Stefan Kneifel

Mcleod syndrome: A novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings

The McLeod syndrome is an X‐linked disorder caused by mutations of the XK gene encoding the XK protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea. Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2‐fluoro‐2‐deoxy‐glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X‐linked trait should be examined for acanthocytosis and Kell/Kx blood group serology. Ann Neurol 2001;49:384–392

Evaluation of Serotonergic Transporters using PET and [11C](+)McN-5652: Assessment of Methods

[11C](+)McN-5652 is an established positron emission tomography tracer used to assess serotonergic transporter density. Several methods have been used to analyze [11C](+)McN-5652 data; however, no evaluation of candidate methods has been published in detail yet. In this study, compartmental modeling using a one-tissue compartment model (K1, k″2), a two-tissue compartment model (K1 to k4), and a noncompartmental method that relies on a reference region devoid of specific binding sites were assessed. Because of its low density of serotonergic transporters, white matter was chosen as reference. Parameters related to transporter density were the total distribution volume DV″ (=K1/k″2, one tissue compartment), DVtot (=K1/k′1 (1 + k3/k4), two tissue compartments), and Rv (=k′3/k4, noncompartmental method). The DV″, DVtot, and Rv values extended over a similar range and reflected the known pattern of serotonergic transporters. However, all parameters related to transporter density were markedly confounded by nonspecific binding. With regard to K1, the one-tissue compartment model yielded markedly lower values, which were, however, more stable. The minimal study duration needed to determine stable values for the distribution volume was ∼60 minutes. The choice of the method to analyze [11C](+)McN-5652 data depends on the situation. Parametric maps of Rv are useful if no information on K1 is needed. If compartmental modeling is chosen, both the one- and the two-tissue compartment models have advantages. The one-tissue compartment model underestimates K1 but yields more robust values. The distribution volumes calculated with both models contain a similar amount of information. None of the parameters reflected serotonergic transporter density in a true quantitative manner, as all were confounded by nonspecific binding.

Active hippocampus during nonconscious memories

The hippocampal formation is known for its importance in conscious, declarative memory. Here, we report neuroimaging evidence in humans for an additional role of the hippocampal formation in nonconscious memory. We maskedly presented combinations of faces and written professions such that subjects were not aware of them. Nevertheless, the masked presentations activated many of the brain regions that unmasked presentations of these stimuli did. To induce a nonconscious retrieval of the faces and face-associated occupational information, subjects were instructed to view the previously masked faces and to guess the professional category of each person--academic, artist, and workman. Guessing the professional category of previously masked versus new faces activated the left and right hippocampal formation and right perirhinal cortex as well as bilateral fusiform areas and fronto-temporal areas known to mediate the retrieval of semantic information. These activations within the semantic processing system suggest that conceptual knowledge acquired during masking was nonconsciously retrieved. Our data provide clues to an analogous role of the hippocampus in conscious and nonconscious memory.

Hierarchical visual processing is dependent on the oculomotor system.

Using functional MRI and eye movement recordings we studied the processing of hierarchical stimuli. In agreement with others, we found a minor left hemispheric dominance during local and right dominance during global processing. When attention was directed locally, well-known oculomotor cortical areas were activated, and saccades were elicited in 41% of the trials. Their latencies were similar to pro-saccades. During global processing virtually no saccades occurred. These results suggest two different operational modes of attention. Attending to local features induces a shift of attention, which simultaneously computes a saccade on any level above the brainstem with a computational burden equal to reflexive saccades. Conversely, attending to global features induces an expansion of the focus of attention, which reinforces fixation.

Increased 18F-FDG uptake mimicking thyroid cancer in a patient with Hashimoto's thyroiditis

Abstract. We report the case of a 68-year-old patient with a known paravertebral malignant schwannoma, sent to us for postoperative staging. A combined whole-body PET/CT scan showed only poor 18F-fluorodeoxyglucose uptake in the region of the primary tumor but distinct increased fluorodeoxyglucose uptake in the left and right thyroid gland. Thyroid sonography showed two hypoechogenic nodules. Ultrasound-guided fine-needle aspiration biopsy of one nodule showed oxyphil transformed cells, compatible with malignancy. Based on these findings, the patient underwent a subtotal thyroidectomy. Histopathology of the specimen revealed a chronic follicular Hashimotos thyroiditis. This case demonstrates that Hashimotos thyroiditis can mimic thyroid cancer in PET but also in sonography and fine-needle aspiration biopsy.

Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P--results from a phase I study.

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA–substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA–substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA–substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA–substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA–substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant.

PET imaging of dopamine transporters in the human brain using [11C]-β-CPPIT, a cocaine derivative lacking the 2β-ester function

Abstract The compound 3β-(4′-chlorophenyl)-2β-(3′-phenylisoxazol-5′-yl)tropane (CPPIT or RTI 177) is a 2β-heterocyclic substituted cocaine congener with high in vitro selectivity and affinity for the dopamine transporter relative to serotonin and norepinephrine transporters. The aim of the present study was to evaluate the in vivo selectivity of [ 11 C]-β-CPPIT and to determine whether [ 11 C]-β-CPPIT may be a suitable alternative to existing DAT PET radioligands. [ 11 C]-β-CPPIT was prepared by N-alkylation of the free amine with [ 11 C]methyl iodide. In mouse brain, the striatal binding of [ 11 C]-β-CPPIT was reduced significantly by preinjecting the dopamine reuptake antagonist GBR 12909 (5 mg/kg). By contrast, radioactivity uptake in the brain was not affected significantly by the preinjection of citalopram (5 mg/kg) and desipramine (5 mg/kg), inhibitors for the serotonin and norepinephrine transporters, respectively. No effect was also observed by pretreatment with ketanserin (2.5 mg/kg) a compound with high affinity for the 5-HT 2A -receptor and the vesicular monoamine transporter. In a PET study with six healthy volunteers high striatal uptake was observed. The distribution pattern of [ 11 C]-β-CPPIT was similar to the known distribution of the dopamine transporter in the human brain. Compared to 123 I labeled β-CIT, the rate of metabolic degradation of [ 11 C]-β-CPPIT was almost twofold slower suggesting that bioisosteric heterocyclic substitution of the ester group at the 2β-position of the tropane ring does have an influence on the rate of metabolism of [ 11 C]-β-CPPIT. The rank order of the distribution volumes obtained via the one-tissue compartment model is also similar to the reported distribution of DAT. These preliminary results suggest that [ 11 C]-β-CPPIT may be a useful PET radioligand for the visualization and quantification of dopamine transporters in man.