Cognitive inhibition impairments in presymptomatic C9orf72 carriers.

OBJECTIVE: To investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates. METHODS: Thirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9- controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B-part A); error score in part B) as well as a 3D MRI. RESULTS: C9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B-part A) compared to C9- individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum. CONCLUSION: The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation.

BACKGROUND: Impulse control disorders (ICD), including pathological gambling, are common in Parkinson's disease (PD) and tend to improve after subthalamic (STN) stimulation after a marked reduction of dopaminergic medication. In order to investigate the effect of STN stimulation on impulsive decision making, we used the Iowa Gambling task (IGT). METHODS: We investigated IGT performance in 20 patients with PD before STN surgery with and without dopaminergic treatment and in 24 age-matched controls. All patients underwent an extensive neuropsychological interview screening for behavioural disorders. Assessment in patients was repeated 3 months after surgery without dopaminergic treatment with and without stimulation. RESULTS: Chronic antiparkinsonian treatment was drastically reduced after surgery (-74%). At baseline, on high chronic dopaminergic treatment 8/20 patients with PD presented with pathological hyperdopaminergic behaviours, which had resolved in 7/8 patients 3 months after surgery on low chronic dopaminergic treatment. Preoperative performance on the IGT was significantly impaired compared to after surgery. CONCLUSIONS: Dopaminergic medication likely contributes to the impairment in decision making underlying ICDs. Deep brain stimulation allows drastic reduction of dopaminergic medication and, thus, concomitant remediation of medication-induced impairment in decision making.

Sensitivity and specificity of ventromedial prefrontal cortex tests in behavioral variant frontotemporal dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early and substantial ventromedial prefrontal cortex (VMPFC) dysfunction. To date, however, there is no consensus regarding which tests are most sensitive and specific to assess VMPFC dysfunction in this condition. METHODS: In this study we compared the sensitivity and specificity of four common VMPFC specific tests (Mini-SEA, Go/No-Go Subtest of the Frontal Assessment Battery, Reversal-Learning Test, and Iowa Gambling Task) at first clinic presentation in two neurodegenerative cohorts (bvFTD, Alzheimer's disease) and age-matched, healthy controls. RESULTS: We found that the Mini-SEA, evaluating theory of mind and emotion processes, emerged as the most sensitive and specific of the VMPFC tests employed. The Mini-SEA alone successfully distinguished bvFTD and Alzheimer's disease (AD) in >82% of subjects at first presentation. Similarly, the FAB Go/No-Go and Reversal-Learning Tests also showed very good discrimination power, but to a lesser degree. The Iowa Gambling Task, one of the most common measures of VMPFC function, was the least specific of these tests. CONCLUSION: Sensitivity to detect VMPFC dysfunction was high across all test employed, but specificity varied considerably. The Mini-SEA emerged as the most promising of the VMPFC-specific diagnostic tests. Clinicians should take into account the variable specificity of currently available VMPFC tests, which can complement current carer-based questionnaires and clinical evaluation to improve the diagnosis of behavioral dysfunctions due to VMPFC dysfunction.

Brain Metabolic Profile in Presymptomatic GRN Carriers Throughout a 5-Year Follow-up.

BACKGROUND AND OBJECTIVES: GRN variants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG)-PET in identifying metabolic changes in presymptomatic GRN carriers (PS-GRN+) and to trace their longitudinal progression. METHODS: Participants were longitudinally evaluated over 5 years in a prospective cohort study focused on GRN disease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed. RESULTS: Among the 80 individuals enrolled in the study, 58 (27 PS-GRN+ and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS-GRN+ and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers (p < 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (-1.37%) was higher than that in controls (-0.21%, p = 0.004). Lower glucose uptake was associated with higher neurofilament increase (p = 0.003) and lower frontal cognitive scores (p = 0.014) in PS-GRN+. DISCUSSION: This study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinical GRN disease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials.

Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression.

BACKGROUND: Behavioural variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease that is clinically characterised by progressive behavioural changes and social interpersonal dysfunctions. Its diagnosis remains a clinical challenge, and depression is one of the main causes of misdiagnoses due to the prevalence of apathy in bvFTD. OBJECTIVE: To evaluate the sensitivity and specificity of the Social Cognition and Emotional Assessment (SEA) and the mini-SEA for differentiating bvFTD from major depressive disorder (MDD). METHODS: Scores for the SEA and mini-SEA for 37 patients with bvFTD (divided into subgroups of 17 with early bvFTD and 20 with moderate bvFTD according to the normal range of the Mattis Dementia Rating Scale), 19 MDD patients and 30 control subjects were compared to define the discrimination power of these tools compared with other standard neuropsychological tests. RESULTS: SEA and mini-SEA scores were significantly lower for both the early and moderate bvFTD groups compared with control subjects and the MDD group, and very few scores overlapped between patients in the bvFTD subgroups and patients in the MDD and control subgroups. SEA and mini-SEA scores distinguished early bvFTD from MDD with sensitivity and specificity rates above 94%. CONCLUSION: Unlike standard executive neuropsychological tests, SEA and the mini-SEA can differentiate MDD from bvFTD in the early stages of the disease. The mini-SEA is an easy tool that can be utilised in neurological or psychiatric departments.

Social Cognition and Emotional Assessment (SEA) is a marker of medial and orbital frontal functions: a voxel-based morphometry study in behavioral variant of frontotemporal degeneration.

The aim of this study was to explore the cerebral correlates of functional deficits that occur in behavioral variant frontotemporal dementia (bvFTD). A specific neuropsychological battery, the Social cognition & Emotional Assessment (SEA; Funkiewiez et al., 2012), was used to assess impaired social and emotional functions in 20 bvFTD patients who also underwent structural MRI scanning. The SEA subscores of theory of mind, reversal-learning tests, facial emotion identification, and apathy evaluation were entered as covariates in a voxel-based morphometry analysis. The results revealed that the gray matter volume in the rostral part of the medial prefrontal cortex [mPFC, Brodmann area (BA) 10] was associated with scores on the theory of mind subtest, while gray matter volume within the orbitofrontal (OFC) and ventral mPFC (BA 11 and 47) was related to the scores observed in the reversal-learning subtest. Gray matter volume within BA 9 in the mPFC was correlated with scores on the emotion recognition subtest, and the severity of apathetic symptoms in the Apathy scale covaried with gray matter volume in the lateral PFC (BA 44/45). Among these regions, the mPFC and OFC cortices have been shown to be atrophied in the early stages of bvFTD. In addition, SEA and its abbreviated version (mini-SEA) have been demonstrated to be sensitive to early impairments in bvFTD (Bertoux et al., 2012). Taken together, these results suggest a differential involvement of orbital and medial prefrontal subregions in SEA subscores and support the use of the SEA to evaluate the integrity of these regions in the early stages of bvFTD.

Unravelling the impact of frontal lobe impairment for social dysfunction in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is an autosomal dominant multisystemic disorder affecting muscular and extra muscular systems, including the central nervous system. Cerebral involvement in myotonic dystrophy type 1 is associated with subtle cognitive and behavioural disorders, of major impact on socio-professional adaptation. The social dysfunction and its potential relation to frontal lobe neuropsychology remain under-evaluated in this pathology. The neuroanatomical network underpinning that disorder is yet to disentangle. Twenty-eight myotonic dystrophy type 1 adult patients (mean age: 46 years old) and 18 age and sex-matched healthy controls were included in the study. All patients performed an exhaustive neuropsychological assessment with a specific focus on frontal lobe neuropsychology (motivation, social cognition and executive functions). Among them, 18 myotonic dystrophy type 1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. Grey matter segmentation, Voxel-based morphometry and cortical thickness estimation were performed with Statistical Parametric Mapping Software SPM12 and Freesurfer software. Furthermore, T2 white matter lesions and subcortical structures were segmented with Automated Volumetry Software. Most patients showed significant impairment in executive frontal functions (auditory working memory, inhibition, contextualization and mental flexibility). Patients showed only minor difficulties in social cognition tests mostly in cognitive Theory of Mind, but with relative sparing of affective Theory of Mind and emotion recognition. Neuroimaging analysis revealed atrophy mostly in the parahippocampal and hippocampal regions and to a lesser extent in basal ganglia, regions involved in social navigation and mental flexibility, respectively. Social cognition scores were correlated with right parahippocampal gyrus atrophy. Social dysfunction in myotonic dystrophy type 1 might be a consequence of cognitive impairment regarding mental flexibility and social contextualization rather than a specific social cognition deficit such as emotion recognition. We suggest that both white matter lesions and grey matter disease could account for this social dysfunction, involving, in particular, the frontal-subcortical network and the hippocampal/arahippocampal regions, brain regions known, respectively, to integrate contextualization and social navigation.

An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia.

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Primary progressive aphasias associated with C9orf72 expansions: Another side of the story.

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant.

OBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. METHODS: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTS: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

Moral Emotions in Frontotemporal Dementia.

BACKGROUND: Emotions, with or without moral valence, appear to be altered in the behavioral variant of frontotemporal dementia (bvFTD) but the relative degree of moral emotion breakdown, which could be a marker of bvFTD diagnosis, remains unexplored. OBJECTIVE: To assess moral emotions in bvFTD, to differentiate bvFTD from typical Alzheimer's disease (AD) based on moral emotion processing, and to provide a sensitive and specific assessment tool contributing to bvFTD diagnosis. METHODS: We investigated moral emotions in 22 bvFTD patients, 15 patients with typical AD having positive CSF AD biomarkers, and 45 healthy controls. The 'Moral Emotions Assessment' task consisted in 42 scenarios exploring positive and negative moral emotions. To control for moral-specificity, we contrasted the 42 moral scenarios with 18 extra-moral scenarios eliciting the emotions without involving any inter-human moral context. RESULTS: bvFTD patients were more impaired in emotion processing than AD patients and healthy controls and had significantly poorer performance in the processing of moral emotions than of emotions without moral valence. ROC analyses of data on moral scenarios showed a high area under the curve (83%), and indicated a cut-off score (< 37/42) for differentiating bvFTD from AD with a sensitivity of 82% and specificity of 73%. CONCLUSION: Our findings demonstrate that bvFTD patients have disorders in emotion processing which is mainly related to failure regarding moral emotions. They also show that this deficit is reliably detected by the 'Moral Emotions Assessment' which represents a sensitive and specific diagnostic tool detecting bvFTD and differentiating it from AD.

Cursive Eye-Writing With Smooth-Pursuit Eye-Movement Is Possible in Subjects With Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing a progressive motor weakness of all voluntary muscles, whose progression challenges communication modalities such as handwriting or speech. The current study investigated whether ALS subjects can use Eye-On-Line (EOL), a novel eye-operated communication device allowing, after training, to voluntarily control smooth-pursuit eye-movements (SPEM) so as to eye-write in cursive. To that aim, ALS participants (n = 12) with preserved eye-movements but impaired handwriting were trained during six on-site visits. The primary outcome of the study was the recognition of eye-written digits (0-9) from ALS and healthy control subjects by naïve "readers." Changes in oculomotor performance and the safety of EOL were also evaluated. At the end of the program, 69.4% of the eye-written digits from 11 ALS subjects were recognized by naïve readers, similar to the 67.3% found for eye-written digits from controls participants, with however, large inter-individual differences in both groups of "writers." Training with EOL was associated with a transient fatigue leading one ALS subject to drop out the study at the fifth visit. Otherwise, itching eyes was the most common adverse event (3 subjects). This study shows that, despite the impact of ALS on the motor system, most ALS participants could improve their mastering of eye-movements, so as to produce recognizable eye-written digits, although the eye-traces sometimes needed smoothing to ease digit legibility from both ALS subjects and control participants. The capability to endogenously and voluntarily generate eye-traces using EOL brings a novel way to communicate for disabled individuals, allowing creative personal and emotional expression.

A mosquito bites and a butterfly flies: A specific response type of frontal patients in a similarity task.

BACKGROUND: Patients with neurodegenerative diseases affecting the frontal lobes have difficulties in categorization tasks, such as the similarity tasks. They give two types of unusual response to the question: "In what way are an orange and a banana alike?", either a differentiation ("one is yellow, the other is orange") or a concrete similarity ("they are sweet"). OBJECTIVE: To characterize the categorization deficit of frontal patients and develop a short diagnostic tool to assess the nature of these difficulties. METHOD: We analyzed the responses provided by frontal and non-frontal neurodegenerative patients in a novel verbal similarity task (SimiCat). We included 40 frontal patients with behavioral variant fronto-temporal dementia (bvFTD) and progressive supranuclear palsy (PSP), 23 patients with Alzheimer's disease (AD) and 41 healthy matched controls. Responses that did not correspond to the expected taxonomic category (e.g.: fruits) were considered as errors. RESULTS: All patients groups were impaired at the SimiCat test compared to controls. Differentiation errors were specific to frontal patients. Receiver operating characteristic analyses showed that a cut-off of two differentiation errors or more achieved 85% sensitivity of 100% specificity to discriminate bvFTD from AD. A short version of the test (<5 min) showed similar discriminative validity as the full version. CONCLUSION: Differentiation responses were specific to frontal patients. The SimiCat demonstrates good discriminative validity to differentiate between bvFTD and AD. The short version of the test is a promising diagnostic tool that will need validation in future studies.

Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease?

The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.

Frontal presentation of Alzheimer's disease: a series of patients with biological evidence by CSF biomarkers.

Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.

Além da típica forma amnésica, apresentações focais atípicas da doença de Alzheimer (DA) foram descritas em estudos anatomopatológicos. Essas variantes fenotípicas da DA ("DA atípica") não seguem o padrão amnésico convencional e incluem síndromes corticais focais não amnésicas, tais como a atrofia cortical posterior e a variante frontal da DA. Essas variantes apresentam lesões histológicas características da DA ao exame patológico post-mortem. O uso de marcadores fisiopatológicos da DA, como os biomarcadores do líquido cefalorraquidiano, permite estabelecer in vivo um diagnóstico biológico de DA nessas síndromes corticais focais. Reportamos uma série de oito pacientes que foram clinicamente diagnosticados como portadores da variante comportamental da demência frontotemporal (de acordo com critérios clínicos, neuropsicológicos e de neuroimagem), mas nos quais a investigação dos biomarcadores do líquor mostrou um perfil biológico de DA, de modo que o diagnóstico da variante frontal de DA foi finalmente estabelecido.

The SEA (Social cognition and Emotional Assessment): a clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration.

OBJECTIVE: The frontal variant of frontotemporal degeneration (fvFTD) is characterized by a predominant behavioral syndrome, which is mostly attributable to an orbital-medial prefrontal dysfunction. The orbital and ventral medial prefrontal functions in humans are difficult to assess in clinical practice. Here, we propose a new tool, the SEA (Social cognition and Emotional Assessment), for use in evaluating the functions of the orbital and ventral-medial portions of the prefrontal cortex. METHOD: The SEA is composed of five subtests, each assessing a specific orbitofrontal-related function: a test of identification of facial emotions, a reversal/extinction task, a behavioral control task, a theory of mind test, and an apathy scale. The maximum score is 55. Three groups have been tested: 22 fvFTD patients, 22 patients with Alzheimer's disease (AD) or amnesic mild cognitive impairment (aMCI), and 30 healthy control subjects, all matched for age and educational level. RESULTS: FvFTD patients showed significantly lower performances in all subtests of the SEA. A cut-off score of 39.4/55 was proposed to separate normal controls from fvFTD patients, with a maximum sensitivity and specificity of 100%. A very high specificity (88.5%) was obtained using the same cut-off with AD/aMCI patients and normal controls versus fvFTD patients. FvFTD patients' performance in the SEA did not correlate with any other neuropsychological scores, particularly the classical cognitive executive tests. CONCLUSIONS: The SEA is a new and useful tool for diagnosing fvFTD and, more generally, all of the diseases affecting the orbital and medial prefrontal functions.

Poor creativity in frontotemporal dementia: a window into the neural bases of the creative mind.

BACKGROUND: The prefrontal cortex (PFC) supports functions critical for creative thinking. Damage to the PFC is expected to impair creativity. Yet, previous works suggested the emergence of artistic talent in patients with frontotemporal lobar degeneration (FTLD), which was interpreted as increased creativity. OBJECTIVE: We designed a study in patients with frontal variant (fv) of FTLD in order to verify whether: (1) creativity is impaired after frontal degeneration, (2) poor creativity is associated with frontal dysfunctions, and (3) poor creativity is related to hypoperfusion in specific PFC regions. MATERIALS AND METHODS: Three groups of subjects were enrolled in the study: fvFTLD patients (n=17), non-demented Parkinson's disease (PD) patients (n=12) and healthy controls (n=17). Participants performed a standardized test of creativity, the Torrance Test of Creative Thinking (TTCT) and tests assessing frontal functions. Brain perfusion was correlated to fvFTLD patients' performance in the TTCT. RESULTS: Patients with fvFTLD were strongly impaired in all dimensions of the TTCT, compared to PD patients and controls. Disinhibited and perseverative responses were observed only in fvFTLD patients, leading to "pseudo-creative" responses. Poor creativity was positively correlated with several frontal tests. Poor creativity was also correlated with prefrontal hypoperfusion, particularly in the frontal pole. CONCLUSIONS: Poor creativity is associated with fvFTLD. The results also suggest that the integrity of the PFC (in particular frontopolar) is strongly associated with creative thinking. The emergence of artistic talent in patients with fvFTLD is explained by the release of involuntary behaviors, rather than by the development of creative thinking.

Frontal presentation of Alzheimer's disease: a series of patients with biological evidence by CSF biomarkers / Apresentação frontal da doença de Alzheimer: uma série de pacientes com evidência biológica por biomarcadores no LCR

Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.

Além da típica forma amnésica, apresentações focais atípicas da doença de Alzheimer (DA) foram descritas em estudos anatomopatológicos. Essas variantes fenotípicas da DA ("DA atípica") não seguem o padrão amnésico convencional e incluem síndromes corticais focais não amnésicas, tais como a atrofia cortical posterior e a variante frontal da DA. Essas variantes apresentam lesões histológicas características da DA ao exame patológico post-mortem. O uso de marcadores fisiopatológicos da DA, como os biomarcadores do líquido cefalorraquidiano, permite estabelecer in vivo um diagnóstico biológico de DA nessas síndromes corticais focais. Reportamos uma série de oito pacientes que foram clinicamente diagnosticados como portadores da variante comportamental da demência frontotemporal (de acordo com critérios clínicos, neuropsicológicos e de neuroimagem), mas nos quais a investigação dos biomarcadores do líquor mostrou um perfil biológico de DA, de modo que o diagnóstico da variante frontal de DA foi finalmente estabelecido.