Effort avoidance as a core mechanism of apathy in frontotemporal dementia.

Apathy is a core symptom in patients with behavioural variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behaviour, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behaviour depends on a cost-benefit optimization trading off the estimated effort (related to the behaviour) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 patients with bvFTD and 40 matched healthy controls using computational analyses of behavioural responses in a comprehensive series of behavioural tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks in patients with bvFTD compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in patients with bvFTD. More broadly, they provide novel behavioural tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of ß-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.

Pathomechanisms behind cognitive disorders following ruptured anterior communicating aneurysms: A diffusion tensor imaging study.

INTRODUCTION: After the rupture of anterior communicating aneurysms, most patients experience debilitating cognitive disorders; and sometimes even without showing morphological anomaly on MRI examinations. Diffusion Tensor Imaging (DTI) may help understanding the pathomechanisms leading to such disorders in this subset of patients. METHODS: After independent assessment, we constituted a population of patients with normal morphological imaging (ACOM group). Then, a case-control study comparing volumetric and voxel-based DTI parameters between the ACOM group and a control population was performed. All patients underwent the full imaging and neuropsychological assessments at 6 months after the aneurysm rupture. Results were considered significant when p<2.02.10-4. RESULTS: Twelve patients were included in the ACOM group: 75% had at least one disabled cognitive domain. Significant differences in DTI parameters of global white matter were noted (average Fractional Anisotropy: 0.915 [±0.05] in ACOM group versus 0.943 (±0.03); p = 1.10-5) and in frontal white matter tracts (superior fronto-occipital fasciculus and anterior parts of the corona radiata) as well as in the fornix. CONCLUSION: Cognitive disorders are under-estimated, and DTI confirmed that, even when conventional MRI examinations were normal, there were still signs of diffuse neuronal injuries that seemed to dominate in frontal areas, close to the site of rupture.

Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications.

OBJECTIVE: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. RESULTS: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades. CONCLUSIONS: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression. TRIAL REGISTRATION NUMBERS: NCT02590276 and NCT04014673.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

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.

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.

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.

Frontotemporal dementia subtypes based on behavioral inhibition deficits.

INTRODUCTION: We aimed to investigate phenotypic heterogeneity in the behavioral variant of frontotemporal dementia (bvFTD) through assessment of inhibition deficits. METHODS: We assessed occurrences of 16 behavioral inhibition deficits from video recordings of 15 bvFTD patients (early stage) and 15 healthy controls (HC) in an ecological setting. We extracted dimensions of inhibition deficit and analyzed their correlations with cognitive and clinical measures. Using these dimensions, we isolated patient clusters whose atrophy patterns were explored. RESULTS: After identifying two patterns of inhibition deficit (compulsive automatic behaviors and socially unconventional behaviors), we isolated three behavioral clusters with distinct atrophy patterns. BvFTD-G0 (N = 3), an outlier group, showed severe behavioral disturbances and more severe ventromedial prefrontal cortex/orbitofrontal cortex atrophy. Compared to bvFTD-G1 (N = 6), bvFTD-G2 (N = 6) presented higher anxiety and depression along with less diffuse atrophy especially in midline regions. DISCUSSION: Identifying clinico-anatomical profiles through behavior observation could help to stratify bvFTD patients for adapted treatments.

Psychiatric symptoms in anti glutamic acid decarboxylase associated limbic encephalitis in adults: a systematic review.

Autoimmune Limbic Encephalitis (LE) is a relatively new category of immune-mediated diseases with a wide range of neuropsychiatric symptoms. LE associated with Glutamic Acid Decarboxylase (GAD) antibodies is difficult to diagnose due to its possible atypical presentation with neuropsychiatric and behavioral features. We performed a systematic review of literature and retrieved 21 cases of anti GAD-associated LE with neuropsychiatric signs. Median age at onset was 27 years with a female predominance (81.0 %) and median diagnostic delay of 6 months. Clinical presentation included typical LE symptoms such as anterograde amnesia (95.2 %) and temporal lobe or tonico-clonic seizures (95.2 %). Psychiatric symptoms were described in 61.9 % of patients, presenting as anxiety, depressive symptoms, apathy and behavioral changes. Extra-limbic symptoms were present in 14.3 % of patients. No neoplasia associated was found. Some patients had poor epileptic, cognitive and psychiatric outcomes requiring prolonged immunosuppressive treatment. The description of the neuropsychiatric spectrum of anti-GAD LE and its specificities aims to improve our understanding of this entity, and may lead to earlier diagnosis as well as better outcome.

Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.

One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).

A Reliable and Rapid Language Tool for the Diagnosis, Classification, and Follow-Up of Primary Progressive Aphasia Variants.

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. Methods: We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). Results: The application duration of the "PARIS" was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. Conclusions: The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.

Plasma progranulin levels for frontotemporal dementia in clinical practice: a 10-year French experience.

GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis.

Exploration Deficits Under Ecological Conditions as a Marker of Apathy in Frontotemporal Dementia.

Apathy is one of the six clinical criteria for the behavioral variant of frontotemporal dementia (bvFTD), and it is almost universal in this disease. Although its consequences in everyday life are debilitating, its underlying mechanisms are poorly known, its assessment is biased by subjectivity and its care management is very limited. In this context, we have developed "ECOCAPTURE," a method aimed at providing quantifiable and objective signature(s) of apathy in order to assess it and identify its precise underlying mechanisms. ECOCAPTURE consists of the observation and recording of the patient's behavior when the participant is being submitted to a multiple-phase scenario reproducing a brief real-life situation. It is performed in a functional exploration platform transformed into a fully furnished waiting room equipped with a video and sensor-based data acquisition system. This multimodal method allowed video-based behavior analyses according to predefined behavioral categories (exploration behavior, sustained activities or inactivity) and actigraphy analyses from a 3D accelerometer. The data obtained were also correlated with behavioral/cognitive tests and scales assessing global cognitive efficiency, apathy, cognitive disinhibition, frontal syndrome, depression and anxiety. Here, bvFTD patients (n = 14) were compared to healthy participants (n = 14) during the very first minutes of the scenario, when the participants discovered the room and were encouraged to explore it. We showed that, in the context of facing a new environment, healthy participants first explored it and then engaged in sustained activities. By contrast, bvFTD patients were mostly inactive and eventually explored this new place, but in a more irregular and less efficient mode than normal subjects. This exploration deficit was correlated with apathy, disinhibition and cognitive and behavioral dysexecutive syndromes. These findings led us to discuss the presumed underlying mechanisms responsible for the exploration deficit (an inability to self-initiate actions, to integrate reward valuation and to inhibit involuntary behavior). Altogether, these results pave the way for simple and objective assessment of behavioral changes that represents a critical step for the evaluation of disease progression and efficacy of treatment in bvFTD.

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.

First European case of Creutzfeldt-Jakob disease with a PRNP G114V mutation.

Genetic Creutzfeldt-Jakob disease is due to mutations in the PRNP gene. Only two families with a PRNP G114V mutation have been described around the world. We report the first European case, who had no family history and initially presented with isolated deficit in hippocampus-dependent memory. Initial investigations were normal except for elevated total tau protein in the cerebrospinal fluid. He died 4 years after disease onset. This case highlights the diagnostic difficulties posed by genetic Creutzfeldt-Jakob disease, and shows that genetic analyses should be considered even in sporadic cases.

Usefulness of magnetic resonance spectroscopy in urea cycle disorders.

Late-onset urea cycle disorders are characterized by chronic encephalopathy and a risk of hyperammonemic crises triggered by environmental stressors. Reported here is the case of a 30-year-old woman with chronic encephalopathy due to argininosuccinate lyase deficiency. Cerebral proton magnetic resonance spectroscopy showed brain creatine deficiency and its normalization during treatment. These findings are in keeping with recent reports suggesting that creatine deficiency is involved in the neurological dysfunction of urea cycle disorders and demonstrate the usefulness of magnetic resonance spectroscopy in the diagnosis and follow-up of urea cycle disorders.

Acute Frontal Lobe Dysfunction Following Prefrontal Low-Frequency Repetitive Transcranial Magnetic Stimulation in a Patient with Treatment-Resistant Depression.

The potential of repetitive transcranial magnetic stimulation (rTMS) to treat numerous neurological and psychiatric disorders has been thoroughly studied for the last two decades. Here, we report for the first time, the case of a 65-year-old woman suffering from treatment-resistant depression who developed an acute frontal lobe syndrome following eight sessions of low-frequency rTMS (LF-rTMS) to the right dorsolateral prefrontal cortex while also treated with sertraline and mianserin. The pathophysiological mechanisms underlying such an unexpected acute frontal lobe dysfunction are discussed in relation to the therapeutic use of LF-rTMS in combination with pharmacotherapy in depressed patients.

White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations.

Frontotemporal lobar degeneration (FTLD) has a high frequency of genetic forms; the 2 most common are GRN (progranulin) and C9ORF72 mutations. Recently, our group reported extensive white matter (WM) lesions in 4 patients with FTLD caused by GRN mutation, in the absence of noteworthy cardiovascular risk factors,(1) in line with other studies in GRN mutation carriers.(2,3) Here we compared the characteristics of frontal WM lesions in patients with behavioral variant of FTLD (bv-FTLD) caused by GRN and C9ORF72 mutations.

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.