Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Brain Perfusion Measurements Using Multidelay Arterial Spin-Labeling Are Systematically Biased by the Number of Delays.

BACKGROUND AND PURPOSE: Multidelay arterial spin-labeling is a promising emerging method in clinical practice. The effect of imaging parameters in multidelay arterial spin-labeling on estimated cerebral blood flow measurements remains unknown. We directly compared 3-delay versus 7-delay sequences, assessing the difference in the estimated transit time and blood flow. MATERIALS AND METHODS: This study included 87 cognitively healthy controls (78.7 ± 3.8 years of age; 49 women). We assessed delay and transit time-uncorrected and transit time-corrected CBF maps. Data analysis included voxelwise permutation-based between-sequence comparisons of 3-delay versus 7-delay, within-sequence comparison of transit time-uncorrected versus transit time-corrected maps, and average CBF calculations in regions that have been shown to differ. RESULTS: The 7-delay sequence estimated a higher CBF value than the 3-delay for the transit time-uncorrected and transit time-corrected maps in regions corresponding to the watershed areas (transit time-uncorrected = 27.62 ± 12.23 versus 24.58 ± 11.70 mL/min/100 g, Cohen's d = 0.25; transit time-corrected = 33.48 ± 14.92 versus 30.16 ± 14.32 mL/min/100 g, Cohen's d = 0.23). In the peripheral regions of the brain, the estimated delay was found to be longer for the 3-delay sequence (1.52408 ± 0.25236 seconds versus 1.47755 ± 0.24242 seconds, Cohen's d = 0.19), while the inverse was found in the center of the brain (1.39388 ± 0.22056 seconds versus 1.42565 ± 0.21872 seconds, Cohen's d = 0.14). Moreover, 7-delay had lower hemispheric asymmetry. CONCLUSIONS: The results of this study support the necessity of standardizing acquisition parameters in multidelay arterial spin-labeling and identifying basic parameters as a confounding factor in CBF quantification studies. Our findings conclude that multidelay arterial spin-labeling sequences with a high number of delays estimate higher CBF values than those with a lower number of delays.

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults.

Attention deficit hyperactivity disorder (ADHD) is accompanied by resting-state alterations, including abnormal activity, connectivity and asymmetry of the default-mode network (DMN). Concurrently, recent studies suggested a link between ADHD and the presence of polymorphisms within the gene BAIAP2 (i.e., brain-specific angiogenesis inhibitor 1-associated protein 2), known to be differentially expressed in brain hemispheres. The clinical and neuroimaging correlates of this polymorphism are still unknown. We investigated the association between BAIAP2 polymorphisms and DMN functional connectivity (FC) asymmetry as well as behavioral measures in ADHD adults. Resting-state fMRI was acquired from 30 ADHD and 15 healthy adults. For each subject, rs7210438 and rs8079626 within the gene BAIAP2 were genotyped. ADHD severity, impulsiveness and anger were assessed for the ADHD group. Using multivariate analysis of variance, we found that genetic features do have an impact on DMN FC asymmetry. In particular, polymorphism rs8079626 affects medial frontal gyrus and inferior parietal lobule connectivity asymmetry, lower for AA than AG/GG carriers. Further, when combining FC asymmetry and the presence of the rs8079626 variant, we successfully predicted increased externalization of anger in ADHD. In conclusion, a complex interplay between genetic vulnerability and inter-hemispherical DMN FC asymmetry plays a role in emotion regulation in adult ADHD.

APOE*E4 Is Associated with Gray Matter Loss in the Posterior Cingulate Cortex in Healthy Elderly Controls Subsequently Developing Subtle Cognitive Decline.

BACKGROUND AND PURPOSE: The presence of apolipoprotein E4 (APOE*E4) is the strongest currently known genetic risk factor for Alzheimer disease and is associated with brain gray matter loss, notably in areas involved in Alzheimer disease pathology. Our objective was to assess the effect of APOE*E4 on brain structures in healthy elderly controls who subsequently developed subtle cognitive decline. MATERIALS AND METHODS: This prospective study included 382 community-dwelling elderly controls. At baseline, participants underwent MR imaging at 3T, extensive neuropsychological testing, and genotyping. After neuropsychological follow-up at 18 months, participants were classified into cognitively stable controls and cognitively deteriorating controls. Data analysis included whole-brain voxel-based morphometry and ROI analysis of GM. RESULTS: APOE*E4-related GM loss at baseline was found only in the cognitively deteriorating controls in the posterior cingulate cortex. There was no APOE*E4-related effect in the hippocampus, mesial temporal lobe, or brain areas not involved in Alzheimer disease pathology. Controls in the cognitively deteriorating group had slightly lower GM concentration in the hippocampus at baseline. Higher GM densities in the hippocampus, middle temporal lobe, and amygdala were associated with a decreased risk for cognitively deteriorating group status at follow-up. CONCLUSIONS: APOE*E4-related GM loss in the posterior cingulate cortex (an area involved in Alzheimer disease pathology) was found only in those elderly controls who subsequently developed subtle cognitive decline but not in cognitively stable controls. This finding might explain the partially conflicting results of previous studies that typically did not include detailed neuropsychological assessment and follow-up. Most important, APOE*E4 status had no impact on GM density in areas affected early by neurofibrillary tangle formation such as the hippocampus and mesial temporal lobe.

Clinicoradiologic Correlations of Cerebral Microbleeds in Advanced Age.

BACKGROUND AND PURPOSE: The presence of cerebral microbleeds has been associated with dementia and cognitive decline, although studies report conflicting results. Our aim was to determine the potential role of the presence and location of cerebral microbleeds in early stages of cognitive decline. MATERIALS AND METHODS: Baseline 3T MR imaging examinations including SWI sequences of 328 cognitively intact community-dwelling controls and 72 subjects with mild cognitive impairment were analyzed with respect to the presence and distribution of cerebral microbleeds. A neuropsychological follow-up of controls was performed at 18 months post inclusion and identified cases with subtle cognitive deficits were referred to as controls with a deteriorating condition. Group differences in radiologic parameters were studied by using nonparametric tests, 1-way analysis of variance, and Spearman correlation coefficients. RESULTS: Cerebral microbleed prevalence was similar in subjects with mild cognitive impairment and controls with stable and cognitively deteriorating conditions (25%-31.9%). In all diagnostic groups, lobar cerebral microbleeds were more common. They occurred in 20.1% of all cases compared with 6.5% of cases with deep cerebral microbleeds. None of the investigated variables (age, sex, microbleed number, location and depth, baseline Mini-Mental State Examination score, and the Fazekas score) were significantly associated with cognitive deterioration with the exception of education of >12 years showing a slight but significant protective effect (OR, 0.44; 95% CI, 0.22-0.92; P = .028). The Mini-Mental State Examination and the Buschke total score were correlated with neither the total number nor lobar-versus-deep location of cerebral microbleeds. CONCLUSIONS: Cerebral microbleed presence, location, and severity are not related to the early stages of cognitive decline in advanced age.

Arterial Spin-Labeling Parameters Influence Signal Variability and Estimated Regional Relative Cerebral Blood Flow in Normal Aging and Mild Cognitive Impairment: FAIR versus PICORE Techniques.

BACKGROUND AND PURPOSE: Arterial spin-labeling is a noninvasive method to map cerebral blood flow, which might be useful for early diagnosis of neurodegenerative diseases. We directly compared 2 arterial spin-labeling techniques in healthy elderly controls and individuals with mild cognitive impairment. MATERIALS AND METHODS: This prospective study was approved by the local ethics committee and included 198 consecutive healthy controls (mean age, 73.65 ± 4.02 years) and 43 subjects with mild cognitive impairment (mean age, 73.38 ± 5.85 years). Two pulsed arterial spin-labeling sequences were performed at 3T: proximal inversion with a control for off-resonance effects (PICORE) and flow-sensitive alternating inversion recovery technique (FAIR). Relative cerebral blood flow maps were calculated by using commercial software and standard parameters. Data analysis included spatial normalization of gray matter-corrected relative CBF maps, whole-brain average, and voxelwise comparison of both arterial spin-labeling sequences. RESULTS: Overall, FAIR yielded higher relative CBF values compared with PICORE (controls, 32.7 ± 7.1 versus 30.0 ± 13.1 mL/min/100 g, P = .05; mild cognitive impairment, 29.8 ± 5.4 versus 26.2 ± 8.6 mL/min/100 g, P < .05; all, 32.2 ± 6.8 versus 29.3 ± 12.3 mL/min/100 g, P < .05). FAIR had lower variability (controls, 36.2% versus 68.8%, P < .00001; mild cognitive impairment, 18.9% versus 22.9%, P < .0001; all, 34.4% versus 64.9% P < .00001). The detailed voxelwise analysis revealed a higher signal for FAIR, notably in both convexities, while PICORE had higher signal predominantly in deep cerebral regions. CONCLUSIONS: Overall, FAIR had higher estimated relative CBF and lower interindividual variability than PICORE. In more detail, there were regional differences between both arterial spin-labeling sequences. In summary, these results highlight the need to calibrate arterial spin-labeling sequences.

DAT1 and DRD4 genes involved in key dimensions of adult ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10(-4)) and trait anger scores (p = 7.66 × 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.

[Psychiatric care for asylum seekers in Geneva: a multidisciplinary approach for individualized care]. / Soins psychiatriques pour les requérants d'asile à geneve. Une approche multidisciplinaire pour préserver la singularité des soins.

Asylum seekers constitute a vulnerable population insofar as they are submitted to numerous stress factors which facilitate the emergence of mental disorders, such as low socio-economic status, forced separation from loved ones and exposure to violence. Asylum seekers who consult at our community psychiatry facility usually have short-term residence permits, live in collective housing and do not speak the local language. The most frequent diagnoses are depressive disorder (64.7%) and post-traumatic stress disorder (34.5%). Due to their specific clinical and social situation and to the involvement of several professionals in these situations, a specialized psychiatric intervention coordinated with the rest of the network seems necessary.

Acute caffeine administration impact on working memory-related brain activation and functional connectivity in the elderly: a BOLD and perfusion MRI study.

In young individuals, caffeine-mediated blockade of adenosine receptors and vasoconstriction has direct repercussions on task-related activations, changes in functional connectivity, as well as global vascular effects. To date, no study has explored the effect of caffeine on brain activation patterns during highly demanding cognitive tasks in the elderly. This prospective, placebo-controlled crossover design comprises 24 healthy elderly individuals (mean age 68.8 ± 4.0 years, 17 females) performing a 2-back working memory (WM) task in functional magnetic resonance imaging (fMRI). Analyses include complimentary assessment of task-related activations (general linear model, GLM), functional connectivity (tensorial independent component analysis, TICA), and baseline perfusion (arterial spin labeling). Despite a reduction in whole-brain global perfusion (-22.7%), caffeine-enhanced task-related GLM activation in a local and distributed network is most pronounced in the bilateral striatum and to a lesser degree in the right middle and inferior frontal gyrus, bilateral insula, left superior and inferior parietal lobule as well as in the cerebellum bilaterally. TICA was significantly enhanced (+8.2%) in caffeine versus placebo in a distributed and task-relevant network including the pre-frontal cortex, the supplementary motor area, the ventral premotor cortex and the parietal cortex as well as the occipital cortex (visual stimuli) and basal ganglia. The inverse comparison of placebo versus caffeine had no significant difference. Activation strength of the task-relevant-network component correlated with response accuracy for caffeine yet not for placebo, indicating a selective cognitive effect of caffeine. The present findings suggest that acute caffeine intake enhances WM-related brain activation as well as functional connectivity of blood oxygen level-dependent fMRI in elderly individuals.

EEG anomalies in adult ADHD subjects performing a working memory task.

Functional imaging studies have revealed differential brain activation patterns in attention deficit hyperactivity disorder (ADHD) adult patients performing working memory (WM) tasks. The existence of alterations in WM-related cortical circuits during childhood may precede executive dysfunctions in this disorder in adults. To date, there is no study exploring the electrophysiological activation of WM-related neural networks in ADHD. To address this issue, we carried out an electroencephalographic (EEG) activation study associated with time-frequency (TF) analysis in 15 adults with ADHD and 15 controls performing two visual N-back WM tasks, as well as oddball detection and passive fixation tasks. Frontal transient (phasic) theta event-related synchronization (ERS, 0-500 msec) was significantly reduced in ADHD as compared to control subjects. Such reduction was equally present in a task-independent manner. In contrast, the power of the later sustained (∼500-1200 msec) theta ERS for all tasks was comparable in ADHD and control groups. In active WM tasks, ADHD patients displayed lower alpha event-related desynchronization (ERD, ∼200-900 msec) and higher subsequent alpha ERS (∼900-2400 msec) compared to controls. The time course of alpha ERD/ERS cycle was modified in ADHD patients compared to controls, suggesting that they are able to use late compensatory mechanisms in order to perform this WM task. These findings support the idea of an ADHD-related dysfunction of neural generators sub-serving attention directed to the incoming visual information. ADHD cases may successfully face WM needs depending on the preservation of sustained theta ERS and prolonged increase of alpha ERS at later post-stimulus time points.

Individual classification of mild cognitive impairment subtypes by support vector machine analysis of white matter DTI.

BACKGROUND AND PURPOSE: MCI was recently subdivided into sd-aMCI, sd-fMCI, and md-aMCI. The current investigation aimed to discriminate between MCI subtypes by using DTI. MATERIALS AND METHODS: Sixty-six prospective participants were included: 18 with sd-aMCI, 13 with sd-fMCI, and 35 with md-aMCI. Statistics included group comparisons using TBSS and individual classification using SVMs. RESULTS: The group-level analysis revealed a decrease in FA in md-aMCI versus sd-aMCI in an extensive bilateral, right-dominant network, and a more pronounced reduction of FA in md-aMCI compared with sd-fMCI in right inferior fronto-occipital fasciculus and inferior longitudinal fasciculus. The comparison between sd-fMCI and sd-aMCI, as well as the analysis of the other diffusion parameters, yielded no significant group differences. The individual-level SVM analysis provided discrimination between the MCI subtypes with accuracies around 97%. The major limitation is the relatively small number of cases of MCI. CONCLUSIONS: Our data show that, at the group level, the md-aMCI subgroup has the most pronounced damage in white matter integrity. Individually, SVM analysis of white matter FA provided highly accurate classification of MCI subtypes.

[Alzheimer disease: from pathogenetic issues to clinical perspectives]. / Maladie d'Alzheimer: de la pathogénie aux perspectives cliniques.

The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field.

Mastoid subperiosteal abscess in children: drainage or mastoidectomy?

OBJECTIVE: To evaluate the management of mastoid subperiosteal abscess using two different surgical approaches: simple mastoidectomy and abscess drainage. METHOD: The medical records of 34 children suffering from acute mastoiditis with subperiosteal abscess were retrospectively reviewed. In these cases, the initial surgical approach consisted of either myringotomy plus simple mastoidectomy or myringotomy plus abscess drainage. RESULTS: Thirteen children were managed with simple mastoidectomy and 21 children were initially managed with abscess drainage. Of the second group, 12 children were cured without further treatment while 9 eventually required mastoidectomy. None of the children developed complications during hospitalisation, or long-term sequelae. CONCLUSION: Simple mastoidectomy remains the most effective procedure for the management of mastoid subperiosteal abscess. Drainage of the abscess represents a simple and risk-free, but not always curative, option. It can be safely used as an initial, conservative approach in association with myringotomy and sufficient antibiotic coverage, with simple mastoidectomy reserved for non-responding cases.

Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.

AIMS: Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analysed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. METHODS: We analysed microvessel diameters in the dorsal and subgenual parts of the ACC in eight patients with schizophrenia, 10 patients with sporadic bipolar disorder, eight patients with sporadic major depression, and seven age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal-Wallis group comparisons with Bonferroni correction as well as multivariate regression models. RESULTS: Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable with controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. CONCLUSIONS: Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings is discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders.

Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates.

Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia.

Magnetic resonance imaging determinants of intraindividual variability in the elderly: combined analysis of grey and white matter.

Elderly individuals display a rapid age-related increase in intraindividual variability (IIV) of their performances. This phenomenon could reflect subtle changes in frontal lobe integrity. However, structural studies in this field are still missing. To address this issue, we computed an IIV index for a simple reaction time (RT) task and performed magnetic resonance imaging (MRI) including voxel based morphometry (VBM) and the tract based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in 61 adults aged from 22 to 88 years. The age-related IIV increase was associated with decreased fractional anisotropy (FA) as well as increased radial (RD) and mean (MD) diffusion in the main white matter (WM) fiber tracts. In contrast, axial diffusion (AD) and grey matter (GM) densities did not show any significant correlation with IIV. In multivariate models, only FA has an age-independent effect on IIV. These results revealed that WM but not GM changes partly mediated the age-related increase of IIV. They also revealed that the association between WM and IIV could not be only attributed to the damage of frontal lobe circuits but concerned the majority of interhemispheric and intrahemispheric corticocortical connections.

Longitudinal analysis of cognitive performances and structural brain changes in late-life bipolar disorder.

OBJECTIVES: Cross-sectional studies in bipolar disorder (BD) suggested the presence of cognitive deficits and subtle magnetic resonance imaging (MRI) changes in limbic areas that may persist at euthymic stages. Whether or not cognitive and MRI changes represent stable attributes of BD or evolve with time is still matter of debate. To address this issue, we performed a 2-year longitudinal study including detailed neuropsychological and magnetic resonance imaging (MRI) analyses of 15 euthymic older BD patients and 15 controls. METHODS: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. MRI analyses included voxel-based morphometry (VBM) analysis of gray matter including region of interest (ROI) analysis and tract-based spatial statistics (TBSS) analysis of white matter of diffusion tensor imaging derived fractional anisotropy (FA). RESULTS: BD patients displayed significantly lower performances in processing speed and episodic memory but not in working memory and executive functions compared to controls. However, BD patients did not differ from controls in the mean trajectory of cognitive changes during the 2 years follow-up. In the same line, longitudinal gray matter (VBM, ROI) and white matter (TBSS FA) changes did not differ between BD patients and controls. CONCLUSION: The lack of distinction between BD patients and controls in respect to the 2-year changes in cognition and MRI findings supports the notion that this disorder does not have a significant adverse impact on cognitive and brain aging. From this point of view, the present results convey a message of hope for patients suffering from BD.