Objective: Neurofilament light chain proteins (NfLs) are considered a promising biomarker of neuroaxonal damage in several neurological diseases. Their measurement in the serum and cerebrospinal fluid (CSF) of patients with dementia may be especially useful. Our aim was to compare the NfL measurement performance of two advanced technologies, specifically the Ella™ microfluidic platform and the Lumipulse™ fully automated system, in patients with cognitive disorders. Methods: Thirty subjects with neurodegenerative cognitive disorders (10 with Alzheimer’s Disease, 10 with Frontotemporal Dementia, and 10 with non-progressive Mild Cognitive Impairment) seen at the Cognitive Neurology Clinic of Modena University Hospital (Italy) underwent CSF and serum NfL measurement with both the Ella™ microfluidic platform (Bio-Techne, Minneapolis, MN, USA)) and the Lumipulse™ fully automated system for the CLEIA (Fujirebio Inc., Ghent, Belgium). Correlation and regression analyses were applied to assess the association between NfL concentrations obtained with the two assays in CSF and serum. The Passing–Bablok regression method was employed to evaluate the agreement between the assays. Results: There were high correlations between the two assays (r = 0.976, 95% CI. 0.950–0.989 for CSF vs. r = 0.923, 95% CI 0.842–0.964 for serum). A Passing–Bablok regression model was estimated to explain the relationship between the two assays, allowing us to switch from one to the other when only one assay was available. Conclusions: We found a good degree of correlation between the two methods in patients with neurocognitive disorders. We also established a method that will allow comparisons between results obtained with either technique, allowing for meta-analyses and larger sample sizes.

Cognitive reserve (CR) reflects brain's resilience to pathology, enabling to maintain function despite structural damage. This study investigates its role in young-onset cognitive impairment (<65 years) beyond brain integrity and neurodegeneration. Participants underwent neuropsychological assessment - including the Cognitive Reserve Index questionnaire (CRIq) -, magnetic resonance imaging (MRI), and blood neurofilaments light-chain (NfLs) measurement. Scores of global cognition and domain-specific cognition were derived from Principal Component Analyses of neuropsychological results. Linear regression models estimated CR's contribution to global and domain-specific cognition, alongside age, sex, MRI measures, and NfLs as predictors. Among the 115 participants, global cognition was significantly explained by CR [effect size (ES) = 0.229], grey matter volume (ES = 0.348), and NfLs (ES = -0.302). The effect of CR was prominent on language and attentional-executive functions: while the CRIq subscore related to education predicted performance in both these domains, the subscore related to leisure activities was positively associated with the language domain only. These findings highlight CR's protective role in young-onset cognitive impairment, particularly for non-amnestic cognitive domains. Since a high CR can mask or compensate for neurological cognitive disorders delaying its diagnosis, our results suggest that measures of CR, including time spent on leisure activities, should be considered when interpreting neuropsychological tests.

The voluntary investment of mental effort is an understudied aspect of cognitive control, whose underlying mechanisms remain poorly understood. Here, we investigated this process using a computational model of the Stroop task within the framework of active inference. In the Stroop task, participants must report the font color of a presented color name, while suppressing the automatic tendency to read the word itself. In this study, we asked twenty healthy young adults to perform the Stroop task under two conditions: with maximum exertion or as relaxed as possible. Their behavior was modeled using a two-layer generative model grounded in active inference, conceptualizing cognitive effort as the extent to which habitual response tendencies are overridden by goal-directed behavior. This approach enabled the estimation of two key latent parameters: (i) the individual’s habitual bias toward word reading over color naming and (ii) the degree of motivation to perform the task correctly. Our findings indicate that voluntary engagement of maximal effort was associated with an increased preference for correct performance, whereas its relationship with the habitual bias toward word reading did not show a consistent group effect. These results support the hypothesis that the voluntary investment of cognitive effort is primarily governed by an increased motivation for accuracy rather than by the direct inhibition of habitual response tendencies. This computational approach holds potential relevance for clinical settings where impaired intentional effort allocation is observed in psychiatric and neurological disorders.

Background and ObjectivesLate-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). A...

Background: Mental effort is a core component of cognitive control, encompassing two key dimensions: exogenous effort (automatic recruitment of cognitive resources; Kahneman, 1973) and endogenous effort (intentional modulation of engagement; Muraven & Baumeister, 2000). This study explores the role of voluntary mental effort in cognitive control using a computational model of the Stroop task. In the Stroop task, participants are presented with colored words (e.g., the word “blue” in red font) and must report the font color while suppressing the automatic tendency to read the word, making the task cognitively demanding. Method: Twenty healthy volunteers (mean age 27.9 ± 5.7 years) were asked to perform the Stroop task on a computer, alternatively with maximum exertion (EXR) or in a relaxed‐as‐possible fashion (RLX; Khachouf et al., 2017). The participants’ behavior was modeled with a two‐layer generative model grounded in the active inference framework (Parr et al., 2022). This approach enables the estimation of two key parameters: e, representing the strength of individual bias toward reading words (versus reporting colors), and c, reflecting individual motivation during task performance (Figure 1). Result: The EXR condition was associated with a significant increase in the motivation parameter but not in the bias parameter (Figure 2). These findings suggest that voluntary engagement of mental effort primarily enhances inner motivation rather than directly altering habitual response tendencies. Since the only difference between EXR and RLX conditions was the instruction to modulate effort, the observed behavioral changes can be attributed to variations in endogenous effort. Conclusion: This study has important clinical implications, as deficits in effort regulation are common in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Furthermore, this computational approach offers a novel framework for inferring internal cognitive and motivational states from behavioral performance, with potential applications in the diagnosis and treatment of psychiatric and neurological conditions.