Unleashing the potential of mRNA therapeutics for inherited neurological diseases.

Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing COVID-19 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the central nervous system, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present, and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders.

Does botulinum toxin affect psycho-social aspects in dystonia?

Dystonia is a movement disorder in which sustained muscle contractions give rise to abnormal postures or involuntary movements. It is a disabling and disfiguring disorder that affects activities of daily living and gives people a bizarre appearance often associated with psychological morbidity, embarrassment and social avoidance. Intramuscular injection of botulinum toxin (BoNT) is the most effective treatment for motor symptoms in focal dystonia, but little is known about its impact on the psycho-social dimension. The main aim of this study was to evaluate psycho-social changes in patients with focal dystonia after starting BoNT treatment using self-reported scales. The Beck Depression Inventory (BDI-II), the 36-Item Short Form Health Survey (SF-36), the Body Uneasiness Test (BUT), the State-Trait Anxiety Inventory (STAI) and the Visual Analogue Scale (VAS) assessing body self-image, satisfaction with physical aspects, social avoidance, self-reported depression, and self-distress were completed by 11 patients with dystonia and 9 patients with hyperhidrosis as a control group before BoNT (T0). VAS was then performed after four weeks (T1) to assess whether BoNT induced changes in the psychosocial dimension. Our results showed that only depressive symptoms and rumination about body defects improved in patients with dystonia after BoNT treatment, while improvement in self-distress and satisfaction with physical aspects was also found in hyperhidrosis. Individuals with hyperhidrosis experience poorer psychological well-being and suffer from higher levels of distress compared to dystonic patients. This suggests that individuals with this disabling condition are more vulnerable to social impact than dystonic patients.

Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.

BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed. METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated. RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences. DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.

Association of APOE genotype and cerebrospinal fluid Aß and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.

OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aß and tau proteins with cognitive and motor phenotype in ALS. METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aß42, Aß40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aß42 (-0.8 vs. 0.1, log-transformed values) and Aß42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aß42 levels, possibly reflecting cerebral Aß deposition. While lower Aß42/40 correlated with lower memory score (ß = 0.20), Aß42 positively correlated with both ALS-specific (ß = 0.24) and ALS-nonspecific (ß = 0.24) scores. Although Aß42/40 negatively correlated with T-tau (ß = -0.29) and P-tau181 (ß = -0.33), we found an unexpected positive association of Aß42 and Aß40 with both tau proteins. Regarding motor phenotype, lower levels of Aß species were associated with lower motor neuron (LMN) signs (Aß40: ß = 0.34; Aß42: ß = 0.22). CONCLUSIONS: APOE haplotype and CSF Aß biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.

The Single-Matrix Digit Cancellation Test, a Screener for Selective Attention Deficits: Standardization in an Italian Population Sample and Clinical Usability in Acute Stroke Patients.

INTRODUCTION: This study aimed at validating and providing Italian norms for the Single-Matrix Digit Cancellation Test (SMDCT), a cancellation task to screen for selective attention deficits, as well as providing clinical usability evidence for it in acute stroke patients. METHODS: The SMDCT stimulus is a specular, 4-quadrant, horizontally oriented matrix, across which target distribution is homogeneous. Both accuracy (-A) and time (-T) outcomes were computed. N = 263 healthy participants (HPs) and N = 76 acute stroke patients were recruited. N = 108 HPs also underwent the Mini-Mental State Examination, Frontal Assessment Battery (FAB), and Trail-Making Test (TMT), while patients were further assessed by the Mental Performance in Acute Stroke (MEPS). Regression-based norms were derived (equivalent scores). Construct and factorial validity, as well as case-control discrimination, were tested. RESULTS: The matrix was underpinned by a two-component structure reflecting left and right hits. The SMDCT-T and -A were associated with TMT and FAB scores, respectively. Education predicted the SMDCT-A/-T, whereas age predicted the SMDCT-T only. In patients, the SMDCT converged with the MEPS, also accurately discriminating them from HPs. An index of right-left difference differentiated right- from left-damaged patients. CONCLUSIONS: The SMDCT is a valid and normed screener for selective attention deficits, encompassing measures of both accuracy and time, whose adoption is encouraged in acute stroke patients. Relatedly, the horizontal disposition of its matrix does allow for the qualitative report of either leftward of rightward biases due to underlying visual or attentional-representational deficits in this population.

Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis.

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC Scale for Muscle Strength and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (P = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (P < 0.001) and with reduced survival (P < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (P = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuospatial ECAS domains. Individuals with regionally entrenching ALS were more frequently female (45.6% versus 36.9%; P = 0.028) and had higher frequencies of symmetric disease onset (40.3% versus 19.7%; P < 0.001) and bulbar phenotype (38.5% versus 16.4%; P < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex, while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, regionally entrenching ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.

Genetic variability in sporadic amyotrophic lateral sclerosis.

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.

Emotional awareness in patients with amyotrophic lateral sclerosis.

INTRODUCTION: It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS). METHODS: Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status. RESULTS: Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008). CONCLUSIONS: Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.

Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients.

BACKGROUND: The present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients. METHODS: N = 88 ALS patients without frontotemporal dementia were assessed for FI-Katz's Basic ADL Scale (BADL) and Lawton-Brody's Instrumental ADL Scale (IADL)-, cognition-Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders-i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King's and Milano-Torino stages. RESULTS: Higher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features-as measured by the Dimensional Apathy Scale (DAS)-were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without. DISCUSSION: Among non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.

Ecological validity of performance-based cognitive screeners in amyotrophic lateral sclerosis: preliminary evidence.

BACKGROUND: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes. METHODS: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview). RESULTS: The ECFI was associated with the total scores on both the ECAS (p = .014) and ALS-CBS™ (p = .017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p = .004) and on the ALS-CBS™ (p = .027). DISCUSSION: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers.

Psychometrics and diagnostics of the Italian version of the Alternate Verbal Fluency Battery (AVFB) in non-demented Parkinson's disease patients.

BACKGROUND: Verbal fluency (VF) tasks are known as suitable for detecting cognitive impairment (CI) in Parkinson's disease (PD). This study thus aimed to evaluate the psychometrics and diagnostics of the Alternate Verbal Fluency Battery (AVFB) by Costa et al. (2014) in an Italian cohort of non-demented PD patients, as well as to derive disease-specific cut-offs for it. METHODS: N = 192 non-demented PD patients were screened with the Montreal Cognitive Assessment (MoCA) and underwent the AVFB-which includes phonemic, semantic and alternate VF tests (PVF; SVF; AVF), as well as a Composite Shifting Index (CSI) reflecting the "cost" of shifting from a single- to a double-cued VF task. Construct validity and diagnostics were assessed for each AVFB measure against the MoCA. Internal reliability and factorial validity were also tested. RESULTS: The MoCA proved to be strongly associated with PVF, SVF and AVF scores, whilst moderately with the CSI. The AVFB was internally consistent and underpinned by a single component; however, an improvement in both internal reliability and fit to its factorial structure was observed when dropping the CSI. Demographically adjusted scores on PVF, SVF and AVF tests were diagnostically sound in detecting MoCA-defined cognitive impairment, whilst this was not true for the CSI. Disease-specific cut-offs for PVF, SVF and AVF tests were derived. DISCUSSION: In conclusion, PVF, SVF and AVF tests are reliable, valid and diagnostically sound instruments to detect cognitive impairment in non-demented PD patients and are therefore recommended for use in clinical practice and research.

Validity, diagnostics and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). METHODS: N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. RESULTS: The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC = .92), yielding optimal diagnostics at the cut-off of < 19.945 (J = .78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p = .037), as well as to differentiate HD patients from both HCs (p < .001) and PD patients (p < .001). CONCLUSIONS: The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research.

Verbal learning in frontal patients: area 9 is critical for employing semantic strategies.

INTRODUCTION: Learning is a long-term memory process heavily influenced by the control processes implemented by working memory, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams. AIM: The aim of this study is to investigate the verbal learning strategies of patients affected by a tumor in the left frontal lobe to highlight the role of area 9. METHOD: Ten patients with frontal low-grade gliomas and ten healthy control subjects, matched for age, sex and education, were recruited and then evaluated with a two-part verbal learning test: multi-trial word list learning in free recall, and multi-trial word list learning preceded by an explicit semantic strategy cue. Frontal patients were divided into two groups: those either with frontal lesions involving or sparing area 9. RESULTS: In comparison to healthy control subjects, frontal patients with lesions involving area 9 memorized fewer words and displayed difficulty in using semantic strategies. When the strategy was suggested by the examiner, their performance improved, but to a lesser extent than the healthy control. Conversely, frontal patients with lesions sparing area 9 showed similar results to healthy control subjects. CONCLUSION: The results suggested that, while the identification of the categorical criterion requires the integrity of the entire dorsolateral prefrontal area, only area 9, and not the surrounding areas, could be responsible for the effective use of semantic strategies in learning tasks.

Longitudinal Feasibility of the Montreal Cognitive Assessment (MoCA) in Non-Demented ALS Patients.

INTRODUCTION: The present study aimed at testing the longitudinal feasibility of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented amyotrophic lateral sclerosis (ALS) patients. METHODS: N = 39 non-demented ALS patients were followed-up at a 5-to-10-month interval (M = 6.8; SD = 1.4) with the MoCA and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Practice effects, test-retest reliability, and predictive validity (against follow-up ECAS scores) were assessed. Reliable change indices (RCIs) were derived via a regression-based approach by accounting for retest interval and baseline confounders (i.e., demographics, disease duration, and severity and progression rate). RESULTS: At retest, 100% and 69.2% of patients completed the ECAS and the MoCA, respectively. Patients who could not complete the MoCA showed a slightly more severe and fast-progressing disease. The MoCA was not subject to practice effects (t[32] = -0.80; p = 0.429) and was reliable at retest (intra-class correlation = 0.82). Moreover, baseline MoCA scores predicted the ECAS at retest. RCIs were successfully derived - with baseline MoCA scores being the only significant predictor of retest performances (ps < 0.001). CONCLUSIONS: As long as motor disabilities do not undermine its applicability, the MoCA appears to be longitudinally feasible at a 5-to-10-month interval in non-demented ALS patients. However, ALS-specific screeners - such as the ECAS - should be preferred whenever possible.

Clinimetrics of the Italian version of the Montreal Cognitive Assessment (MoCA) in adult-onset idiopathic focal dystonia.

This study aimed at assessing the clinimetrics of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of patients with adult-onset idiopathic focal dystonia (AOIFD). N = 86 AOIFD patients and N = 92 healthy controls (HCs) were administered the MoCA. Patients further underwent the Trail-Making Test (TMT) and Babcock Memory Test (BMT), being also screened via the Beck Depression Inventory-II (BDI-II) and the Dimensional Apathy Scale (DAS). Factorial structure and internal consistency were assessed. Construct validity was tested against TMT, BMT, BDI-II and DAS scores, whilst diagnostics against the co-occurrence of a defective performance on at least one TMT measure and on the BMT. Case-control discrimination was examined. The association between MoCA scores and motor-functional measures was explored. The MoCA was underpinned by a mono-component structure and acceptably reliable at an internal level. It converged towards TMT and BMT scores, as well as with the DAS, whilst diverging from the BDI-II. Its adjusted scores accurately detected cognitive impairment (AUC = .86) at a cut-off of < 17.212. The MoCA discriminated patients from HCs (p < .001). Finally, it was unrelated to disease duration and severity, as well as to motor phenotypes. The Italian MoCA is a valid, diagnostically sound and feasible cognitive screener in AOIFD patients.

Clinimetrics and feasibility of the Italian version of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease patients.

BACKGROUND: This study aimed at assessing the cross-sectional and longitudinal clinimetrics and feasibility of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease (PD) patients. METHODS: N = 109 PD patients underwent the FAB and the Montreal Cognitive Assessment (MoCA). A subsample of patients further underwent a thorough motor, functional and behavioral evaluation (the last including measures of anxiety, depression and apathy). A further subsample was administered a second-level cognitive battery tapping on attention, executive functioning, language, memory, praxis and visuo-spatial abilities. The following properties of the FAB were tested: (1) concurrent validity and diagnostics against the MoCA; (2) convergent validity against the second-level cognitive battery; (4) association with motor, functional and behavioral measures; (5) capability to discriminate patients from healthy controls (HCs; N = 96); (6) assessing its test-retest reliability, susceptibility to practice effects and predictive validity against the MoCA, as well as deriving reliable change indices (RCIs) for it, at a ≈ 6-month interval, within a subsample of patients (N = 33). RESULTS: The FAB predicted MoCA scores at both T0 and T1, converged with the vast majority of second-level cognitive measures and was associated with functional independence and apathy. It accurately identified cognitive impairment (i.e., a below-cut-off MoCA score) in patients, also discriminating patients from HCs. The FAB was reliable at retest and free of practice effects; RCIs were derived according to a standardized regression-based approach. DISCUSSION: The FAB is a clinimetrically sound and feasible screener for detecting dysexecutive-based cognitive impairment in non-demented PD patients.

Prevalence and determinants of language impairment in non-demented amyotrophic lateral sclerosis patients.

BACKGROUND AND PURPOSE: This study aimed at estimating the prevalence of language impairment (LI) in a large, clinic-based cohort of non-demented amyotrophic lateral sclerosis (ALS) patients and assessing its underpinnings at motor and non-motor levels. METHODS: Non-demented ALS patients (N = 348) underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as well as an assessment of behavioural/psychiatric and motor-functional features. The prevalence of LI was estimated based on the proportion of patients showing a performance below the age- and education-adjusted cut-off on the ECAS-Language. Multiple regression models were run to assess the determinants of language functioning and impairment. RESULTS: The prevalence of LI was 22.7%. 46.6% of the variance of ECAS-Language scores remained unexplained, with only the ECAS-Executive positively predicting them (p < 0.001; η2  = 0.07). Similarly, only a lower score on the ECAS-Executive predicted a higher probability of a below cut-off ECAS-Language performance (p < 0.001). Spelling and Naming tasks were the major drivers of ECAS-Language performance. CONCLUSIONS: This study suggests that, in non-demented ALS patients, LI occurs in ≈23% of cases, is significantly driven by executive dysfunction but, at the same time, partially independent of it and is not associated with other motor or non-motor features.

Diagnostic properties of the Italian ECAS Carer Interview (ECAS-CI).

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).

Feasibility and diagnostics of the Frontal Assessment Battery (FAB) in amyotrophic lateral sclerosis.

BACKGROUND: The present study aimed at evaluating the diagnostic properties of the Frontal Assessment Battery (FAB) in non-demented ALS patients by addressing the Edinburgh Cognitive Behavioural ALS Screen (ECAS) as the gold standard, as well as by examining the association between its administrability and scores with motor-functional measures. MATERIALS: N = 348 consecutive patients were administered the ECAS and FAB. Disease severity (ALSFRS-R), duration, progression rate (ΔFS), and stages (via King's and Milano-Torino systems) were considered. Administrability rates and prevalence of below-cut-off FAB scores were compared across clinical stages; regression models allowed to test whether, net of the ECAS-Total, motor features predicted the probability of the FAB not being administrable and of a defective FAB score. Intrinsic and post-test diagnostics were explored against a combined defective ECAS-Executive and ECAS-Fluency scores. RESULTS: 85.3% of patients managed to complete the FAB. FAB administrability rates decreased with advanced clinical stages, whereas the prevalence of below-cut-off FAB scores did not. The probability of the FAB not being administrable was predicted only by lower ALSFRS-R-bulbar and ALSFRS-R-upper-limb scores; no motor features, but the ECAS-Total, predicted a below-cut-off performance on the FAB. Raw and adjusted FAB scores showed high accuracy (AUC = .85 and .81, respectively) and good intrinsic and post-test properties. DISCUSSION: The FAB is featured by optimal diagnostics for detecting executive deficits in ALS, provided that it can be administered according to its original, standardized procedure, and thus that patients have sufficiently spared motor abilities to complete the test.

Psychometrics and diagnostics of the Italian version of the Beck Depression Inventory-II (BDI-II) in Parkinson's disease.

INTRODUCTION: Depression is one of the most disabling neuropsychiatric manifestations of Parkinson's disease (PD) and requires proper screening and diagnosis because it affects the overall prognosis and quality of life of patients. This study aimed to assess the psychometric and diagnostic properties of the Beck Depression Inventory-II (BDI-II) in an Italian PD cohort. MATERIALS AND METHODS: Fifty consecutive outpatients with PD underwent the Italian version of the BDI-II and other questionnaires to evaluate anxiety and apathetic symptoms. Patients' caregivers completed the depression/dysphoria domain of the Neuropsychiatric Inventory (NPI-D). We evaluated the internal consistency, convergent and divergent validity, and factorial structure of BDI-II. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were computed using ROC analyses, and an optimal cutoff was defined using the Youden index. RESULTS: The BDI-II proved to be internally consistent (Cronbach's α = 0.840) and substantially met the bi-factorial structure. Regarding construct validity, the BDI-II was substantially related to anxiety measures, but not to apathy. With the combination of the NPI-D and anxiety score used as the gold standard, the BDI-II overall showed good accuracy (AUC = 0.859) with adequate sensitivity (75%) and specificity (87%). The optimal cutoff point was defined at 14.50. CONCLUSIONS: We provide evidence of the psychometric and diagnostic properties of the Italian version of the BDI-II as a screening tool for depression in patients with PD. The BDI-II was found to be reliable and valid for the measurement of depression in patients with PD; therefore, it is available for use in clinical research and practice.