Progression of behavioural disturbances in frontotemporal dementia: a longitudinal observational study.

BACKGROUND AND PURPOSE: Behavioural disturbances are the core features of frontotemporal dementia (FTD); however, symptom progression is still not well characterized during the entire course of the disease. The aim of the present study was to investigate behavioural symptoms at baseline and during the disease course in a large cohort of patients with behavioural variant FTD (bvFTD), non-fluent/agrammatic variant primary progressive aphasia (nfvPPA) and semantic variant primary progressive aphasia (PPA). METHODS: We evaluated 403 patients with FTD, 167 of whom had at least 1-year follow-up evaluation (for a total of 764 assessments). Behavioural symptoms were assessed and rated through the Neuropsychiatric Inventory (NPI) and Frontal Behavioural Inventory (FBI). Disease severity was evaluated through the Frontotemporal Lobar Degeneration -Clinical Dementia Rating scale (FTLD-CDR). Linear mixed models were used to model behavioural measures (NPI, FBI and the five FBI-behavioural core criteria scores) as a function of disease severity (FTLD-CDR score) and clinical phenotype. RESULTS: At baseline, patients with bvFTD showed more behavioural disturbances compared with those with nfvPPA (P = 0.004). Negative symptoms (apathy and loss of empathy) showed a trend to an increase throughout the course of the disease in both bvFTD and PPA (P < 0.001 until intermediate stages). Positive symptoms (disinhibition, perseverations and hyperorality) increased until intermediate phases (P < 0.001) followed by a progressive reduction in later phases, whereas they were less common in nfvPPA throughout the disease course. CONCLUSION: We demonstrated that behavioural disturbances differed in FTD and with disease severity. Positive symptoms appeared to improve in the advanced stages, highlighting the importance of taking into account the disease severity as outcome measure in clinical trials.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

BACKGROUND AND PURPOSE: Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. METHODS: We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. RESULTS: We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. CONCLUSIONS: Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

Technique of injection of onabotulinumtoxin A for chronic migraine: the PREEMPT injection paradigm.

In 2013 the Italian Pharmacy Agency (AIFA) approved onabotulinumtoxin A injection to prevent headaches in adult patients with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine) that has not responded to at least three prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication overuse. In the present paper we report the method of injection of Onabotulinumtoxin A for chronic migraine based on the PREEMPT paradigm as described by Blumenfeld et al. (Headache 50:1406-1418, 2010) adapted to our clinical setting.

The brain in late-onset glycogenosis II: a structural and functional MRI study.

BACKGROUND: Late-onset glycogenosis type II (GSD II) is a rare, multisystem disorder mainly affecting limb and respiratory muscles due to acid alpha glucosidase deficiency. Despite evidence at autopsy of glycogen accumulation in the brain, no study exploring brain functions is yet available. OBJECTIVE: Our objective in this study was to assess brain changes in late-onset GSD II. METHODS: Each patient underwent a standardized neuropsychological assessment, regional grey-matter (GM) atrophy, and resting-state functional magnetic resonance imaging (RS-fMRI). Functional connectivity maps of the salience (SN) and default-mode (DMN) networks were considered. A group of age- and gender-matched healthy controls was enrolled for MRI comparisons. P values family-wise error (FWE) cluster level corrected inferior to 0.05 were considered. RESULTS: Nine GSD II patients (age 46.6 ± 8.0; 55% male) were recruited. No significant GM atrophy was found in patients compared with controls (n = 18; age 48.0 ± 9.8,;40% male). Functional connectivity within the SN was selectively reduced in patients, and cingulate gyrus and medial frontal cortex were mainly involved. Accordingly, patients had significant impairment of executive functions (as measured by Wisconsin Card Sorting test), whereas other cognitive domains were within mean normal ranges. CONCLUSIONS: Our findings extend the clinical spectrum of GSD II by indicating that brain changes occur in this muscular disorder. Above all, these results should lead to better examinations of therapeutic approaches and perspectives for the affected patients. Further studies evaluating in depth these issues are warranted.

Publisher Correction: Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.

Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.

Source-Based Morphometry Multivariate Approach to Analyze [123I]FP-CIT SPECT Imaging.

PURPOSE: [123I]FP-CIT (DaTSCAN®) single-photon emission computed tomography (SPECT) imaging is widely used to study neurodegenerative parkinsonism, by measuring presynaptic dopamine transporter (DAT) in striatal regions. Beyond DAT, [123I]FP-CIT may be considered for other monoaminergic systems, in particular the serotonin transporter (SERT). Independent component analysis (ICA) implemented in source-based morphometry (SBM) could represent an alternative method to explore monoaminergic pathways, studying the relationship among voxels and grouping them into "neurotransmission" networks. PROCEDURES: One hundred forty-three subjects [84 with Parkinson's disease (PD) and 59 control individuals (CG)] underwent DATSCAN® imaging. The [123I]FP-CIT binding was evaluated by multivariate SBM approach, as well as by a whole-brain voxel-wise univariate (statistical parametric mapping, SPM) approach. RESULTS: As compared to the univariate whole-brain approach (SPM) (only demonstrating striatal [123I]FP-CIT binding reduction in PD group), SBM identified six sources of non-artefactual origin, including basal ganglia and cortical regions as well as brainstem. Among them, three sources (basal ganglia and cortical regions) presented loading scores (as index of [123I]FP-CIT binding) significantly different between PD and CG. Notably, even if not significantly different between PD and CG, the remaining three non-artefactual sources were characterized by a predominant frontal, brainstem, and occipito-temporal involvement. CONCLUSION: The concept of source blind separation by the application of ICA (as implemented in SBM) represents a feasible approach to be considered in [123I]FP-CIT (DaTSCAN®) SPECT imaging. Taking advantage of this multivariate analysis, specific patterns of variance can be identified (involving either striatal than extrastriatal regions) that could be useful in differentiating neurodegenerative parkinsonisms.

Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.

Subcortical matter in the α-synucleinopathies spectrum: an MRI pilot study.

α-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.

Impulse control disorder in PD: A lateralized monoaminergic frontostriatal disconnection syndrome?

BACKGROUND: Impulse Control Disorder symptoms (ICD) in Parkinson's disease (PD) has been recently associated by magnetic Resonance imaging with impaired cortico-striatal connectivity, especially between left putamen and frontal associative areas. METHODS: 84 patients entered the study (21 PD-ICD+ and 64 PD-ICD-) and underwent DATSCAN imaging. The striatal tracer uptake was evaluated using BRASS software (Hermes, Sweden). The whole-brain analysis was performed with Statistical Parametric Mapping (SPM). RESULTS: PD-ICD+ showed a significant reduction of left putaminal and left inferior frontal gyrus tracer uptake compared to PD-ICD-. Functional covariance analysis using left putamen as the seed point showed that, in contrast to ICD-patients, ICD+ patients had no functional covariance with contralateral basal ganglia and ipsilateral cingulate cortex, as index of an impaired inter- and intra-hemispheric dopamine binding in PD-ICD+. DISCUSSION: the results support and expand the concept of a functional disconnection syndrome linked to ICD symptoms in PD patients through an asymmetric molecular frontostriatal network breakdown with left basal ganglia as central hub.

Neuroanatomical correlates of behavioural phenotypes in behavioural variant of frontotemporal dementia.

BACKGROUND: Behavioural variant of frontotemporal dementia (bvFTD) frequently presents complex behavioural changes, that rarely occur in isolation. Targeting behavioural phenotypes instead of single behavioural symptoms may potentially provide a disease model in which to investigate brain substrates of behavioural abnormalities. OBJECTIVE: To identify behavioural phenotypes and to assess the associated brain correlates in a cohort of patients with bvFTD. METHODS: Two hundred and seven consecutive individuals fulfilling clinical criteria for bvFTD were enrolled. Each participant's caregiver completed frontal behavioural inventory on 24 key behavioural disturbances. Confirmatory factor analysis (CFA) models were applied, and behavioural phenotypes identified. For each phenotype, a score was derived based on the "best" CFA model (Bifactor CFA). One hundred two participants underwent SPECT scan. A regression analysis between scores for each factor and regional cerebral blood flow was carried out (P<0.001). RESULTS: One "general" behavioural phenotype and four factors were identified, that were termed "disinhibited", "apathetic", "aggressive", and "language" phenotypes. The most robust brain correlate was identified for "disinhibited" phenotype, in the region of the anterior cingulated and anterior temporal cortex, bilaterally, and for apathetic phenotype in the left dorsolateral frontal cortex. As expected, language phenotype correlated with greater hypoperfusion in the left frontotemporal lobes. No significant correlation between aggressive phenotype and regional cerebral blood flow was found. Moreover, the "general" behavioural severity was associated with greater damage in the right frontal lobe. CONCLUSIONS: Behavioural phenotypes are associated with specific brain damage in bvFTD, involving distinct cerebral networks.