Search Results (641)

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

Background/Objectives: Neuropsychological assessments are valuable tools for evaluating the cognitive performance of older adults. Limitations associated with these in-person paper-and-pencil tests have inspired efforts to develop digital assessments, which would expand access to cognitive screening. Digital tests, however, often lack validity relative to gold-standard paper-and-pencil versions that have been robustly validated. Speech-to-text (STT) technology has the potential to improve the validity of digital tests through its ability to capture verbal responses, yet the effect of its performance on standardized scores used for cognitive characterization is unknown. Methods: The present study evaluated the accuracy of Apple’s STT engine relative to ground-truth transcriptions (RQ1), as well as the effect of the engine’s transcription errors on resulting standardized scores (RQ2). Our study analyzed data from 223 older adults who completed a digital assessment on an iPad that used STT to transcribe and score task responses. These automated transcriptions were then compared against ground-truth transcriptions that were human-corrected via external recordings. Results: Results showed differences between STT and ground-truth transcriptions (RQ1). Nevertheless, these differences were not large enough to practically affect standardized measures of cognitive performance (RQ2). Conclusions: Our results demonstrate the practical utility of Apple’s STT engine for digital neuropsychological assessment and cognitive characterization. These findings support the possibility that speech-to-text, with its ability to capture and process verbal responses, will be a viable tool for increasing the validity of digital neuropsychological assessments. Full article

Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer’s dementia or consequent to Parkinson’s disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms. Full article

Objectives: Neurocognitive disorders (NCDs) refer to a broad spectrum of conditions characterized by declining cognitive functions, such as memory, attention, language, and executive abilities. It is estimated that up to half of patients affected by NCDs remain undiagnosed or are diagnosed at an advanced stage of the disease. This study aimed to analyze the utility of subclinical organ damage markers, which could be used in primary care for the detection and prevention of NCD. Methods: The study participants (n = 137) completed neuropsychological tests (Addenbrooke’s Cognitive Examination/ACE and Mini-Mental State Examination/MMSE), a sociodemographic survey, an interview on past illnesses, and had their ankle-brachial index (ABI) and pulse wave velocity (PWV) values measured. Results: Based on the MMSE test, 26 participants (19.0%) were diagnosed with mild cognitive impairment (MCI) and 8 participants (5.8%) with NCDs. The study found that lower ABI values were associated with worse cognitive performance, suggesting that the ABI may be a useful tool for identifying individuals at increased risk of NCDs, while PWV cannot be used as a predictor for this group of diseases. Conclusions: Lower ABI values were associated with reduced cognitive performance, whereas PWV showed no significant relationship. The secondary findings suggest that physical activity, regular computer use, and better mental well-being were linked to improved cognitive outcomes. A low ABI value could potentially serve as a predictor of cognitive disorders, and as a diagnostic tool that is easily accessible and quick, it may improve diagnostics and the overall health of primary care patients. Health education regarding modifiable risk factors for dementia is also of crucial importance. Full article

COVID-19 infection is often accompanied by psychological symptoms, which may persist long after the end of the infection (long COVID). The symptoms include fatigue, cognitive impairment, and anxiety. The reason for these long-term effects is currently unclear. Therapeutic approaches have included cognitive rehabilitation therapy, physical activity, and serotonin reuptake inhibitors (SSRIs) if depression co-exists. The neuropsychological evaluation of subjects with suspected cognitive issues is essential for the correct diagnosis. Most of the COVID-19 studies used the Montreal Cognitive Assessment (MoCA) or the Mini Mental State Examination (MMSE). However, MoCA scores can be confusing if not interpreted correctly. For this reason, we have developed an original technique to map cognitive domains and motor performance on various brain areas in COVID-19 patients aiming at improving the follow-up of long-COVID-19 symptoms. To this end, we retrospectively reanalyzed data from a cohort of 40 patients hospitalized for COVID-19 without requiring intubation or hemodialysis. Cognitive function was tested during hospitalization and six months after. Global cognitive function and cognitive domains were retrieved using MoCA tests. Laboratory data were retrieved regarding kidney function, electrolytes, acid–base, blood pressure, TC score, and P/F ratio. The dimensionality of cognitive functions was represented over cortical brain structures using a transformation matrix derived from fMRI data from the literature and the Cerebroviz mapping tool. Memory function was linearly dependent on the P/F ratio. We also used the UMAP method to reduce the dimensionality of the data and represent them in low-dimensional space. Six months after hospitalization, no cases of severe cognitive deficit persisted, and the number of moderate cognitive deficits reduced from 14% to 4%. Most cognitive domains (visuospatial abilities, executive functions, attention, working memory, spatial–temporal orientation) improved over time, except for long-term memory and language skills, which remained reduced or slightly decreased. The Cerebroviz algorithm helps to visualize which brain regions might be involved in the process. Many patients with COVID-19 continue to suffer from a subclinical cognitive deficit, particularly in the memory and language domains. Cerebroviz’s representation of the results provides a new tool for visually representing the data. Full article

Background/Objectives: Behavioral variant frontotemporal dementia (bvFTD), the most prevalent clinical subtype within the frontotemporal lobar degeneration spectrum disorders, is characterized by early and prominent changes that significantly disrupt everyday functioning. This study aims to identify the key correlates of functional status in bvFTD by investigating the relative contributions of cognitive deficits, behavioral disturbances, personality changes, and brain perfusion abnormalities. Additionally, it seeks to develop a theoretical framework to elucidate how these factors may interconnect and shape unique functional profiles. Methods: A total of 26 individuals diagnosed with bvFTD were recruited from the 2nd Neurology Clinic of “AHEPA” University Hospital in Thessaloniki, Greece, and underwent a comprehensive neuropsychological assessment to evaluate their cognitive functions. Behavioral disturbances, personality traits, and functional status were rated using informant-based measures. Regional cerebral blood flow was assessed using Single Photon Emission Computed Tomography (SPECT) imaging to evaluate brain perfusion patterns. Penalized Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was performed to identify the most robust correlates of functional impairment, followed by path analyses using structural equation modeling to explore how these factors may interrelate and contribute to functional disability. Results: The severity of negative behavioral symptoms (e.g., apathy), conscientiousness levels, and performance on neuropsychological measures of semantic verbal fluency, visual attention, visuomotor speed, and global cognition were identified as the strongest correlates of performance in activities of daily living. Neuroimaging analysis revealed hypoperfusion in the right prefrontal (Brodmann area 8) and inferior parietal (Brodmann area 40) cortices as statistically significant neural correlates of functional impairment in bvFTD. Path analyses indicated that reduced brain perfusion was associated with attentional and processing speed deficits, which were further linked to more severe negative behavioral symptoms. These behavioral disturbances were subsequently correlated with declines in global cognition and conscientiousness, which were ultimately associated with poorer daily functioning. Conclusions: Hypoperfusion in key prefrontal and parietal regions, along with the subsequent cognitive and neuropsychiatric manifestations, appears to be associated with the pronounced functional limitations observed in individuals with bvFTD, even in early stages. Understanding the key determinants of the disease can inform the development of more targeted, personalized treatment strategies aimed at mitigating functional deterioration and enhancing the quality of life for affected individuals. Full article

Background: The aim of this study was to systematically explore point-of-care biomarkers as diagnostic indicators for the detection and exclusion of mild traumatic brain injury (mTBI) in an emergency room (ER) setting using Eye-Tracking and Virtual Reality (ET/VR) technology. The primary target group included patients who had suffered an acute trauma to the head and presented within 24 h to the emergency department. Methods: The BG Unfallkrankenhaus Berlin and the BG Klinikum Hamburg participated in this explorative, prospective, single-arm accuracy study. This study included patients who presented to the emergency department with suspected mTBI and were examined using ET/VR glasses. All further steps corresponded to clinical routine (e.g., decision on hospital admission, imaging diagnostics). After the completion of treatment, the patients were divided into mTBI and non-TBI subgroups by consensus between two independent clinical experts, who were blinded to the results of the index test (examination using ET/VR glasses) in the form of a clinical synopsis. The diagnosis was based on all clinical, neurological, neurofunctional, neuropsychological, and imaging findings. Routine trauma and neurological history, examination, and diagnosis were performed in each case. All statistical analyses were performed with exploratory intent. Results: The use of ET/VR glasses was found to be predominantly unproblematic. Two of the fifty-two analyzed parameters can be statistically distinguished from a random decision. No difference in oculomotor function was found between the two subgroups, and no correlations between the parameters recorded by the VR goggles and the detection of mTBI were found. Conclusions: At present, the use of VR goggles for the diagnosis of mTBI in an ER setting cannot be recommended. Full article

(1) Background: The convergence of digital twin technology, artificial intelligence, and multimodal biomarkers heralds a transformative era in neuropsychological assessment and intervention. Digital twin cognition represents an emerging paradigm that creates dynamic, personalized virtual models of individual cognitive systems, enabling continuous monitoring, predictive modeling, and precision interventions. This systematic review comprehensively examines the integration of AI-driven biomarkers within biomimetic neuropsychological frameworks to advance personalized cognitive health. (2) Methods: Following PRISMA 2020 guidelines, we conducted a systematic search across six major databases spanning medical, neuroscience, and computer science disciplines for literature published between 2014 and 2024. The review synthesized evidence addressing five research questions examining framework integration, predictive accuracy, clinical translation, algorithm effectiveness, and neuropsychological validity. (3) Results: Analysis revealed that multimodal integration approaches combining neuroimaging, physiological, behavioral, and digital phenotyping data substantially outperformed single-modality assessments. Deep learning architectures demonstrated superior pattern recognition capabilities, while traditional machine learning maintained advantages in interpretability and clinical implementation. Successful frameworks, particularly for neurodegenerative diseases and multiple sclerosis, achieved earlier detection, improved treatment personalization, and enhanced patient outcomes. However, significant challenges persist in algorithm interpretability, population generalizability, and the integration of healthcare systems. Critical analysis reveals that high-accuracy claims (85–95%) predominantly derive from small, homogeneous cohorts with limited external validation. Real-world performance in diverse clinical settings likely ranges 10–15% lower, emphasizing the need for large-scale, multi-site validation studies before clinical deployment. (4) Conclusions: Digital twin cognition establishes a new frontier in personalized neuropsychology, offering unprecedented opportunities for early detection, continuous monitoring, and adaptive interventions while requiring continued advancement in standardization, validation, and ethical frameworks. Full article

Background: The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) allows quantitative evaluation of the degree of an individual’s brain atrophy through statistical comparison of brain magnetic resonance imaging (MRI) of their brain to a normative database of healthy Japanese individuals. Currently, the VSRAD is used in routine clinical practice in the diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Recent studies using VSRAD have explored its utility in the assessment of brain atrophy associated with various conditions, including diabetes, oral health status, and olfactory dysfunction. This review summarizes the principles of the VSRAD and its foundational method, voxel-based morphometry (VBM), and their clinical and research applications. Methods: This narrative review was conducted by performing a literature search of PubMed to identify articles regarding VBM and the VSRAD that were published between 2005 and 2025. Results: VSRAD yields four indices for quantifying the severity and extent of gray matter atrophy, especially in the medial temporal lobe. Studies have demonstrated its high diagnostic accuracy in distinguishing among AD, mild cognitive impairment (MCI), and DLB. Furthermore, it is correlated with neuropsychological test scores and has been applied to evaluate brain changes associated with diabetes, olfactory dysfunction, and physical inactivity. Motion-corrected MR images, which utilize AI techniques, have also been validated using VSRAD-derived metrics. Conclusions: Quantifying brain atrophy using the VSRAD allows objective evaluation and facilitates the investigation of its association with various diseases. Specifically, VSRAD can be considered a useful adjunctive tool for diagnosing AD and DLB. Full article

Background: Cognitive and neuropsychological effects of cancer and its treatments have gained increasing attention over the past decade, with growing evidence of persistent deficits across multiple cancer types. While numerous studies have examined these effects, the literature remains fragmented, and no comprehensive bibliometric synthesis has been conducted to map the field’s intellectual structure and emerging trends. Methods: A bibliometric and science mapping analysis was performed using the Scopus database to identify peer-reviewed articles published between 2015 and 2025 on neuropsychological or cognitive outcomes in adult cancer populations. Data from 179 eligible publications were analyzed with VOSviewer and Microsoft Power BI, applying performance metrics and network mapping techniques, including co-authorship, bibliographic coupling, co-citation, and keyword co-occurrence analyses. Results: Publication output increased steadily over the decade, with leading contributions from the Journal of Neuro-Oncology, Psycho-Oncology, and Brain Imaging and Behavior. Co-citation analysis identified three core intellectual pillars: (i) clinical characterization of cancer-related cognitive impairment, (ii) mechanistic and neuroimaging-based investigations, and (iii) neurosurgical and neuropathological research in brain tumors. Keyword mapping revealed emerging themes in sleep and circadian rhythm research, biological contributors to cognitive decline, and scalable rehabilitation strategies such as web-based cognitive training. Collaborative networks, while showing dense local clusters, remained moderately fragmented across disciplines. Conclusions: This review provides the first quantitative, decade-spanning map of cognitive oncology research, highlighting both consolidated knowledge areas and underexplored domains. Future efforts should prioritize methodological standardization, cross-disciplinary collaboration, and integration of cognitive endpoints into survivorship care, with the ultimate aim of improving functional outcomes and quality of life for cancer survivors. Full article

Background: The Weekly Calendar Planning Activity (WCPA) is one of the assessments of functional cognition, including executive function, by the cognitive instrumental activities of daily living (C-IADL). It is translated and adapted in many countries, but not in Japan. Methods: This study aimed to examine the validity of the Japanese version of the WCPA-10 (WCPA-10-J) in patients with acquired brain injury (ABI), and to explore the characteristics of cognitive strategy use among that population. Fifty-three patients with ABI aged 27–81 years and 52 healthy controls (HCs) completed the WCPA-10-J, three neuropsychological tests, and the assessment of the instrumental activities of daily living (IADL). Results: Results demonstrated that the WCPA-10-J was able to discriminate between the patients with ABI and the HCs. We found significant limitations in ABI patients’ ability to use strategies. Concurrent, convergent, and ecological validities were partly demonstrated through correlations between the neuropsychological test scores, IADL, and the WCPA-10-J performance. Conclusions: This study provides initial evidence for the validity of the WCPA-10-J for patients with ABI and suggests the need to use performance-based tests even in patients with normal cognitive screening test results. The WCPA-10-J could provide useful information for strategy-based interventions for patients with ABI. Full article

Background: Children with diplegic Cerebral Palsy often exhibit upper-limb (UL) motor impairments compounded by deficits in visuospatial, sensory, and executive functions. Despite this, research has primarily focused on lower-limb rehabilitation, leaving the treatment of UL function in diplegic Cerebral Palsy underexplored. Action Observation Therapy (AOT), based on Mirror Neuron System activation, has shown promise in promoting motor recovery, but evidence specific to this population is limited. This exploratory randomized controlled trial (RCT) aims to assess the feasibility and effectiveness of a home-based AOT program—ACT ON DIP—for improving upper-limb function in children and adolescents with diplegic Cerebral Palsy. Methods: Fifty-four participants with spastic diplegic Cerebral Palsy (MACS and GMFCS levels I–III, aged 5–16 years) will be randomly assigned to an experimental group (receiving an 8-week home-based AOT program) or a control group (receiving standard care). The ACT ON DIP system includes an ad hoc software, kits of objects for daily tasks, and wearable sensors. The system allows for delivering structured uni- and bimanual AOT activities tailored to the child’s profile. Primary outcome is the Both Hands Assessment (BoHA); secondary outcomes include motor (MA-2, BBT, ABILHAND), neuropsychological (NEPSY-II, Corsi Test, BRIEF), and participation measures (COPM, PEM-CY, CP-QOL). A subgroup will undergo fMRI to explore neural correlates of training-related changes. Results: Feasibility, compliance, and user experience with the home-based system will be assessed. This study will evaluate short-, medium-, and long-term changes in UL performance and related neuropsychological functions. Conclusions: ACT ON DIP represents a novel, personalized, and accessible tele-rehabilitation intervention for children with diplegic Cerebral Palsy. If effective, it could expand treatment opportunities for UL rehabilitation in this population and support broader implementation of home-based AOT. Full article

Background: Obstructive sleep apnea (OSA) is highly prevalent in the early stages of Alzheimer’s disease (AD), and its hallmark, sleep fragmentation, may accelerate cognitive decline. Continuous positive airway pressure (CPAP) improves OSA-related hypoxia during slow-wave sleep, but its cognitive benefits in AD remain unclear. Methods: We performed a 12-month sub-analysis of a prospective, longitudinal pilot study that enrolled 21 adults (median age = 77 yr; 71% women) with Mild Cognitive Impairment (MCI) with AD confirmed biomarkers and polysomnography-diagnosed OSA. All participants underwent baseline overnight polysomnography (PSG) and neuropsychological testing (Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)) that were repeated after 12 months. Twelve participants were CPAP-compliant (moderate/severe OSA) and nine were non-users (mild OSA/intolerance). Cognitive change scores (Δ = 12 months -baseline) were compared with Generalized Linear Models (GLM) adjusted for baseline cognition and Apnea–Hypopnea Index (AHI); associations between baseline sleep parameters and cognitive trajectories were examined. And the association of sleep variables with the use of CPAP was also evaluated. Results: Compared with non-users, CPAP users showed significantly slower global decline (Δ MMSE: p = 0.016) and improvements in overall cognition (Δ RBANS Total: p = 0.028) and RBANS sub-domains (Δ RBANS FC: p = 0.010; Δ RBANS SF: p = 0.045). Longer baseline non-rapid eye movement (NREM) stage 3 and rapid eye movement (REM) sleep, greater total sleep time and sleep efficiency, and right-side sleeping were each linked to better cognitive outcomes, whereas extended NREM stage 2, wakefulness, and supine sleeping were associated with poorer trajectories. Conclusions: Twelve months of CPAP use was associated with attenuated cognitive decline and domain-specific gains in AD-related MCI with OSA. Sleep architecture and body position during sleep predicted cognitive outcomes, underscoring the therapeutic relevance of optimizing breathing and sleep quality. Larger, longer-term trials are warranted to confirm CPAP’s disease-modifying potential and to clarify the mechanistic role of sleep in AD progression. Full article

The COVID-19 pandemic has left millions worldwide with persistent cognitive difficulties, making long-term studies essential to understand their trajectory and inform rehabilitation strategies. This research is presented within the context of Long COVID, emphasizing that cognitive symptoms (including deficits in attention, memory, and executive functions) are reported even in non-hospitalized individuals, yet longitudinal evidence beyond two years remains scarce. An observational, cross-sectional, and retrospective design was applied to a sample of 297 adults with their cognition assessed, divided into mild, moderate, and severe COVID-19 groups, and evaluated using standardized cognitive tests. Findings showed that cognitive performance declined with increasing severity of COVID-19 symptoms, particularly in divided attention, working memory, executive control, verbal fluency, recognition memory, and general intelligence. Age consistently predicted lower scores across cognitive domains, especially in moderate and severe groups, whereas education level did not exert a significant protective effect. The study shows that cognitive deficits can persist at least three years after infection, affecting older adults and those with the more severe symptoms. These results highlight the need for long-term neuropsychological monitoring and individualized rehabilitation strategies to mitigate impacts on autonomy and quality of life. Full article

Background: Phenylketonuria (PKU) is a rare autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to hyperphenylalaninemia (HPA). Untreated, elevated phenylalanine (Phe) levels cause severe neurocognitive, developmental, and psychiatric complications. Management relies on a Phe-restricted diet, which is challenging to maintain, particularly in adolescents and adults. Sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), can enhance residual PAH activity, lowering blood Phe levels and increasing dietary tolerance in responsive patients. However, real-world alignment with best practices remains underexplored. This study aims to report a tertiary referral center’s experience with sapropterin treatment in PKU and assess adherence to international guidelines. Methods: We retrospectively analyzed 23 PKU patients treated with sapropterin from 2007 to 2025. Patients with baseline Phe levels of 360–2000 µmol/L underwent a 10 mg/kg/day loading test over two weeks. Responsiveness was defined as a ≥30% reduction in blood Phe levels. Phe levels were measured pre- and post-test, and dietary tolerance was evaluated. Adherence to best practices was critically reviewed. Results: All patients showed significant Phe reductions (mean 71.43%, p < 0.0001), exceeding responsiveness thresholds. Most achieved substantial increases in dietary Phe tolerance, with three patients partially responsive (800–1200 mg/day). Responsiveness was unrespectful of the patient’s genotype, for those individuals for whom this was known (8/23 patients). Although effective, the test dose and duration differed from guideline recommendations (20 mg/kg/day). Neuropsychological and QoL assessments were not systematically performed, representing a key limitation. Conclusions: Sapropterin dihydrochloride effectively identified responders and improved dietary flexibility even with lower dosing protocols. Greater adherence to international standards, particularly regarding long-term neuropsychological monitoring, is needed to optimize patient care. Full article