Ulrich Bogdahn

Neuroplasticity: Changes in grey matter induced by training

Does the structure of an adult human brain alter in response to environmental demands? Here we use whole-brain magnetic-resonance imaging to visualize learning-induced plasticity in the brains of volunteers who have learned to juggle. We find that these individuals show a transient and selective structural change in brain areas that are associated with the processing and storage of complex visual motion. This discovery of a stimulus-dependent alteration in the brains macroscopic structure contradicts the traditionally held view that cortical plasticity is associated with functional rather than anatomical changes.

CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles

Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.

Doublecortin expression levels in adult brain reflect neurogenesis.

Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX‐expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re‐expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions.

Degeneration of substantia nigra in chronic Parkinson's disease visualized by transcranial color-coded real-time sonography

Article abstract-To detect morphologic abnormalities in Parkinsons disease (PD), we examined 30 patients with PD and 30 age- and sex-matched nonparkisonian controls by transcranial color-coded real-time sonography (TCCS). In 12 severely affected PD patients, the echogenicity of the substantia nigra was distinctly increased. In the remaining 18 PD patients and in all controls, the substantia nigra was poorly visualized or nondetectable by TCCS. The degree of hyperechogenicity of the substania nigra closely correlated with the severity and duration of PD (p < 0.001). The increased echogenicity of the substania nigra notably results from nigral gliosis and reflects the stage of degeneration. NEUROLOGY 1995;45: 182-184

Gray matter decrease in patients with chronic tension type headache

Using MRI and voxel-based morphometry, the authors investigated 20 patients with chronic tension type headache (CTTH) and 20 patients with medication-overuse headache and compared them to 40 controls with no headache history. Only patients with CTTH demonstrated a significant gray matter decrease in regions known to be involved in pain processing. The finding implies that the alterations are specific to CTTH rather than a response to chronic head pain or chronification per se.

Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients

&NA; Although chronic back pain is one of the most frequent reasons for permanent impairment in people under 65, the neurobiological mechanisms of chronification remain vague. Evidence suggests that cortical reorganisation, so‐called functional plasticity, may play a role in chronic back pain patients. In the search for the structural counterpart of such functional changes in the CNS, we examined 18 patients suffering from chronic back pain with voxel‐based morphometry and compared them to 18 sex and age matched healthy controls. We found a significant decrease of gray matter in the brainstem and the somatosensory cortex. Correlation analysis of pain unpleasantness and the intensity of pain on the day of scanning revealed a strong negative correlation (i.e. a decrease in gray matter with increasing unpleasantness/increasing intensity of pain) in these areas. Additionally, we found a significant increase in gray matter bilaterally in the basal ganglia and the left thalamus. These data support the hypothesis that ongoing nociception is associated with cortical and subcortical reorganisation on a structural level, which may play an important role in the process of the chronification of pain.

Effects of the implementation of a telemedical stroke network: the Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria, Germany.

BACKGROUND Telemedical networks are a new approach to improve stroke care in community settings. We aimed to assess the effects of a stroke network with telemedical support in Germany on quality of care, according to acute processes and long-term outcome. METHODS Five community hospitals without pre-existing specialised stroke care were included in a network with telemedical support by two academic hospitals. In a non-randomised, open intervention study, five community hospitals without specialised stroke care served as the control group, matched individually to the network hospitals by predefined characteristics. Stroke patients admitted consecutively to one of the participating hospitals between July 7, 2003, and March 31, 2005, were included in the study. Patients in network and control hospitals were assessed in the same manner and were followed up for vital status, living situation, and disability at 3 months. Poor outcome was defined by death, institutional care, or disability (Barthel index <60 or modified Rankin scale >3). Predefined indicators for quality of acute stroke care were achieved. FINDINGS A total of 5696 patients with a sudden, non-convulsive loss of neurological function who were diagnosed with having suspected stroke were admitted to the ten hospitals participating in the study. After exclusion, 3122 were included in the final analysis, of whom 1971 (63%) were treated in the network hospitals. All indicators related to quality of acute stroke care were more commonly met in the network than in the control hospitals. After 3 months, 44% of patients treated in network hospitals versus 54% treated in control hospitals had a poor outcome (p<0.0001). In multivariate regression analysis, treatment in network hospitals independently reduced the probability of a poor outcome (odds ratio 0.62, 95% CI 0.52-0.74; p<0.0001). INTERPRETATION Telemedical networks with academic stroke centres offer new and innovative approaches to improve acute stroke care at community level for stroke patients living in non-urban areas.

Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk–benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

Striatal grey matter increase in patients suffering from fibromyalgia – A voxel-based morphometry study

Abstract Fibromyalgia (FM), among other chronic pain syndromes, such as chronic tension type headache and atypical face pain, is classified as a so‐called dysfunctional pain syndrome. Patients with fibromyalgia suffer from widespread, “deep” muscle pain and often report concomitant depressive episodes, fatigue and cognitive deficits. Clear evidence for structural abnormalities within the muscles or soft tissue of fibromyalgia patients is lacking. There is growing evidence that clinical pain in fibromyalgia has to be understood in terms of pathological activity of central structures involved in nociception. We applied MR‐imaging and voxel‐based morphometry, to determine whether fibromyalgia is associated with altered local brain morphology. We investigated 20 patients with the diagnosis of primary fibromyalgia and 22 healthy controls. VBM revealed a conspicuous pattern of altered brain morphology in the right superior temporal gyrus (decrease in grey matter), the left posterior thalamus (decrease in grey matter), in the left orbitofrontal cortex (increase in grey matter), left cerebellum (increase in grey matter) and in the striatum bilaterally (increase in grey matter). Our data suggest that fibromyalgia is associated with structural changes in the CNS of patients suffering from this chronic pain disorder. They might reflect either a consequence of chronic nociceptive input or they might be causative to the pathogenesis of fibromyalgia. The affected areas are known to be both, part of the somatosensory system and part of the motor system.

Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma

The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.