RESUMEN

Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population. Posture and gait control does not happen automatically, as previously believed, but rather requires continuous involvement of central nervous mechanisms. To effectively exert control over the body, the brain must integrate multiple streams of sensory information, including visual, vestibular, and somatosensory signals. The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work. Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults. Insufficient emphasis, however, has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance. In the present work, we review the contributions of somatosensory, visual, and vestibular modalities, along with their multisensory intersections to gait and balance in older adults and patients with Parkinson's disease. We also review evidence of vestibular contributions to multisensory temporal binding windows, previously shown to be highly pertinent to fall risk in older adults. Lastly, we relate multisensory vestibular mechanisms to potential neural substrates, both at the level of neurobiology (concerning positron emission tomography imaging) and at the level of electrophysiology (concerning electroencephalography). We hope that this integrative review, drawing influence across multiple subdisciplines of neuroscience, paves the way for novel research directions and therapeutic neuromodulatory approaches, to improve the lives of older adults and patients with neurodegenerative diseases.

RESUMEN

Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson's disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic "Parkinson-Disease-related-Pattern (PDRP)"-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient's FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

Asunto(s)

RESUMEN

The cholinergic system has been implicated in postural deficits, in particular falls, in Parkinson's disease (PD). Falls and freezing of gait typically occur during dynamic and challenging balance and gait conditions, such as when initiating gait, experiencing postural perturbations, or making turns. However, the precise cholinergic neural substrate underlying dynamic postural and gait changes remains poorly understood. The aim of this study was to investigate whether brain vesicular acetylcholine transporter binding, as measured with [18F]-fluoroethoxybenzovesamicol binding PET, correlates with dynamic gait and balance impairments in 125 patients with PD (mean age 66.89 ± 7.71 years) using the abbreviated balance evaluation systems test total and its four functional domain sub-scores (anticipatory postural control, reactive postural control, dynamic gait, and sensory integration). Whole brain false discovery-corrected (P < 0.05) correlations for total abbreviated balance evaluation systems test scores included the following bilateral or asymmetric hemispheric regions: gyrus rectus, orbitofrontal cortex, anterior part of the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, cingulum, frontotemporal opercula, insula, fimbria, right temporal pole, mesiotemporal, parietal and visual cortices, caudate nucleus, lateral and medial geniculate bodies, thalamus, lingual gyrus, cerebellar hemisphere lobule VI, left cerebellar crus I, superior cerebellar peduncles, flocculus, and nodulus. No significant correlations were found for the putamen or anteroventral putamen. The four domain-specific sub-scores demonstrated overlapping cholinergic topography in the metathalamus, fimbria, thalamus proper, and prefrontal cortices but also showed distinct topographic variations. For example, reactive postural control functions involved the right flocculus but not the upper brainstem regions. The anterior cingulum associated with reactive postural control whereas the posterior cingulum correlated with anticipatory control. The spatial extent of associated cholinergic system changes were least for dynamic gait and sensory orientation functional domains compared to the anticipatory and reactive postural control functions. We conclude that specific aspects of dynamic balance and gait deficits in PD associate with overlapping but also distinct patterns of cerebral cholinergic system changes in numerous brain regions. Our study also presents novel evidence of cholinergic topography involved in dynamic balance and gait in PD that have not been typically associated with mobility disturbances, such as the right anterior temporal pole, right anterior part of the dorsomedial prefrontal cortex, gyrus rectus, fimbria, lingual gyrus, flocculus, nodulus, and right cerebellar hemisphere lobules VI and left crus I.

RESUMEN

Objective: Cognitive decline in Parkinson disease (PD) is a disabling and highly variable non-motor feature. While cholinergic systems degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [ 18 F]-fluoroethoxybenzovesamicol ([ 18 F]-FEOBV) binding predicts longitudinal cognitive changes in mild to moderate, non-demented PD subjects. Methods: Seventy-five non-demented, mild-moderate PD subjects received baseline standardized cognitive evaluations and [ 18 F]-FEOBV PET imaging with repeat cognitive evaluations 2 years later. Participants were classified into four cognitive classes based on stability or change in cognition: Persistent normal (no MCI at baseline and follow-up), Persistent MCI, MCI conversion, and MCI reversion. Whole-brain voxel comparisons with normal controls, and voxel-based and cluster volume-of-interest correlation analyses with longitudinal cognitive changes were performed. Results: Whole-brain voxel comparisons of each class with a matched control group revealed unique bi-directional differences in baseline regional [ 18 F]-FEOBV binding. Increased regional [ 18 F]-FEOBV binding in predominantly anterior cortical and sub-cortical regions was found in the persistent normal and MCI reversion groups. Whole-brain voxel correlation analysis between baseline [ 18 F]-FEOBV binding and two-year longitudinal percent changes in cognition identified a specific regional pattern of reduced posterior cortical, limbic and paralimbic [ 18 F]-FEOBV binding predictive of global cognitive declines and across five cognitive domains at two-year follow-ups. Interpretation: Cholinergic system changes correlate with varying cognitive trajectories in mild-moderate PD. Upregulation of cholinergic neurotransmission may be an important compensatory process in mild-moderate PD.

Asunto(s)

RESUMEN

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Asunto(s)

RESUMEN

BACKGROUND: Pru p 7 was the first gibberellin-regulated protein (GRP) to be identified as a food allergen as the basis of a pollen food allergy syndrome. OBJECTIVE: To clinically and biologically characterize a group of patients with suspected allergy to Pru p 7 to optimize the diagnostic workup of GRP sensitization. METHODS: Allergy to Pru p 7 was suspected in the presence of a systemic allergic reaction to plant food, positive skin prick test results for cypress pollen and lipid-transfer protein-enriched peach extract, and absence of Pru p 3-specific immunoglobulin E. Controls were patients with food allergies, patients sensitized to Pru p 3, and patients with cypress allergy without food allergy. Diagnostic workup included skin tests, basophil activation test, Western blot, and single and multiplex assays. RESULTS: In total, 23 patients and 14 controls were enrolled. The most implicated food was peach (91.3%). Approximately 70% of patients reacted to multiple foods. Mueller 4 reactions were 8.7%. In 26.1% of cases, a cofactor triggered the reaction. The basophil activation test results were positive for rPru p 7 in 87% of the patients. Specific immunoglobulin E to Pru p 7 was detected in 95.7% by singleplex and in 73.9% by multiplex assays in patients with suspected allergies; 73.9% of them also reacted to cypress pollen GRP (Cup s 7) in Western blot analysis. CONCLUSION: Patients with Pru p 7-Cup s 7 allergy in our cohort confirm a mild-to-severe clinical syndrome characterized by pollen and food allergy. The diagnosis may benefit from the proposed selection criteria that can be used as preliminary steps to further characterize the cross-reactive GRP sensitization.

Asunto(s)

RESUMEN

Positron Emission Tomography (PET) brain imaging is increasingly utilized in clinical and research settings due to its unique ability to study biological processes and subtle changes in living subjects. However, PET imaging is not without its limitations. Currently, bias introduced by partial volume effect (PVE) and poor signal-to-noise ratios of some radiotracers can hamper accurate quantification. Technological advancements like ultra-high-resolution scanners and improvements in radiochemistry are on the horizon to address these challenges. This will enable the study of smaller brain regions and may require more sophisticated methods (e.g., data-driven approaches like unsupervised clustering) for reference region selection and to improve quantification accuracy. This review delves into some of these critical aspects of PET molecular imaging and offers suggested strategies for improvement. This will be illustrated by showing examples for dopaminergic and cholinergic nerve terminal ligands.

RESUMEN

BACKGROUND: Brain imaging with [18F]FDG-PET can support the diagnostic work-up of patients with α-synucleinopathies. Validated data analysis approaches are necessary to evaluate disease-specific brain metabolism patterns in neurodegenerative disorders. This study compared the univariate Statistical Parametric Mapping (SPM) single-subject procedure and the multivariate Scaled Subprofile Model/Principal Component Analysis (SSM/PCA) in a cohort of patients with α-synucleinopathies. METHODS: We included [18F]FDG-PET scans of 122 subjects within the α-synucleinopathy spectrum: Parkinson's Disease (PD) normal cognition on long-term follow-up (PD - low risk to dementia (LDR); n = 28), PD who developed dementia on clinical follow-up (PD - high risk of dementia (HDR); n = 16), Dementia with Lewy Bodies (DLB; n = 67), and Multiple System Atrophy (MSA; n = 11). We also included [18F]FDG-PET scans of isolated REM sleep behaviour disorder (iRBD; n = 51) subjects with a high risk of developing a manifest α-synucleinopathy. Each [18F]FDG-PET scan was compared with 112 healthy controls using SPM procedures. In the SSM/PCA approach, we computed the individual scores of previously identified patterns for PD, DLB, and MSA: PD-related patterns (PDRP), DLBRP, and MSARP. We used ROC curves to compare the diagnostic performances of SPM t-maps (visual rating) and SSM/PCA individual pattern scores in identifying each clinical condition across the spectrum. Specifically, we used the clinical diagnoses ("gold standard") as our reference in ROC curves to evaluate the accuracy of the two methods. Experts in movement disorders and dementia made all the diagnoses according to the current clinical criteria of each disease (PD, DLB and MSA). RESULTS: The visual rating of SPM t-maps showed higher performance (AUC: 0.995, specificity: 0.989, sensitivity 1.000) than PDRP z-scores (AUC: 0.818, specificity: 0.734, sensitivity 1.000) in differentiating PD-LDR from other α-synucleinopathies (PD-HDR, DLB and MSA). This result was mainly driven by the ability of SPM t-maps to reveal the limited or absent brain hypometabolism characteristics of PD-LDR. Both SPM t-maps visual rating and SSM/PCA z-scores showed high performance in identifying DLB (DLBRP = AUC: 0.909, specificity: 0.873, sensitivity 0.866; SPM t-maps = AUC: 0.892, specificity: 0.872, sensitivity 0.910) and MSA (MSARP: AUC: 0.921, specificity: 0.811, sensitivity 1.000; SPM t-maps: AUC: 1.000, specificity: 1.000, sensitivity 1.000) from other α-synucleinopathies. PD-HDR and DLB were comparable for the brain hypo and hypermetabolism patterns, thus not allowing differentiation by SPM t-maps or SSM/PCA. Of note, we found a gradual increase of PDRP and DLBRP expression in the continuum from iRBD to PD-HDR and DLB, where the DLB patients had the highest scores. SSM/PCA could differentiate iRBD from DLB, reflecting specifically the differences in disease staging and severity (AUC: 0.938, specificity: 0.821, sensitivity 0.941). CONCLUSIONS: SPM-single subject maps and SSM/PCA are both valid methods in supporting diagnosis within the α-synucleinopathy spectrum, with different strengths and pitfalls. The former reveals dysfunctional brain topographies at the individual level with high accuracy for all the specific subtype patterns, and particularly also the normal maps; the latter provides a reliable quantification, independent from the rater experience, particularly in tracking the disease severity and staging. Thus, our findings suggest that differences in data analysis approaches exist and should be considered in clinical settings. However, combining both methods might offer the best diagnostic performance.

Asunto(s)

RESUMEN

PURPOSE: Isolated REM sleep behaviour disorder (iRBD) patients are at high risk of developing clinical syndromes of the α-synuclein spectrum. Progression markers are needed to determine the neurodegenerative changes and to predict their conversion. Brain imaging with 18F-FDG PET in iRBD is promising, but longitudinal studies are scarce. We investigated the regional brain changes in iRBD over time, related to phenoconversion. METHODS: Twenty iRBD patients underwent two consecutive 18F-FDG PET brain scans and clinical assessments (3.7 ± 0.6 years apart). Seventeen patients also underwent 123I-MIBG and 123I-FP-CIT SPECT scans at baseline. Four subjects phenoconverted to Parkinson's disease (PD) during follow-up. 18F-FDG PET scans were compared to controls with a voxel-wise single-subject procedure. The relationship between regional brain changes in metabolism and PD-related pattern scores (PDRP) was investigated. RESULTS: Individual hypometabolism t-maps revealed three scenarios: (1) normal 18F-FDG PET scans at baseline and follow-up (N = 10); (2) normal scans at baseline but occipital or occipito-parietal hypometabolism at follow-up (N = 4); (3) occipital hypometabolism at baseline and follow-up (N = 6). All patients in the last group had pathological 123I-MIBG and 123I-FP-CIT SPECT. iRBD converters (N = 4) showed occipital hypometabolism at baseline (third scenario). At the group level, hypometabolism in the frontal and occipito-parietal regions and hypermetabolism in the cerebellum and limbic regions were progressive over time. PDRP z-scores increased over time (0.54 ± 0.36 per year). PDRP expression was driven by occipital hypometabolism and cerebellar hypermetabolism. CONCLUSIONS: Our results suggest that occipital hypometabolism at baseline in iRBD implies a short-term conversion to PD. This might help in stratification strategies for disease-modifying trials.

Asunto(s)

RESUMEN

BACKGROUND: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive. OBJECTIVE: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. METHODS: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. RESULTS: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determinant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardial perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. CONCLUSION: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamineinduced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.

Asunto(s)

RESUMEN

Objectives: Attention-deficit hyperactivity disorder (ADHD) in adulthood shows high co-occurrence rates with cocaine use disorder (CoUD). The self-medication hypothesis (SMH) provides a theoretical explanation for this comorbidity. This study investigates the neurobiological mechanisms that could support SMH in adult patients with attention-deficit hyperactivity disorder with cocaine use disorder (ADHD-CoUD). Materials and Methods: We included 19 ADHD-CoUD patients (84.2% male; age: 32.11 years [7.18]) and 16 CoUD patients (68.7% male; age: 36.63 years [8.12]). All subjects underwent a fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) brain scan. We tested brain metabolism differences between ADHD-CoUD and CoUD patients using voxel-based and regions of interest (ROIs)-based analyses. The correlation between dependence/abstinence duration and regional brain metabolism was also assessed in the two groups. Lastly, we investigated the integrity of brain metabolic connectivity of mesocorticolimbic and nigrostriatal dopaminergic systems, and large-scale brain networks involved in ADHD and addictions. Results: The voxel-wise and ROIs-based approaches showed that ADHD-CoUD patients had a lower metabolism in the thalamus and increased metabolism in the amygdala and parahippocampus, bilaterally, than CoUD subjects and healthy controls (HCs). Metabolism in the thalamus negatively correlated with years of dependence in ADHD-CoUD patients. Moreover, connectivity analyses revealed that ADHD-CoUD patients had a more preserved metabolic connectivity than CoUD patients in the dopaminergic networks and large-scale networks involved in self-regulation mechanisms of attention and behaviors (i.e., anterior default mode network [ADMN], executive network [ECN], and anterior salience network [aSAN]). Conclusions: We demonstrated distinct neuropathological substrates underlying substance-use behaviors in ADHD-CoUD and CoUD patients. Furthermore, we provided neurobiological evidence in support of SMH, demonstrating that ADHD-CoUD patients might experience short-term advantages of cocaine assumption (i.e., compensation of dopaminergic deficiency and related cognitive-behavioral deficits).

Asunto(s)

RESUMEN

Isolated rapid-eye-movement sleep behaviour disorder (RBD) is considered the prodromal stage of α-synucleinopathies (e.g., Parkinson's disease and dementia with Lewy bodies); however, iRBD patients show a wide variety in the progression timing (5-15 years). The model of cognitive reserve (CR) might contribute to explaining this phenomenon. Our exploratory study aimed to evaluate, for the first time, the impact of CR level on cognitive performance in polysomnography-confirmed iRBD patients. Fifty-five iRBD patients (mean age ± SD: 66.38 ± 7.51; M/F 44/11) underwent clinical and neuropsychological evaluations at the time of diagnosis. The CR Index questionnaire was part of the clinical assessment. We found that iRBD patients with high levels of CR showed: (i) the lowest percentage of mild cognitive impairment (10%), and (ii) the best performance in visuo-constructive and verbal memory functions (i.e., the recall of the Rey-Osterrieth complex figure test). Our results suggest that CR might help iRBD patients better cope with the cognitive decline related to the neurodegenerative process, providing the first preliminary findings supporting CR as a possible protective factor in this condition. This might pave the way for future longitudinal studies to evaluate the role of CR as a modulating factor in the timing of iRBD conversion and cognitive deterioration development.

RESUMEN

Objective: This study investigates the effects of manual and semi-automatic methods for assessing MIBG semi-quantitative indices in a clinical setting. Materials and methods: We included 123I-MIBG scans obtained in 35 patients with idiopathic Parkinson's Disease. Early and late heart-to-mediastinum (H/M) ratios were calculated from 123I-MIBG images using regions of interest (ROIs) placed over the heart and the mediastinum. The ROIs were derived using two approaches: (i) manually drawn and (ii) semi-automatic fixed-size ROIs using anatomical landmarks. Expert, moderate-expert, and not expert raters applied the ROIs procedures and interpreted the 123I-MIBG images. We evaluated the inter and intra-rater agreements in assessing 123I-MIBG H/M ratios. Results: A moderate agreement in the raters' classification of pathological and non-pathological scores emerged regarding early and late H/M ratio values (κ = 0.45 and 0.69 respectively), applying the manual method, while the early and late H/M ratios obtained with the semi-automatic method reached a good agreement among observers (κ = 0.78). Cohen-Kappa values revealed that the semi-automatic method improved the agreement between expert and inexpert raters: the agreement improved from a minimum of 0.29 (fair, for early H/M) and 0.69 (substantial, in late H/M) with the manual method, to 0.90 (perfect, in early H/M) and 0.87 (perfect, in late H/M) with the semi-automatic method. Conclusion: The use of the semi-automatic method improves the agreement among raters in classifying' H/M ratios as pathological or non-pathological, namely for inexpert readers. These results have important implications for semi-quantitative assessment of 123I-MIBG images in clinical routine.

RESUMEN

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype.

RESUMEN

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [18F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.

Asunto(s)

RESUMEN

Functional network-level alterations in the semantic variant of Primary Progressive Aphasia (sv-PPA) are relevant to understanding the clinical features and the neural spreading of the pathology. We assessed the effect of neurodegeneration on brain systems reorganization in early sv-PPA, using advanced brain metabolic connectivity approaches. Forty-four subjects with sv-PPA and forty-four age-matched healthy controls (HC) were included. We applied two multivariate approaches to [18F]FDG-PET data - i.e., sparse inverse covariance estimation and seed-based interregional correlation analysis - to assess the integrity of (i) the whole-brain metabolic connectivity and (ii) the connectivity of brain regions relevant for cognitive and behavioral functions. Whole-brain analysis revealed a global-scale connectivity reconfiguration in sv-PPA, with widespread changes in metabolic connections of frontal, temporal, and parietal regions. In comparison to HC, the seed-based analysis revealed a) functional isolation of the left anterior temporal lobe (ATL), b) decreases in temporo-occipital connections and contralateral homologous regions, c) connectivity increases to the dorsal parietal cortex from the spared posterior temporal cortex, d) a disruption of the large-scale limbic brain networks. In sv-PPA, the severe functional derangement of the left ATL may lead to an extensive connectivity reconfiguration, encompassing several brain regions, including those not yet affected by neurodegeneration. These findings support the hypothesis that in sv-PPA the focal vulnerability of the core region (i.e., ATL) can potentially drive the widespread cerebral connectivity changes, already present in the early phase.

Asunto(s)

RESUMEN

Parkinson's disease (PD) is characterized by heterogeneity in clinical syndromes, prognosis, and pathophysiology mechanisms. Gender differences in neural anatomy and function are emerging as fundamental determinants of phenotypic variability. Different clinical subtypes, defined as mild motor predominant, intermediate, and diffuse-malignant, have been recently proposed in PD. This study investigated gender influence on clinical features, dopaminergic dysfunction, and connectivity in patients with de novo idiopathic PD stratified according to the clinical criteria for subtypes (i.e., mild motor, intermediate, and diffuse-malignant). We included 286 drug-naïve patients (Males/Females: 189/97, age [mean ± standard deviation]: 61.99 ± 9.67; disease duration: 2.08 ± 2.21) with available [123I]FP-CIT-SPECT and high-resolution T1-weighted MRI from the Parkinson's Progression Markers Initiative. We assessed gender differences for clinical and cognitive features, and dopaminergic presynaptic dysfunction in striatal or extra-striatal regions using molecular analysis of [123I]FP-CIT-bindings. We applied an advanced multivariate analytical approach - partial correlations molecular connectivity analyses - to assess potential gender differences in the vulnerability of the nigrostriatal and mesolimbic dopaminergic pathways. In the mild motor and intermediate subtypes, male patients with idiopathic PD showed poorer cognitive performances than females, who - in contrast - presented more severe anxiety symptoms. The male vulnerability emerged also in the motor system in the same subtypes with motor impairment associated with a lower dopamine binding in the putamen and more severe widespread connectivity alterations in the nigrostriatal dopaminergic pathway in males than in females. In the diffuse-malignant subtype, males showed more severe motor impairments, consistent with a lower dopamine uptake in the putamen than females. On the other hand, a severe dopaminergic depletion in several dopaminergic targets of the mesolimbic pathway, together with extensive altered connectivity in the same system, characterized females with idiopathic PD in all the subtypes. The anxiety level was associated with a lower dopaminergic binding in the amygdala only in females. This study provides evidence on gender differences in idiopathic PD across clinical subtypes, and, remarkably, since the early phase. The clinical correlations with the nigrostriatal or mesolimbic systems in males and females support different vulnerabilities and related disease expressions. Gender differences must be considered in a precision medicine approach to preventing, diagnosing, and treating idiopathic PD.

Asunto(s)

RESUMEN

BACKGROUND: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized. METHOD: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed. RESULTS: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable. CONCLUSIONS: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated.

Asunto(s)

RESUMEN

BACKGROUND: Glucosylceramidase (GBA) mutations are considered the most common genetic risk factors for developing Parkinson's disease (PD). OBJECTIVES: We aimed to assess, at different time points, the integrity of brain striatal and extra-striatal dopamine pathways and clinical phenotype of a group of PD subjects bearing heterozygous GBA mutations (GBA-PD), compared with a group of idiopathic PD patients (iPD) stratified by age at disease onset. A longitudinal approach was adopted to evaluate the progression over time for clinical and 123 I-FP-CIT SPECT imaging features. METHODS: We considered 46 GBA-PD patients and 339 iPD patients, subdivided into two groups according to age at PD onset (n = 58 < 50 years and n = 281 > 50 years). We measured differences in the occurrence/severity/progression of motor and non-motor features, 123 I-FP-CIT standard uptake value ratios (SUVr) in striatal and extra-striatal regions, and global cognitive deterioration over time in a subset of 168 cases with available follow-up. RESULTS: At baseline, the GBA-PD cohort showed more severe motor and cognitive deficits than the early-iPD cohort. The 123 I-FP-CIT SUVr reduction in the striatal and the extra-striatal regions was more marked in the GBA-PD than the early- and late-iPD cohorts. Both GBA-PD and late-iPD patients had a significant annual deterioration in their global cognitive performance, while the early-iPD group showed global cognitive stability over time. At follow-up, the iPD cohorts became similar to the GBA-PD group in 123 I-FP-CIT SUVr reduction. CONCLUSION: These new findings support the hypothesis of a biological role of GBA mutations in accelerating the early neurodegenerative processes in PD, leading to the malignant clinical phenotype. © 2021 International Parkinson and Movement Disorder Society.

Asunto(s)