Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado-Joseph disease models.

Machado-Joseph disease (MJD) is a neurodegenerative disorder caused by an abnormal expansion of citosine-adenine-guanine trinucleotide repeats in the disease-causing gene. This mutation leads to an abnormal polyglutamine tract in the protein ataxin-3 (Atx3), resulting in formation of mutant Atx3 aggregates. Despite several attempts to develop a therapeutic option for MJD, currently there are no available therapies capable of delaying or stopping disease progression. Recently, our group reported that reducing the expression levels of mutant Atx3 lead to a mitigation of several MJD-related behavior and neuropathological abnormalities. Aiming a more rapid translation to the human clinics, in this study we investigate a pharmacological inhibitor of translation-cordycepin-in several preclinical models. We found that cordycepin treatment significantly reduced (i) the levels of mutant Atx3, (ii) the neuropathological abnormalities in a lentiviral mouse model, (iii) the motor and neuropathological deficits in a transgenic mouse model and (iv) the number of ubiquitin aggregates in a human neural model. We hypothesize that the effect of cordycepin is mediated by the increase of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) levels, which is accompanied by a reduction in the global translation levels and by a significant activation of the autophagy pathway. Overall, this study suggests that cordycepin might constitute an effective and safe therapeutic approach for MJD, and probably for the other polyglutamine diseases.

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

Game-based interventions for neuropsychological assessment, training and rehabilitation: Which game-elements to use? A systematic review.

Game-based interventions (GBI) have been used to promote health-related outcomes, including cognitive functions. Criteria for game-elements (GE) selection are insufficiently characterized in terms of their adequacy to patients' clinical conditions or targeted cognitive outcomes. This study aimed to identify GE applied in GBI for cognitive assessment, training or rehabilitation. A systematic review of literature was conducted. Papers involving video games were included if: (1) presenting empirical and original data; (2) using video games for cognitive intervention; and (3) considering attention, working memory or inhibitory control as outcomes of interest. Ninety-one papers were included. A significant difference between the number of GE reported in the assessed papers and those composing video games was found (p < .001). The two most frequently used GE were: score system (79.2% of the interventions using video games; for assessment, 43.8%; for training, 93.5%; and for rehabilitation, 83.3%) and narrative context (79.2% of interventions; for assessment, 93.8%; for training, 73.9% and for rehabilitation, 66.7%). Usability assessment was significantly associated with six of the seven GE analyzed (p-values between p ≤ 0.001 and p. = 027). The use of GE that act as extrinsic motivation promotors (e.g., numeric feedback system) may jeopardize patients' long-term adherence to interventions, mainly if associated with progressive difficulty-increase of gaming experience. Lack of precise description of GE and absence of a theoretical framework supporting GE selection are important limitations of the available clinical literature.

Digital health and patient adherence: A qualitative study in older adults.

Introduction: Computer confidence and computer self-efficacy can impact an individual's perceived ease of use and usefulness of technology, ultimately determining adherence to digital healthcare services. However, few studies focus on assessing the impact of non-clinical factors on the efficacy and adherence to digital healthcare platforms. Objective: We aimed to analyse the role of non-clinical factors (i.e. computer confidence and computer self-efficacy) in the interaction experience (IX) and the feasibility of a digital neuropsychological platform called NeuroVRehab.PT in a group of older adults with varying levels of computer confidence. Methods: Eight older adults (70.63 ± 6.1 years) evaluated the platform, and data was collected using the Think-Aloud method and a semi-structured interview. Sessions were audio-recorded and analysed through an inductive-deductive informed Thematic Analysis protocol. This study was conducted according to the Consolidated Criteria for Reporting Qualitative Research guidelines. Results: Three main themes were identified (Interaction Experience, Digital Literacy, and Attitudes toward NeuroVRehab.PT). Computer anxiety and fear of making errors were not uncommon, even among older adults who perceive themselves as confident in technology use, and negatively impacted IX. Moreover, some game elements (e.g. three-star system, progression bar) were not intuitive to all participants, leading to misleading interpretations. On the other hand, human support and the platform's realism seemed to impact participants' IX positively. Conclusions: This study shed light on the barriers raised by non-clinical factors in adopting and using digital healthcare services by older adults. Furthermore, a critical analysis of the platform's features that promote user adoption is done, and suggestions for overcoming limitations are presented.

Widespread, Specific, and Efficient Transgene Expression in Oligodendrocytes After Intracerebral and Intracerebroventricular Delivery of Viral Vectors in Rodent Brain.

Several neurodegenerative disorders are characterized by oligodendroglial pathology and myelin loss. Oligodendrogliopathies are a group of rare diseases for which there currently is no therapy. Gene delivery through viral vectors to oligodendrocytes is a potential strategy to deliver therapeutic molecules to oligodendrocytes for disease modification. However, targeting oligodendroglial cells in vivo is challenging due to their widespread distribution in white and gray matter. In this study, we aimed to address several of these difficulties by designing and testing different oligodendroglial targeting vectors in rat and mouse brain, utilizing different promoters, serotypes, and delivery routes. We found that different oligodendroglial promoters (myelin basic protein [MBP], cytomegalovirus-enhanced MBP, and myelin-associated glycoprotein [MAG]) vary considerably in their ability to drive oligodendroglial transgene expression and different viral vector serotypes (rAAV2/7, rAAV2/8, and rAAV2/9) exhibit varying efficacies in transducing oligodendrocytes. Different administration routes through intracerebral or intraventricular injection allow widespread targeting of mature oligodendrocytes. Delivery of rAAV2/9-MAG-GFP into the cerebrospinal fluid results in GFP expression along the entire rostrocaudal axis of the spinal cord. Collectively, these results show that oligodendrocytes can be targeted with high specificity and widespread expression, which will be useful for gene therapeutic interventions or disease modeling purposes.

Are Video Games Effective to Promote Cognition and Everyday Functional Capacity in Mild Cognitive Impairment/Dementia Patients? A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Mild cognitive impairment (MCI) and dementia are associated with increased age. MCI is a clinical entity described as a transitional state between normal cognition and dementia. Video games (VGs) can potentially promote cognition and functional capacity since multiple cognitive domains are recruited during gameplay. However, there is still a lack of consensus regarding the efficacy of VGs as therapeutic tools, particularly in neurodegenerative diseases. OBJECTIVE: We aimed to analyze the impact of VGs on cognition and functional capacity outcomes in MCI/dementia patients. METHODS: We conducted a systematic review and meta-analysis study (PROSPERO [CRD42021229445]). PubMed, Web of Science, Epistemonikos, CENTRAL, and EBSCO electronic databases were searched for RCT (2000-2021) that analyzed the impact of VGs on cognitive and functional capacity outcomes in MCI/dementia patients. RESULTS: Nine studies were included (n = 409 participants), and Risk of Bias (RoB2) and quality of evidence (GRADE) were assessed. Data regarding attention, memory/learning, visual working memory, executive functions, general cognition, functional capacity, quality of life were identified, and pooled analyses were conducted. An effect favoring VGs interventions was observed on Mini-Mental State Examination (MMSE) score (MD = 1.64, 95%CI 0.60 to 2.69). CONCLUSION: Although promising, the effects observed should be interpreted with caution since serious methodological shortcomings were identified in the studies included. Nonetheless, the effect observed is higher than the minimum clinically important difference (1.4 points) established to MMSE. Future studies on the current topic urge. Recommendations for the design and conduction of cognitive RCT studies are presented.

Dissecting Digital Card Games to Yield Digital Biomarkers for the Assessment of Mild Cognitive Impairment: Methodological Approach and Exploratory Study.

BACKGROUND: Mild cognitive impairment (MCI), the intermediate cognitive status between normal cognitive decline and pathological decline, is an important clinical construct for signaling possible prodromes of dementia. However, this condition is underdiagnosed. To assist monitoring and screening, digital biomarkers derived from commercial off-the-shelf video games may be of interest. These games maintain player engagement over a longer period of time and support longitudinal measurements of cognitive performance. OBJECTIVE: This paper aims to explore how the player actions of Klondike Solitaire relate to cognitive functions and to what extent the digital biomarkers derived from these player actions are indicative of MCI. METHODS: First, 11 experts in the domain of cognitive impairments were asked to correlate 21 player actions to 11 cognitive functions. Expert agreement was verified through intraclass correlation, based on a 2-way, fully crossed design with type consistency. On the basis of these player actions, 23 potential digital biomarkers of performance for Klondike Solitaire were defined. Next, 23 healthy participants and 23 participants living with MCI were asked to play 3 rounds of Klondike Solitaire, which took 17 minutes on average to complete. A generalized linear mixed model analysis was conducted to explore the differences in digital biomarkers between the healthy participants and those living with MCI, while controlling for age, tablet experience, and Klondike Solitaire experience. RESULTS: All intraclass correlations for player actions and cognitive functions scored higher than 0.75, indicating good to excellent reliability. Furthermore, all player actions had, according to the experts, at least one cognitive function that was on average moderately to strongly correlated to a cognitive function. Of the 23 potential digital biomarkers, 12 (52%) were revealed by the generalized linear mixed model analysis to have sizeable effects and significance levels. The analysis indicates sensitivity of the derived digital biomarkers to MCI. CONCLUSIONS: Commercial off-the-shelf games such as digital card games show potential as a complementary tool for screening and monitoring cognition. TRIAL REGISTRATION: ClinicalTrials.gov NCT02971124; https://clinicaltrials.gov/ct2/show/NCT02971124.

Photo-Realistic Interactive Virtual Environments for Neurorehabilitation in Mild Cognitive Impairment (NeuroVRehab.PT): A Participatory Design and Proof-of-Concept Study.

Mild cognitive impairment (MCI) is characterized by cognitive, psychological, and functional impairments. Digital interventions typically focus on cognitive deficits, neglecting the difficulties that patients experience in instrumental activities of daily living (IADL). The global conjecture created by COVID-19 has highlighted the seminal importance of digital interventions for the provision of healthcare services. Here, we investigated the feasibility and rehabilitation potential of a new design approach for creating highly realistic interactive virtual environments for MCI patients' neurorehabilitation. Through a participatory design protocol, a neurorehabilitation digital platform was developed using images captured from a Portuguese supermarket (NeuroVRehab.PT). NeuroVRehab.PT's main features (e.g., medium-sized supermarket, the use of shopping lists) were established according to a shopping behavior questionnaire filled in by 110 older adults. Seven health professionals used the platform and assessed its rehabilitation potential, clinical applicability, and user experience. Interviews were conducted using the think-aloud method and semi-structured scripts, and four main themes were derived from an inductive semantic thematic analysis. Our findings support NeuroVRehab.PT as an ecologically valid instrument with clinical applicability in MCI neurorehabilitation. Our design approach, together with a comprehensive analysis of the patients' past experiences with IADL, is a promising technique to develop effective digital interventions to promote real-world functioning.