Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model.

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.

Prodromal features for Parkinson's disease--baseline data from the TREND study.

BACKGROUND AND PURPOSE: A number of non-motor features are known to precede motor manifestations of Parkinson's disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD. METHODS: From the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, 698 healthy individuals aged 50-80 years reporting one or more of the selected prodromal markers (SPMs), but without neurodegenerative disorders, were evaluated and classified according to the status of prodromal markers. Other prodromal PD-related features were assessed with a 23-item questionnaire and compared between participants with and without the three SPMs. RESULTS: Individuals with the SPMs for PD endorsed more of the additional possible prodromal features of PD than those without; of 23 possible prodromal features, the median number identified amongst participants with no SPMs was two, compared with four with one marker, five with two and seven with three (P < 0.001). Regarding individual SPMs, participants with depression and RBD endorsed five of 23 markers, compared with three for those with hyposmia (P = 0.001). There was no significant increase in the number of prodromal features amongst those with two SPMs compared with those with only one marker. CONCLUSIONS: Individuals with the SPMs for PD report a higher prevalence of other prodromal PD symptoms. This may indicate that these markers can identify individuals at risk for PD.

The PRIPS study: screening battery for subjects at risk for Parkinson's disease.

BACKGROUND AND PURPOSE: Screening batteries to narrow down a target-at-risk population are essential for trials testing neuroprotective compounds aiming to delay or prevent onset of Parkinson's disease (PD). METHODS: The PRIPS study focuses on early detection of incident PD in 1847 at baseline PD-free subjects, and assessed age, male gender, positive family history, hyposmia, subtle motor impairment and enlarged substantia nigra hyperechogenicity (SN+). RESULTS: After 3 years follow-up 11 subjects had developed PD. In this analysis of the secondary outcome parameters, sensitivity and specificity of baseline markers for incident PD were calculated in 1352 subjects with complete datasets (10 PD patients). The best approach for prediction of incident PD comprised three steps: (i) prescreening for age, (ii) primary screening for positive family history and/or hyposmia, and (iii) secondary screening for SN+. CONCLUSION: With this approach, one out of 16 positively screened participants developed PD compared to one out of 135 in the original cohort. This corresponds to a sensitivity of 80.0%, a specificity of 90.6% and a positive predictive value of 6.1%. These values are higher than for any single screening instrument but still too low for a feasible and cost-effective screening strategy which might require longer follow-up intervals and application of additional instruments.

The influence of Nordic Walking training on sit-to-stand transfer in Parkinson patients.

Neurodegenerative processes in Parkinson's disease (PD) particularly affect activities of daily living (ADL). Problems of patients with PD in sit-to-stand (STS) performance have been verified before, but not the effects of training on biomechanical measures of STS function. This pilot study aimed to analyse effects of 12 weeks of Nordic Walking training and severity of PD: healthy controls (CO), least (UPDRS A) and more severe (UPDRS B) affected PA on selected functional outcome measures. We expected improvements in PD similar to CO, with better performance of the unstable second phase and faster execution of the entire movement with higher velocities of centre of gravity (COG). 3D kinematics of 22 PD and 18 CO subjects before and after training, were recorded using a motion analysis system (Vicon, Oxford). We compared five outcome measures for STS in 11 PD and 11 CO, matched according to age, gender, height, and weight. Effects of Nordic Walking training were not statistically significant but indicated different patterns which depended on the values of patient's UPDRS score (part III, motor functions). Time required for STS performance increased and horizontal and vertical velocity of COG decreased in UPDRS B, which could be due to progression of PD during the training period. In contrast, UPDRS A showed similar effects as CO. The effects of Nordic Walking as an easy, economic and low-risk intervention on STS in PD depend on the degree of PD. Our findings may help scientists, patients, and therapists to adjust sport-physiological interventions.

Relation of risk factors and putative premotor markers for Parkinson's disease.

As both risk and premotor markers are increasingly discussed to play a key role in the pre-diagnostic phase of Parkinson's disease (PD) the aim of this study was to determine the relation between the risk factors hyperechogenicity of the substantia nigra (SN+) and/or positive family history of PD (faPD+) and putative premotor markers for PD. In a cross-sectional analysis of data of the PRIPS cohort, 1,149 volunteers older than 50 years free of PD were included. In addition to the risk factors SN+ and faPD+, olfactory dysfunction was tested using the Sniffin' sticks test and motor examination was performed. History of depression and constipation was evaluated by a semi-structured interview. Of all 1,149 individuals, 880 had none of the risk markers (76.6%), 143 persons (12.4%) had SN+, 84 (7.3%) were classified as faPD+ and 42 (3.7%) persons had both risk factors. Volunteers with SN+ showed olfactory dysfunction and mild motor impairment (p ≤ 0.001) more often. Depression was more prominent in individuals having two risk factors (p = 0.05). An accumulation of premotor markers was seen in the SN+ group with or without concomitant faPD+, but not in persons with faPD+ only. The profile of premotor markers seems to differ in participants having SN+ and/or faPD+, with SN+ showing the overall highest association with most premotor markers, which implies that SN+ might be a strong indicator for a neurodegenerative process.

Microglia activation is related to substantia nigra echogenicity.

Hyperechogenicity of the substantia nigra (SN) is a sensitive marker for Parkinson's disease (PD). Previously, a relation between SN echogenicity and iron as well as neuromelanin content could be described in 60 human brains. In the present study on a subset of 33 brains, SN echogenicity was found to be correlated with microglia activation (ρ = 0.46, p = 0.008) after correction for iron and neuromelanin content. These findings strengthen the hypothesis of a close pathophysiological connection between SN hyperechogenicity and PD pathology.

Cross-sectional study discloses a positive family history for Parkinson's disease and male gender as epidemiological risk factors for substantia nigra hyperechogenicity.

Hyperechogenicity of the substantia nigra (SN) has been proposed to be a typical finding in Parkinson's disease (PD) and a marker of vulnerability to nigrostriatal dysfunction in healthy subjects. This large cross-sectional study including 1120 subjects older than 50 years without any signs of PD was performed to evaluate the association of SN hyperechogenicity and other proposed epidemiological risk factors for PD. Among all variables assessed only family history of PD and male gender proved to be significantly associated with SN hyperechogenicity, indicating a genetic predisposition for the ultrasound marker.