Positron emission tomography (PET) represents a unique molecular tool to get
access to a wide spectrum of biological and neuropathological processes, of crucial relevance for neurodegenerative ...conditions. Although most PET findings are based on massive univariate approaches, in the last decade the increasing interest in multivariate methods has paved the way to the assessment of unexplored cerebral features, spanning from resting state brain networks to whole-brain connectome properties. Currently, the combination of molecular neuroimaging techniques with multivariate connectivity methods represents one of the most powerful, yet still emerging, approach to achieve novel insights into the pathophysiology of neurodegenerative diseases. In this review, we will summarize the available evidence in the field of PET molecular connectivity, with the aim to provide an overview of how these studies may increase the understanding of the pathogenesis of neurodegenerative diseases, over and above "traditional" structural/functional connectivity studies. Considering the available evidence, a major focus will be represented by molecular connectivity studies using 18FFDG-PET, today applied in the major neuropathological spectra, from amyloidopathies and tauopathies to synucleinopathies and beyond. Pioneering studies using PET tracers targeting brain neuropathology and neurotransmission systems for connectivity studies will be discussed, their strengths and limitations highlighted with reference to both applied methodology and results interpretation. The most common methods for molecular connectivity assessment will be reviewed, with particular emphasis on the available strategies to investigate molecular connectivity at the single-subject level, of potential relevance for not only research but also diagnostic purposes. Finally, we will highlight possible future perspectives in the field, with reference in particular to newly available PET tracers, which will expand the application of molecular connectivity to new, exciting, unforeseen possibilities.
Neurodegeneration elicits neuroinflammatory responses to kill pathogens, clear debris and support tissue repair. Neuroinflammation is a dynamic biological response characterized by the recruitment of ...innate and adaptive immune system cells in the site of tissue damage. Resident microglia and infiltrating immune cells partake in the restoration of central nervous system homeostasis. Nevertheless, their activation may shift to chronic and aggressive responses, which jeopardize neuron survival and may contribute to the disease process itself. Positron Emission Tomography (PET) molecular imaging represents a unique tool contributing to in vivo investigating of neuroinflammatory processes in patients. In the present review, we first provide an overview on the molecular basis of neuroinflammation in neurodegenerative diseases with emphasis on microglia activation, astrocytosis and the molecular targets for PET imaging. Then, we review the state-of-the-art of in vivo PET imaging for neuroinflammation in dementia conditions associated with different proteinopathies, such as Alzheimer's disease, frontotemporal lobar degeneration and Parkinsonian spectrum.
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 123IFP-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 123IFP-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.
•Dopaminergic systems show specific gender-related vulnerability in PD.•Males present a prevalent nigrostriatal derangement associated with motor symptoms severity.•Females show major changes in the mesolimbic system also related to anxiety levels.•Males and females maintain these different PD expressions regardless of the clinical subtypes.
•Visual crowding is one of the main bottlenecks for visual object perception.•Parietal and right fronto-parietal beta (15–25 Hz) activity is linked to crowding.•We used beta (18 Hz) tACS over ...bilateral parietal and right fronto-parietal sensors.•Bilateral parietal 18 Hz tACS reduced the influence of crowding in both hemifields.•EEG beta power was reduced after bilateral parietal 18 Hz tACS.
Visual crowding is the difficulty in identifying an object when surrounded by neighbouring flankers, representing a bottleneck for object perception. Crowding arises not only from the activity of visual areas but also from parietal areas and fronto-parietal network activity. Parietal areas would provide the dorsal-to-ventral guidance for object identification and the fronto-parietal network would modulate the attentional resolution. Several studies highlighted the relevance of beta oscillations (15–25 Hz) in these areas for visual crowding and other connatural visual phenomena. In the present study, we investigated the differential contribution of beta oscillations in the parietal cortex and fronto-parietal network in the resolution of visual crowding. During a crowding task with letter stimuli, high-definition transcranial Alternating Current Stimulation (tACS) in the beta band (18 Hz) was delivered bilaterally on parietal sites, on the right fronto-parietal network, and in a sham regime. Resting-state EEG was recorded before and after stimulation to measure tACS-induced aftereffects. The influence of crowding was reduced only when tACS was delivered bilaterally on parietal sites. In this condition, beta power was reduced after the stimulation. Furthermore, the magnitude of tACS-induced aftereffects varied as a function of individual differences in beta oscillations. Results corroborate the link between parietal beta oscillations and visual crowding, providing fundamental insights on brain rhythms underlying the dorsal-to-ventral guidance in visual perception and suggesting that beta tACS can induce plastic changes in these areas. Remarkably, these findings open new possibilities for neuromodulatory interventions for disorders characterised by abnormal crowding, such as dyslexia.
Purpose
An appropriate healthy control dataset is mandatory to achieve good performance in voxel-wise analyses. We aimed at evaluating 18FFDG PET brain datasets of healthy controls (HC), based on ...publicly available data, for the extraction of voxel-based brain metabolism maps at the single-subject level.
Methods
Selection of HC images was based on visual rating, after Cook’s distance and jack-knife analyses, to exclude artefacts and/or outliers. The performance of these HC datasets (ADNI-HC and AIMN-HC) to extract hypometabolism patterns in single patients was tested in comparison with the standard reference HC dataset (HSR-HC) by means of Dice score analysis. We evaluated the performance and comparability of the different HC datasets in the assessment of single-subject SPM-based hypometabolism in three independent cohorts of patients, namely, ADD, bvFTD and DLB.
Results
Two-step Cook’s distance analysis and the subsequent jack-knife analysis resulted in the selection of
n
= 125 subjects from the AIMN-HC dataset and
n
= 75 subjects from the ADNI-HC dataset. The average concordance between SPM hypometabolism t-maps in the three patient cohorts, as obtained with the new datasets and compared to the HSR-HC standard reference dataset, was 0.87 for the AIMN-HC dataset and 0.83 for the ADNI-HC dataset. Pattern expression analysis revealed high overall accuracy (> 80%) of the SPM t-map classification according to different statistical thresholds and sample sizes.
Conclusions
The applied procedures ensure validity of these HC datasets for the single-subject estimation of brain metabolism using voxel-wise comparisons. These well-selected HC datasets are ready-to-use in research and clinical settings.
Purpose
Given the challenges posed by the clinical diagnosis of atypical Alzheimer’s disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we ...assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of
18
FFDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI).
Methods
We retrospectively collected
N
= 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included
N
= 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions.
Results
W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific
18
FFDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up.
Conclusions
The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.
Neural language networks at birth Perani, Daniela; Saccuman, Maria C; Scifo, Paola ...
Proceedings of the National Academy of Sciences - PNAS,
09/2011, Letnik:
108, Številka:
38
Journal Article
Recenzirano
Odprti dostop
The ability to learn language is a human trait. In adults and children, brain imaging studies have shown that auditory language activates a bilateral frontotemporal network with a left hemispheric ...dominance. It is an open question whether these activations represent the complete neural basis for language present at birth. Here we demonstrate that in 2-d-old infants, the language-related neural substrate is fully active in both hemispheres with a preponderance in the right auditory cortex. Functional and structural connectivities within this neural network, however, are immature, with strong connectivities only between the two hemispheres, contrasting with the adult pattern of prevalent intrahemispheric connectivities. Thus, although the brain responds to spoken language already at birth, thereby providing a strong biological basis to acquire language, progressive maturation of intrahemispheric functional connectivity is yet to be established with language exposure as the brain develops.
The hypothesis that the brain constitutively encodes observed manipulable objects for the actions they afford is still debated. Yet, crucial evidence demonstrating that, even in the absence of ...perceptual awareness, the mere visual appearance of a manipulable object triggers a visuomotor coding in the action representation system including the premotor cortex, has hitherto not been provided. In this fMRI study, we instantiated reliable unaware visual perception conditions by means of continuous flash suppression, and we tested in 24 healthy human participants (13 females) whether the visuomotor object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices is activated even under subliminal perceptual conditions. We found consistent activation in the target visuomotor cortices, both with and without perceptual awareness, specifically for pictures of manipulable versus non-manipulable objects. By means of a multivariate searchlight analysis, we also found that the brain activation patterns in this visuomotor network enabled the decoding of manipulable versus non-manipulable object picture processing, both with and without awareness. These findings demonstrate the intimate neural coupling between visual perception and motor representation that underlies manipulable object processing: manipulable object stimuli specifically engage the visuomotor object-directed action representation system, in a constitutive manner that is independent from perceptual awareness. This perceptuo-motor coupling endows the brain with an efficient mechanism for monitoring and planning reactions to external stimuli in the absence of awareness.
Our brain constantly encodes the visual information that hits the retina, leading to a stimulus-specific activation of sensory and semantic representations, even for objects that we do not consciously perceive. Do these unconscious representations encompass the motor programming of actions that could be accomplished congruently with the objects' functions? In this fMRI study, we instantiated unaware visual perception conditions, by dynamically suppressing the visibility of manipulable object pictures with mondrian masks. Despite escaping conscious perception, manipulable objects activated an object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices. This demonstrates that visuomotor encoding occurs independently of conscious object perception.
•PD showed lower 123I-FP-CIT-binding than SWEDD at the same symptoms’ severity.•PD and SWEDD showed altered molecular connectivity but with different patterns.•Motor symptoms and dopaminergic ...deficits worsened after 2 years in PD only.•SWEDD were unlikely to have PD.
A proportion of patients clinically diagnosed with Parkinson’s disease (PD) can have a 123I-FP-CIT-SPECT scan without evidence of dopaminergic deficit (SWEDD), generating a debate about the underlying biological mechanisms. This study investigated differences in clinical features, 123I-FP-CIT binding, molecular connectivity, as well as clinical and imaging progression between SWEDD and PD patients.
We included 36 SWEDD, 49 de novo idiopathic PD, and 49 healthy controls with 123I-FP-CIT-SPECT from the Parkinson’s Progression Markers Initiative. Clinical and imaging 2-year follow-ups were available for 27 SWEDD and 40 PD. Regional-based and voxel-wise analysis assessed dopaminergic integrity in dorsal and ventral striatal, as well as extrastriatal regions, at baseline and follow-up. Molecular connectivity analyses evaluated dopaminergic pathways. Spatial correlation analyses tested whether 123I-FP-CIT-binding alterations would also pertain to the serotoninergic system.
SWEDD and PD patients showed comparable symptoms at baseline, except for hyposmia, which was more severe for PD. PD showed significantly lower striatal and extrastriatal 123I-FP-CIT-binding compared to SWEDD and controls. SWEDD exhibited lower binding than controls in striatal regions, insula, and olfactory cortex. Both PD and SWEDD showed extensive altered connectivity of dopaminergic pathways, however, with major impairment in the mesocorticolimbic system for SWEDD. Motor symptoms and dopaminergic deficits worsened after 2 years for PD only.
The limited dopaminergic impairment and its stability over time observed for SWEDD, as well as the presence of extrastriatal 123I-FP-CIT binding alterations and prevalent mesocorticolimbic connectivity impairment, suggest other mechanisms contributing to SWEDD pathophysiology.
PDF
