Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study.

OBJECTIVE: The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. METHODS: Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). RESULTS: Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. CONCLUSIONS: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Cerebral blood flow and oxygen metabolism in symptomatic internal carotid artery occlusion by (traumatic) cervical artery dissection.

The present study investigates whether cerebral infarction resulting from internal carotid artery occlusion by cervical dissection is due to emboli, released from a superimposed luminal thrombus, or is due to haemodynamic failure and hypoperfusion. Ten patients with a history of stroke and with a visible cerebral infarct on computed tomographic scan, due to cervical dissection and thrombosis of the internal carotid artery, were studied with positron emission tomography in order to assess the regional cerebral blood flow (rCBF), the regional cerebral metabolic rate of oxygen (rCMRO2) and the regional oxygen extraction fraction (rOEF) in different regions of the brain. rCBF and rCMRO2 were only decreased in the infarct area but not in the peri-infarct zone or elsewhere in the brain. As rOEF was not increased in the affected cerebral hemisphere, the present study suggests artery-to-artery embolism rather than a haemodynamic event as the cause of the stroke. Use of anticoagulants thus appears to be the appropriate treatment in the acute stage.

Cerebral bloodflow and oxygen metabolism in borderzone and territorial infarcts due to symptomatic carotid artery occlusion.

It remains controversial whether borderzone infarcts are due to compromised cerebral perfusion and whether territorial infarcts are caused by artery-to-artery emboli in case of occlusion of the internal carotid artery. The present positron emission tomography study compares with normal controls, the average regional cerebral bloodflow (rCBF), regional oxygen extraction fraction (rOEF) and regional cerebral metabolic rate for oxygen (rCMRO(2)) in the infarct area, the peri-infarct zone, the remaining homolateral hemisphere and in the contralateral hemisphere of 10 patients with borderzone and 17 patients with territorial infarcts, due to internal carotid artery occlusion by atherosclerosis and by cervical dissection. The steady-state technique with oxygen-15 was used. A nearly significant increase of rOEF with lowered rCBF and rCMRO(2) was observed in the peri-infarct zone of patients with territorial infarcts. In patients with borderzone infarcts rCMRO(2) was decreased in the peri-infarct zone, in the remaining homolateral hemisphere and in the contralateral hemisphere without changes in rCBF and rOEF. The present study finds no arguments that impaired cerebral perfusion is a more frequent cause of borderzone than of territorial infarcts.

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195.

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.

Positron emission tomographic study of post-ischaemic-hypoxic amnesia.

BACKGROUND: Despite extensive research, it still remains controversial as to what the precise location of the critical lesions underlying amnesia actually is. The amnesic syndrome is believed to be heterogeneous and due to several distinct functional deficits. PATIENTS AND METHODS: Two patients, a 45-year-old woman and a 56-year-old man, with sudden cardiopulmonary arrest and successful resuscitation, were left with a clear amnesic syndrome as main neurological sequela. During their revalidation period, they underwent a positron emission tomographic (PET) examination, utilizing the (13)NH(3) bolus technique at rest and after intravenous acetazolamide administration. RESULTS: Both PET studies showed more or less similar features with a decrease in regional cerebral blood flow (rCBF) in the frontal, temporal and parietal lobes. In addition, the rCBF was increased in both thalami of the 45-year-old woman and in the striata of the 56-year-old man. Acetazolamide vasoreactivity was most lost in the frontal lobes. CONCLUSIONS: In the present PET study, we demonstrated that destruction of the inhibitory pathways to the thalamus and basal ganglia by ischaemic-hypoxic frontal lesions could be one of the mechanisms leading to amnesia.

Cobalt-55 positron emission tomography in vascular dementia: significance of white matter changes.

BACKGROUND: Vascular dementia (VaD) is still used as a covering term to indicate the relationship between cerebrovascular disease and the progressive cognitive disorder. The contribution of white matter changes (WMCs), seen with computed tomography (CT) and magnetic resonance imaging (MRI) of the brain, to dementia had not been fully elucidated. Cobalt-55 (55Co) positron emission tomography (PET) allows us to distinguish between recent and old infarcts. PURPOSE: The present study investigates whether 55Co PET can detect the lesions responsible for the progression of the cognitive disorder in VaD patients. PATIENTS AND METHODS: 20 consecutive patients with a previous history of repeated strokes occurring more than 6 months before and with multiple cortical infarcts, lacunes and WMCs on CT and 5 age-matched controls were investigated with 55Co PET. The stroke patients were divided in two groups: 8 with and 12 without VaD. Average 55Co counts in cerebral cortex, deep gray nuclei and white matter were compared to the value in the cerebellum used as reference. RESULTS: In the control group, the 55Co uptake was identical in the cerebral cortex and in the cerebellum, but lower in the deep gray nuclei and the cerebral white matter. When comparing the stroke groups with the control, the 55Co uptake was similar for the cerebral cortex and deep gray nuclei, but significantly increased in the cerebral white matter. The 55Co uptake was also more increased in the stroke group with VaD compared to the non-demented group. CONCLUSION: 55Co PET shows that the WMCs are due to the ongoing damage of probably ischaemic origin which is more prominent in stroke patients with progressive cognitive decline.

Non-ideal behaviour of free vanadate on a Superose 12 size-exclusion column. Application to in vivo 48V-labelled rat spleen homogenate.

Seven chromatographic columns were evaluated for the recovery of 48V-radiolabelled vanadate. Further, the behaviour of vanadate (H2VO4-) was studied on a size-exclusion column Superose 12 as a function of (a) buffer salt molarity, (b) different buffer salts, (c) different buffers and (d) organic solvents added to the buffer. As opposed to the unsatisfactory recovery of V-compounds on other columns, we recovered the vanadium quantitatively. We observed that in most cases vanadate eluted after the total volume of the Superose 12 column. This indicates a non-ideal behaviour of vanadate. However, through this non-ideal behaviour it was possible to separate low-molecular-mass bound (Mr<5000) and unbound vanadium which would not be possible under normal behaviour. A possible explanation for this non-ideal behaviour of vanadium is put forward. The method has been successfully applied for the fractionation of different vanadium species in rat spleen homogenate.

Parkinsonism in patients with vascular dementia: clinical, computed- and positron emission-tomographic findings.

PURPOSE: The present study investigates the vascular nature of parkinsonian features in patients with 'probable' vascular dementia. PATIENTS AND METHODS: Forty patients with vascular dementia were studied with positron emission tomography (PET) using the steady state technique with (15)O in order to assess regional cerebral blood flow (rCBF), regional oxygen extraction rate (rOER) and regional metabolic rate for oxygen (rCMRO(2)) in different brain regions. The findings in 10 patients with (VaDP) were compared to 30 without parkinsonism (VaD). RESULTS: The clinical and computed tomographic findings in the parkinsonian patients were similar to those described in the literature as probable vascular parkinsonism. The PET results showed decreased rCBF and rCMRO(2) in the frontal and parietal cortices and in the striatum of the VaDP compared to the VaD group. The decrease of rCBF and rCMRO(2) in frontal and parietal cortices is due to the more severe mental changes in the VaDP group. In the VaDP patients rCBF and rCMRO(2) were more decreased and rOER increased in the striatum contralateral to the most affected parkinsonian side. CONCLUSION: Our PET findings show that local ischemic changes in the striatum contribute to parkinsonism in vascular dementia patients.

Differential regional cerebral uptake of (18)F-fluoro-2-deoxy-D-glucose in Alzheimer's disease and frontotemporal dementia at initial diagnosis.

In this paper, the cerebral uptake of (18)F-fluoro-2-deoxy-D-glucose (FDG) was studied in a relatively small group of patients suffering from either clinically diagnosed Alzheimer's disease (AD) or frontotemporal dementia during the initial differential diagnostic workup. The image analysis was done visually and semiquantitatively using three different reference regions. Visual analysis confirmed earlier literature findings on the distribution of decreased FDG uptake and demonstrated prevalent asymmetric patterns in both groups. Only semiquantitative analysis using the sensorimotor cortex as a reference region confirmed the visual findings. Moreover, there were no differences in medial temporal lobe activities between both groups, and there was no correlation of medial temporal lobe activity with dementia severity. In the AD group, a correlation of parietal FDG uptake with MMSE scores was found.

The isochronous cyclotron: principles and recent developments.

The principals of a cyclotron are described. A magnetic field guides the ions in circular paths, while an electric field accelerates them. The main problem in any accelerator is not to accelerate ions, but to focus them. An isochronous cyclotron overrules the problems related to relativistic mass increase during acceleration. Harmonic operation and negative (vs positive) ion acceleration (and extraction) are explained, as they make dedicated PET cyclotrons a simple, reliable, and suitable tool. The characteristics of such PET cyclotrons are described, as well as their technical implementation. The IBA 18/9 PET cyclotron is given as an example.

Cobalt-55 positron emission tomography in late-onset epileptic seizures after thrombo-embolic middle cerebral artery infarction.

The pathogenesis of late-onset epileptic seizures after thrombo-embolic cerebral infarction is poorly understood. Our previous positron emission tomographic (PET) studies with 15O have demonstrated that post-apoplectic epilepsy is associated with more severe brain ischemia, but we were unable to determine if this was the cause or the consequence of the seizures. Using cobalt-55 (55Co) as PET tracer we can now distinguish recurrent, recent infarction in patients with a previous old infarct in the same vascular territory. In seven out of twelve patients with post-apoplectic seizures an increased uptake of 55Co was observed in the border area and in two of them also within the old infarct core. In the control group, composed of eight seizure-free patients with also an old infarct involving the cortical territory of the middle cerebral artery, no increase in 55Co uptake was observed on PET examination. The present study indicates that in a significant number of patients late-onset epilepsy is the clinical expression of recurrent strokes, occurring in the same vascular territory.

Feasibility study on the characterization of thin layers by charged-particle activation analysis

The purpose of this feasibility study was to investigate the possibilities and limitations of Charged-Particle Activation Analysis (CPAA) as a thin layer characterization method, i.e., the determination of the mass thickness or the composition of a thin layer. Therefore industrially important layers of sputtered Al, AlOx, TiQx (all three from the packaging industry), YBa2Cu3O6+delta, and Y2O3-stabilized ZrO2 (both superconducting industry) on different substrates were analyzed, and thereby the accuracy, the detection limits, and the precision of the method were studied. To test the accuracy, the same materials were also analyzed with neutron activation analysis (NAA) and inductively coupled plasma mass spectrometry (ICPMS). The results of CPAA compared with the results of NAA and ICPMS showed no significant difference at the 95% confidence level. The detection limits expressed as mass thickness were about 10-2 microg cm-2 or expressed as thickness 0.04 nm for a monatomic layer of Al. The experiments showed that the precision of the method depends only on the counting statistics. Generally we can conclude that CPAA is an absolute method for the characterization of "thin" layers, with respect to composition and mass thickness determinations.

55Cobalt (Co) as a PET-tracer in stroke, compared with blood flow, oxygen metabolism, blood volume and gadolinium-MRI.

Several studies have shown the feasibility of divalent cobalt (Co)-isotopes (55Co and 57Co) in imaging of neuronal damage in stroke, multiple sclerosis, cerebral tumors and traumatic brain injury. Little is known how regional Co uptake relates to other pathophysiological changes after stroke. Therefore, we compared 55Co-PET with functional parameters such as regional cerebral blood flow (rCBF) using C(15)O(2), regional oxygen metabolism (rCMRO(2)) using 15O(2), regional cerebral blood volume (rCBV) and post-gadolinium (Gd) T(1)w-MRI to assess the permeability of the blood-brain-barrier (BBB). Sixteen patients (10 female; six male) aged 43 to 84 (mean 69) years with first ever stroke, as shown by CT or MRI, were examined with 55Co-PET and C(15)O(2)-, 15O(2)- and C(15)O-PET in one single session, in a period varying from 0 to 30 days after stroke-onset. Regions of infarction on C(15)O(2)- and 15O(2)-PET (defined by rCMRO(2)<65% or rCBF<45% of the contralateral value) were subsequently superimposed on the 55Co-PET scan. Clinical status was established using the Orgogozo stroke scale, which was assessed both at day 1 and at discharge (at least 6 weeks after day 1). Accumulation of 55Co was seen in eight out of 16 patients, occurring in areas showing a diminished oxygen metabolism, was only partially related to blood flow, and was located mainly outside the extent of the infarction or luxury perfusion as seen on post-Gd T(1)w-MRI. Statistical analysis showed a negative correlation between the Orgogozo score at discharge and the uptake of radioactive cobalt.

[Methyl-11C]thymidine positron emission tomography in tumoral and non-tumoral cerebral lesions.

BACKGROUND: No ideal radiopharmaceutical exists for positron emission tomography (PET) that fulfills all clinical requirements for the study of brain tumors. PURPOSE: The usefulness of a recently developed PET tracer, [methyl-11C]thymidine ([methyl-11C]TdR) is explored in brain tumors. PATIENTS AND METHODS: Twenty patients with confirmed tumoral and non-tumoral brain lesions were investigated with [methyl-11C] TdR PET. The 11C activity was visually and quantitatively assessed. In two patients, dynamic scans were performed. The PET findings were compared to those of magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and to the final diagnosis. RESULTS: Eight out of ten patients with confirmed tumoral lesions or tumor recurrence had increased 11C activity within the lesion. In ten non-tumoral lesions no increased 11C uptake was found. The dynamic PET studies showed that [methyl-11C] TdR first acts as a blood flow tracer, but that later on the uptake of 11C activity is due to labeled metabolites, crossing the blood-brain barrier. Increased tracer activity was only observed in tumoral and not in non-tumoral contrast-enhanced lesions on MRI or CT. CONCLUSIONS: [Methyl-11C] TdR is not a selective PET radiopharmaceutical for brain tumors, but can be used as a tracer for tumoral blood-brain barrier disruption.

Cobalt-55 positron emission tomography in recurrent ischaemic stroke.

The present study investigates if Cobalt-55 (55Co) positron emission tomography (PET) allows us to distinguish and detect recent, recurrent strokes in patients who had already suffered a previous infarct in the same vascular territory. Fourteen patients with recurrent strokes underwent a 55Co PET scan of the brain. Recently infarcted areas, less than 2 months old, had a high 55Co uptake ratio, whereas infarcts of 6 months to 1 year had an uptake ratio comparable to normal brain tissue. In infarcts older than 2 years the 55Co uptake ratio was decreased compared to the control values. The evolution in 55Co uptake ratios with time can be explained by the dynamics of the inflammatory response within the infarct core. 55Co PET allows to demonstrate stroke recurrence and suggests that single photon emission tomography, using 57Co as the tracer, could be a more easy alternative to be used in routine neurological practice.

Cobalt-55 positron emission tomography of ipsilateral thalamic and crossed cerebellar hypometabolism after supratentorial ischaemic stroke.

Cobalt-55 (55Co) is a positron emission tomography (PET) tracer used to demonstrate brain damage, possibly associated to calcium-mediated processes. The degree of 55Co accumulation correlates with the severity of ischaemia in stroke patients. It is still a matter of debate whether ipsilateral thalamic hypometabolism (ITH) and crossed cerebellar hypometabolism (CCH), occurring after middle cerebral artery (MCA) infarcts, represent only a metabolic depression of these remote regions or can lead to structural damage. The present study investigates whether an increased 55Co influx can be demonstrated with PET in ITH and CCH after MCA infarcts. About half of the patients with ITH and CCH had a significant degree of 55Co uptake in, respectively, the ipsilateral thalamus and the contralateral cerebellar hemisphere. It was observed in patients with severe signs of stroke on admission and poor clinical outcome, and correlated well with the degree of 55Co influx within the supratentorial infarct. The present study demonstrates that ITH and CCH after MCA infarction can represent structural damage in these remote areas that occurs during the second week after stroke onset.

Acetazolamide vasoreactivity in vascular dementia: a positron emission tomographic study.

The present study investigates the vasoreactivity of the brain in patients with large infarcts and dementia (multi-infarct dementia; MID) and in patients with microangiopathy, lacunes, white matter changes and dementia (lacunar dementia; LD) using positron emission tomography (PET) and 13NH3 as regional cerebral blood flow (rCBF) tracer. In the control group, an increase in rCBF ranging from 32 to 43% was found in all brain regions after intravenous acetazolamide administration. In both the MID group and the group with multiple infarcts without dementia, moderate loss of vasoreactivity was observed in the frontal, temporal and parietal cortex compared to the control values. Vasoreactivity was severely impaired in all cerebral regions of the LD group and restricted to the thalamus in the group with lacunes and white matter changes without dementia (lacunar stroke; LS). This suggests that global loss of vasoreactivity is not a determining factor in the occurrence of MID, but might be important in LD. The present study shows that loss of the vascular reserve leading to exhausted metabolic reserve of the whole brain is one of the possible mechanisms for the occurrence of vascular dementia.

The significance of cobalt-55 positron emission tomography in ischemic stroke.

Cobalt-55 ((55)Co) has been shown to be an interesting positron emission tomography (PET) tracer that may reflect calcium (Ca) influx in damaged cerebral tissue. Because Ca load is important in the ischemic cascade, the exact meaning of (55)Co PET in stroke patients has to be shown. The present study compares the degree of (55)Co uptake to regional cerebral blood flow (rCBF) and regional cerebral metabolic rate for oxygen (rCMRO(2)) values in brains of patients with ischemic stroke. Eighteen patients with an ischemic event in the middle cerebral artery territory were examined with PET using, in the same session, (55)Co and the (15)O steady state technique. The (55)Co ratio was assessed in ischemic and infarcted regions and compared with the corresponding rCBF and rCMRO(2) values. The average (55)Co ratio is inversely correlated to the rCBF and rCMRO(2) values. Also (55)Co accumulation tends to increase during the weeks after the onset of stroke and decreases down to normal levels after 6 months. The degree of (55)Co uptake corresponds to the severity of the ischemic damage within the first month after stroke. As it increases with time, it probably reflects the Ca accumulation caused by the progression of the inflammatory response within and around the infarct core.

Positron emission tomography in vascular dementia.

BACKGROUND: Vascular dementia (VaD) is an ill-defined entity. It is not known how acute brain failure related to stroke becomes chronic leading to dementia. PURPOSE: The present study investigates whether positron emission tomography (PET) can detect different metabolic patterns in VaD. PATIENTS AND METHODS: Four groups of stroke patients were selected. The PET findings of 14 stroke patients with multiple large infarcts and dementia (MID) and 14 without dementia (MS) were compared. Sixteen stroke patients with lacunes, leukoaraiosis and dementia (LD) were assessed against nine without dementia (LS). The PET examination utilised the 15-O-steady-state technique in order to determine regional cerebral blood flow (rCBF), regional oxygen extraction rate (rOER) and regional cerebral metabolic rate for oxygen (rCMRO2) in different pre-established cortical, subcortical and cerebellar regions. RESULTS: Decreased coupled mean rCBF and rCMRO2 with comparable rOER values were observed in all cerebral regions except in the cerebellum of the MID compared to the MS group. In the LD group mean rCBF and rCMRO2 were decreased with increased rOER in all cerebral regions except in the cerebellum compared to the LS group. CONCLUSIONS: The PET findings in demented patients with multiple large infarcts are in agreement with the concept of multi-infarct dementia. In demented patients with lacunes and leukoaraiosis, the PET pattern suggests a state of misery perfusion not only in the deep structures but also in the whole cerebral cortex. The present PET study argues that there are at least two possible mechanisms that can explain the occurrence of VaD in stroke patients.