotransmitter equilibrium in the rostral brainstem for REM sleep alterations in PD.