Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

TNFα Rescues Dendritic Cell Development in Hematopoietic Stem and Progenitor Cells Lacking C/EBPα.

Dendritic cells (DCs) are crucial effectors of the immune system, which are formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep process regulated by cytokines and distinct transcriptional mechanisms. C/EBPα is an important myeloid transcription factor, but its role in DC formation is not well defined. Using a CebpaCre-EYFP reporter mouse model, we show that the majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked reduced ability to form mature DCs after in vitro culture with FLT3L. Differentiation analysis revealed that C/EBPα was needed for the formation of monocytic dendritic progenitors and their transition to common dendritic progenitors. Gene expression analysis and cytokine profiling of culture supernatants showed significant downregulation of inflammatory cytokines, including TNFα and IL-1ß as well as distinct chemokines in KO HSPCs. In addition, TNFα-induced genes were among the most dysregulated genes in KO HSPCs. Intriguingly, supplementation of in vitro cultures with TNFα at least partially rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In conclusion, these results reveal an important role of C/EBPα in early DC development, which in part can be substituted by the inflammatory cytokine TNFα.

Plants use identical inhibitors to protect their cell wall pectin against microbes and insects.

As fundamentally different as phytopathogenic microbes and herbivorous insects are, they enjoy plant-based diets. Hence, they encounter similar challenges to acquire nutrients. Both microbes and beetles possess polygalacturonases (PGs) that hydrolyze the plant cell wall polysaccharide pectin. Countering these threats, plant proteins inhibit PGs of microbes, thereby lowering their infection rate. Whether PG-inhibiting proteins (PGIPs) play a role in defense against herbivorous beetles is unknown. To investigate the significance of PGIPs in insect-plant interactions, feeding assays with the leaf beetle Phaedon cochleariae on Arabidopsis thaliana pgip mutants were performed. Fitness was increased when larvae were fed on mutant plants compared to wild-type plants. Moreover, PG activity was higher, although PG genes were downregulated in larvae fed on PGIP-deficient plants, strongly suggesting that PGIPs impair PG activity. As low PG activity resulted in delayed larval growth, our data provide the first in vivo correlative evidence that PGIPs act as defense against insects.

Melatonin Effects in REM Sleep Behavior Disorder Associated with Obstructive Sleep Apnea Syndrome: A Case Series.

OBJECTIVES: REM sleep behavior disorder (RBD), with its main clinical symptoms of nightmares with dream-enacting behavior, is considered as a possible precursor of neurodegenerative disease. Obstructive Sleep Apnea Syndrome (OSAS) is known to be capable of provoking RBD-like symptoms by apneic event related arousals. The two sleep related pathologies must coincide in a relevant number of individuals because of overlapping prevalence in similar age groups. Until now RBD symptoms coexisting with OSAS are rarely described in scientific literature and in fact considered as OSAS mimicking RBD. METHODS: We report four cases with a severe clinical RBD syndrome which were polysomnographically also diagnosed with concomitant OSAS (AHI range: 10.1 -53.2/h). RESULTS: Treatment with 2 mg prolonged release melatonin led to a relevant clinical improvement of RBD symptoms in all patients, so far untreated for the sleep related breathing disorder. Measure of REM sleep without atonia (RSWA) in polysomnography showed values ranging from 5.1 to 20.4% determined with the Montplaisir method. Surprisingly, RSWA values in PSG with melatonin were high, probably because of the still untreated OSAS. CONCLUSION: We presume that in patients with RBD and OSAS both pathologies contribute in varying degrees to the emergence of RBD symptoms by a destabilization of REM sleep. We suggest by consequence to consider a therapeutic strategy including the treatment of both disorders for an optimal therapeutic response.

Clinical usefulness of carotid ultrasound to improve stroke risk assessment: ten-year results from the Carotid Atherosclerosis Progression Study (CAPS).

BACKGROUND AND PURPOSE: To prevent strokes it is essential to correctly classify people according to their risk of stroke. The aim of the present study was to assess whether carotid ultrasound improves the stroke risk prediction in asymptomatic individuals. METHODS: The baseline visit of the Carotid Atherosclerosis Progression Study (CAPS) included assessment of conventional risk factors and carotid ultrasound. During the 10-year follow-up of 4995 subjects, strokes, transient ischaemic attacks (TIA) and deaths were recorded. We assessed the additional usefulness of carotid ultrasound compared to the Framingham Stroke Risk Score (FSRS) with reclassification statistics using four risk categories. RESULTS: Most risk models were not improved by carotid ultrasound. For individual stroke prediction, intima-media thickness (IMT) or plaque of the internal carotid arteries were more useful than common carotid or bifurcational IMT. The model predicting 'any stroke or death' was significantly improved when ultrasound parameters were included - 339 subjects (7.2%) were reclassified to another risk category (122 were shifted to a higher, 217 to a lower risk category); 182 (53.7%) were correctly reclassified. The net reclassification improvement (NRI) was 7.7% (p = 0.029) and the integrated discrimination improvement (IDI) was 0.73% (p = 0.023). CONCLUSIONS: When carotid ultrasound is not restricted to the common carotid artery but includes the internal carotid segments, the inclusion of ultrasound data into stroke risk models may improve the risk classification of individuals. Further validation in primary prevention cohorts is warranted.

Is carotid intima media thickness useful for individual prediction of cardiovascular risk? Ten-year results from the Carotid Atherosclerosis Progression Study (CAPS).

AIMS: Carotid intima media thickness (cIMT) is an intermediate phenotype of early atherosclerosis that independently predicts vascular events. It is often suggested that cIMT be used as a screening tool to select subjects with an elevated event risk. Whether cIMT adds information to traditional risk models has so far received little investigation. METHODS AND RESULTS: The 10-year follow-up of 4904 subjects from the Carotid Atherosclerosis Progression Study (CAPS) without pre-existing vascular disease included cardiovascular events and total mortality. Using Cox models and reclassification statistics, we investigated the usefulness of cIMT in individual risk prediction beyond the Framingham and the SCORE models, using risk strata of 0-5, 5-10, 10-20, and >or=20% over 10 years. Carotid intima media thickness was significantly and independently predictive for cardiovascular events. Compared with a model using the Framingham risk factors, a second model that included the common carotid-IMT led to the reclassification of 357 subjects (8.1%). In 107 subjects (30.0%), this reclassification was correct as confirmed with the actual outcome over 10 years. Net reclassification improvement was -1.41% (P = NS); integrated discrimination improvement was 0.04% (P = NS). More subjects were shifted to lower than to higher risk categories by the inclusion of cIMT. Analyses including other endpoint definitions, other carotid segments, and the SCORE risk model for baseline prediction did not result in consistently better risk prediction with cIMT. CONCLUSION: Despite cIMT being predictive for cardiovascular endpoints, it did not consistently improve the risk classification of individuals. Carotid intima media thickness may not be useful for the risk stratification of individuals in the general population.