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The aim of this meta-analysis is twofold: (a) to assess cognitive impairments in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients compared to healthy controls (HC); (b) to quantitatively estimate the risk of developing a neurodegenerative disease in iRBD patients according to baseline cognitive assessment. To address the first aim, cross-sectional studies including polysomnography-confirmed iRBD patients, HC, and reporting neuropsychological testing were included. To address the second aim, longitudinal studies including polysomnography-confirmed iRBD patients, reporting baseline neuropsychological testing for converted and still isolated patients separately were included. The literature search was conducted based on PRISMA guidelines and the protocol was registered at PROSPERO (CRD42021253427). Cross-sectional and longitudinal studies were searched from PubMed, Web of Science, Scopus, and Embase databases. Publication bias and statistical heterogeneity were assessed respectively by funnel plot asymmetry and using I-2. Finally, a random-effect model was performed to pool the included studies. 75 cross-sectional (2,398 HC and 2,460 iRBD patients) and 11 longitudinal (495 iRBD patients) studies were selected. Cross-sectional studies showed that iRBD patients performed significantly worse in cognitive screening scores (random-effects (RE) model = -0.69), memory (RE model = -0.64), and executive function (RE model = -0.50) domains compared to HC. The survival analyses conducted for longitudinal studies revealed that lower executive function and language performance, as well as the presence of mild cognitive impairment (MCI), at baseline were associated with an increased risk of conversion at follow-up. Our study underlines the importance of a comprehensive neuropsychological assessment in the context of iRBD.

Rhythm and vocal production learning are building blocks of human music and speech. Vocal learning has been hypothesized as a prerequisite for rhythmic capacities. Yet, no mammalian vocal learner but humans have shown the capacity to flexibly and spontaneously discriminate rhythmic patterns. Here we tested untrained rhythm discrimination in a mammalian vocal learning species, the harbour seal ( Phoca vitulina ). Twenty wild-born seals were exposed to music-like playbacks of conspecific call sequences varying in basic rhythmic properties. These properties were called length, sequence regularity, and overall tempo. All three features significantly influenced seals' reaction (number of looks and their duration), demonstrating spontaneous rhythm discrimination in a vocal learning mammal. This finding supports the rhythm–vocal learning hypothesis and showcases pinnipeds as promising models for comparative research on rhythmic phylogenies.

BACKGROUND: Two distinct insomnia disorder (ID) phenotypes have been proposed, distinguished on the basis of an objective total sleep time less or more than 6 hr. In particular, it has been recently reported that patients with objective short sleep duration have a blunted response to cognitive behavioral therapy for insomnia (CBT-I). The aim of this study was to investigate the differences of CBT-I response in two groups of ID patients subdivided according to total sleep time.METHODS: Two hundred forty-six ID patients were subdivided into two groups, depending on their reported total sleep time (TST) assessed by sleep diaries. Patients with a TST greater than 6 hr were classified as "normal sleepers" (NS), while those with a total sleep time less than 6 hr were classified as "short sleepers" (SS).RESULTS: The delta between Insomnia Severity Index scores and sleep efficiency at the beginning as compared to the end of the treatment was significantly higher for SS in comparison to NS, even if they still exhibit more insomnia symptoms. No difference was found between groups in terms of remitters; however, more responders were observed in the SS group in comparison to the NS group.CONCLUSIONS: Our results demonstrate that ID patients with reported short total sleep time had a beneficial response to CBT-I of greater magnitude in comparison to NS. However, these patients may still experience the presence of residual insomnia symptoms after treatment.

The ability to discriminate between familiar and unfamiliar calls may play a key role in pinnipeds’ communication and survival, as in the case of mother-pup interactions. Vocal discrimination abilities have been suggested to be more developed in pinniped species with the highest selective pressure such as the otariids; yet, in some group-living phocids, such as harbor seals (Phoca vitulina), mothers are also able to recognize their pup’s voice. Conspecifics’ vocal recognition in pups has never been investigated; however, the repeated interaction occurring between pups within the breeding season suggests that long-term vocal discrimination may occur. Here we explored this hypothesis by presenting three rehabilitated seal pups with playbacks of vocalizations from unfamiliar or familiar pups. It is uncommon for seals to come into rehabilitation for a second time in their lifespan, and this study took advantage of these rare cases. A simple visual inspection of the data plots seemed to show more reactions, and of longer duration, in response to familiar as compared to unfamiliar playbacks in two out of three pups. However, statistical analyses revealed no significant difference between the experimental conditions. We also found no significant asymmetry in orientation (leftvs. right) towards familiar and unfamiliar sounds. While statistics do not support the hypothesis of an established ability to discriminate familiar vocalizations from unfamiliar ones in harbor seal pups, further investigations with a larger sample size are needed to confirm or refute this hypothesis.

N.H. is supported by funding from an International Max Planck Research School (IMPRS) for language sciences fellowship grant, and the work of N.H. and S.C.V. was supported by a Max Planck Research Group (MPRG) awarded to S.C.V. The work of L.V. and A.R. was supported by a Max Planck Research Group (MPRG) awarded to A.R. S.C.V. was also supported by a Human Frontiers Science Program (HFSP) Research grant (grant no. RGP0058/2016) and a UKRI Future Leaders Fellowship (grant no. MR/T021985/1). Comparative animal studies of complex behavioural traits, and their neurobiological underpinnings, can increase our understanding of their evolution, including in humans. Vocal learning, a potential precursor to human speech, is one such trait. Mammalian vocal learning is under-studied: most research has either focused on vocal learning in songbirds or its absence in non-human primates. Here, we focus on a highly promising model species for the neurobiology of vocal learning: grey seals (Halichoerus grypus). We provide a neuroanatomical atlas (based on dissected brain slices and magnetic resonance images), a labelled MRI template, a three-dimensional model with volumetric measurements of brain regions, and histological cortical stainings. Four main features of the grey seal brain stand out: (i) it is relatively big and highly convoluted; (ii) it hosts a relatively large temporal lobe and cerebellum; (iii) the cortex is similar to that of humans in thickness and shows the expected six-layered mammalian structure; (iv) there is expression of FoxP2 present in deeper layers of the cortex; FoxP2 is a gene involved in motor learning, vocal learning, and spoken language. Our results could facilitate future studies targeting the neural and genetic underpinnings of mammalian vocal learning, thus bridging the research gap from songbirds to humans and non-human primates. Our findings are relevant not only to vocal learning research but also to the study of mammalian neurobiology and cognition more in general. Postprint

The presence of vocal learning and rhythm capacities in only a few mammals drives a cross-species hypothesis in evolutionary neuroscience: vocal learning and rhythm perception and synchronization may be causally related. Harbor seals ( Phoca vitulina) are among these mammals, and their puppyhood is the most active vocal period in their lives. Building on both comparative psychology and animal behavior, this research integrates methods from human cognition with attention to species’ ecological sensory niches. We present data from seal pups in four different setups: recordings of semi-natural vocal interactions in (1) individual and (2) group settings, (3) playback experiments to elicit vocal responses, and (4) perceptual listening experiments to measure behavioral responses. We complement empirical data with agent-based computational modeling aimed at reverse-engineering the putative mechanisms underlying rhythmic vocal interactions. Our data suggest that seal pups have developed capacities to produce and perceive rhythmic patterns. Seals’ vocal exchanges show rhythmic interactivity and antisynchronous coordination. Evidence for antisynchrony, rather than synchrony, in seals suggests that the rhythm-vocal learning link across species is more complex than previously surmised.

COVID-19, caused by SARS-CoV-2, has become a global threat in a matter of months. In particular, Italy has been one of the most affected areas worldwide. Data regarding the clinical picture and clinical course of COVID-19 are still lacking, especially in non-Asian populations. COVID-19 usually causes an influenza-like syndrome, including cough, fever, sore throat, muscle pain, and in some cases a more severe clinical picture, including interstitial pneumonia with acute respiratory distress syndrome, which may be fatal.1 Acute kidney failure has been reported in a substantial proportion of patients with COVID-19,1 2 but little is known regarding the mechanisms leading to kidney injury. Besides fluid depletion, which is expected to be common, a direct damage caused by the virus could be potentially responsible for kidney injury. In fact, as it has been recently hypothesised, SARS-CoV-2 may reach the kidney, as well as other organs, via viral sepsis.3 In turn, this process might be favoured by a defective immune response towards the virus, as in the case of patients treated with immunomodulant drugs, including biological therapies. The impact of COVID-19 in patients suffering from inflammatory bowel disease, particularly those treated with biological agents, is poorly characterised, and data are still emerging. We here describe the unique clinical course of a COVID-19 patient with Crohn’s disease (CD) under biological therapy who was admitted to our internal medicine unit for acute kidney injury. A 25-year-old man has been suffering from CD since the age of 18, when he underwent a colonoscopy that showed multiple ulcers …

The study of human language is progressively moving toward comparative and interactive frameworks, extending the concept of turn‐taking to animal communication. While such an endeavor will help us understand the interactive origins of language, any theoretical account for cross‐species turn‐taking should consider three key points. First, animal turn‐taking must incorporate biological studies on animal chorusing, namely how different species coordinate their signals over time. Second, while concepts employed in human communication and turn‐taking, such as intentionality, are still debated in animal behavior, lower level mechanisms with clear neurobiological bases can explain much of animal interactive behavior. Third, social behavior, interactivity, and cooperation can be orthogonal, and the alternation of animal signals need not be cooperative. Considering turn‐taking a subset of chorusing in the rhythmic dimension may avoid overinterpretation and enhance the comparability of future empirical work., The study of human language is progressively moving toward comparative and interactive frameworks. While such an endeavor will help us understand the interactive origins of language, any theoretical account for cross‐species turn‐taking should consider three key points. First, animal turn‐taking must incorporate biological studies on animal chorusing. Second, lower‐level mechanisms with clear neurobiological bases can explain much of animal interactive behavior. Third, social behavior, interactivity, and cooperation can be orthogonal.

TO THE EDITOR: Diagnosis of amyloidosis, with the possible exception of cardiac transthyretin amyloidosis (ATTR) in patients without monoclonal components,[1][1] requires demonstration of tissue amyloid deposits and identification of the amyloidogenic protein.[2][2],[3][3] The gold standard for

In a multi- and inter-cultural world, we daily encounter new words. Adult learners often rely on a situational context to learn and understand a new word's meaning. Here, we explored whether interactive learning facilitates word learning by directing the learner's attention to a correct new word referent when a situational context is non-informative. We predicted larger involvement of inferior parietal, frontal, and visual cortices involved in visuo-spatial attention during interactive learning. We scanned participants while they played a visual word learning game with and without a social partner. As hypothesized, interactive learning enhanced activity in the right Supramarginal Gyrus when the situational context provided little information. Activity in the right Inferior Frontal Gyrus during interactive learning correlated with post-scanning behavioral test scores, while these scores correlated with activity in the Fusiform Gyrus in the non-interactive group. These results indicate that attention is involved in interactive learning when the situational context is minimal and suggest that individual learning processes may be largely different from interactive ones. As such, they challenge the ecological validity of what we know about individual learning and advocate the exploration of interactive learning in naturalistic settings.

Several studies report an association between REM Sleep Behavior Disorder (RBD) and neurodegenerative diseases, in particular synucleinopathies. Interestingly, the onset of RBD precedes the development of neurodegeneration by several years. This review and meta-analysis aims to establish the rate of conversion of RBD into neurodegenerative diseases. Longitudinal studies were searched from the PubMed, Web of Science, and SCOPUS databases. Using random-effect modeling, we performed a meta-analysis on the rate of RBD conversions into neurodegeneration. Furthermore, we fitted a Kaplan-Meier analysis and compared the differences between survival curves of different diseases with log-rank tests. The risk for developing neurodegenerative diseases was 33.5% at five years follow-up, 82.4% at 10.5 years and 96.6% at 14 years. The average conversion rate was 31.95% after a mean duration of follow-up of 4.75±2.43 years. The majority of RBD patients converted to Parkinson's Disease (43%), followed by Dementia with Lewy Bodies (25%). The estimated risk for RBD patients to develop a neurodegenerative disease over a long-term follow-up is more than 90%. Future studies should include control group for the evaluation of REM sleep without atonia as marker for neurodegeneration also in non-clinical population and target RBD as precursor of neurodegeneration to develop protective trials.

Background Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII. Case presentation Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (−) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype. Conclusions This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis.

Despite great efforts, it is not known which oligomeric population of amyloid beta (Aß) peptides is the main neurotoxic mediator in Alzheimer's disease. In vitro and in vivo experiments are challenging, mainly because of the high aggregation tendency of Aß (in particular of Aß 1–42 peptide), as well as because of the dynamic and non covalent nature of the prefibrillar aggregates. As a step forward in these studies, an analytical platform is here proposed for the identification and characterization of Aß 1–42 oligomeric populations resulting from three different sample preparation protocols. To preserve the transient nature of aggregates, capillary electrophoresis is employed for monitoring the oligomerization process in solution until fibril precipitation, which is probed by transmission electron microscopy. Based on characterization studies by ultrafiltration and SDS-PAGE/Western Blot, we find that low molecular weight oligomers build up over time and form bigger aggregates (> dodecamers) and that the kinetics strongly depends on sample preparations. The use of phosphate buffer results to be more aggregating, since trimers are the smallest species found in solution, whereas monomers and dimers are obtained by solubilizing Aß 1–42 in a basic mixture. For the first time, attenuated total reflection-Fourier transform infrared spectroscopy is used to assign secondary structure to the separated oligomers. Random coil and/or α-helix are most abundant in smaller species, whereas ß-sheet is the predominant conformation in bigger aggregates, which in turn are demonstrated to be responsible for Aß 1–42 toxicity.

Summary Aims We recently described multifunctional tools (2a–c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. Methods We determined the inhibitory potency of 2a–c on Aβ1–42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-preformed fibrils were computationally analyzed. 2a–c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Results Our prototypical pluripotent analogue 2a interferes with Aβ oligomerization process thus reducing Aβ oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. Conclusion Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1–42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

A major challenge in second language acquisition is to build up new vocabulary. How is it possible to identify the meaning of a new word among several possible referents? Adult learners typically use contextual information, which reduces the number of possible referents a new word can have. Alternatively, a social partner may facilitate word learning by directing the learner's attention toward the correct new word meaning. While much is known about the role of this form of 'joint attention' in first language acquisition, little is known about its efficacy in second language acquisition. Consequently, we introduce and validate a novel visual word learning game to evaluate how joint attention affects the contextual learning of new words in a second language. Adult learners either acquired new words in a constant or variable sentence context by playing the game with a knowledgeable partner, or by playing the game alone on a computer. Results clearly show that participants who learned new words in social interaction (i) are faster in identifying a correct new word referent in variable sentence contexts, and (ii) temporally coordinate their behavior with a social partner. Testing the learned words in a post-learning recall or recognition task showed that participants, who learned interactively, better recognized words originally learned in a variable context. While this result may suggest that interactive learning facilitates the allocation of attention to a target referent, the differences in the performance during recognition and recall call for further studies investigating the effect of social interaction on learning performance. In summary, we provide first evidence on the role joint attention in second language learning. Furthermore, the new interactive learning game offers itself to further testing in complex neuroimaging research, where the lack of appropriate experimental set-ups has so far limited the investigation of the neural basis of adult word learning in social interaction.

A long-standing debate in cognitive neurosciences concerns the effect of music on verbal learning and memory. Research in this field has largely provided conflicting results in both clinical as well as non-clinical populations. Although several studies have shown a positive effect of music on the encoding and retrieval of verbal stimuli, music has also been suggested to hinder mnemonic performance by dividing attention. In an attempt to explain this conflict, we review the most relevant literature on the effects of music on verbal learning and memory. Furthermore, we specify several mechanisms through which music may modulate these cognitive functions. We suggest that the extent to which music boosts these cognitive functions relies on experimental factors, such as the relative complexity of musical and verbal stimuli employed. These factors should be carefully considered in further studies, in order to reliably establish how and when music boosts verbal memory and learning. The answers to these questions are not only crucial for our knowledge of how music influences cognitive and brain functions, but may have important clinical implications. Considering the increasing number of approaches using music as a therapeutic tool, the importance of understanding exactly how music works can no longer be underestimated.

Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of Aβ peptides into oligomers and fibrils, neuroinflammation, and oxidative stress. To date, no effective treatments are available, and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic Aβ oligomers, by shifting the equilibrium toward smaller nontoxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind Aβ structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and antioxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worthy to be further investigated and exploited in the Alzheimer's disease multitarget context.

Language is a multi-faceted form of communication. It is not until recently though that language research moved on from simple stimuli and protocols toward a more ecologically valid approach, namely "shifting" from words and simple sentences to stories with varying degrees of contextual complexity. While much needed, the use of ecologically valid stimuli such as stories should also be explored in interactive rather than individualistic experimental settings leading the way to an interactive neuroscience of language. Indeed, mounting evidence suggests that cognitive processes and their underlying neural activity significantly differ between social and individual experiences. We aim at reviewing evidence, which indicates that the characteristics of linguistic and extra-linguistic contexts may significantly influence communication - including spoken language comprehension. In doing so, we provide evidence on the use of new paradigms and methodological advancements that may enable the study of complex language features in a truly interactive, ecological way.

Perceptual and sensorimotor timing skills can be comprehensively assessed with the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). The battery has been used for testing rhythmic skills in healthy adults and patient populations (e.g., with Parkinson disease), showing sensitivity to timing and rhythm deficits. Here we assessed the test-retest reliability of the BAASTA in 20 healthy adults. Participants were tested twice with the BAASTA, implemented on a tablet interface, with a 2-week interval. They completed 4 perceptual tasks, namely, duration discrimination, anisochrony detection with tones and music, and the Beat Alignment Test (BAT). Moreover, they completed motor tasks via finger tapping, including unpaced and paced tapping with tones and music, synchronization-continuation, and adaptive tapping to a sequence with a tempo change. Despite high variability among individuals, the results showed stable test-retest reliability in most tasks. A slight but significant improvement from test to retest was found in tapping with music, which may reflect a learning effect. In general, the BAASTA was found a reliable tool for evaluating timing and rhythm skills.

Muscle involvement in AL amyloidosis is a rare condition, and the diagnosis of amyloid myopathy is often delayed and underdiagnosed. Amyloid myopathy may be the initial manifestation and may precede the diagnosis of systemic AL amyloidosis. Here, we report the case of a 73-year-old man who was referred to our center for a monoclonal gammopathy of undetermined significance (MGUS) diagnosed since 1999. He reported a progressive weakness of proximal muscles of the legs with onset six months previously. Muscle biopsy showed mild histopathology featuring alterations of nonspecific type with a mixed myopathic and neurogenic involvement, and the diagnostic turning point was the demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of perimysial vessels. Transmission electron microscopy (TEM) confirmed amyloid fibrils around perimysial vessels associated with collagen fibrils. A stepwise approach to diagnosis and staging of this disorder is critical and involves confirmation of amyloid deposition, identification of the fibril type, assessment of underlying amyloidogenic disorder, and evaluation of the extent and severity of amyloidotic organ involvement.

The Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA) is a new tool for the systematic assessment of perceptual and sensorimotor timing skills. It spans a broad range of timing skills aimed at differentiating individual timing profiles. BAASTA consists of sensitive time perception and production tasks. Perceptual tasks include duration discrimination, anisochrony detection (with tones and music), and a version of the Beat Alignment Task. Perceptual thresholds for duration discrimination and anisochrony detection are estimated with a maximum likelihood procedure (MLP) algorithm. Production tasks use finger tapping and include unpaced and paced tapping (with tones and music), synchronization-continuation, and adaptive tapping to a sequence with a tempo change. BAASTA was tested in a proof-of-concept study with 20 non-musicians (Experiment 1). To validate the results of the MLP procedure, less widespread than standard staircase methods, three perceptual tasks of the battery (duration discrimination, anisochrony detection with tones, and with music) were further tested in a second group of non-musicians using 2 down / 1 up and 3 down / 1 up staircase paradigms (n = 24) (Experiment 2). The results show that the timing profiles provided by BAASTA allow to detect cases of timing/rhythm disorders. In addition, perceptual thresholds yielded by the MLP algorithm, although generally comparable to the results provided by standard staircase, tend to be slightly lower. In sum, BAASTA provides a comprehensive battery to test perceptual and sensorimotor timing skills, and to detect timing/rhythm deficits.

The knowledge of the mechanism underlying the cardiac damage in immunoglobulin light chain (LC) amyloidosis (AL) is essential to develop novel therapies and improve patients' outcome. Although an active role of reactive oxygen species (ROS) in LC-induced cardiotoxicity has already been envisaged, the actual mechanisms behind their generation remain elusive. This study was aimed at further dissecting the action of ROS generated by cardiotoxic LC in vivo and investigating whether transition metal ions are involved in this process. In the absence of reliable vertebrate model of AL, we used the nematode Caenorhabditis elegans, whose pharynx is an "ancestral heart."LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and when administered to C. elegans induced ROS production, activation of the DAF-16/forkhead transcription factor (FOXO) pathway, and expression of proteins involved in stress resistance and survival. Profound functional and structural ROS-mediated mitochondrial damage, similar to that observed in amyloid-affected hearts from AL patients, was observed. All these effects were entirely dependent on the presence of metal ions since addition of metal chelator or metal-binding 8-hydroxyquinoline compounds (chelex, PBT2, and clioquinol) permanently blocked the ROS production and prevented the cardiotoxic effects of amyloid LC. Innovation and Conclusion: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance that paves the way for new pharmacological strategies aimed at not only counteracting but also totally inhibiting the vicious cycle of redox damage. Antioxid. Redox Signal. 27, 567-582.

The auditory scene is a mental representation of individual sounds extracted from the summed sound waveform reaching the ears of the listeners. Musical contexts represent particularly complex cases of auditory scenes. In such a scenario, melody may be seen as the main object moving on a background represented by the accompa- niment. Both melody and accompaniment vary in time according to harmonic rules, forming a typical texture with melody in the most prominent, salient voice. In the present sparse acquisition functional magnetic reso- nance imaging study, we investigated the interplay between melody and accompaniment in trained pianists, by observing the activation responses elicited by processing: (1) melody placed in the upper and lower texture voices, leading to, respectively, a higher and lower auditory salience; (2) harmonic violations occurring in either the melody, the accompaniment, or both. The results indicated that the neural activation elicited by the process- ing of polyphonic compositions in expert musicians depends upon the upper versus lower position of the melodic line in the texture, and showed an overall greater activation for the harmonic processing of melody over accom- paniment. Both these two predominant effects were characterized by the involvement of the posterior cingulate cortex and precuneus, among other associative brain regions. We discuss the prominent role of the posterior me- dial cortex in the processing of melodic and harmonic information in the auditory stream, and propose to frame this processing in relation to the cognitive construction of complex multimodal sensory imagery scenes.

In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (A beta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with A beta aggregation and with the A beta self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site These moieties are likely responsible for the observed reduction of hAChE-induced A beta aggregation since they physically hamper A beta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with A beta self-oligornerization, while 2b,c showed improved inhibition of hAChE-induced A beta aggregation.

Considering the important advances in treating specific types of systemic amyloidoses, unequivocal typing of amyloid deposits is now essential. Subcutaneous abdominal fat aspiration is the easiest, most common diagnostic procedure. We developed a novel, automated approach, based on Multidimensional Protein Identification Technology, for typing amyloidosis. Fat aspirates were obtained from patients with the most common systemic amyloidoses (ALλ, ALκ, transthyretin, and reactive amyloidosis), with Congo red score more than or equal to 3+, and nonaffected controls. Peptides from extracted and digested proteins were analyzed by Multidimensional Protein Identification Technology. On semiquantitative differential analysis (patients vs controls) of mass spectrometry data, specific proteins up-represented in patients were identified and used as deposit biomarkers. An algorithm was developed to classify patients according to type and abundance of amyloidogenic proteins in samples; in all cases, proteomic characterization was concordant with fibril identification by immunoelectron microscopy and consistent with clinical presentation. Our approach allows reliable amyloid classification using readily available fat aspirates.

Soluble and toxic oligomers of amyloid beta (A beta) protein have been identified as the true neurotoxic species involved in Alzheimer's disease and considering them as targets to inhibit A beta aggregation might have a therapeutic value. We previously set up a CE method that enables the separation and quantification of transient oligomers of A beta protein-containing 42 amino acids (A beta(1-42)) along the pathway leading to fibrils and we now demonstrate how this method can be successfully applied to examine the in vitro inhibitory effects of small molecules on A beta oligomerization. To this end, we investigated mitoxantrone and pixantrone, two well-known anticancer drugs, as well as suramin and a suramin-like compound. By using CE, it is here shown how mitoxantrone and pixantrone either reduce or block A beta(1-42) oligomerization, while Thioflavin T spectrofluorimetric assay and transmission electron microscopy demonstrate how these two compounds also display antifibrillogenic activity. Interestingly, in vitro cell viability experiments indicated that pixantrone significantly reduces A beta(1-42) neurotoxicity.

Learning new words is an increasingly common necessity in everyday life. External factors, among which music and social interaction are particularly debated, are claimed to facilitate this task. Due to their influence on the learner’s temporal behavior, these stimuli are able to drive the learner’s attention to the correct referent of new words at the correct point in time. However, do music and social interaction impact learning behavior in the same way? The current study aims to answer this question. Native German speakers (N = 80) were requested to learn new words (pseudo-words) during a contextual learning game. This learning task was performed alone with a computer or with a partner, with or without music. Results showed that music and social interaction had a different impact on the learner’s behavior: Participants tended to temporally coordinate their behavior more with a partner than with music, and in both cases more than with a computer. However, when both music and social interaction were present, this temporal coordination was hindered. These results suggest that while music and social interaction do influence participants’ learning behavior, they have a different impact. Moreover, impaired behavior when both music and a partner are present suggests that different mechanisms are employed to coordinate with the two types of stimuli. Whether one or the other approach is more efficient for word learning, however, is a question still requiring further investigation, as no differences were observed between conditions in a retrieval phase, which took place immediately after the learning session. This study contributes to the literature on word learning in adults by investigating two possible facilitating factors, and has important implications for situations such as music therapy, in which music and social interaction are present at the same time.

The diagnosis of amyloidosis requires that amyloid deposits are demonstrated in patient’s tissues. Congo red staining is still the most commonly used method to detect amyloid deposits. Nevertheless, the results of Congo red stain may be ambiguous, especially if it is performed in centers with limited expertise in its execution and/or interpretation. Furthermore, Congo red stain does not provide any information concerning the nature of amyloidogenic protein. The characterization of amyloid proteins by light microscopic immunohistochemistry in paraffin-embedded samples frequently yields nonspecific results. On the basis of our experience at the Amyloid Center and Pathology Unit of IRCCS Policlinico San Matteo/University of Pavia, the ultrastructural examination of abdominal fat aspirate and other tissue biopsies is capable of confirming or ruling out a diagnosis of amyloidosis and can detect even very small deposits of amyloid fibrils. Moreover, immuno-electron microscopy can correctly characterize the amyloidogenic protein in all the commonest forms of amyloidosis, i.e., AL, AA, ATTR, A(beta)2M, and AApoAI.

Knowledge on the chemical structure of beta2-microglobulin in natural amyloid fibrils is quite limited because of the difficulty in obtaining tissue samples suitable for biochemical studies. We have reviewed the available information on the chemical modifications and we present new data of beta2-microglobulin extracted from non-osteotendinous tissues. beta2-microglobulin can accumulate in these compartments after long-term haemodialysis but rarely forms amyloid deposits. We confirm that truncation at the N-terminus is an event specific to beta2-microglobulin derived from fibrils but is not observed in the beta2-microglobulin from plasma or from the insoluble non-fibrillar material deposited in the heart and spleen. We also confirm the partial deamidation of Asn 17 and Asn 42, as well as the oxidation of Met 99 in fibrillar beta2-microglobulin. Other previously reported chemical modifications cannot be excluded, but should involve less than 1-2% of the intact molecule.

We evaluated the role of electron microscopy and immuno-electron microscopy studies on abdominal fat fine-needle biopsy samples in diagnosis and characterization of cardiac amyloidosis. The series consists of 15 patients with echocardiographic evidence of "restrictive cardiomyopathy" suspected to be due to amyloidosis. Patients underwent: clinical examination, electrocardiography, 2-D and Doppler echocardiography, immunofixation of serum and urine for detection of monoclonal immunoglobulins, and abdominalfat biopsies that were investigated with polarized light (Congo red), electron and immuno-electron microscopy using specific antibodies to kappa and lambda light chains, apolipoprotein A1, serum amyloid A (SAA), and transthyretin (TTR). Ultrastructural study of abdominal fat samples identified amyloid deposits in 15/15 cases. Immuno-electron microscopy specifically stained amyloid fibrils with antibodies anti-lambda (n = 8), -kappa (n = 2), -apolipoprotein A1 (n = 2) and -TTR (n = 3). Immuno-electron microscopy revealed TTR immuno-labelling in 2 patients with accidental monoclonal components, and a A reaction in I patient without monoclonal components. TTR and apolipoprotein A1 positive cases carried missense mutations in the corresponding genes. Our results demonstrate that amyloid deposits are present in the abdominalfat of patients suspected to have cardiac amyloidosis and that immuno-electron microscopy was able to characterize the amyloid protein in all cases.

Accurate diagnosis of systemic amyloidosis is necessary both for assessing the prognosis and for delineating the appropriate treatment. It is based on histologic evidence of amyloid deposits and characterization of the amyloidogenic protein. We prospectively evaluated the diagnostic performance of immunoelectron microscopy (IEM) of abdominal fat aspirates from 745 consecutive patients with suspected systemic amyloidoses. All cases were extensively investigated with clinical and laboratory data, with a follow-up of at least 18 months. The 423 (56.8%) cases with confirmed systemic forms were used to estimate the diagnostic performance of IEM. Compared with Congo-red-based light microscopy, IEM was equally sensitive (75% to 80%) but significantly more specific (100% vs 80%; P.001). In amyloid light-chain (AL) amyloidosis, κ cases were more difficult to diagnose (sensitivity 71%), whereas the analysis of abdominal aspirate was informative in only 40% of patients with transthyretin amyloidosis. We found a high prevalence (20%) of a monoclonal component in patients with non-AL amyloidosis, highlighting the risk of misdiagnosis and the need for unequivocal amyloid typing. Notably, IEM identified correctly the specific form of amyloidosis in99% of the cases. IEM of abdominal fat aspirates is an effective tool in the routine diagnosis of systemic amyloidoses.

Amyloidoses are a group of rare diseases characterized by the extracellular deposition of amyloid fibrils in tissues and organs [1]. The kidney, heart, liver and the peripheral nervous system are predominantly involved, whereas the skin is only rarely affected. More than 28 proteins have been identified to date as amyloidogenic, causing either systemic or a localized, sporadic or hereditary disease. Among the hereditary systemic amyloidoses, the number of mutated proteins known to be amyloidogenic [...]