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Background: This study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-spectrum disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels. Methods: This review was pre-registered (osf.io/ds8m4) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD. Results: Out of 546 initial records, 56 studies were included. As to case reports/series (N = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) TBK1 mutations represent the most frequent genetic risk factors for PPA-MND. As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%). Discussion: Insights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD spectrum.

Background: The present study aimed at (1) assessing the diagnostic properties of the Montreal Cognitive Assessment (MoCA) in non-demented ALS patients and at (2) exploring the MoCA administrability according to motor-functional status. Materials: N = 348 patients were administered the MoCA and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Administrability rates and prevalence of defective MoCA scores were compared across King’s and Milano-Torino clinical stages. Regression models were run to test whether the non-administrability of the MoCA and a defective score on it were predicted, net of the ECAS-Total, by disease duration, ALS Functional Rating Scale-Revised (ALSFRS-R) and progression rate, computed as (48: ALSFRS-R)/disease duration. Intrinsic and post-test diagnostics were tested against a below-cut-off ECAS-total score. Results: The 79.9% of patients successfully underwent the MoCA, whose administrability rates decreased with advanced clinical stages, at variance with its defective score prevalence. The probability of the FAB not being administrable was predicted only by lower ALSFRS-R-bulbar and-upper-limb scores; no motor features, but the ECAS-Total, predicted a defective MoCA performance. The MoCA showed high accuracy (AUC = 0.82) and good intrinsic and post-test properties—being slightly more specific than sensitive. Discussion: In non-demented ALS patients, the MoCA is featured by optimal diagnostics as a screener for cognitive impairment, especially for ruling-out its occurrence, as long as patients are in the early stages of the disease and have sufficiently spared bulbar and upper-limb functions.

Background: This study aimed at providing diagnostic properties and normative cut-offs for the Italian ECAS Carer Interview (ECAS-CI). Materials: N = 292 non-demented ALS patients and N = 107 healthy controls (HCs) underwent the ECAS-CI and the Frontal Behavioural Inventory (FBI). Two ECAS-CI measures were addressed: (1) the number of symptoms (NoS; range = 0–13) and (2) that of individual symptom clusters (SC; range = 0–6). Diagnostics were explored against an FBI score ≥ than the 95th percentile of the patients’ distribution. Results: Both the NoS and SC discriminated patient from HCs. High accuracy, sensitivity, and specificity were detected for both the NoS and SC; however, at variance with SC, the NoS showed better post-test features and did not overestimate the occurrence of behavioural changes. The ECAS-CI converged with the FBI and diverged from the cognitive section of the ECAS. Discussion: The ECAS-CI is a suitable screener for behavioural changes in ALS patients, with the NoS being its best outcome measure (cut-off: ≥ 3).

Background: This study aimed at assessing the diagnostic properties of the Frontal Assessment Battery (FAB) as to its capability to (1) discriminate healthy controls (HCs) from patients with Huntington’s disease (HD) and (2) identify cognitive impairment in this population. Materials: Thirty-eight consecutive HD patients were compared to 73 HCs on the FAB. Patients further underwent the Montreal Cognitive Assessment (MoCA) and the Unified Huntington’s Disease Rating Scale (UHDRS). Receiver-operating characteristics (ROC) analyses were run to assess both intrinsic—i.e., sensitivity (Se) and specificity (Sp), and post-test diagnostics, positive and negative predictive values (PPV; NPV) and likelihood ratios (LR+; LR–), of the FAB both in a case–control setting and to identify, within the patient cohort, cognitive impairment (operationalized as a below-cut-off MoCA score). In patients, its diagnostic accuracy was also compared to that of the cognitive section of the UHDRS (UHDRS-II). Results: The FAB and UHDRS-II were completed by 100 and 89.5% of patients, respectively. The FAB showed optimal case–control discrimination accuracy (AUC = 0.86–0.88) and diagnostic properties (Se = 0.68–0.74; Sp = 0.88–0.9; PPV = 0.74–0.8; NPV = 0.84–0.87; LR+ = 5.6–7.68; LR– = 0.36–0.29), performing even better (AUC = 0.9–0.91) at identifying cognitive impairment among patients (Se = 0.73–1; Sp = 0.86–0.71; PPV = 0.79–0.71; NPV = 0.82–1; LR+ =5.13–3.5; LR– = 0.31–0) and comparably to the UHDRS-II (89% vs. 85% of accuracy, respectively; p = 0.46). Discussion: In HD patients, the FAB is highly feasible for cognitive screening aims, being also featured by optimal intrinsic/post-test diagnostics within both case-control and case-finding settings.

Eye movement abnormalities in association with cognitive and emotional deficits have been described in neurological, neurodevelopmental, and psychiatric disorders. Eye-Tracking (ET) techniques could therefore enhance cognitive interventions by contingently providing feedback to patients. Since no consensus has been reached thus far on this approach, this study aimed at systematically reviewing the current evidence. This review was performed and reported according to PRISMA guidelines. Records were searched for in PubMed, Web of Science, and Scopus (1990–2021) through the following string: (‘Eye Tracking’ OR ‘Eye-Tracking’ OR ‘Oculomotor’) AND (‘Neuropsychol*’ OR ‘Cognitive’) AND (‘Rehabilitation’ OR ‘Training’ OR ‘Stimulation’). Study outcomes were thematically classified and qualitatively synthesized. A structured quality assessment was performed. A total of 24 articles were included, addressing neurodevelopmental (preterm infants and children with autism spectrum disorder, Rett syndrome, or ADHD; N = 14), psychiatric (mood and anxiety disorders or alcohol dependence; N = 7), and neurological conditions (stroke; N = 3). Overall, ET gaze-contingent training proved to be effective in improving cognitive and emotional alterations. However, population heterogeneity limits the generalizability of results. ET gaze-contingent protocols allow researchers to directly and dynamically train attentional functions; together with the recruitment of implicit, “bottom-up” strategies, these protocols are promising and possibly integrable with traditional cognitive approaches.

Background: The semiology and determinants of apathy are largely unknown across amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Huntington’s disease (HD), due to both motor and non-motor confounders. This study thus aimed at (1) profiling apathy in ALS, PD, and HD and (2) exploring its clinical determinants. Materials: Consecutive ALS (N = 99), PD (N = 73), and HD (N = 25) patients underwent a motor-free assessment of apathy (Dimensional Apathy Scale, DAS), global cognition, anxiety and depression. Function was assessed through disease-specific scales. The DAS was also completed by N = 101 healthy controls (HCs). Between-group comparisons on DAS scores were implemented by covarying for all applicable confounders. Predictive models on DAS scores were built through multiple, stepwise regressions. Results: Parkinson’s disease and HD, but not ALS, patients were more apathetic than HCs—with HD patients also selectively showing lower initiation and poorer goal-directed planning than HCs. Higher apathetic features were detected in PD and HD as compared to ALS. Education was a protective factor against apathy in ALS. Anxiety was a risk factor for global apathy in ALS, HD, and to a lesser extent, in PD, whereas, protective only toward affective disintegration in PD and ALS. Cognitive inefficiency was a risk factor toward apathy in both PD and ALS. Depression was a risk factor for executive-related apathy in PD. Discussion: This study provides unprecedented insights into the heterogeneous semiology and determinants of apathy across ALS, PD, and HD via the DAS, in turn informing clinical practice and research.

Background: The aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test (RMET) in non-demented patients with amyotrophic lateral sclerosis (ALS). Materials: A total of 61 consecutive patients and 50 healthy controls (HCs) were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task (SET), which encompasses three subtests targeting Causal Inference, Emotion Attribution (SET-EA), and Intention Attribution (SET-IA), as well as global cognitive [the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and behavioral screening [the Frontal Behavioral Inventory (FBI); the Dimensional Apathy Scale (DAS); the Beck Depression Inventory (BDI); and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics (ROC) analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance. Results: The RMET was solely predicted by the SET-EA (p = 0.003) and SET-IA (p = 0.005). RMET scores showed high accuracy both in discriminating patients from HCs (AUC = 0.81) and in identifying patients with a defective SET-EA score (AUC = 0.82), with adequate-to-optimal both intrinsic and post-test properties. Discussion: The RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios.

Objective: Angiogenin (ANG) is a pro-angiogenic and neurotrophic factor with an important role in stress-induced injury, by promoting neovascularization and neuronal survival. Identification of loss-of-function mutations and evidence of beneficial effect of ANG administration in transgenic SOD1G93A mice have linked ANG to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), stimulating interest in considering circulating ANG levels as an ALS disease biomarker although robust evidence is still lacking. Aim of our study was to assess differences of ANG levels in the cerebrospinal fluid (CSF) of a large cohort of patients with ALS and frontotemporal dementia (FTD) compared to controls and to explore correlations between ANG content and disease-related clinical variables. Methods: ANG levels were measured in CSF samples using a commercially available ELISA kit in 88 patients affected with ALS and/or FTD and 46 unrelated individuals (control group). Results: ANG levels didn’t differ significantly between cases and controls. Patients with FTD or ALS-FTD showed significantly increased CSF concentration of ANG compared to ALS patients without dementia and controls in a multivariate regression model (p < 0.001). No correlations were found in ALS/FTD patients between ANG levels and clinical parameters, including age, presence of C9orf72 repeat expansion, body mass index (BMI). Conclusions: our findings highlight a role of ANG as CSF biomarker useful to identify ALS patients with concurrent FTD and suggest that it should be further explored as potential biomarker for FTD.

Objective: The study presents data on the longitudinal administration of the Italian Edinburgh Cognitive and Behavioral ALS Screen (ECAS). We investigated cognitive-behavioral performance in a group of ALS patients over time and the feasibility of repeating the ECAS longitudinally compared with standard neuropsychological tests. Finally, correlations between clinical/genetic and cognitive/behavioral data were considered. Methods: One hundred and sixty-eight ALS patients were tested at baseline (T0). Among these, 48 patients performed the ECAS after 6 months (T1), 18 patients performed it at T2 (12 months), and five patients were assessed after 24 months (T3). Participants were also administered two cognitive test (FAB; MoCA) and psychological questionnaires (BDI; STAI/Y). The FBI was carried out with caregivers. Results: No cognitive deterioration was found across follow-ups. In contrast, although scores did not change between T0 and T1, scores improved significantly for ECAS Total/ALS Non-specific and Memory domains when the ECAS was repeated on three occasions (T0, T1, T2). Apathy/Inertia was the most common behavioral symptom, but no worsening of behavioral scores was detected over time. After 12–24 months, patients were still able to perform the ECAS in total, in contrast to FAB and MoCA, which were only partially administrable. Conclusions: The significant improvement of some ECAS scores over time supports the presence of possible practice effects, particularly in the memory domain, highlighting the need to accommodate for these in longitudinal assessments, through healthy controls groups or alternate versions. This work represents the first Italian ECAS follow-up study and confirms ECAS feasibility in patients with increasing physical disability.

Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS. Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson's correlation coefficient was used to assess the degree of association between cognitive and psychological measures. Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS. Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behav

This study presents the Italian validation of the recently developed Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a short screen for cognitive/behavioural alterations in patients with amyotrophic lateral sclerosis (ALS). We evaluated the psychometric properties of the ECAS Italian version in terms of reliability and convergent validity for both cognitive and behavioural features. Furthermore, we investigated the relationship with affective and clinical variables, in addition to ECAS usability and patients’ insight into cognitive/behaviour changes. Finally, correlations between genetic and cognitive/behavioural data were analysed. We recruited 107 patients with ALS. Normative data were collected on 248 healthy subjects. Participants were administered the ECAS and two standard cognitive screening tools (FAB, MoCA), two psychological questionnaires (BDI, STAI/Y) and an ad hoc usability questionnaire. The FBI was also carried out with caregivers. Results showed that the ECAS Italian version discriminated well between patients and controls. The most prevalent deficit occurred in executive functions and fluency. Correlations were observed between the ECAS and standard cognitive screening tools and between the ECAS carer interview and the FBI, supporting its full convergent validity. In conclusion, the ECAS Italian version provides clinicians with a rapid, feasible and sensitive tool, useful to identify different profiles of cognitive-behavioural impairment in ALS.

New technologies to enable augmentative and alternative communication in Amyotrophic Lateral Sclerosis (ALS) have been recently used in several studies. However, a comprehensive battery for cognitive assessment has not been implemented yet. Brain computer interfaces are innovative systems able to generate a control signal from brain responses conveying messages directly to a computer. Another available technology for communication purposes is the Eye-tracker system, that conveys messages from eye-movement to a computer. In this study we explored the use of these two technologies for the cognitive assessment of executive functions in a healthy population and in a ALS patient, also verifying usability, pleasantness, fatigue, and emotional aspects related to the setting. Our preliminary results may have interesting implications for both clinical practice (the availability of an effective tool for neuropsychological evaluation of ALS patients) and ethical issues.

ware as an assessment tool for executive functions. In particular, the Multiple Errands Test is an assessment of executive functions in daily life which consists of tasks that abide by certain rules and is performed in a shopping mall-like setting where there are items to be bought and information to be obtained. The study population included three groups: post-stroke participants (n = 9), healthy young participants (n = 10), and healthy older participants (n = 10). The general purpose of the study was investigated through the following specific objectives: (1) to examine the relationships between the performance of three groups of participants in the Virtual Multiple Errands Test (VMET) and in the traditional neuropsychological tests employed to assess executive functions; and (2) to compare the performance of post-stroke participants to those of healthy young and older controls in the Virtual Multiple Errands Test and in the traditional neuropsychological tests employed to assess executive functions. Correlations between Virtual Multiple Errands Test variables and some traditional executive functions measures provide preliminary support for the ecological and construct validity of the VMET; further performance obtained at the Virtual Multiple Errands Test provided a distinction between the clinical and healthy population, and between the two age control groups. These results suggest a possible future application of such an ecological approach for cognitive assessment and rehabilitation of stroke patients and elderly population with age-related cognitive decline. © 2012 the Massachusetts Institute of Technology.

The use of augmentative and alternative communication (AAC) tools in patients with amyotrophic lateral sclerosis (ALS), as effective means to compensate for the progressive loss of verbal and gestural communication, has been deeply investigated in the recent literature. The development of advanced AAC systems, such as eye-tracking (ET) and brain-computer interface (BCI) devices, allowed to bypass the important motor difficulties present in ALS patients. In particular, BCIs could be used in moderate to severe stages of the disease, since they do not require preserved ocular-motor ability, which is necessary for ET applications. Furthermore, some studies have proved the reliability of BCIs, regardless of the severity of the disease and the level of physical decline. However, the use of BCI in ALS patients still shows some limitations, related to both technical and neuropsychological issues. In particular, a range of cognitive deficits in most ALS patients have been observed. At the moment, no effective verbal-motor free measures are available for the evaluation of ALS patients' cognitive integrity; BCIs could offer a new possibility to administer cognitive tasks without the need of verbal or motor responses, as highlighted by preliminary studies in this field. In this review, we outline the essential features of BCIs systems, considering advantages and challenges of these tools with regard to ALS patients and the main applications developed in this field. We then outline the main findings with regard to cognitive deficits observed in ALS and some preliminary attempts to evaluate them by means of BCIs. The definition of specific cognitive profiles could help to draw flexible approaches tailored on patients' needs. It could improve BCIs efficacy and reduce patients' efforts. Finally, we handle the open question, represented by the use of BCIs with totally locked in patients, who seem unable to reliably learn to use such tool.

The purpose of this study was to establish ecological validity and initial construct validity of the Virtual Reality (VR) version of the Multiple Errands Test (MET) (Shallice & Burgess, 1991; Fortin et al., 2003) based on the NeuroVR software as an assessment tool for executive functions. In particular, the MET is an assessment of executive functions in daily life, which consists of tasks that abide by certain rules and is performed in a shopping mall-like setting where items need to be bought and information needs to be obtained. The study population included three groups: post-stroke participants (n = 5), healthy, young participants (n = 5), and healthy, older participants (n = 5). Specific objectives were (1) to examine the relationships between the performance of three groups of participants in the Virtual Multiple Errands Test (VMET) and at the traditional neuropsychological tests employed to assess executive functions and (2) to compare the performance of post-stroke participants to those of healthy, young controls and older controls in the VMET and at the traditional neuropsychological tests employed to assess executive functions.

Background: To go from one place to another, we routinely generate internal representations of surrounding spaces, which can include egocentric (body-centred) and allocentric (world-centred) coordinates, combined into route and survey representations. Recent studies have shown how both egocentric and allocentric representations exist in parallel and are joined to support behaviour according to the task. Our study investigated the transfer from survey (map-like) to route representations in healthy and brain-damaged subjects. The aim was two-fold: first, to understand how this ability could change with age in a sample of healthy participants, aged from 40 to 71 years old; second, to investigate how it is affected after a brain lesion in a 8 patients' sample, with reference to specific neuropsychological frames. Methods: Participants were first required to perform the paper and pencil version of eight mazes, then to translate the map-like paths into egocentric routes, in order to find the right way into equivalent Virtual Reality (VR) mazes. Patients also underwent a comprehensive neuropsychological evaluation, including a specific investigation of some topographical orientation components. Results: As regards the healthy sample, we found age-related deterioration in VR task performance. While education level and gender were not found to be related to performance, global cognitive level (Mini Mental State Examination), previous experience with computer and fluidity of navigation into the VR appeared to influence VR task results. Considering the clinical sample, there was a difficulty in performing the VR Maze task; executive functions and visuo-spatial abilities deficits appeared to be more relevant for predicting patients' results. Conclusions: Our study suggests the importance of developing tools aimed at investigating the survey to route transfer ability in both healthy elderly and clinical samples, since this skill seems high cognitive demanding and sensitive to co

The purpose of this study was to establish ecological validity and initial construct validity of the Virtual Reality (VR) version of the Multiple Errands Test (MET) (Shallice & Burgess, 1991; Fortin et al., 2003) based on the NeuroVR software as an assessment tool for executive functions. In particular, the MET is an assessment of executive functions in daily life, which consists of tasks that abide by certain rules and is performed in a shopping mall-like setting where items need to be bought and information needs to be obtained. The study population included three groups: post-stroke participants (n = 5), healthy, young participants (n = 5), and healthy, older participants (n = 5). Specific objectives were (1) to examine the relationships between the performance of three groups of participants in the Virtual Multiple Errands Test (VMET) and at the traditional neuropsychological tests employed to assess executive functions and (2) to compare the performance of post-stroke participants to those of healthy, young controls and older controls in the VMET and at the traditional neuropsychological tests employed to assess executive functions.

When we exercise real choice, we gain increased control over our lives and are able to change ourselves. However for many subjects it is not easy to exercise effective choices: patients often don have the knowledge, skills, assertiveness, or self esteem needed. In this situation Virtual Reality (VR), an artificial reality that projects the user into a 3D space generated by the computer, may offer a critical advantage to the therapist. The enriched experience and the total level of control on its features, transform VR in an "empowering environment", where patients can start to explore and act without feeling actually threatened. The attempt of defining, developing and testing VR tools supporting personal empowerment is the main goal of the Applied Technology for Neuro-Psychology Laboratory -ATN-P Lab-at the Istituto Auxologico ltaliano. The paper describes the actual work done by the ATN-P Lab. in this area. Specifically, the open source "NeuroVR" system and its potential clinical applications -anxiety disorders, obesity and eating disorders- are presented and discussed. © 2009, Facultat de Psicologia Universitat de Barcelona.

At CT 2007, we presented NeuroVR (http://www.neurovr.org), a free virtual reality platform based on open-source software. The software allows non-expert users to adapt the content of 14 pre-designed virtual environments to the specific needs of the clinical or experimental setting. Following the feedbacks of the 700 users who downloaded the first version, we developed a new version - NeuroVR 1.5 - that improves the possibility for the therapist to enhance the patient's feeling of familiarity and intimacy with the virtual scene, by using external sounds, photos or videos. The key characteristics that make NeuroVR suitable for most clinical applications are the high level of control of the interaction with the tool, and the enriched experience provided to the patient. Actually, NeuroVR is used in the assessment and treatment of Obesity, Alcohol Abuse, Anxiety Disorders, Generalized Anxiety Disorders, and Cognitive Rehabilitation.