Anders Lilja

Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report)

SummaryBased on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimers disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of11C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: a method for early therapy evaluation?

PURPOSE To investigate if sequential positron emission tomographic (PET) scans with the glucose analog 18F-2-fluoro-2-deoxy-D-glucose (18FDG) and/or L-methyl-11C-methionine (11C-methionine) in patients with breast cancer could provide early information on the efficacy of polychemotherapy. PATIENTS AND METHODS Sixteen patients with breast cancer (11 with locally advanced tumors, three with recurrent disease in the contralateral breast, two of them with distant and regional metastases, and two with distant metastases) underwent a baseline and two follow-up PET scans after the first and third/fourth polychemotherapy course. Tumor response was determined clinically/radiographically after three/four polychemotherapy courses. RESULTS Five patients were investigated with 18FDG, seven with both 11C-methionine and 18FDG, and four with only 11C-methionine before polychemotherapy. 11C-methionine presented a more distinct visualization of primary/contralateral breast cancers in five of seven patients when compared with 18FDG. Twelve of 16 patients demonstrated a response using conventional methods after the third/fourth course of polychemotherapy. Eight of these 12 clinical responders had a significant decrease in tracer uptake at the first PET scan performed 6 to 13 days after the first polychemotherapy course, and these reductions were further augmented after the third/fourth course and corresponded to the conventional therapy evaluation (clinical examination, computed tomography [CT], ultrasonography, and mammography). CONCLUSION Our data indicate that PET may be of clinical value in predicting response to chemotherapy in patients with locally advanced breast cancer and/or metastatic disease earlier than any other method used.

Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains--in vivo assessment using positron emission tomography.

SummaryA compartment model has been developed and validated for the kinetic analysis of (S)(-)11C-nicotine binding in the brain including a compensation for the influence of regional cerebral blood flow (rCBF). The model was applied to eight patients with Alzheimer disease (AD) and three age-matched healthy volunteers who received intravenous injections of (S)(-)11C-nicotine and 11C-butanol. The uptake and time course of radioactivity in different brain regions were assessed by positron emission tomography (PET). The rate constant k* was formulated by dividing the K2 rate constant for 11C-nicotine with the K, rate constant for 11C-butanol and thereby minimizing the influence of CBF on the quantitated binding of 11C-nicotine. The rate constant k2* for 11C-nicotine giving a quantitative measure of binding in the brain tissue was significantly higher in the temporal and frontal cortices as well as in the hippocampus of AD brains as compared with controls, indicating deficits in specific nicotinic binding in these brain areas of AD patients. A significant and negative correlation was obtained between cognitive function (Mini-Mental State Examination) and k2* of 11C-nicotine in the temporal and frontal cortices as well as in the hippocampus. The described kinetic model allowed in vivo quantification of nicotinic receptor binding in brain, which will be of importance in the future for evaluation of diagnosis, progress of disease, as well as the therapeutic effects in the treatment of AD.

Discrepancies in Brain Tumor Extent as Shown by Computed Tomography and Positron Emission Tomography Using [68Ga]EDTA, [11C]Glucose, and [11C]Methionine

A patient with an anaplastic (malignant) astrocytoma was examined with computed tomography (CT) and with positron emission tomography (PET), in the latter case using [68Ga]EDTA, [11C]glucose, and [11C]methionine. The CT examination as well as the [68Ga]EDTA study showed a small tumor located in the region of the head of the left caudate nucleus. The [11C]glucose examination showed increased uptake on the same region, as did the [11C]methionine examination, but the latter also showed a considerable uptake in the entire left thalamic region. The patient died 15 days after the [11C]methionine study and a histologic evaluation of thin sections obtained at autopsy showed excellent agreement between tumor extent and activity distribution after [11C]methionine administration. The tumor tissue seen only with [11C]methionine was histologically different from that part of the tumor observed with the other tracers. Although cytologically similar, the latter showed large necrotic areas and an ability to induce marked endothelial proliferation, whereas in the former neither necroses nor notable endothelial proliferation was seen. In this case more than 50% of the tumor would have remained radiologically imperceptible without the [11C]methionine PET examination.

Preterm Children Have Disturbances of White Matter at 11 Years of Age as Shown by Diffusion Tensor Imaging

Preterm birth frequently involves white matter injury and affects long-term neurologic and cognitive outcomes. Diffusion tensor imaging has been used to show that the white matter microstructure of newborn, preterm children is compromised in a regionally specific manner. However, until now it was not clear whether these lesions would persist and be detectible on long-term follow-up. Hence, we collected diffusion tensor imaging data on a 1.5-T scanner, and computed fractional anisotropy and coherence measures to compare the white matter integrity of children born preterm to that of control subjects. The subjects for the preterm group (10.9 ± 0.29 y; n = 9; birth weight ≤ 1500 g; mean gestational age, 28.6 ± 1.05 wk) possessed attention deficits, a common problem in preterms. They were compared with age- and sex-matched control children (10.8 ± 0.33 y; n = 10; birth weight ≥ 2500; gestational age, ≥ 37 wk). We found that the preterm group had lower fractional anisotropy values in the posterior corpus callosum and bilaterally in the internal capsules. In the posterior corpus callosum this difference in fractional anisotropy values may partially be related to a difference in white matter volume between the groups. An analysis of the coherence measure failed to indicate a group difference in the axonal organization. These results are in agreement with previous diffusion tensor imaging findings in newborn preterm children, and indicate that ex-preterm children with attention deficits have white matter disturbances that are not compensated for or repaired before 11 y of age.

Simultaneous Intracerebral Microdialysis and Positron Emission Tomography in the Detection of Ischemia in Patients with Subarachnoid Hemorrhage

Intracerebral microdialysis (MD) was applied in patients with subarachnoid hemorrhage. The regional CBF, the CMRO2, and oxygen extraction ratio (OER) were measured with simultaneous positron emission tomography (PET). The aim was to directly correlate alterations in dialysate levels of energy-related metabolites (lactate, lactate/pyruvate ratio, hypoxanthine) and excitatory amino acids (EAAs) (glutamate and aspartate) to the energy state in the MD probe region as determined by PET. Regional ischemia was defined according to Heiss et al. and Lassen (Heiss et al., 1992; Lassen, 1966). Whole-brain ischemia was considered present when the OER for the whole brain exceeded the mean whole-brain OER + 2 SD of six reference patients. In general, the presence of whole-brain ischemia and/or regional ischemia within the region of the MD probe was associated with increased levels of energy-related metabolites and EAAs retrieved by MD. Increased levels of energy-related metabolites and EAAs were only occasionally seen when PET did not show any signs of ischemia or when signs of regional ischemia were found remote from the MD probe region. Thus, the energy-related metabolites and EAAs may be used as extracellular “markers” of ischemia. PET may be of use in defining critical ischemic regions (tissue at risk) where the MD probe can be inserted for- chemical monitoring.

Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography.

Abstract Regional cerebral blood flow was measured with positron emission tomography (PET) in six healthy volunteers at rest and during experimentally induced, sustained cutaneous pain on the dorsum of the right hand or on the dorsum of the right foot. Pain was inflicted by intracutaneous injection of capsaicin, providing a mainly C-fibre nociceptive stimulus. Statistical analysis showed significant activations along the central sulcus (SI) area when comparing pain in the hand to pain in the foot. Separate comparison of both pain states to a baseline revealed different locations along the central sulcus for hand pain and foot pain. The encountered differences are consistent with what is previously known about the somatotopics of non-painful stimuli. When comparing painful stimuli to baseline, the contralateral anterior cingulate gyrus, the ipsilateral anterior insular cortex and the ipsilateral prefrontal cortex were implicated. The results are consistent with an involvement of SI in the spatial discrimination of acute cutaneous pain.

Positron emission tomography with ([11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA in supratentorial tumors.

Sixteen patients with supratentorial tumors were examined with positron emission tomography (PET) using [( 11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA as well as CT. There were nine astrocytomas (grade II), three oligoastrocytomas (grade II), two anaplastic astrocytomas (grade III), and two meningiomas. Six patients with low-grade astrocytomas and all three patients with oligoastrocytomas had an accumulation of [11C]methionine varying from slightly to intensely increased as compared with normal brain tissue. There was a markedly increased uptake of methionine in the anaplastic astrocytomas. Three of the low-grade astrocytomas had a decreased uptake of [11C]methionine in at least part of the tumor as compared with normal brain tissue. Contrast enhancement on CT or uptake of [68Ga]EDTA was not a prerequisite for increased accumulation of methionine. Uptake of [11C]glucose was lower than or equal to that of normal brain tissue in the low-grade tumors and also in one of the two anaplastic astrocytomas and in the bulk of the other. In each individual case the methionine uptake tended to be higher--or less decreased--than the glucose uptake. In the low-grade tumors the uptake of methionine and that of glucose were often different, occasionally markedly different, as far as the tumoral-peritumoral areas involved. These differences were even more remarkable in the two anaplastic astrocytomas. An increased uptake of methionine was often seen in areas appearing normal on CT. It appears that PET with [11C]glucose has limitations with regard to delineation of the low-grade astrocytomas, whereas PET with [11C]methionine usually better reflects the extent of these tumors and, to a lesser degree, the extent of the high-grade neoplasms. The results of PET with [68Ga]EDTA were similar to those with postcontrast CT in most patients. The two meningiomas exhibited a high uptake of all tracers used for PET as well as a marked contrast enhancement on CT. The extent of the meningiomas judged by PET with the various tracers correlated well with the extent assessed by postcontrast CT.

Intracranial infusion of purified nerve growth factor to an Alzheimer patient : the first attempt of a possible future treatment strategy

We report on the clinical outcome of a first case of intracranial infusion of nerve growth factor (NGF) to an Alzheimer patient. The therapeutic attempt is based on animal research showing that NGF stimulates central cholinergic neurons of the type known to be lost during the development of Alzheimers disease (AD). Furthermore, our own previous clinical experience of infusing NGF to support the survival of intracranially transplanted adrenal chromaffin cells to Parkinsonian patients indicate this approach to be technically possible and safe and clinically of significant potential. Our first case was a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF over three months resulted in a marked transient increase in uptake and binding of [11C]nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF infusion, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects of the NGF infusion were found. The results of this single case indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Non-synchronous behavior of neuronal activity, oxidative metabolism and blood supply during mental tasks in man.

In near-infrared spectroscopic studies during mental tasks such as problem solving and mental arithmetic, we found that 9 of 33 healthy volunteers showed decreases in both the regional cerebral blood flow (r-CBF) and oxygen consumption rate (CMRO2) in the frontal region of the dominant hemisphere. To confirm these unexpected observations, we performed simultaneous measurements by positron emission tomography (PET) and near-infrared spectroscopy (NIRS) in two such subjects. PET images also showed that CBF decreased within the presumptive area illuminated by near-infrared light during mental task. However, CBF decreased in almost all regions while the subject gave a correct answer. Thus, the questions arose: Are mental tasks always associated with increases in r-CBF and/or CMRO2?