Jobst Rudolf

Role of the contralateral inferior frontal gyrus in recovery of language function in poststroke aphasia: a combined repetitive transcranial magnetic stimulation and positron emission tomography study.

Background and Purpose— Functional neuroimaging studies have demonstrated right inferior frontal gyrus (IFG) activation in poststroke aphasia. It remains unclear whether this activation is essential for language performance. We tested this hypothesis in a positron emission tomography (PET) activation study during a semantic task with repetitive transcranial magnetic stimulation (rTMS) on right-handed patients experiencing poststroke aphasia and examined whether rTMS stimulation over the right and left IFG would interfere with language performance. Methods— Eleven patients with left-sided middle cerebral arterial infarction, 50 to 75 years of age, were tested with the Aachen Aphasia Test Battery and underwent 15O-H2O PET activation during a semantic task within 2 weeks after stroke. PET activation images were coregistered to T1-weighted MRIs. Stimulation sites were determined on renderings of head and brain over the maximum activation within left and right IFG. rTMS was performed with 20% maximum output (2.1 T), 10-s train duration, at 4Hz frequency. A positive rTMS effect was defined as an increased reaction time latency or error rate in the semantic task. Results— PET activations of the IFG were observed on the left (3 patients) and bilaterally (8 patients). Right IFG stimulation was positive in 5 patients with right IFG activation, indicating essential language function. In a verbal fluency task, these patients had a lower performance than patients without right-sided TMS effect. Conclusions— In some poststroke aphasics, right IFG activation is essential for residual language function. However, its compensatory potential seems to be less effective than in patients who recover left IFG function. These results suggest a hierarchy in recovery from poststroke aphasia and a (limited) compensatory potential of the nondominant hemisphere.

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.

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.

Early [11C]Flumazenil/H2O Positron Emission Tomography Predicts Irreversible Ischemic Cortical Damage in Stroke Patients Receiving Acute Thrombolytic Therapy

BACKGROUND AND PURPOSE Central benzodiazepine receptor ligands, such as [(11)C]flumazenil (FMZ), are markers of neuronal integrity and therefore might be useful in the differentiation of functionally and morphologically damaged tissue early in ischemic stroke. We sought to assess the value of a benzodiazepine receptor ligand for the early identification of irreversible ischemic damage to cortical areas that cannot benefit from reperfusion. METHODS Eleven patients (7 male, 4 female, aged 52 to 75 years) with acute, hemispheric ischemic stroke were treated with alteplase (recombinant tissue plasminogen activator; 0.9 mg/kg according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms. At the beginning of thrombolysis, cortical cerebral blood flow ([(15)O]H(2)O) and FMZ binding were assessed by positron emission tomography (PET). Those early PET findings were related to the change in neurological deficit (National Institutes of Health Stroke Scale) and to the extent of cortical damage on MRI or CT 3 weeks after the stroke. RESULTS Hypoperfusion was observed in all cases, and in 8 patients the values were below critical thresholds estimated at 12 mL/100 g per minute, comprising 1 to 174 cm(3) of cortical tissue. Substantial reperfusion was seen in most of these regions 24 hours after thrombolysis. In 4 cases, distinct areas of decreased FMZ binding were detected. Those patients suffered permanent lesions in cortical areas corresponding to their FMZ defects (112 versus 146, 3 versus 3, 2 versus 1, and 128 versus 136 cm(3)). In the other patients no morphological defects were detected on MRI or CT, although blood flow was critically decreased in areas ranging in size up to 78 cm(3) before thrombolysis. CONCLUSIONS These findings suggest that imaging of benzodiazepine receptors by FMZ PET distinguishes between irreversibly damaged and viable penumbra tissue early after acute stroke.

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.

The Right Inferior Frontal Gyrus and Poststroke Aphasia A Follow-Up Investigation

Background and Purpose— Recently, a combined repetitive transcranial magnetic stimulation (rTMS) and activation positron emission tomography (PET) study showed essential language function of the right inferior frontal gyrus (IFG) in some right-handed acute poststroke aphasics. We reexamined these patients in the chronic phase to test whether the right IFG remained essential for language performance. Methods— We reexamined 9 male right-handed patients, age 41 to 75 years, with aphasia 8 weeks after left hemispheric stroke. rTMS was performed over the maximum activation within the left and right IFG as defined by 15[O]water PET to interfere with language function. A positive rTMS effect was defined as increased reaction time latency or error rate in the semantic task relative to no stimulation. Results— PET activations of the IFG were observed on the left (2 patients) and bilaterally (7). During rTMS interference over the left IFG, all patients had positive TMS effects, indicating that the left IFG remained essential. Stimulation over the right IFG yielded positive rTMS effects in 2 patients with persisting right IFG activation. Two patients with positive rTMS effects over the right side in the initial study did not show these effects at follow-up. Language performance improved in all patients. Conclusions— Successful regeneration from poststroke aphasia seems to depend more on the integration of available language-related brain regions than on recruiting new brain regions during the rehabilitation process. Restoration of the left hemisphere network seems to be more effective, although in some cases, right hemisphere areas are integrated successfully.

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.

FDG transport and phosphorylation in human gliomas measured with dynamic PET

Twenty-six patients with gliomas of WHO-grades two to four were examined with dynamic positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG). FDG rate constants and derived glucose metabolic rates (MRdyn) were determined in solid tumor tissue and in tumor-free brain tissue. In addition, glucose metabolism was also calculated from single scans recorded 30 to 40 min after injection (MRstat).All three rate constants, K1, k2, and k3, were significantly correlated with MRdyn in tumor-free brain. In contrast, in gliomas only k3 was significantly correlated with MRdyn. The ratio of k3 in tumors to k3 in tumor-free brain was also significantly related to histological tumor grade. The results indicate that FDG uptake in brain tumors is governed by FDG phosphorylation and is rather independent from the variation of FDG transport. A comparison between glucose metabolic rates calculated by an autoradiographic approach (MRstat) with the calculation based on individually fitted rate constants (MRdyn) revealed a very close correlation in spite of a moderate systematic difference in absolute values.

Acetylsalicylic acid pretreatment, concomitant heparin therapy and the risk of early intracranial hemorrhage following systemic thrombolysis for acute ischemic stroke.

Background: The risk of intracerebral hemorrhage in systemic thrombolysis for acute ischemic stroke after acetylsalicylic acid (ASA) pretreatment or with subsequent heparin is controversially discussed. Methods: 300 consecutive stroke patients were treated with recombinant tissue-type plasminogen activator (rt-PA) in a prospective open study (92 pretreated with ASA, 202 ASA nonusers) with 3 months of follow-up. After thrombolysis, 122 patients received low-dose, 153 patients high-dose heparin. Results: Logistic regression analysis showed no relationship of hemorrhagic complications within the first 48 h to ASA pretreatment (p = 0.15), or heparin application (p = 0.38), but dependency on stroke severity (NIHSS) at baseline (p = 0.01). Conclusion: ASA pretreatment does not increase the risk of symptomatic bleeding after systemic thrombolysis with rt-PA, even if thrombolysis is followed by anticoagulation.

The cologne stroke experience: safety and outcome in 450 patients treated with intravenous thrombolysis

Background: Predictors of outcome and safety in intravenous thrombolysis within 3 h in clinical routine is a matter of ongoing debate. Available reports contain small patient numbers or summarize heterogeneous multicenter data. Methods: Four hundred and fifty patients received intravenous thrombolysis within 3 h after stroke. Pretreatment NIHSS score and detailed medical history were analyzed. Noncontrast CT was performed before thrombolysis, 24–36 h later and in case of clinical deterioration. Symptomatic intracranial hemorrhage (SICH; any bleeding with an NIHSS increase of ≧4 points) and clinical outcome (modified Rankin Scale, mRS) after 3 months were recorded. Logistic regression identified parameters predictive of independence (mRS 0–2) and SICH. Results: Median onset to admission, door to needle and onset to treatment time was 75, 50 and 135 min, respectively. Direct presentation by emergency service (64%) was the fastest way of referral. Median pretreatment NIHSS was 11 points. Independence (mRS 0–2) was reached by 53%. Mortality was 11% (7% intracerebral, 4% extracerebral complications). Logistic regression identified low NIHSS, low age and absent diabetes as predictors of independence. Overall hemorrhagic complications and SICH were found in 18 and 4% of the patients, respectively. Extracerebral bleeding complications and allergic reactions were found in 3 and 1%, respectively. Conclusion: This largest single center report presents a sample in the range of the 3 h rt-PA cohort of all randomized controlled trials. Outcome was comparable to randomized studies with a higher rate of independence and a lower rate of mortality and SICH.