A one-year follow-up study of treatment-compliant suicide attempt survivors: relationship of CYP2D6-CYP2C19 and polypharmacy with suicide reattempts.

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (ß = 0.561, p = 0.005) and violent suicide survivors (ß = -0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (ß = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (ß = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (ß = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.

The Five-Point Test: Normative data for middle-aged and elderly Spaniards.

The Five-Point Test (5PT) is a neuropsychological tool for examining design or figural fluency. In this study, we aimed to provide normative data for the 5PT in Spain. Also, we aimed to compare the norms collected in our research with other normative studies from other populations to evaluate a potential cross-cultural application of 5PT. One hundred and ninety-two healthy subjects aged were enrolled. The mean age was 68.48 ± 9.68 years old (range 50-89), and mean years of education were 10.65 ± 5.22. There were 117 (60.9%) women. The overlapping interval strategy was used to maximize the sample size. Age- and education-adjusted scores were estimated using linear regression analysis. Intraclass correlation coefficient was used to calculate agreement with norms from other countries. Age and years of formal education showed moderate correlations with the scores, while the influence of sex was non-significant. Intraclass correlation coefficient (absolute agreement) between Spanish and German norms was 0.956 (95% confidence interval 0.906-0.978). Norms for unique designs at 1, 2, and 3 minutes are provided. Our study confirms the influence of age and education on design fluency and provides normative data for people older than 50 years old. We hypothesize that 5PT might be a useful test in cross-cultural settings.

Development, Spanish Normative Data, and Validation of a Social Cognition Battery in Prodromal Alzheimer's Disease and Multiple Sclerosis.

OBJECTIVES: The assessment of social cognition changes may be challenging, especially in the earliest stages of some neurodegenerative diseases. Our objective was to validate a social cognition battery from a multidomain perspective. In this regard, we aimed to adapt several tests, collect normative data, and validate them in prodromal Alzheimer's disease (AD) and multiple sclerosis (MS). METHODS: A total of 92 healthy controls, 25 prodromal AD, and 39 MS patients were enrolled. Age-, gender-, and education-matched control groups were created for comparisons. Social cognition battery was composed of an emotion-labeling task developed from FACES database, the Story-based Empathy test (SET), the Faux Pas test, and the Interpersonal Reactivity Index. Patients were also evaluated with a comprehensive cognitive battery to evaluate the other cognitive domains. Automatic linear modeling was used to predict each social cognition test's performance using the neuropsychological tests examining other cognitive domains. RESULTS: The reliability of the battery was moderate-high. Significant intergroup differences were found with medium-large effect sizes. Moderate correlations were found between social cognition battery and neuropsychological tests. The emotion labeling task and SET showed moderate correlations with age and education, and age, respectively. Regression-based norms were created considering the relevant demographic variables. Linear regression models including other neuropsychological tests explained between 7.7% and 68.8% of the variance of the social cognition tests performance. CONCLUSIONS: Our study provides a battery for the assessment of social cognition in prodromal AD and MS with Spanish normative data to improve the evaluation in clinical and research settings.

Memory Impairment in Relapsing-Remitting Multiple Sclerosis Using a Challenging Semantic Interference Task.

Objective: Episodic memory is frequently impaired in Multiple Sclerosis (MS), but the cognitive characteristics and neuropsychological processes involved remain controversial. Our aim was to study episodic memory dysfunction in MS, using the LASSI-L, a novel memory-based cognitive stress test that uses a new paradigm that capitalizes on semantic interference. Methods: Cross-sectional study in which 93 patients with MS (relapsing-remitting) and 124 healthy controls were included. The LASSI-L test was administered to all participants, as well as a comprehensive neuropsychological battery including a selective reminding test. MS patients were divided into two groups, with cognitive impairment (CI-MS) and cognitively preserved (CP-MS). Results: Reliability of the LASSI-L test was high (Cronbach's alpha 0.892) and there were less ceiling effects. MS patients scored lower than controls on all LASSI-L subtests, except for maximum storage of the initial target items (CRA2). Effect sizes were moderate-large. A delay in learning, difficulties in retroactive semantic interference, failure to recover from proactive semantic interference, and delayed recall were the most frequent findings in MS patients. Scores associated with maximum storage capacity, and retroactive semantic interference were the most strongly associated with cognitive impairment and employment status. Conclusion: We found that deficits in maximum learning, difficulties in recovery from the effects of proactive semantic interference and retroactive semantic interference are three important breakdowns in episodic memory deficits among patients with MS. The LASSI-L showed good psychometric and diagnostic properties. Overall, our study supports the utility of the LASSI-L, as a new cognitive test, useful for neuropsychological assessment in MS in clinical and research settings.

Validation of the Neuronorma battery for neuropsychological assessment in multiple sclerosis.

BACKGROUND: Cognitive dysfunction is prevalent among patients with multiple sclerosis (MS). In recent years, several (generally brief) neuropsychological batteries have been proposed for cognitive assessment. There is a need for comprehensive batteries providing complete cognitive assessment of patients with MS. The Neuronorma battery includes several standardised neuropsychological tests examining the main cognitive domains, and is available in several countries. The aim of this study was to validate the battery for cognitive assessment in a sample of patients with MS and healthy controls, and to find the most appropriate criteria for defining cognitive impairment using this battery. METHODS: Five hundred and sixty participants (280 with MS and 280 controls matched for age, sex, and years of education) were included. Inter-group differences were calculated using the Mann-Whitney U test and effect sizes with Cohen's d. Several criteria for definition of cognitive impairment were evaluated, according to different cut-off points, and the number of tests and cognitive domains impaired. Receiver operating characteristic curves with 95% confidence intervals were estimated and they were compared using the DeLong method. RESULTS: Patients with MS showed poorer performance in almost all cognitive tests, with large effect sizes for the Symbol Digit Modalities Test and Judgement of Line Orientation, and moderate effects for Digit Span Backward, the Corsi test, Trail Making Test, Free and Cued Selective Reminding Test, Rey-Osterrieth Complex Figure (recall), verbal fluency (P words), and the Stroop Color-Word Interference Test. The area under the curve was superior for classification by cognitive domain than for the mean scaled score of the tests or the number of tests showing impairment according to different cut-off points for the adjusted scaled scores. CONCLUSIONS: Our study validates the Neuronorma battery for cognitive assessment of patients with MS. The battery is currently available in several countries with reliable normative data, and may be useful in both the clinical and the research settings when comprehensive neuropsychological examination is warranted.

Amyloid PET findings in multiple sclerosis are associated with cognitive decline at 18 months.

OBJECTIVE: To study the clinical, cognitive, and radiological progression of a cohort of patients with MS, taking into account the amyloid PET with 18F-florbetaben analyses. METHODS: Twenty-nine patients with MS were assessed with longitudinal structural MRI and a clinical and comprehensive neuropsychological protocol, with a mean interval between assessments of 18 ± 3.31 months. 18F-florbetaben PET was performed at baseline. Uptake was analysed in demyelinating plaques (DWM) and normal-appearing white matter (NAWM). Results were correlated with clinical, cognitive and MRI data. RESULTS: Patients with cognitive decline over the follow-up period showed a lower standardised uptake value ratio in NAWM and lower thalamic volume and a higher lesion load in the baseline MRI. Myelin status was correlated with EDSS and cognitive tests mainly evaluating visuospatial function and working memory. Lower uptake in NAWM at baseline was also associated with a growth in white matter lesion volume over time. CONCLUSIONS: Lower white matter uptake in amyloid PET is associated with cognitive decline and an increase in white matter lesion volume during the follow-up. Our study suggests that 18F-florbetaben may be a useful biomarker in assessing myelin status in MS, understanding MS pathophysiology, and predicting cognitive outcomes.

Cognitive Processes Underlying Verbal Fluency in Multiple Sclerosis.

Background: Verbal fluency (VF) has been associated with several cognitive functions, but the cognitive processes underlying verbal fluency deficits in Multiple Sclerosis (MS) are controversial. Further knowledge about VF could be useful in clinical practice, because these tasks are brief, applicable, and reliable in MS patients. In this study, we aimed to evaluate the cognitive processes related to VF and to develop machine-learning algorithms to predict those patients with cognitive deficits using only VF-derived scores. Methods: Two hundred participants with MS were enrolled and examined using a comprehensive neuropsychological battery, including semantic and phonemic fluencies. Automatic linear modeling was used to identify the neuropsychological test predictors of VF scores. Furthermore, machine-learning algorithms (support vector machines, random forest) were developed to predict those patients with cognitive deficits using only VF-derived scores. Results: Neuropsychological tests associated with attention-executive functioning, memory, and language were the main predictors of the different fluency scores. However, the importance of memory was greater in semantic fluency and clustering scores, and executive functioning in phonemic fluency and switching. Machine learning algorithms predicted general cognitive impairment and executive dysfunction, with F1-scores over 67-71%. Conclusions: VF was influenced by many other cognitive processes, mainly including attention-executive functioning, episodic memory, and language. Semantic fluency and clustering were more explained by memory function, while phonemic fluency and switching were more related to executive functioning. Our study supports that the multiple cognitive components underlying VF tasks in MS could serve for screening purposes and the detection of executive dysfunction.

What is the meaning of PASAT rejection in multiple sclerosis?

BACKGROUND: Paced Auditory Serial Addition Test (PASAT) is one of the most used neuropsychological tests in multiple sclerosis (MS), specially for screening. However, the applicability of the test is limited because of the rejection of the test completion in a proportion of patients. We aimed to investigate the clinical, neuropsychological, and MRI findings associated to PASAT rejection. METHODS: Cross-sectional and observational study. A total of 343 patients with MS underwent neuropsychological testing and structural MRI. RESULTS: One hundred and twenty-one (35.3%) of patients declined the administration of the test. Among those patients that declined the administration, rejection occurred before the onset of test in 35.5%, during or after the practice in 43%, and during the test administration in 21.5%. Rejection of the test was associated to a worse performance in all cognitive tests administered, but not to depression or baseline fatigue scales. In regression analysis, education, cognitive impairment, EDSS, and white matter lesion load were independently associated to rejection of the test. CONCLUSIONS: Paced Auditory Serial Addition Test rejection is associated with a higher probability of cognitive impairment in MS. This suggests that patients that reject the administration of PASAT should be further examined with a neuropsychological battery to evaluate the possibility of cognitive dysfunction.

Structural MRI correlates of PASAT performance in multiple sclerosis.

BACKGROUND: The Paced Auditory Serial Addition Test (PASAT) is a useful cognitive test in patients with multiple sclerosis (MS), assessing sustained attention and information processing speed. However, the neural underpinnings of performance in the test are controversial. We aimed to study the neural basis of PASAT performance by using structural magnetic resonance imaging (MRI) in a series of 242 patients with MS. METHODS: PASAT (3-s) was administered together with a comprehensive neuropsychological battery. Global brain volumes and total T2-weighted lesion volumes were estimated. Voxel-based morphometry and lesion symptom mapping analyses were performed. RESULTS: Mean PASAT score was 42.98 ± 10.44; results indicated impairment in 75 cases (31.0%). PASAT score was correlated with several clusters involving the following regions: bilateral precuneus and posterior cingulate, bilateral caudate and putamen, and bilateral cerebellum. Voxel-based lesion symptom mapping showed no significant clusters. Region of interest-based analysis restricted to white matter regions revealed a correlation with the left cingulum, corpus callosum, bilateral corticospinal tracts, and right arcuate fasciculus. Correlations between PASAT scores and global volumes were weak. CONCLUSION: PASAT score was associated with regional volumes of the posterior cingulate/precuneus and several subcortical structures, specifically the caudate, putamen, and cerebellum. This emphasises the role of both cortical and subcortical structures in cognitive functioning and information processing speed in patients with MS.

Identification of Cortical and Subcortical Correlates of Cognitive Performance in Multiple Sclerosis Using Voxel-Based Morphometry.

Objective: Cognitive impairment is an important feature in multiple sclerosis (MS) and has been associated to several Magnetic Resonance Imaging (MRI) markers, but especially brain atrophy. However, the relationship between specific neuropsychological tests examining several cognitive functions and brain volumes has been little explored. Furthermore, because MS frequently damage subcortical regions, it may be an interesting model to examine the role of subcortical areas in cognitive functioning. Our aim was to identify correlations between specific brain regions and performance in neuropsychological tests evaluating different cognitive functions in a large series of patients with MS. Methods: A total of 375 patients were evaluated with a comprehensive neuropsychological battery and with MRI. Voxel-based morphometry was conducted to analyse the correlation between cognitive performance and gray matter damage, using Statistical Parametric Mapping with the toolboxes VBM8 and Lesion Segmentation Tool. Results: The following correlations were found: Corsi block-tapping test with right insula; Trail Making Test with caudate nucleus, thalamus, and several cortical regions including the posterior cingulate and inferior frontal gyrus; Symbol Digit Modalities Test with caudate nucleus, thalamus, posterior cingulate, several frontal regions, insula, and cerebellum; Stroop Color and Word Test with caudate nucleus and putamen; Free and Cued Selective Reminding Test and Rey-Osterrieth Complex Figure with thalamus, precuneus, and parahippocampal gyrus; Boston Naming Test with thalamus, caudate nucleus, and hippocampus; semantic verbal fluency with thalamus and phonological verbal fluency with caudate nucleus; and Tower of London test with frontal lobe, caudate nucleus, and posterior cingulate. Conclusion: Our study provides valuable data on the cortical and subcortical basis of cognitive function in MS. Neuropsychological tests mainly assessing attention and executive function showed a stronger association with caudate volume, while tests primarily evaluating memory were more strongly correlated with the thalamus. Other relevant regions were the posterior cingulate/precuneus, which were associated with attentional tasks, and several frontal regions, which were found to be correlated with planning and higher order executive functioning. Furthermore, our study supports the brain vertical organization of cognitive functioning, with the participation of the cortex, thalamus, basal ganglia, and cerebellum.

Conversion between Addenbrooke's Cognitive Examination III and Mini-Mental State Examination.

ABSTRACTBackground:We aim to provide a conversion between Addenbrooke's Cognitive Examination III (ACE-III) and Mini-Mental State Examination (MMSE) scores, to predict the MMSE result based on ACE-III, thus avoiding the need for both tests, and improving their comparability. METHODS: Equipercentile equating method was used to elaborate a conversion table using a group of 400 participants comprising healthy controls and Alzheimer's disease (AD) patients. Then, reliability was assessed in a group of 100 healthy controls and patients with AD, 52 with primary progressive aphasia and 22 with behavioral variant frontotemporal dementia. RESULTS: The conversion table between ACE-III and MMSE denoted a high reliability, with intra-class correlation coefficients of 0.940, 0.922, and 0.902 in the groups of healthy controls and AD, behavioral variant frontotemporal dementia, and primary progressive aphasia, respectively. CONCLUSION: Our conversion table between ACE-III and MMSE suggests that MMSE may be estimated based on the ACE-III score, which could be useful for clinical and research purposes.

Functional Components of Cognitive Impairment in Multiple Sclerosis: A Cross-Sectional Investigation.

BACKGROUND: Cognitive impairment is frequent and disabling in multiple sclerosis (MS). Changes in information processing speed constitute the most important cognitive deficit in MS. However, given the clinical and topographical variability of the disease, cognitive impairment may vary greatly and appear in other forms in addition to slower information processing speed. Our aim was to determine the frequency of cognitive impairment, the principal cognitive domains, and components involved in MS and to identify factors associated with presence of cognitive impairment in these patients in a large series of patients. METHODS: Cross-sectional study of 311 patients with MS [236 with relapsing-remitting MS (RRMS), 52 with secondary progressive MS (SPMS), and 23 with primary progressive MS (PPMS)]. Patients' cognitive function was assessed with a comprehensive neuropsychological assessment protocol. Patients displaying deficits in 2 or more cognitive domains were considered to have cognitive impairment associated with MS. We conducted a principal component analysis to detect different cognitive patterns by identifying clusters of tests highly correlated to one another. RESULTS: Cognitive impairment was detected in 41.5% of the sample, and it was more frequent in patients with SPMS and PPMS (P = 0.002). Expanded Disability Status Scale scores and education were independent predictors of cognitive impairment. Principal component analysis identified seven clusters: attention and basic executive function (including information processing speed), planning and high-level executive function, verbal memory and language, executive and visuospatial performance time, fatigue-depression, visuospatial function, and basic attention and verbal/visual working memory. Mean scoring of components 2 (high-order executive functioning) and 3 (verbal memory-language) was higher in patients with RRMS than in those with PPMS (component 2) and SPMS (component 3). CONCLUSION: MS is linked to multiple cognitive profiles and disturbances in different domains. This suggests that cognitive alterations in MS are heterogeneous and affect other domains in addition to information processing speed.

Amyloid PET in pseudotumoral multiple sclerosis.

BACKGROUND: Pseudotumoral multiple sclerosis is a rare form of demyelinating disease of the central nervous system. Positron emission tomography (PET) using amyloid-tracers has also been suggested as a marker of damage in white matter lesions in multiple sclerosis due to the nonspecific uptake of these tracers in white matter. METHOD: We present the case of a 59 year-old woman with a pathological-confirmed pseudotumoral multiple sclerosis, who was studied with the amyloid tracer 18F-florbetaben. The patient had developed word-finding difficulties and right hemianopia twelve years ago. In that time, MRI showed a lesion on the left hemisphere with an infiltrating aspect in frontotemporal lobes. Brain biopsy showed demyelinating areas and inflammation. During the following years, two new clinical relapses occurred. RESULTS: 18F-florbetaben PET showed lower uptake in the white matter lesion visualized in the CT and MRI images. Decreased tracer uptake was also observed in a larger area of the left hemisphere beyond the lesions observed on MRI or CT. White matter lesion volume on FLAIR was 44.2mL, and tracer uptake change between damaged white matter and normal appearing white matter was - 40.5%. Standardized uptake value was inferior in the pseudotumoral lesion than in the other white matter lesions. CONCLUSION: We report the findings of amyloid PET in a patient with pseudotumoral multiple sclerosis. This case provides further evidence on the role of amyloid PET in the assessment of white matter and demyelinating diseases.

Addenbrooke's cognitive examination III: diagnostic utility for mild cognitive impairment and dementia and correlation with standardized neuropsychological tests.

BACKGROUND: Addenbrooke's Cognitive Examination III (ACE-III) is a screening test that was recently validated for diagnosing dementia. Since it assesses attention, language, memory, fluency, and visuospatial function separately, it may also be useful for general neuropsychological assessments. The aim of this study was to analyze the tool's ability to detect early stages of Alzheimer's disease and to examine the correlation between ACE-III scores and scores on standardized neuropsychological tests. METHODS: Our study included 200 participants categorized as follows: 25 healthy controls, 48 individuals with subjective memory complaints, 47 patients with amnestic mild cognitive impairment and 47 mild Alzheimer's disease, and 33 patients with other neurodegenerative diseases. RESULTS: The ACE-III memory and language domains were highly correlated with the neuropsychological tests specific to those domains (Pearson correlation coefficient of 0.806 for total delayed recall on the Free and Cued Selective Reminding Test vs. 0.744 on the Boston Naming Test). ACE-III scores discriminated between controls and patients with amnestic mild cognitive impairment (AUC: 0.906), and between controls and patients with mild Alzheimer's disease (AUC: 0.978). CONCLUSION: Our results suggest that ACE-III is a useful neuropsychological test for assessing the cognitive domains of attention, language, memory, and visuospatial function. It also enables detection of Alzheimer's disease in early stages.

Normative Data for the Spanish Version of the Addenbrooke's Cognitive Examination III.

BACKGROUND: Addenbrooke's Cognitive Examination III (ACE-III) is a cognitive test that has been validated for the diagnosis of cognitive disorders. The aim of this study was to provide normative data for the ACE-III for age, education and gender. METHODS: The Spanish version of the ACE-III was administered to a group of 273 healthy subjects in a multicenter study in Spain. Correlation and determination coefficients for age, education and gender were estimated. The overlapping interval strategy and linear regression analyses were used to provide adjusted norms for demographic factors and to explore the potential influence of these factors in the performance of the test. RESULTS: Age and education correlated significantly with the total score and with all the domains. Gender correlated only with the domains of attention and visuospatial skills. Norms for the total score and for cognitive domains (attention, memory, fluency, language, and visuospatial skills) are provided. CONCLUSION: This study confirms the influence of demographic factors (especially age and education) on the performance in the ACE-III and provides normative data for the Spanish version of the ACE-III.