The role of obstructive sleep apnea syndrome in the pathogenesis and evolution of dementia

Premessa e scopo. Il sonno è coinvolto nel mantenimento dell’ integrità anatomica e funzioni cerebrale attraverso meccanismi diversi, tra cui la promozione della plasticità sinaptica, il consolidamento della memoria e l'attività scavenger. Studi epidemiologici suggeriscono che la sindrome delle apnee ostruttive del sonno (OSAS) può aumentare il rischio di deterioramento cognitivo. Una conoscenza più approfondita del legame fisiopatologico tra OSAS e demenza e la dimostrazione che l’OSAS è in grado di influenzare direttamente lo sviluppo di alterazioni cognitive, potrebbe portare ad un miglioramento delle strategie di prevenzione e trattamento. L'obiettivo principale di questo studio è stato quello di valutare la correlazione tra deficit cognitivo e la presenza / gravità dell’OSAS, così come la possibile influenza di fattori vascolari. Soggetti e metodi. Sono stati arruolati 41 soggetti senza demenza affetti da OSAS, diagnosticata con una polisonnografia. Al basale, tutti i soggetti sono stati sottoposti ad uno screening vascolare completo e standardizzato, incluso uno studio della reattività cerebrovascolare mediante il calcolo dell’indice di apnea volontaria (BHI) sulla base della valutazione con Doppler transcranico. E’ stata inoltre eseguita una valutazione neuropsicologica per studiare i principali domini cognitivi. Come controlli, sono sati arruolati e sottoposti allo stesso protocollo di valutazione vascolare e cognitiva soggetti con caratteristiche anagrafiche simili, non affetti da OSAS. Tutti i pazienti con OSAS sono stati sottoposti al miglior protocollo di trattamento in base alle raccomandazioni delle linee guida internazionali e rivalutati dopo 6 mesi. In questo momento, ogni paziente ha ripetuto gli esami polisomnografici, neuropsicologici e ultrasonografici. Risultati. Al basale, le prestazioni cognitive erano più basse nei pazienti rispetto ai controlli nei seguenti compiti: Stroop test T1 e T2 e E1 ed E2 (p = 0,001), test delle parole di Rey per l’apprendimento verbale a breve termine / lungo termine (p = 0,0001 e 0,001, rispettivamente) e test di fluenza semantica e fonetica (p = 0,001). Considerando la reattività cerebrovascolare, una differenza significativa tra pazienti e controlli era presente per il BHI medio (p <0.05). Alla valutazione a 6 mesi, sulla base dei risultati del confronto tra le due valutazioni polisonnografiche, 21 pazienti presentavano un miglioramento della gravità dell’OSAS (gruppo 1) e 20 erano rimasti stabili (gruppo 2). Nel gruppo 1 è stato trovato un miglioramento significativo nel BHI sinistro (p = 0.001) e medio (p = 0.001) e nel test delle parole di Rey per l’apprendimento verbale a breve termine (p = 0.02) e a lungo termine (p = 0,001). Nessun cambiamento nella reattività cerebrovascolare e nel profilo cognitivo è stato rilevato nei pazienti del gruppo. Conclusioni. Il dato più significativo di questo studio riguarda la dimostrazione di una significativa associazione tra OSAS e riduzione dell’efficienza in alcuni compiti cognitivi in pazienti senza una storia di demenza. Il legame tra la riduzione delle prestazioni cognitive e le alterazioni emodinamiche cerebrali suggerisce un possibile ruolo patogenetico di una condizione circolatoria sfavorevole nel sostenere la disfunzione cerebrale nell’OSAS. La possibilità di migliorare le alterazioni vascolari e cognitive con trattamenti specifici merita una attenta considerazione per una strategia terapeutica completa e tempestiva nei pazienti con OSAS al fine di ridurre il rischio di sviluppo di un deterioramento cognitivo.ABSTRACT Background. Sleep is involved in maintaining cerebral anatomic integrity and functions through different mechanisms including promotion of synaptic plasticity, memory consolidation and scavenger activity. Epidemiological studies suggest that obstructive sleep apnea syndrome (OSAS) may increase the risk of cognitive impairment. A deeper knowledge of the pathophysiological link between OSAS and dementia and the demonstration that OSAS may directly influence the development of cognitive alterations, would improve prevention and treatment strategies. The main aim of this study was to evaluate the correlation between cognitive impairment and presence/severity of OSAS, as well as the possible influence of vascular factors. Subjects and methods. Forty-one non demented subjects with OSAS, diagnosed with an all-night polysomnography were enrolled. At baseline, all subjects underwent a complete and standardized vascular screening including a study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation based on transcranial Doppler evaluation. A neuropsychological evaluation to study main cognitive domains was also performed. As controls, an age- and sex-matched group of subjects without OSAS were enrolled and submitted to the same protocol of vascular and cognitive assessment. All OSAS patients were submitted to the best treatment protocol according with International specific guidelines and re-evaluated after 6 months. At this time, each patient repeated polisomnographic, neuropsychologic and transcranial Doppler assessment. Results. At baseline, the cognitive performances were lower in patients with respect to controls in the following tasks: Stroop Test T1 and T2 and E1 and E2 (p=0.001), Rey auditory verbal learning test (AVLT) short-term/long-term (p=0.0001 and 0.001, respectively) and semantic and phonetic fluency test (p=0.001). Considering cerebrovascular reactivity, a significant difference between patients and controls was present in mean BHI (p<0.05). At the 6-month evaluation, based on the results of the comparison between the polisomnographic evaluations, 21 patients had an improvement of OSAS severity (group 1) and 20 remained stable (group 2). In group 1 patients, a significant improvement was found in left and mean BHI (p=0.001) and in short-term (p=0.02) and long-term Rey AVLT (p=0.001) No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. Conclusions. The main finding of the present study was the demonstration of a significant association between OSAS and reduced efficiency in some cognitive tasks in patients without a history of dementia. The link between reduced cognitive performances and alteration in cerebral hemodynamics suggests a possible pathogenic role of unfavorable circulatory changes in sustaining the cerebral dysfunction in OSAS. The possibility to improve vascular and cognitive alterations with specific treatments deserves full consideration for a comprehensive and timely therapeutic strategy in OSAS patients in order to reduce the risk of cognitive impairment

Complexities of 5'splice site definition: Implications in clinical analyses

In higher eukaryotes, the 5' splice site (5'ss) is initially recognized through an RNA-RNA interaction by U1 small nuclear ribonucleoprotein (U1 snRNP). This event represents one of the key steps in initial spliceosomal assembly and many disease-associated mutations in humans often disrupt this process. Beside base pair complementarity, 5'ss recognition can also be modified by additional factors such as RNA secondary structures or the specific binding of other nuclear proteins. In this work, we have focused on investigating a few examples of changes detected within the 5'ss in patients, that would not be immediately considered "disease causing mutations". We show that the splicing outcome of very similar mutations can be very different due to variations in trans-acting factor(s) interactions and specific context influences. Using several NF1 donor sites and SELEX approaches as experimental models, we have examined the binding properties of particular sequence motifs such as GGGU found in donor sites, and how the sequence context can change their interaction with hnRNPs such as H/F and A1/A2. Our results clearly show that even minor differences in local nucleotide context can differentially affect the binding ability of these factors to the GGGU core. Finally, using a previously identified mutation in KCNH2 that resulted in intron retention we show how very similar 5'ss mutations found in patients can have a very different splicing outcome due to the neighbouring sequence context, thus highlighting the general need to approach splicing problems with suitable experimental approaches

TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways

In recent times, high-throughput screening analyses have broadly defined the RNA cellular targets of TDP-43, a nuclear factor involved in neurodegeneration. A common outcome of all these studies is that changing the expression levels of this protein can alter the expression of several hundred RNAs within cells. What still remains to be clarified is which changes represent direct cellular targets of TDP-43 or just secondary variations due to the general role played by this protein in RNA metabolism. Using an HTS-based splicing junction analysis we identified at least six bona fide splicing events that are consistent with being controlled by TDP-43. Validation of the data, both in neuronal and non-neuronal cell lines demonstrated that TDP-43 substantially alters the levels of isoform expression in four genes potentially important for neuropathology: MADD/IG20, STAG2, FNIP1 and BRD8. For MADD/IG20 and STAG2, these changes could also be confirmed at the protein level. These alterations were also observed in a cellular model that successfully mimics TDP-43 loss of function effects following its aggregation. Most importantly, our study demonstrates that cell cycle alterations induced by TDP-43 knockdown can be recovered by restoring the STAG2, an important component of the cohesin complex, normal splicing profile

Sleep actigraphic patterns and cognitive status

none9noWe performed an actigraphic assessment of sleep characteristics in healthy subjects and patients with cognitive impairment. Thirty subjects were included and classified into controls (10 subjects), mild cognitive impairment (10 patients) and mild-to-moderate Alzheimer's disease (10 patients). Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Participants had a 7-day actigraphic record. Sleep parameters collected were time in bed, total sleep time, sleep efficiency, sleep latency, wakefulness after sleep onset, number of awakenings, and mean motor activity. Significant differences between mild cognitive impairment and controls patients were found for sleep latency (p = 0.05); Alzheimer's disease patients had significantly worse scores for Pittsburgh Sleep Quality Index (p = 0.01), time in bed (p = 0.001), total sleep time (p = 0.04), sleep latency, sleep efficiency, motor activity (p = 0.0001) and wakefulness after sleep onset (p = 0.001) compared to controls. When comparing Alzheimer's disease and mild cognitive impairment, differences were significant for sleep latency (p = 0.01), wakefulness after sleep onset (p = 0.004), sleep efficiency, number of awakenings and motor activity (p = 0.0001). In addition to showing a high prevalence of sleep alterations in subjects with cognitive impairment, our data suggest that they are evident from the earliest stages of cognitive decline. Further studies are needed to assess whether early correction of sleep alterations can positively influence the evolution of cognitive impairment. The opportunity to provide clinically meaningful information with a simple assessment of sleep characteristics based on actigraphy suggests that wider use of the approach in patients with cognitive decline should be considered.openBuratti, Laura; Camilletti, Roberta; Pulcini, Alessandra; Rocchi, Chiara; Viticchi, Giovanna; Falsetti, Lorenzo; Baldinelli, Sara; Fiori, Chiara; Silvestrini, MauroBuratti, Laura; Camilletti, Roberta; Pulcini, Alessandra; Rocchi, Chiara; Viticchi, Giovanna; Falsetti, Lorenzo; Baldinelli, Sara; Fiori, Chiara; Silvestrini, Maur

Somatic TARDBP variants as a cause of semantic dementia

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1-3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders

Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia

INTRODUCTION: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. METHODS: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. RESULTS: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. DISCUSSION: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients

Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia

Introduction: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. Methods: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. Results: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P&nbsp;&lt;&nbsp;0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. Discussion: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients

On-line monitoring of food fermentation processes using electronic noses and electronic tongues: A review

Fermentation processes are often sensitive to even slight changes of conditions that may result in unacceptable end-product quality. Thus, close follow-up of this type of processes is critical for detecting unfavorable deviations as early as possible in order to save downtime, materials and resources. Nevertheless the use of traditional analytical techniques is often hindered by the need for expensive instrumentation and experienced operators and complex sample preparation. In this sense, one of the most promising ways of developing rapid and relatively inexpensive methods for quality control in fermentation processes is the use of chemical multisensor systems. In this work we present an overview of the most important contributions dealing with the monitoring of fermentation processes using electronic noses and electronic tongues. After a brief description of the fundamentals of both types of devices, the different approaches are critically commented, their strengths and weaknesses being highlighted. Finally, future trends in this field are also mentioned in the last section of the article. (C) 2013 Elsevier B.V. All rights reserved.Peris Tortajada, M.; Escuder Gilabert, L. (2013). On-line monitoring of food fermentation processes using electronic noses and electronic tongues: A review. Analytica Chimica Acta. 804:29-36. doi:10.1016/j.aca.2013.09.048S293680

The NASA Roadmap to Ocean Worlds

In this article, we summarize the work of the NASA Outer Planets Assessment Group (OPAG) Roadmaps to Ocean Worlds (ROW) group. The aim of this group is to assemble the scientific framework that will guide the exploration of ocean worlds, and to identify and prioritize science objectives for ocean worlds over the next several decades. The overarching goal of an Ocean Worlds exploration program as defined by ROW is to identify ocean worlds, characterize their oceans, evaluate their habitability, search for life, and ultimately understand any life we find. The ROW team supports the creation of an exploration program that studies the full spectrum of ocean worlds, that is, not just the exploration of known ocean worlds such as Europa but candidate ocean worlds such as Triton as well. The ROW team finds that the confirmed ocean worlds Enceladus, Titan, and Europa are the highest priority bodies to target in the near term to address ROW goals. Triton is the highest priority candidate ocean world to target in the near term. A major finding of this study is that, to map out a coherent Ocean Worlds Program, significant input is required from studies here on Earth; rigorous Research and Analysis studies are called for to enable some future ocean worlds missions to be thoughtfully planned and undertaken. A second finding is that progress needs to be made in the area of collaborations between Earth ocean scientists and extraterrestrial ocean scientists