Attività autonomica cardiaca e funzioni neurocognitive nei pazienti affetti da sindrome delle gambe senza riposo (RLS): effetto dei farmaci dopamino agonisti in acuto e a lungo termine

Several studies showed that sleep loss/fragmentation may have a negative impact on cognitive performance, mood and autonomic activity. Specific neurocognitive domains, such as executive function (i.e.,prefrontal cortex), seems to be particularly vulnerable to sleep loss. Pearson et al.(2006) evaluated 16 RLS patients compared to controls by cognitive tests, including those particularly sensitive to prefrontal cortical (PFC) functioning and sleep loss. RLS patients showed significant deficits on two of the three PFC tests. It has been recently reported that RLS is associated with psychiatric manifestations. A high prevalence of depressive symptoms has been found in patients with RLS(Rothdach AJ et al., 2000). RLS could cause depression through its adverse influences on sleep and energy. On the other hand, symptoms of depression such as sleep deprivation, poor nutrition or lack of exercise may predispose an individual to the development of RLS. Moreover, depressed patients may amplify mild RLS, making occasional RLS symptoms appear to meet threshold criteria. The specific treatment of depression could be also implicated, since antidepressant compounds may worsen RLS and PLMD(Picchietti D et al., 2005; Damsa C et al., 2004). Interestingly, treatments used to relieve RLS symptoms (dopamine agonists) seem to have an antidepressant effects in RLS depressed patients(Saletu M et al., 2002&2003). During normal sleep there is a well-regulated pattern of the autonomic function, modulated by changes in sleep stages. It has been reported that chronic sleep deprivation is associated with cardiovascular events. In patients with sleep fragmentation increased number of arousals and increased cyclic alternating pattern rate is associated with an increase in sympathetic activity. It has been demonstrated that PLMS occurrence is associated with a shift to increased sympathetic activity without significant changes in cardiac parasympathetic activity (Sforza E et al., 2005). An increased association of RLS with hypertension and heart disease has been documented in several studies(Ulfberg J et al., 2001; Ohayon MM et al., 2002).

Genotype-phenotype correlation in trisomy 21

Down syndrome (DS) or trisomy 21 (T21) is the most common genetic cause of intellectual disability (ID). Subjects with DS are characterized by complex and variable clinical features including intellectual disability (ID) and craniofacial dysmorphisms. The aim of the thesis is to uncover genotype-phenotype relationships in DS possibly useful to devise therapies based on molecular and cellular mechanisms. In this work, we have investigated different aspects of DS: - we have collected clinical data of children with DS and we have evaluated the cognitive impairment through specific cognitive tests - we have analysed genomics of DS through the study of partial trisomy (PT21) cases. We have described new PT21 cases confirming the hypothesis of the highly restricted DS critical region (HR-DSCR) recently identified as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS, while it is absent in all PT21 non-DS subjects. Moreover, we have characterized new transcripts included in the HR-DSCR; - we have studied gene expression through RNAseq in blood cells of children with DS; -metabolic alterations in plasma of children with DS were identified through different methods: Nuclear Magnetic resonance, routine blood exams performed during the follow up of the subjects and enzyme-linked immunosorbent assay (ELISA); - to test possible correlations between specific Hsa21 regions and alterations in transcriptomics and metabolomics, we have used trisomic iPSCs and differentiated them into neuronal derivatives. Significant alterations in gene expression and metabolic profiles have been identified, as well as significant correlations with clinical and cognitive aspects. Specific genes and the HR-DSCR may play a role in these alterations: cell models need to be developed to investigate this role. Neural derivatives from trisomic iPSCs are a promising model to better understand genotype-phenotype correlations in DS.

Sonno e funzioni cognitive: ruolo della microstruttura del sonno NREM

STUDY OBJECTIVE: Cyclic Alternating Pattern (CAP) is a fluctuation of the arousal level during NREM sleep and consists of the alternation between two phases: phase A (divided into three subtypes A1, A2, and A3) and phase B. A1 is thought to be generated by the frontal cortex and is characterized by the presence of K complexes or delta bursts; additionally, CAP A1 seems to have a role in the involvement of sleep slow wave activity in cognitive processing. Our hypothesis was that an overall CAP rate would have a negative influence on cognitive performance due to excessive fluctuation of the arousal level during NREM sleep. However, we also predicted that CAP A1 would be positively correlated with cognitive functions, especially those related to frontal lobe functioning. For this reason, the objective of our study was to correlate objective sleep parameters with cognitive behavioral measures in normal healthy adults. METHODS: 8 subjects (4 males; 4 females; mean age 27.75 years, range 2334) were recruited for this study. Two nocturnal polysomnography (night 2 and 3 = N2 and N3) were carried out after a night of adaptation. A series of neuropsychological tests were performed by the subjects in the morning and afternoon of the second day (D2am; D2pm) and in the morning of the third day (D3am). Raw scores from the neuropsychological tests were used as dependent variables in the statistical analysis of the results. RESULTS: We computed a series of partial correlations between sleep microstructure parameters (CAP, A1, A2 and A3 rate) and a number of indices of cognitive functioning. CAP rate was positively correlated with visuospatial working memory (Corsi block test), Trial Making Test Part A (planning and motor sequencing) and the retention of words from the Hopkins Verbal Learning Test (HVLT). Conversely, CAP was negatively correlated with visuospatial fluency (Ruff Figure Fluency Test). CAP A1 were correlated with many of the tests of neuropsychological functioning, such as verbal fluency (as measured by the COWAT), working memory (as measured by the Digit Span – Backward test), and both delay recall and retention of the words from the HVLT. The same parameters were found to be negatively correlated with CAP A2 subtypes. CAP 3 were negatively correlated with the Trial Making Test Parts A and B. DISCUSSION: To our knowledge this is the first study indicating a role of CAP A1 and A2 on behavioral cognitive performance of healthy adults. The results suggest that high rate of CAP A1 might be related to an improvement whereas high rate of CAP A2 to a decline of cognitive functions. Further studies need to be done to better determine the role of the overall CAP rate and CAP A3 on cognitive behavioral performances.

Longitudinal evolution of cognitive functions in patients with multiple system atrophy: a prospective study

Introduction and Background: Multiple system atrophy (MSA) is a sporadic, adult-onset, progressive neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, and autonomic failure. We investigated cognitive functions longitudinally in a group of probable MSA patients, matching data with sleep parameters. Patients and Methods: 10 patients (7m/3f) underwent a detailed interview, a general and neurological examination, laboratory exams, MRI scans, a cardiovascular reflexes study, a battery of neuropsychological tests, and video-polysomnographic recording (VPSG). Patients were revaluated (T1) a mean of 16±5 (range: 12-28) months after the initial evaluation (T0). At T1, the neuropsychological assessment and VPSG were repeated. Results: The mean patient age was 57.8±6.4 years (range: 47-64) with a mean age at disease onset of 53.2±7.1 years (range: 43-61) and symptoms duration at T0 of 60±48 months (range: 12-144). At T0, 7 patients showed no cognitive deficits while 3 patients showed isolated cognitive deficits. At T1, 1 patient worsened developing multiple cognitive deficits from a normal condition. At T0 and T1, sleep efficiency was reduced, REM latency increased, NREM sleep stages 1-2 slightly increased. Comparisons between T1 and T0 showed a significant worsening in two tests of attention and no significant differences of VPSG parameters. No correlation was found between neuropsychological results and VPSG findings or RBD duration. Discussion and Conclusions: The majority of our patients do not show any cognitive deficits at T0 and T1, while isolated cognitive deficits are present in the remaining patients. Attention is the cognitive function which significantly worsened. Our data confirm the previous findings concerning the prevalence, type and the evolution of cognitive deficits in MSA. Regarding the developing of a condition of dementia, our data did not show a clear-cut diagnosis of dementia. We confirm a mild alteration of sleep structure. RBD duration does not correlate with neuropsychological findings.

Studio longitudinale sulle capacità cognitive del cane: discriminazione di quantità ed apprendimento per imitazione in relazione all'attaccamento

Il presente studio ha indagato e valutato alcune abilità cognitive del cane: la capacità di discriminare quantità e le capacità di apprendimento mediante imitazione; quest’ultima è poi stata messa in relazione con l’attaccamento nei confronti del proprietario. Per l’esecuzione della prima indagine sono stati messi appunto due test: il primo si è basato esclusivamente sulla presentazione di uno stimolo visivo: diversi quantitativi di cibo, differenti tra loro del 50%, sono stati presentati al cane; la scelta effettuata dai soggetti testati è stata premiata con differenti tipi di rinforzo differenziale o non differenziale. Il secondo test è stato diviso in due parti: sono stati presentati al cane diversi quantitativi di cibo sempre differenti tra loro del 50% ma nella prima parte del test l’input sensoriale per il cane è stato esclusivamente uditivo mentre nella seconda parte è stato sia uditivo che visivo. Ove è stato possibile è stato applicato ai cani un cardiofrequenzimetro al fine di eseguire una valutazione delle variazioni della frequenza cardiaca nel corso del test. Lo scopo è stato quello di valutare se i soggetti testati erano in grado di discriminare la quantità maggiore. La seconda indagine ha analizzato le capacità di apprendimento di 36 soggetti che sono stati suddivisi in cani da lavoro e pet. I soggetti protagonisti dello studio hanno eseguito il Mirror Test per la valutazione dell’apprendimento per imitazione. I soggetti presi in considerazione, sono stati sottoposti a scansione termografica all’inizio ed al termine del test ed è stata rilevata la loro frequenza respiratoria nella fase iniziale e finale del test. In 11 soggetti che hanno eseguito il precedente test è stato possibile eseguire anche il Strange Situation Test per la valutazione dell’attaccamento al proprietario; i test in questione sono stati videoregistrati ed analizzati per mezzo di un software preposto (OBSERVER XT 10).