Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility.

Posterior cortical atrophy: a single case cognitive and radiological follow-up.

Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.

Performance of Patients with Early Parkinson Disease on an Executive and Social Cognition Battery.

OBJECTIVE: To demonstrate the usefulness of incorporating the Executive and Social Cognition Battery (ESCB) to detect executive and social cognition deficits, which are otherwise not captured by more "classical" executive tests in early Parkinson disease (PD). BACKGROUND: PD is a neurodegenerative disorder that includes executive and social cognition deficits. While cognitive assessment in PD still relies on classical executive tasks to detect frontal deficits, these traditional tests often fail to uncover subtle, yet relevant, frontal impairment. METHODS: We evaluated 39 PD patients and 47 controls with a battery of classical executive tests and the ESCB. The ESCB includes a series of tasks that more closely resemble real-life activities and have been previously shown to be useful in detecting executive deficits in other neuropsychiatric disorders with frontal involvement. RESULTS: We observed that both batteries used in a complementary way yielded better results, as 15 of the 39 patients presented deficits only on some of the ESCB tests, but not on the classical battery, while 5 patients presented deficits only on some tests of the classical battery, but not on the ESCB. Fourteen patients presented deficits on some tests of either battery, and 5 patients did not present deficits on any of the tests. CONCLUSIONS: We found that, used along with traditional neuropsychological tasks, the ESCB may be useful in providing a more comprehensive evaluation of frontal dysfunction among patients with PD, thus contributing to the early diagnosis of cognitive disorders in this patient population.

Tackling variability: A multicenter study to provide a gold-standard network approach for frontotemporal dementia.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease-modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples' socio-cultural background, and, more troublingly still, no gold-standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral-variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold-standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter-regional connectivity, and several graph-theory approaches. Only graph-theory analysis, based on weighted-matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph-theory as a potential gold-standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804-3822, 2017. © 2017 Wiley Periodicals, Inc.

Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

OBJECTIVES: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. METHODS: Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. RESULTS: Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. CONCLUSIONS: bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

Integration of Intention and Outcome for Moral Judgment in Frontotemporal Dementia: Brain Structural Signatures.

BACKGROUND: Moral judgment has been proposed to rely on a distributed brain network. This function is impaired in behavioral variant frontotemporal dementia (bvFTD), a condition involving damage to some regions of this network. However, no studies have investigated moral judgment in bvFTD via structural neuroimaging. METHODS: We compared the performance of 21 bvFTD patients and 19 controls on a moral judgment task involving scenarios that discriminate between the contributions of intentions and outcomes. Voxel-based morphometry was used to assess (a) the atrophy pattern in bvFTD patients, (b) associations between gray matter (GM) volume and moral judgments, and (c) structural differences between bvFTD subgroups (patients with relatively preserved moral judgment and patients with severer moral judgment impairments). RESULTS: Patients judged attempted harm as more permissible and accidental harm as less permissible than controls. The groups' performance on accidental harm was associated with GM volume in the precuneus. In controls, it was al- so associated with the ventromedial prefrontal cortex (VMPFC). Also, both groups' performance on attempted harm was associated with GM volume in the temporoparietal junction. Patients exhibiting worse performance displayed smaller GM volumes in the precuneus and temporal pole. CONCLUSIONS: Results suggest that moral judgment abnormalities in bvFTD are associated with impaired integration of intentions and outcomes, which depends on an extended brain network. In bvFTD, moral judgment seems to critically depend on areas beyond the VMPFC.

Verbal Fluency as a Rapid Screening Test for Cognitive Impairment in Early Parkinson's Disease.

The phonological verbal fluency test can act as a fast screening test to detect cognitive deficits in neurological conditions. In the present study, its utility in the detection of executive deficits in patients with early Parkinson's disease is demonstrated.

Differential Cognitive and Affective Theory of Mind Abilities at Mild and Moderate Stages of Behavioral Variant Frontotemporal Dementia.

OBJECTIVE: To study the affective and cognitive components of theory of mind (ToM) performance in patients with behavioral variant frontotemporal dementia (bvFTD), focusing on differential impairment at mild and moderate disease stages. BACKGROUND: ToM, a central capacity for appropriate social behavior, is critically impaired in patients with bvFTD, even early in the disease. No previous study has explored how the cognitive and affective components of ToM may relate differentially to disease severity. METHODS: We assessed 40 patients with an established diagnosis of bvFTD and 18 healthy controls, using a complete neuropsychological battery that featured executive function and ToM tasks. We used patients' Clinical Dementia Rating scores to classify them as having either mild or moderate bvFTD. RESULTS: Both groups of patients showed deficits in the affective and cognitive components of ToM relative to the controls. The patients with mild bvFTD outperformed the group with moderate bvFTD in cognitive ToM capacities; however, affective ToM was equally impaired in both bvFTD groups. The cognitive, but not the affective, component of ToM correlated with performance on the executive function tests. CONCLUSIONS: Our results suggest that affective ToM is markedly diminished even during the initial stages of bvFTD; as the disease progresses, deficits in cognitive ToM become more prominent. These findings may relate to the pattern of cortical atrophy described for bvFTD. We also found significant correlations between the cognitive component of ToM and executive functions.

Personality changes in dementia: are they disease specific and universal?

Previous studies about personality changes in dementia suggest that they may be due to the disruption of the biological basis of personality traits, and hence, that they are disease specific and universal. However, evidence about its specificity is still limited and scarce regarding culturally diverse populations. Accordingly, our aim was to compare personality changes in Argentinean patients with Alzheimer disease, behavioral variant of frontotemporal dementia, and primary progressive aphasia. The closest living relatives of patients diagnosed with Alzheimer disease (n=19), behavioral variant of frontotemporal dementia (n=16), and primary progressive aphasia (n=15) were asked to complete 2 versions of the personality inventory NEO Personality Inventory-Revised, one for assessing patients' premorbid personality traits, and the other for assessing current traits. All groups showed changes in several domains and facets of the NEO Personality Inventory-Revised. Globally, the observed pattern of changes was fairly consistent with previous studies based on the same model of personality. Nevertheless, our results regarding disease-specificity were less conclusive. Even if there were some indicators of specific differences between groups, most traits varied similarly across the 3 groups, revealing a pattern of generalized changes in personality expression after illness onset. More studies are needed that help to distinguish real personality changes from other affective or cognitive symptoms that accompany dementia, as well as further data from culturally diverse populations.

Functional connectivity and temporal variability of brain connections in adults with attention deficit/hyperactivity disorder and bipolar disorder.

OBJECTIVES: To assess brain functional connectivity and variability in adults with attention deficit/hyperactivity disorder (ADHD) or euthymic bipolar disorder (BD) relative to a control (CT) group. METHODS: Electroencephalography (EEG) was measured in 35 participants (BD = 11; ADHD = 9; CT = 15) during an eyes-closed 10-min rest period, and connectivity and graph theory metrics were computed. A coefficient of variation (CV) computed also the connectivity's temporal variability of EEG. Multivariate associations between functional connectivity and clinical and neuropsychological profiles were evaluated. RESULTS: An enhancement of functional connectivity was observed in the ADHD (fronto-occipital connections) and BD (diffuse connections) groups. However, compared with CTs, intrinsic variability (CV) was enhanced in the ADHD group and reduced in the BD group. Graph theory metrics confirmed the existence of several abnormal network features in both affected groups. Significant associations of connectivity with symptoms were also observed. In the ADHD group, temporal variability of functional connections was associated with executive function and memory deficits. Depression, hyperactivity and impulsivity levels in the ADHD group were associated with abnormal intrinsic connectivity. In the BD group, levels of anxiety and depression were related to abnormal frontotemporal connectivity. CONCLUSIONS: In the ADHD group, we found that intrinsic variability was associated with deficits in cognitive performance and that connectivity abnormalities were related to ADHD symptomatology. The BD group exhibited less intrinsic variability and more diffuse long-range brain connections, and those abnormalities were related to interindividual differences in depression and anxiety. These preliminary results are relevant for neurocognitive models of abnormal brain connectivity in both disorders.

Cognitive but not affective theory of mind deficits in mild relapsing-remitting multiple sclerosis.

OBJECTIVE: We studied theory of mind (ToM) in patients with mild relapsing-remitting multiple sclerosis (MS), seeking possible dissociations between its 2 components: cognitive ToM (the ability to infer others' intentions) and affective ToM (the ability to infer others' emotional states). We analyzed the relationship of ToM to executive function, depression, and fatigue. BACKGROUND: Dissociations between cognitive and affective ToM have been found in several neurologic and neuropsychiatric diseases. Most ToM studies in patients with MS have shown general ToM deficits but have not analyzed the cognitive and affective aspects individually. METHODS: We used the Faux Pas test of ToM and tests of executive function to assess 18 patients with mild relapsing-remitting MS and 16 control participants. RESULTS: Our patients showed deficits in cognitive ToM, but their affective ToM seemed to be spared. Their cognitive ToM deficits were not related to executive dysfunction, depression, or fatigue. CONCLUSIONS: Our study is the first differential analysis showing cognitive but not affective ToM deficits in mild relapsing-remitting MS. Further research is needed to determine the exact nature and the real impact of these deficits, and to establish their relationship with the neuropathology and progression of MS.

Validity and norms for young adults for the Aggie Figures Learning Test.

The Aggie Figures Learning Test (AFLT) is a visual memory assessment tool, which was constructed as an analog to the Rey Auditory Verbal Learning Test (RAVLT). Since the test holds close resemblance to the RAVLT, it is possible to make meaningful comparisons between these two tests. These comparisons are notably relevant in the assessment of material-specific memory impairments in epilepsy. However, the AFLT convergent validity has not yet been established. OBJECTIVE: The purpose of the present study was to demonstrate the convergent validity of the AFLT and to provide norms for an adult population ranging from 18 to 58. METHOD: 140 healthy volunteers participated in the study. They ranged in age from 18 to 58 years, with 12 to 25 years of education. Subjects were assessed with a comprehensive neuropsychological battery which included the ALFT (A version) and the Rey-Osterrieth Complex Figure (ROCF). RESULTS: Positive correlations were found between the scores of both tests for recent memory (r = 0.606, p < 0.01), delayed free recall (r = 0.534, p < 0.01) and recognition memory (r = 0.202, p < 0.05). These results demonstrate the convergent validity of the AFLT. CONCLUSIONS: The AFLT is a visual memory assessment tool with adequate psychometric properties, which allows a comprehensive evaluation of visual memory processes.

Attentional ERPs in consumers of smoked and insufflated cocaine associated with neuropsychological performance.

BACKGROUND: Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced amplitude of the P3a, while both SCD and IC dependent (ICD) would show reduced amplitude of the P3b. METHODS: We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks. RESULTS: At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. The amplitude of P3a and P3b was lower in Users groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down. CONCLUSIONS: Different routes of administration lead to distinct attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance Dependence.

The overlap of symptomatic dimensions between frontotemporal dementia and several psychiatric disorders that appear in late adulthood.

Several factors make diagnosis of a possible behavioural variant of frontotemporal dementia (bvFTD) particularly challenging, especially the overlap of certain symptomatic dimensions such as apathy, disinhibition, depression, anhedonia, stereotyped behaviour, and psychosis between bvFTD and several psychiatric disorders that appear in late adulthood. We discuss the most frequent psychiatric conditions that can simulate early bvFTD symptoms, including late onset bipolar disorder, late onset schizophrenia-like psychosis, late onset depression, and attention deficit hyperactivity disorder in middle and older age.

Fluid intelligence loss linked to restricted regions of damage within frontal and parietal cortex.

Tests of fluid intelligence predict success in a wide range of cognitive activities. Much uncertainty has surrounded brain lesions producing deficits in these tests, with standard group comparisons delivering no clear result. Based on findings from functional imaging, we propose that the uncertainty of lesion data may arise from the specificity and complexity of the relevant neural circuit. Fluid intelligence tests give a characteristic pattern of activity in posterolateral frontal, dorsomedial frontal, and midparietal cortex. To test the causal role of these regions, we examined fluid intelligence in 80 patients with focal cortical lesions. Damage to each of the proposed regions predicted fluid intelligence loss, whereas damage outside these regions was not predictive. The results suggest that coarse group comparisons (e.g., frontal vs. posterior) cannot show the neural underpinnings of fluid intelligence tests. Instead, deficits reflect the extent of damage to a restricted but complex brain circuit comprising specific regions within both frontal and posterior cortex.

Sensitivity and specificity of the INECO frontal screening (IFS) in the detection of patients with traumatic brain injury presenting executive deficits.

Executive dysfunction (EF) is a common feature of adult traumatic brain injury (TBI), especially in moderate to severe cases. Assessing EF usually requires the administration of an extensive neuropsychological battery, which is time consuming and expensive. The INECO frontal screening (IFS) is a brief, easy-to-administer screening test which has previously shown to be useful in the detection of executive deficits in different psychiatric and neurological populations. The aim of the present study was to assess the usefulness of the IFS in the detection of executive dysfunction in TBI patients. Twenty-eight TBI patients and thirty-two healthy controls were assessed with a battery that included classical executive tests and the IFS. Our results indicated that with a cutoff score of 26.25 points, the IFS showed good sensitivity and specificity in the detection of executive impairments in TBI patients. It also showed good positive and negative predicted values. Our results suggest that the IFS can be considered a useful tool for identifying executive dysfunction in patients with TBI.

The limitations and challenges in the assessment of executive dysfunction associated with real-world functioning: The opportunity of serious games.

Nowadays, there is a broad range of methods for detecting and evaluating executive dysfunction ranging from clinical interview to neuropsychological evaluation. Nevertheless, a critical issue of these assessments is the lack of correspondence of the neuropsychological test's results with real-world functioning. This paper proposes serious games as a new framework to improve the neuropsychological assessment of real-world functioning. We briefly discuss the contribution and limitations of current methods of evaluation of executive dysfunction (paper-and-pencil tests, naturalistic observation methods, and Information and Communications Technologies) to inform on daily life functioning. Then, we analyze what are the limitations of these methods to predict real-world performance: (1) A lack of appropriate instruments to investigate the complexity of real-world functioning, (2) the vast majority of neuropsychological tests assess well-structured tasks, and (3) measurement of behaviors are based on simplistic data collection and statistical analysis. This work shows how serious games offer an opportunity to develop more efficient tools to detect executive dysfunction in everyday life contexts. Serious games provide meaningful narrative stories and virtual or real environments that immerse the user in natural and social environments with social interactions. In those highly interactive game environments, the player needs to adapt his/her behavioral performance to novel and ill-structured tasks which are suited for collecting user interaction evidence. Serious games offer a novel opportunity to develop better tools to improve diagnosis of the executive dysfunction in everyday life contexts. However, more research is still needed to implement serious games in everyday clinical practice.

Deficits in tasks of executive functioning that mimic real-life scenarios in bipolar disorder.

BACKGROUND: A growing body of evidence suggests that patients with bipolar disorder (BD) have cognitive impairments even during euthymic periods. The main cognitive domains affected are verbal memory, attention, and executive function. Nevertheless, some studies suggest that at least a subgroup of euthymic patients demonstrates intact executive functioning in classic neuropsychological tests, which could be due to the lack of real-life, or ecological validity. OBJECTIVE: In this study, we highlight the usefulness of incorporating more ecological tests of executive function in assessment batteries in order to detect specific cognitive deficits in BD patients with otherwise normal performance in standard executive tests. METHODS: Nineteen euthymic BD patients and 15 healthy controls completed a standard neuropsychological battery assessment and two experimental tasks (the Multiple Errands Test-Hospital Version and the Hotel Task) to measure executive functioning in highly demanding cognitive settings that mimic real-life scenarios. RESULTS: No significant differences were found between the groups' demographic variables. We found, as predicted, that the group of euthymic BD patients who had control-comparable performance in classic executive tasks showed important deficits in more ecological tasks of executive functioning of the type that mimic real-life scenarios. CONCLUSIONS: Together, these data suggest that the inclusion of ecological tests in the assessment of BD patients can contribute to providing a more realistic cognitive profile of this patient population, which will undoubtedly allow for a better design of therapeutic and rehabilitation strategies that can help patients to minimize impact in real-life settings.

Decision-making in frontotemporal dementia: clinical, theoretical and legal implications.

BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive changes in personality and social interaction, loss of empathy, disinhibition and impulsivity, most of which generally precede the onset of cognitive deficits. In this study, we investigated decision-making cognition in a group of patients with an early bvFTD diagnosis whose standard neuropsychological performance was within normal range for all variables. METHODS: The Iowa Gambling Task was administered to this group of early bvFTD patients, to a group of early bvFTD patients who had shown impaired performance on the classical neuropsychological battery and to healthy controls. RESULTS: Decision-making was impaired in both bvFTD patient groups, whether they had shown impaired or normal performance in the classical neuropsychological evaluation. CONCLUSIONS: Patients with early bvFTD may perform normally on standard cognitive tests, and yet develop severe deficits in judgment and decision-making. In many current legal systems, early bvFTD patients showing preserved cognitive functioning who commit unlawful acts run the risk of not being able to plead insane or not guilty on the grounds of diminished responsibility beyond reasonable doubt. This represents a unique legal and ethical dilemma. Our findings have important implications for medicolegal decisions relating to capacity and culpability, and regarding the philosophical concept of 'free will'.

Executive function and fluid intelligence after frontal lobe lesions.

Many tests of specific 'executive functions' show deficits after frontal lobe lesions. These deficits appear on a background of reduced fluid intelligence, best measured with tests of novel problem solving. For a range of specific executive tests, we ask how far frontal deficits can be explained by a general fluid intelligence loss. For some widely used tests, e.g. Wisconsin Card Sorting, we find that fluid intelligence entirely explains frontal deficits. When patients and controls are matched on fluid intelligence, no further frontal deficit remains. For these tasks too, deficits are unrelated to lesion location within the frontal lobe. A second group of tasks, including tests of both cognitive (e.g. Hotel, Proverbs) and social (Faux Pas) function, shows a different pattern. Deficits are not fully explained by fluid intelligence and the data suggest association with lesions in the right anterior frontal cortex. Understanding of frontal lobe deficits may be clarified by separating reduced fluid intelligence, important in most or all tasks, from other more specific impairments and their associated regions of damage.