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Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.
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Doenças do Sistema Nervoso , Doenças Raras , Adulto , Humanos , Doenças Raras/epidemiologia , Centros de Atenção Terciária , HospitalizaçãoRESUMO
INTRODUCTION: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult onset leukodystrophy, causally related to mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We report the unique case of a Greek HDLS patient, demonstrating an unusual phenotype, reminiscent of primary progressive aphasia (PPA). METHODS: A 63-year-old woman was referred with a 2-year history of deteriorating language and memory deficits, apathy, and two generalized tonic-clonic seizures. Neurological and neuropsychological examination revealed prominent aphasia with a pattern consistent with nonfluent variant of PPA. However, brain MRI disclosed confluent T2 and FLAIR white matter hyperintensities with frontal emphasis, whereas genetic testing corroborated the diagnosis of HDLS. DISCUSSION: PPA-like patterns may rarely develop in the context of HDLS. Prompt diagnosis of this leukoencephalopathy is essential, since preliminary data suggest that it could represent a potentially treatable disorder.
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Afasia Primária Progressiva , Leucoencefalopatias , Adulto , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/genética , Feminino , Grécia , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Receptor de Fator Estimulador de Colônias de Macrófagos/genéticaRESUMO
Theory of Mind (ToM) is a critical component of social cognition, and thus, its impairment may adversely affect social functioning and quality of life. Recent evidence has suggested that it is impaired in epilepsy. What is not clear, however, is whether it is related to particular types of epilepsy or other factors. We undertook the present study to explore ToM in patients with focal versus those with generalized epilepsy, the particular pattern of ToM deficits, and the potential influence of antiepileptic medication load. Our sample included 149 adults: 79 patients with epilepsy (34 with generalized epilepsy and 45 with focal epilepsy) and 70 healthy controls. Theory of Mind tasks included a) comprehension of hinting, b) comprehension of sarcasm and metaphor, c) comprehension of false beliefs and deception, d) recognition of faux pas, and e) a visual ToM task in cartoon form. We found significant ToM impairment in the group with focal epilepsy relative to the performance of both the healthy group and the group with generalized epilepsy on all tasks, with the exception of faux pas, on which the group with generalized epilepsy also performed more poorly than the healthy group. Additionally, early age at seizure onset, but not antiepileptic drug (AED) load, was associated with ToM performance. Our findings suggest that focal temporal and frontal lobe, but not generalized, epilepsies were associated with impaired ToM. This may reflect the neuroanatomical abnormalities in the relevant neuronal networks and may have implications for differential cognitive-behavioral interventions based on epilepsy type.
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Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/psicologia , Epilepsia Generalizada/diagnóstico por imagem , Epilepsia Generalizada/psicologia , Teoria da Mente/fisiologia , Adulto , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Compreensão/fisiologia , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Qualidade de Vida/psicologia , Convulsões/fisiopatologia , Convulsões/psicologia , Comportamento Social , Adulto JovemRESUMO
We report a case of a 19-year-old woman with a subacute onset of visual disturbance and gait instability in the last three months. The neurological examination revealed horizontal nystagmus in the lateral gaze with a change of phase. The patient also described double vision in various gaze positions, with no clear opthalmoparesis. In her next visits to our clinic, the symptoms had progressed. In this presentation, we discuss the approach of subacute cerebellar ataxia in a young adult patient.
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Background: Alzheimer's disease (AD) and epilepsy represent two complex neurological disorders with distinct clinical manifestations, yet recent research has highlighted their intricate interplay. This review examines the association between AD and epilepsy, with particular emphasis on late-onset epilepsy of unknown etiology, increasingly acknowledged as a prodrome of AD. It delves into epidemiology, pathogenic mechanisms, clinical features, diagnostic characteristics, treatment strategies, and emerging biomarkers to provide a comprehensive understanding of this relationship. Methods: A comprehensive literature search was conducted, identifying 128 relevant articles published between 2018 and 2024. Results: Findings underscore a bidirectional relationship between AD and epilepsy, indicating shared pathogenic pathways that extend beyond traditional amyloid-beta and Tau protein pathology. These pathways encompass neuroinflammation, synaptic dysfunction, structural and network alterations, as well as molecular mechanisms. Notably, epileptic activity in AD patients may exacerbate cognitive decline, necessitating prompt detection and treatment. Novel biomarkers, such as subclinical epileptiform activity detected via advanced electroencephalographic techniques, offer promise for early diagnosis and targeted interventions. Furthermore, emerging therapeutic approaches targeting shared pathogenic mechanisms hold potential for disease modification in both AD and epilepsy. Conclusions: This review highlights the importance of understanding the relationship between AD and epilepsy, providing insights into future research directions. Clinical data and diagnostic methods are also reviewed, enabling clinicians to implement more effective treatment strategies.
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Background: Neuronal nicotinic acetylcholine receptors (nAChRs) are abundant in the central nervous system (CNS), playing critical roles in brain function. Antigenicity of nAChRs has been well demonstrated with antibodies to ganglionic AChR subtypes (i.e., subunit α3 of α3ß4-nAChR) and muscle AChR autoantibodies, thus making nAChRs candidate autoantigens in autoimmune CNS disorders. Antibodies to several membrane receptors, like NMDAR, have been identified in autoimmune encephalitis syndromes (AES), but many AES patients have yet to be unidentified for autoantibodies. This study aimed to develop of a cell-based assay (CBA) that selectively detects potentially pathogenic antibodies to subunits of the major nAChR subtypes (α4ß2- and α7-nAChRs) and its use for the identification of such antibodies in "orphan" AES cases. Methods: The study involved screening of sera derived from 1752 patients from Greece, Turkey and Italy, who requested testing for AES-associated antibodies, and from 1203 "control" patients with other neuropsychiatric diseases, from the same countries or from Germany. A sensitive live-CBA with α4ß2-or α7-nAChR-transfected cells was developed to detect antibodies against extracellular domains of nAChR major subunits. Flow cytometry (FACS) was performed to confirm the CBA findings and indirect immunohistochemistry (IHC) to investigate serum autoantibodies' binding to rat brain tissue. Results: Three patients were found to be positive for serum antibodies against nAChR α4 subunit by CBA and the presence of the specific antibodies was quantitatively confirmed by FACS. We detected specific binding of patient-derived serum anti-nAChR α4 subunit antibodies to rat cerebellum and hippocampus tissue. No serum antibodies bound to the α7-nAChR-transfected or control-transfected cells, and no control serum antibodies bound to the transfected cells. All patients positive for serum anti-nAChRs α4 subunit antibodies were negative for other AES-associated antibodies. All three of the anti-nAChR α4 subunit serum antibody-positive patients fall into the AES spectrum, with one having Rasmussen encephalitis, another autoimmune meningoencephalomyelitis and another being diagnosed with possible autoimmune encephalitis. Conclusion: This study lends credence to the hypothesis that the major nAChR subunits are autoimmune targets in some cases of AES and establishes a sensitive live-CBA for the identification of such patients.
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Autoanticorpos , Receptores Nicotínicos , Humanos , Autoanticorpos/imunologia , Autoanticorpos/sangue , Receptores Nicotínicos/imunologia , Animais , Masculino , Feminino , Ratos , Adulto , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Central/imunologia , Idoso , Adulto Jovem , Encefalite/imunologia , Adolescente , Neurônios/imunologia , Neurônios/metabolismoRESUMO
Memory deficits are common in patients with dementia, such as Alzheimer's disease, but also in patients with other neurological and psychiatric disorders, such as brain injury, multiple sclerosis, ischemic stroke and schizophrenia. Memory loss affects patients' functionality and, by extension, their quality of life. Non-invasive brain training methods, such as EEG neurofeedback, are used to address cognitive deficits and behavioral changes in dementia and other neurological disorders by training patients to alter their brain activity via operant activity. In this review paper, we analyze various protocols of EEG neurofeedback in memory rehabilitation in patients with dementia, multiple sclerosis, strokes and traumatic brain injury. The results from the studies show the effectiveness of the ΕΕG-NFB method in improving at least one cognitive domain, regardless of the number of sessions or the type of protocol applied. In future research, it is important to address methodological weaknesses in the application of the method, its long-term effects as well as ethical issues.
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BACKGROUND: Epileptic patients frequently encounter cognitive impairment. Functions that are mostly affected involve memory, attention, and executive function; however, this is mainly dependent on the location of the epileptic activity. The aim of the present study is to assess cognitive functions in MRI-negative epilepsy patients by means of neurophysiological and neuropsychological measures, as well as study the concept of transient cognitive impairment in patients with epileptiform discharges during EEG acquisition. METHODS: The patients were enrolled from an outpatient Epilepsy/Clinical Neurophysiology clinic over a time period of 6 months. The study sample comprised 20 MRI-negative epilepsy patients (mean age ± standard deviation (SD), 30.3 ± 12.56 years; age range, 16-60 years; average disease duration, 13.95 years) and 10 age-matched controls (mean age ± SD, 24.22 ± 15.39 years), who were also education-matched (p > 0.05). Patients with epileptogenic lesions were excluded from the study. Informed consent was obtained from all subjects involved in the study. Auditory ERPs and the cognitive screening tool EpiTrack were administered to all subjects. RESULTS: Latencies of P300 and slow waves were prolonged in patients compared to controls (p < 0.05). The ASM load and patients' performance in the EpiTrack maze subtest were the most significant predictors of P300 latency. A decline in the memory, attention, and speed of information processing was observed in patients with cryptogenic epilepsy compared to age-matched controls, as reflected by P300 latency and EpiTrack scores.
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Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. We present a case of a 20-year-old male with severe spastic gait, intellectual disability and seizures. Metabolic tests revealed high levels of arginine in blood serum. Hyperargininemia was attributed to a likely pathogenic rare mutation of ARG1 gene [Chr6: g131905002_131905002 G>A (p.Arg308Gln) homozygous] detected in Whole Exome Sequencing resulting in deficiency in arginase I enzyme. Following the diagnosis, the patient has been treated with low protein diet, aminoacid and vitamin supplements. The accumulation of arginine, may contribute to the pathogenesis of severe neurological manifestations, however, low protein intake diet may lead to a favorable outcome. Therefore, clinicians should screen for hyperargininemia in early childhood in case of strong clinical suspicion.
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Transtornos Neurológicos da Marcha/genética , Hiperargininemia/genética , Deficiência Intelectual/genética , Mutação , Convulsões/genética , Arginina/sangue , Transtornos Neurológicos da Marcha/sangue , Humanos , Hiperargininemia/sangue , Deficiência Intelectual/sangue , Masculino , Convulsões/sangue , Sequenciamento do Exoma , Adulto JovemRESUMO
Progressive multifocal leukoencephalopathy (PML) is attributed to reactivation of the John Cunningham virus (JCV), in the central nervous system as a result of immunosuppression. Low L-selectin (CD62L) expression on cryopreserved T-cells has been advocated as a biomarker for natalizumab related PML in patients with Relapsing-Remitting Multiple Sclerosis. A rare case of PML in an elderly patient without known factors of immunosuppression or immunomodulation is hereby presented. T-cell L-selectin expression levels and serum anti-JCV antibody index were evaluated in order to explore mechanistic insight to the pathways that presumably contribute towards PML development in this rare clinical setting.
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Selectina L/biossíntese , Leucoencefalopatia Multifocal Progressiva/imunologia , Linfócitos T/imunologia , Idoso , Biomarcadores/sangue , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Humanos , Imunocompetência , Imunossenescência/imunologia , Vírus JC/imunologia , Selectina L/sangue , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Imageamento por Ressonância MagnéticaRESUMO
Dementia is the clinical syndrome characterized by progressive loss of cognitive and emotional abilities to a degree severe enough to interfere with daily functioning. Alzheimer's disease (AD) is the most common neurogenerative disorder, making up 50-70% of total dementia cases. Another dementia type is frontotemporal dementia (FTD), which is associated with circumscribed degeneration of the prefrontal and anterior temporal cortex and mainly affects personality and social skills. With the rapid advancement in electroencephalogram (EEG) sensors, the EEG has become a suitable, accurate, and highly sensitive biomarker for the identification of neuronal and cognitive dynamics in most cases of dementia, such as AD and FTD, through EEG signal analysis and processing techniques. In this study, six supervised machine-learning techniques were compared on categorizing processed EEG signals of AD and FTD cases, to provide an insight for future methods on early dementia diagnosis. K-fold cross validation and leave-one-patient-out cross validation were also compared as validation methods to evaluate their performance for this classification problem. The proposed methodology accuracy scores were 78.5% for AD detection with decision trees and 86.3% for FTD detection with random forests.
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Background: Natalizumab (NTZ) and fingolimod (FTY) are second-line disease modifying treatments (DMTs) approved for Relapsing - Remitting Multiple Sclerosis (RRMS). Few studies are available on a direct comparison between NTZ and FTY, based on post-marketing experience, with conflicting results and reporting relatively short follow-up period. Aim: We hereby report real-world experience of a MS Center with respect to NTZ vs. FTY comparison in terms of efficacy and safety, referencing long-term follow-up. Methods: We used retrospective data for all patients that received 2nd-line treatment NTZ (since May 2007) or FTY (since September 2011). Primary endpoints were, among others, annual EDSS score (mean change from baseline), time to disability worsening or improvement, Annualized Relapse Rate (ARR) after 12 and 24 months and upon total treatment duration, time to first relapse and time to radiological progression. Results: A total of 138 unmatched patients, 84 treated with NTZ and 54 treated with FTY were included. Following Propensity Score (PS) matching, 31 patients in each group were retained. Mean follow-up period for NTZ- and FTY-treated patients was 4.43 ± 0.29 and 3.59 ± 0.32 years (p = 0.057), respectively. In the matched analysis, time to disability improvement and time to disability worsening was comparable between groups. A higher proportion of patients remained free of relapse under NTZ, compared to FTY (Log Rank test p = 0.021, HR: 0.25, 95% CI: 0.08-0.8), as well as free of MRI activity (Log Rank test p = 0.006, HR: 0.26, 95% CI: 0.08-0.6). Treatment discontinuation due to MRI activity was significantly higher for FTY-treated patients compared to NTZ (Log Rank test p = 0.019, HR: 0.12, 95% CI: 0.05-0.76). Conclusion: Our results indicate toward NTZ superiority with respect to relapse and MRI activity outcomes. The fact that NTZ-treated patients may achieve long-standing clinical and radiological remission points toward the need for long follow-up data.
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Objectives: Natalizumab (NTZ), a treatment indicated for patients with highly active Relapsing - Remitting Multiple Sclerosis (RRMS), is known to induce increased relative frequency of lymphocytes. Progressive Multifocal Leukoencephalitis (PML) is a rare but serious adverse event related to NTZ. Moreover, reduced L-selectin (CD62L) expression in T-cells in cryopreserved samples of patients with RRMS under NTZ has been proposed as a biomarker of pre-PML state. We explore the association between L-selectin expression in T-cells and hematological parameters in freshly processed samples of patients with RRMS under NTZ.Methods: We studied L-selectin expression in patients with: RRMS under NTZ (n=34), fingolimod (FTY, n=14), interferon-beta (IFNß, n=22), glatiramer acetate (GA, N=17); in 9 patients with secondary progressive (SP) MS and in 6 healthy controls. Twenty-two patients under NTZ and 6 patients under FTY were followed for 18 months. One NTZ-treated patient developed PML during the study.Results: Patients under NTZ exhibited increased relative frequency of lymphocytes (40.02±1.45) compared to patients under first-line treatment (30.57±1.68, p<0.001) and to patients with SPMS (29±1.56, p=0.02), and a lower mean L-selectin expression in (69.39±1.73) compared to patients under first-line treatment (79.1±1.17, p=0.003). A negative correlation between the relative frequency of CD4+CD62L+ T-cells and the absolute lymphocyte counts (Pearson's r=0.367, p=0.033) was observed.Discussion: We hereby provide mechanistic insight in a possible pathway implicated in NTZ-related PML risk. These results further underline the need for thorough validation of L-selectin expression in T-cells as a potential pre-PML biomarker.
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Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Fatores Imunológicos/efeitos adversos , Selectina L/metabolismo , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fatores de RiscoRESUMO
Alzheimer's Disease (AD) is a neurogenerative disorder and the most common type of dementia with a rapidly increasing world prevalence. In this paper, the ability of several statistical and spectral features to detect AD from electroencephalographic (EEG) recordings is evaluated. For this purpose, clinical EEG recordings from 14 patients with AD (8 with mild AD and 6 with moderate AD) and 10 healthy, age-matched individuals are analyzed. The EEG signals are initially segmented in nonoverlapping epochs of different lengths ranging from 5 s to 12 s. Then, a group of statistical and spectral features calculated for each EEG rhythm (δ, θ, α, ß, and γ) are extracted, forming the feature vector that trained and tested a Random Forests classifier. Six classification problems are addressed, including the discrimination from whole-brain dynamics and separately from specific brain regions in order to highlight any alterations of the cortical regions. The results indicated a high accuracy ranging from 88.79% to 96.78% for whole-brain classification. Also, the classification accuracy was higher at the posterior and central regions than at the frontal area and the right side of temporal lobe for all classification problems.
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BACKGROUND: Induction of T-cell apoptosis constitutes a mechanism of action for Glatiramer Acetate (GA). We investigated whether activation of apoptotic T-cell death may be indicative of optimal treatment response in patients with relapsing-remitting Multiple Sclerosis (RRMS), with respect to radiological activity. METHODS: We studied apoptotic markers on blood T-cells of forty patients with RRMS, 19 patients under GA and 21 patients under interferon-ß (IFNß), by flow cytometry. Patients were relapse-free and were further classified into optimal and sub-optimal responders based on radiological activity. Eighteen patients (8 patients under GA and 10 patients under IFNß were additionally evaluated at a 12-month follow-up and were relapse- and radiological activity-free. For these patients, apoptosis was also evaluated by molecular techniques. RESULTS: At inclusion, optimal responders to GA exhibited increased (23.6⯱â¯1.976) relative % frequency of CD4(+)AnnexinV(+)7AAD(-) T-cells, compared to sub-optimal responders (14.478⯱â¯1.204, pâ¯=â¯0.001). Similarly, relative % frequency of caspase-3(+) T-cells was 1.517⯱â¯0.436 versus 0.45⯱â¯0.149 (pâ¯=â¯0.041), respectively. Anti-apoptotic molecule bcl-2 showed an inverse pattern 4.532⯱â¯1.321 versus 13.094⯱â¯3.987, pâ¯=â¯0.044, respectively. These differences were not evident for IFNß-treated patients. CONCLUSIONS: T-cell apoptotic markers may be applied as a biomarker useful in evaluating optimal treatment response under GA, thus allowing for personalized treatment decisions.
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Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Acetato de Glatiramer/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Apoptose/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Feminino , Citometria de Fluxo/métodos , Seguimentos , Acetato de Glatiramer/farmacologia , Humanos , Imunossupressores/farmacologia , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Resultado do TratamentoRESUMO
The Multiple Sclerosis Neuropsychological Questionnaire is a brief screening questionnaire for the assessment of everyday neuropsychological competence of patients with Multiple Sclerosis. The aim of the present study was to examine psychometric properties of the Greek version of the instrument. One hundred and three MS patients and 60 informants participated in the present study and completed the questionnaire. From the initial patient sample, 51 participants completed broadly used neuropsychological tests and measures estimating cognitive failures and depression. Moreover, after a six-month interval the MSNQ was administered to 58 patients from the initial sample in order to explore test-retest reliability. Cronbach's α was 0.92 and 0.93 for patient and informant forms, respectively. The patient form was correlated significantly with measures of cognitive failures and depression. Low correlations were found between the informant form and performance on cognitive tests. In regard to the patient form, significant correlation was observed between repeated administrations and, psychometrically, the three-factor structure was preferable than the one-factor structure. The present study confirms the already established pattern of correlations among the two MSNQ forms, neuropsychological test performance and depression measurements. Additional research is needed in order to define a cut-off score for the MSNQ-I providing further information about the diagnostic interpretability of the instrument.