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

BACKGROUND: Learning is a long-term memory process, influenced by working memory control processes, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams. AIM: The aim of the study is to investigate the verbal learning strategies of Parkinson's disease patients. METHODS: Thirty patients with idiopathic Parkinson's disease and thirty normal control subjects were tested with a multi-trial word list learning, under two conditions: without cue and then with an explicit cue suggesting the categories in the list, respectively. RESULTS AND CONCLUSIONS: In comparison to healthy control subjects, parkinsonian patients recalled fewer words and achieved a reduced number of categorical clusters; strategical cue did not improve their performance. This suggests, besides a difficulty in identifying the correct learning strategy, a deficit in working memory, which undermines the strategy implementation. We hypothesize that this function pertains to the dorsolateral cognitive circuit of the extrapyramidal system.

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.

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)=-.80; p=.429) and was reliable at retest (ICC=.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<.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.

Clinical and neuroanatomical characterization of the semantic behavioral variant of frontotemporal dementia in a multicenter Italian cohort.

BACKGROUND: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients. METHODS: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry. RESULTS: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants. CONCLUSION: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD.

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.

Cervical motion alterations and brain functional connectivity in cervical dystonia.

INTRODUCTION: Evaluating the neural correlates of sensorimotor control deficits in cervical dystonia (CD) is fundamental to plan the best treatment. This study aims to assess kinematic and resting-state functional connectivity (RS-FC) characteristics in CD patients relative to healthy controls. METHODS: Seventeen CD patients and 14 age-/sex-matched healthy controls were recruited. Electromagnetic sensors were used to evaluate dystonic pattern, mean/maximal cervical movement amplitude and joint position error with eyes open and closed, and movement quality during target reaching with the head. RS-fMRI was acquired to compare the FC of brain sensorimotor regions between patients and controls. In patients, correlations between motion analysis and FC data were assessed. RESULTS: CD patients relative to controls showed reduced mean and maximal cervical range of motion (RoM) in rotation both towards and against dystonia pattern and reduced total RoM in rotation both with eyes open and closed. They had less severe dystonia pattern with eyes open vs eyes closed. CD patients showed an altered movement quality and sensorimotor control during target reaching and a higher joint position error. Compared to controls, CD patients showed reduced FC between supplementary motor area (SMA), occipital and cerebellar areas, which correlated with lower cervical RoM in rotation both with eyes open and closed and with worse movement quality during target reaching. CONCLUSIONS: FC alterations between SMA and occipital and cerebellar areas may represent the neural basis of cervical sensorimotor control deficits in CD patients. Electromagnetic sensors and RS-fMRI might be promising tools to monitor CD and assess the efficacy of rehabilitative interventions.

Behavioral Disorders of Spatial Cognition in Patients with Mild Cognitive Impairment due to Alzheimer's Disease: Preliminary Findings from the BDSC-MCI Project.

(1) Background: Spatial cognition (SC) is one of the earliest cognitive domains to be impaired in the course of Alzheimer's disease (AD), resulting in spatial disorientation and becoming lost even in familiar surroundings as later dementia symptoms. To date, few studies have identified initial alterations of spatial navigation (SN) in the premorbid AD phase by real-world paradigms, and none have adopted an innovative technological apparatus to better detect gait alterations as well as physiological aspects correlated to spatial disorientation (SD). The present study aimed at exploring initial SN defects in patients with prodromal AD via a naturalistic task by using a sensory garment. (2) Methods: 20 community-dwelling patients with Mild Cognitive Impairment (MCI) due to AD and 20 age/education controls were assessed on their sequential egocentric and allocentric navigation abilities by using a modified version of the Detour Navigation Test (DNT-mv). (3) Results: When compared to controls, patients with MCI due to AD exhibited higher wrong turns (WT) and moments of hesitation (MsH) in the DNT-mv, reflecting difficulties both in sequential egocentric and allocentric navigation, depending on hippocampal deterioration. Moreover, they reported more complaints about their SN competencies and lower long-term visuospatial memory abilities than controls. Remarkably, WTs and MsH manifested in the allocentric naturalistic task of the DNT-mv were associated with autonomic nervous system alteration pertaining to cardiac functioning in the whole sample. (4) Conclusions: Naturalistic navigation tests of hippocampal function using a continuous non-invasive monitoring device can provide early markers of spatial disorientation in patients with MCI due to AD. Future studies should develop cognitive remediation techniques able to enhance SC residual abilities in patients at high risk of conversion into dementia and ecological paradigms to be replicated on a large scale.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

Shaping the Neurovascular Unit Exploiting Human Brain Organoids.

Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research. Experimentally, the creation of vascularized brain organoids has primarily focused on the fusion of vascular and brain organoids, on organoid transplantation in vivo, and on the use of microfluidic devices to replicate the intricate microenvironment of the human brain in vitro. This review summarizes these efforts and highlights the importance of studying the neurovascular unit in a forward-looking perspective of leveraging their use for understanding and treating neurological disorders.

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.

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.

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.

The value of routine blood work-up in clinical stratification and prognosis of patients with amyotrophic lateral sclerosis.

BACKGROUND: There is an unmet need in amyotrophic lateral sclerosis (ALS) to provide specific biomarkers for the disease. Due to their easy availability, we aimed to investigate whether routine blood parameters provide useful clues for phenotypic classification and disease prognosis. METHODS: We analyzed a large inpatient cohort of 836 ALS patients who underwent deep phenotyping with evaluation of the clinical and neurophysiological burden of upper (UMN) and lower (LMN) motor neuron signs. Disability and progression rate were measured through the revised ALS Functional Rating Scale (ALSFRS-R) and its changes during time. Cox regression analysis was performed to assess survival associations. RESULTS: Creatinine significantly correlated with LMN damage (r = 0.38), active (r = 0.18) and chronic (r = 0.24) denervation and baseline ALSFRS-R (r = 0.33). Creatine kinase (CK), alanine (ALT) and aspartate (AST) transaminases correlated with active (r = 0.35, r = 0.27, r = 0.24) and chronic (r = 0.37, r = 0.20, r = 0.19) denervation, while albumin and C-reactive protein significantly correlated with LMN score (r = 0.20 and r = 0.17). Disease progression rate showed correlations with chloride (r = -0.19) and potassium levels (r = -0.16). After adjustment for known prognostic factors, total protein [HR 0.70 (95% CI 0.57-0.86)], creatinine [HR 0.86 (95% CI 0.81-0.92)], chloride [HR 0.95 (95% CI 0.92-0.99)], lactate dehydrogenase [HR 0.99 (95% CI 0.99-0.99)], and AST [HR 1.02 (95% CI 1.01-1.02)] were independently associated with survival. CONCLUSIONS: Creatinine is a reliable biomarker for ALS, associated with clinical features, disability and survival. Markers of nutrition/inflammation may offer additional prognostic information and partially correlate with clinical features. AST and chloride could further assist in predicting progression rate and survival.

Analysis of normal C9orf72 repeat length as possible disease modifier in amyotrophic lateral sclerosis.

The C9orf72 hexanucleotide repeat (HR) expansion is the main genetic cause of amyotrophic lateral sclerosis (ALS), with expansion size from 30 to >4000 units. Normal C9orf72 HR length is polymorphic (2-23 repeats) with alleles >8 units showing a low frequency in the general population. This study aimed to investigate if the normal C9orf72 HR length influences C9orf72 gene expression and acts as disease modifier in ALS patients negative for C9orf72 mutation (ALS-C9Neg). We found that the distribution of HR alleles was similar in 325 ALS-C9Neg and 303 healthy controls. Gene expression analysis in blood revealed a significant increase of total C9orf72 and V3 mRNA levels in ALS-C9Neg carrying two long alleles (L/L; ≥8 units) compared to patients homozygous for the 2-unit short allele (S/S). However, HR allele genotypes (L/L, S/L, S/S) correlated with no clinical parameters. Our data suggest that normal C9orf72 HR length does not act as disease modifier in ALS-C9Neg despite increasing gene expression.

Exploring epigenetic drift and rare epivariations in amyotrophic lateral sclerosis by epigenome-wide association study.

During the last decades, our knowledge about the genetic architecture of sporadic amyotrophic lateral sclerosis (sALS) has significantly increased. However, besides the recognized genetic risk factors, also the environment is supposed to have a role in disease pathogenesis. Epigenetic modifications reflect the results of the interaction between environmental factors and genes and may play a role in the development and progression of ALS. A recent epigenome-wide association study (EWAS) in blood identified differentially methylated positions mapping to 42 genes involved in cholesterol biosynthesis and immune-related pathways. Here we performed a genome-wide DNA methylation analysis in the blood of an Italian cohort of 61 sALS patients and 61 healthy controls. Initially, a conventional genome-wide association analysis was performed, and results were subsequently integrated with the findings from the previous EWAS using a meta-analytical approach. To delve deeper into the significant outcomes, over-representation analysis (ORA) was employed. Moreover, the epigenetic signature obtained from the meta-analysis was examined to determine potential associations with chemical compounds, utilizing the Toxicogenomic Database. Expanding the scope of the epigenetic analysis, we explored both epigenetic drift and rare epivariations. Notably, we observed an elevated epigenetic drift in sALS patients compared to controls, both at a global and single gene level. Interestingly, epigenetic drift at a single gene level revealed an enrichment of genes related to the neurotrophin signaling pathway. Moreover, for the first time, we identified rare epivariations exclusively enriched in sALS cases associated with 153 genes, 88 of whom with a strong expression in cerebral areas. Overall, our study reinforces the evidence that epigenetics may contribute to the pathogenesis of ALS and that epigenetic drift may be a useful diagnostic marker. Moreover, this study suggests the potential role of epivariations in ALS.

An exploratory study on counterfactual thinking in amyotrophic lateral sclerosis.

Objectives: This study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment. Methods: N = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs. Results: The CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total. Conclusion: CFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.

Genomic and transcriptomic advances in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.

Early Detection of Depression in Parkinson's Disease: Psychometrics and Diagnostics of the Spanish Version of the Beck Depression Inventory.

OBJECTIVE: Depression is one of the most disabling non-motor symptoms in Parkinson's disease (PD) and requires proper diagnosis as it negatively impacts patients' and their relatives quality of life. The present study aimed to examine the psychometric and diagnostic properties of the Beck Depression Inventory-I (BDI-I) in a Spanish PD cohort. METHOD: Consecutive PD outpatients completed the Spanish version of the BDI-I and other questionnaires assessing anxiety and apathy. Patients' caregivers completed the depression/dysphoria domain of the Neuropsychiatric Inventory (NPI-D). The internal consistency, convergent and divergent validity and the factorial structure of BDI-I were evaluated, and an optimal cut-off was defined by means of the Youden index. RESULTS: The BDI-I proved to have a good internal consistency and was underpinned by a mono-component structure. Regarding construct validity, the BDI-I was substantially related to anxiety and apathy measures in PD. Furthermore, the BDI-I overall showed good accuracy with adequate sensitivity and specificity. The optimal cut-off point was defined at 10. CONCLUSIONS: We provided evidence of the psychometric and diagnostic properties of the Spanish version of the BDI-I as a screening tool for depression in Spanish speaking PD patients, suggesting its usefulness in clinical research and practice.

Verbal Learning Impairment in Parkinson's Disease: Role of the Frontostriatal System in Working and Strategic Memory.

INTRODUCTION: Learning is a long-term memory process, influenced by working memory control processes, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams. The aim of the study was to investigate the verbal learning strategies of individuals with Parkinson's disease (PD). METHODS: Thirty individuals with idiopathic PD and healthy control (HC) subjects were tested with a multi-trial word list learning, under two conditions: without cue and then with an explicit cue suggesting the categories in the list, respectively. RESULTS: In comparison to HC subjects, individuals with PD recalled fewer words and achieved a reduced number of categorical clusters; the strategical cue did not improve their performance. CONCLUSION: This suggests, besides a difficulty in identifying the correct learning strategy, a deficit in working memory, which undermines the strategy implementation.