Purpose
The aim of this study was to evaluate the supportive role of molecular and structural biomarkers (CSF protein levels, FDG PET and MRI) in the early differential diagnosis of dementia in a ...large sample of patients with neurodegenerative dementia, and in determining the risk of disease progression in subjects with mild cognitive impairment (MCI).
Methods
We evaluated the supportive role of CSF Aβ
42
, t-Tau, p-Tau levels, conventional brain MRI and visual assessment of FDG PET SPM t-maps in the early diagnosis of dementia and the evaluation of MCI progression.
Results
Diagnosis based on molecular biomarkers showed the best fit with the final diagnosis at a long follow-up. FDG PET SPM t-maps had the highest diagnostic accuracy in Alzheimer’s disease and in the differential diagnosis of non-Alzheimer’s disease dementias. The p-tau/Aβ
42
ratio was the only CSF biomarker providing a significant classification rate for Alzheimer’s disease. An Alzheimer’s disease-positive metabolic pattern as shown by FDG PET SPM in MCI was the best predictor of conversion to Alzheimer’s disease.
Conclusion
In this clinical setting, FDG PET SPM t-maps and the p-tau/Aβ
42
ratio improved clinical diagnostic accuracy, supporting the importance of these biomarkers in the emerging diagnostic criteria for Alzheimer’s disease dementia. FDG PET using SPM t-maps had the highest predictive value by identifying hypometabolic patterns in different neurodegenerative dementias and normal brain metabolism in MCI, confirming its additional crucial exclusionary role.
The auditory scene is a mental representation of individual sounds extracted from the summed sound waveform reaching the ears of the listeners. Musical contexts represent particularly complex cases ...of auditory scenes. In such a scenario, melody may be seen as the main object moving on a background represented by the accompaniment. Both melody and accompaniment vary in time according to harmonic rules, forming a typical texture with melody in the most prominent, salient voice. In the present sparse acquisition functional magnetic resonance imaging study, we investigated the interplay between melody and accompaniment in trained pianists, by observing the activation responses elicited by processing: (1) melody placed in the upper and lower texture voices, leading to, respectively, a higher and lower auditory salience; (2) harmonic violations occurring in either the melody, the accompaniment, or both. The results indicated that the neural activation elicited by the processing of polyphonic compositions in expert musicians depends upon the upper versus lower position of the melodic line in the texture, and showed an overall greater activation for the harmonic processing of melody over accompaniment. Both these two predominant effects were characterized by the involvement of the posterior cingulate cortex and precuneus, among other associative brain regions. We discuss the prominent role of the posterior medial cortex in the processing of melodic and harmonic information in the auditory stream, and propose to frame this processing in relation to the cognitive construction of complex multimodal sensory imagery scenes.
•We investigated with sparse sampling fMRI harmony processing in trained musicians.•Harmony violations were instantiated as occurring in either melody or accompaniment.•We found a greater salience of harmonic processing of melody over accompaniment.•Violations in melody modulated the posterior medial cortex (precuneus, cingulate).•This brain region mediates the formation of complex multimodal sensory imageries.
PDGF-CC is a member of the platelet-derived growth factor (PDGF) family that stimulates PDGFRα phosphorylation and thereby activates intracellular signalling events essential for development but also ...in cancer, fibrosis and neuropathologies involving blood-brain barrier (BBB) disruption. In order to elucidate the biological and pathological role(s) of PDGF-CC signalling, we have generated high affinity neutralizing monoclonal antibodies (mAbs) recognizing human PDGF-CC. We determined the complementarity determining regions (CDRs) of the selected clones, and mapped the binding epitope for clone 6B3. Using the monoclonal 6B3, we determined the expression pattern for PDGF-CC in different human primary tumours and control tissues, and explored its ability to neutralize PDGF-CC-induced phosphorylation of PDGFRα. In addition, we showed that PDGF-CC induced disruption of the blood-retinal barrier (BRB) was significantly reduced upon intraperitoneal administration of a chimeric anti-PDGF-CC antibody. In summary, we report on high affinity monoclonal antibodies against PDGF-CC that have therapeutic efficacy in vivo.
Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods ...have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test–retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal (“long_T1s” and “long_T1s_FLAIR”) and one cross-sectional (“long_T1s_FLAIR_crossT2”). Volume reproducibility was quantified in magnitude (reproducibility error—RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4–3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1–7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (
p
= 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm
3
had better RE (1–2%) and DICE (0.7–0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.
There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive ...disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT2A) and dopamine (D2) receptor distribution. For this, we used 11CMDL and 11CRaclopride, highly selective antagonists of 5-HT2Aand D2receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT2Areceptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT2Areceptor availability in orbitofrontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of 11CRaclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.
The timing and neural processing of the understanding of social interactions was investigated by presenting scenes in which 2 people performed cooperative or affective actions. While the role of the ...human mirror neuron system (MNS) in understanding actions and intentions is widely accepted, little is known about the time course within which these aspects of visual information are automatically extracted. Event-Related Potentials were recorded in 35 university students perceiving 260 pictures of cooperative (e.g., 2 people dragging a box) or affective (e.g., 2 people smiling and holding hands) interactions. The action's goal was automatically discriminated at about 150-170 ms, as reflected by occipito/temporal N170 response. The swLORETA inverse solution revealed the strongest sources in the right posterior cingulate cortex (CC) for affective actions and in the right pSTS for cooperative actions. It was found a right hemispheric asymmetry that involved the fusiform gyrus (BA37), the posterior CC, and the medial frontal gyrus (BA10/11) for the processing of affective interactions, particularly in the 155-175 ms time window. In a later time window (200-250 ms) the processing of cooperative interactions activated the left post-central gyrus (BA3), the left parahippocampal gyrus, the left superior frontal gyrus (BA10), as well as the right premotor cortex (BA6). Women showed a greater response discriminative of the action's goal compared to men at P300 and anterior negativity level (220-500 ms). These findings might be related to a greater responsiveness of the female vs. male MNS. In addition, the discriminative effect was bilateral in women and was smaller and left-sided in men. Evidence was provided that perceptually similar social interactions are discriminated on the basis of the agents' intentions quite early in neural processing, differentially activating regions devoted to face/body/action coding, the limbic system and the MNS.
Objective
Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic ...acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.
Methods
We enrolled 10 SCA38 patients, and carried out a double‐blind randomized placebo‐controlled study for 16 weeks, followed by an open‐label study with overall 40‐week DHA treatment. At baseline and at follow‐up visit, patients underwent standardized clinical assessment, brain 18‐fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.
Results
After 16 weeks, we showed a significant pre–post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference MD = +2.70, 95% confidence interval CI = +0.13 to + 5.27, p = 0.042). At 40‐week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients’ blood at 40 weeks as compared to baseline. No side effect was recorded.
Interpretation
DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615–621
Purpose
This study was conducted to prospectively investigate the interobserver reproducibility of controlled attenuation parameter (CAP) measurements and the relationship among the CAP and body mass ...index (BMI), gender and age.
Methods
Consecutive subjects were studied using the M+ probe of the FibroScan device (Echosens, Paris, France). Measurements were performed by two raters (rater1 and rater2). Interobserver agreement was assessed by using the concordance correlation coefficient (CCC). The Pearson
r
coefficient was used to test correlation between two study variables, and linear regression was used for the multivariate model.
Results
Three hundred fifty-one subjects (227 males and 124 females) were prospectively studied. The CCC was 0.82 (95 % CI 0.78–0.85) overall, 0.80 (95 % CI 0.75–0.85) for BMI <25 kg/m
2
, 0.76 (95 % CI 0.69–0.84) for BMI 25–29 kg/m
2
and 0.65 (95 % CI 0.41–0.88) for BMI ≥30 kg/m
2
. The CCC was 0.44 (95 % CI 0.31–0.56) for CAP values ≤240 dB/m and 0.72 (95 % CI 0.65–0.79) for CAP values >240 dB/m. In univariate analysis, age and BMI by gender were correlated with the CAP. Multiple regression analysis confirmed the relationship of the CAP with age and BMI, but not with gender.
Conclusions
The results of this study show that the interreader agreement in CAP measurement is good. In healthy volunteers, the CAP is strongly correlated with age and BMI.
Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of fragment crystallizable (Fc) mutations targeting the ...neonatal Fc receptor (FcRn) site on a Lewis Y (Le
) binding IgG1, hu3S193. The hu3S193 variants displayed shortened
half-lives and may have potential for radioimaging or radiotherapy of Le
-positive tumors. Here, we report Fc crystal structures of wild-type hu3S193, seven FcRn-binding site variants, and a variant lacking C1q binding or complement-dependent cytotoxicity (CDC) activity. The Fc conformation of the FcRn-binding sites was similar for wild-type and all mutants of hu3S193 Fc, which suggests that FcRn interactions were directly affected by the amino acid substitutions. The C1q-binding site mutant Fc was nearly identical with the wild-type Fc. Surprisingly, several hu3S193 Fc variants showed large changes in global structure compared with wild-type Fc. All hu3S193 Fc mutants had similar antibody-dependent cellular cytotoxicity, despite some with conformations expected to diminish Fc gamma receptor binding. Several hu3S193 variants displayed altered CDC, but there was no correlation with the different Fc conformations. All versions of hu3S193, except the C1q-binding site mutant, bound C1q, suggesting that the altered CDC of some variants could result from different propensities to form IgG hexamers after engaging Le
on target cells. Overall, our findings support the concept that the antibody Fc is both flexible and mobile in solution. Structure-based design approaches should take into account the conformational plasticity of the Fc when engineering antibodies with optimal effector properties.
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