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Background: Postpartum blues (PPB) is a frequent syndrome of sad mood, crying spells, anxiety, restlessness, reduced appetite, and irritability, typically peaking day 5 postpartum. When severe, it greatly increases risk for later postpartum depression. This trial compared a dietary supplement to placebo on PPB severity. The supplement was designed to counter downstream effects of elevated monoamine oxidase A level, implicated in causing PPB. Methods: Participants recruited by advertisement from the Toronto region completed procedures at CAMH, Canada and/or participants' homes. Oral supplement or identical appearing relatively inert placebo were administered in randomised, double-blind fashion. Supplement was blueberry juice and extract given four times between nighttime day 3 and morning day 5 postpartum; tryptophan 2 g nighttime day 4 postpartum, and tyrosine 10 g morning day 5 postpartum. On day 5, depressed mood induction procedure (MIP) and postpartum blues were assessed. All data is presented (NCT03296956 closed, clinicaltrials.gov). Findings: Between January 2019 and December 2022, participants took supplement (n = 51) or placebo (n = 52). There was no significant effect on primary outcome MIP on visual analogue scale for depressed mood (mean difference = -0.39 mm, 95% CI: -6.42 to 5.65 mm). Stein Maternity Blues scores, exploratory PPB measure, was lower in the active group (effect size 0.62; median, interquartile range (IQR): active 2.00 (IQR 1, 4); placebo 4.00 (IQR 1.5, 6); regression with general linear model, supplement effect, ß coefficient = -1.50 (95%: CI -2.60, -0.40), p = 0.008; effect of CES-D crying category before supplement, p = 0.03-0.00000023). Twenty-six and 40 different adverse events occurred within 25% and 42% of supplement and placebo cases respectively (Chi-Square, p = 0.06). Interpretation: The primary outcome was negative for effect on depressed mood induction, however the supplement moderately reduced PPB. Funding: CAMH/Exeltis.
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Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B (MAO-B) total distribution volume (11C-SL25.1188 VT), an index of MAO-B density, was measured in 29 TBI and 29 similarly aged healthy control cases with 11C-SL25.1188 PET, prioritizing prefrontal cortex (PFC) and cortex proximal to cortical convexity. Correlations of PFC 11C-SL25.1188 VT with psychomotor and processing speed; and serum blood measures implicated in astrogliosis were determined. 11C-SL25.1188 VT was greater in TBI in PFC (P = 0.00064) and cortex (P = 0.00038). PFC 11C-SL25.1188 VT inversely correlated with Comprehensive Trail Making Test psychomotor and processing speed (r = -0.48, P = 0.01). In participants scanned within 2 years of last TBI, PFC 11C-SL25.1188 VT correlated with serum glial fibrillary acid protein (r = 0.51, P = 0.037) and total tau (r = 0.74, P = 0.001). Elevated 11C-SL25.1188 VT argues strongly for astrogliosis and therapeutics modifying astrogliosis towards curative phenotypes should be tested in TBI with persistent symptoms. Given substantive effect size, astrogliosis PET markers should be applied to stratify cases and/or assess target engagement for putative therapeutics targeting astrogliosis.
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Lesões Encefálicas Traumáticas , Gliose , Humanos , Idoso , Radioisótopos de Carbono/metabolismo , Gliose/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/metabolismo , Monoaminoxidase/metabolismoRESUMO
Auditory rhythm-based therapeutic interventions such as rhythmic auditory stimulation (RAS) are effective in improving gait and balance and preventing falls in idiopathic Parkinson's disease (PD). Research showing associated neuromodulatory effects of RAS on brain oscillations is also emerging. The neuromodulation may be induced by neural entrainment and cross-frequency oscillatory coupling. Auditory rhythm and RAS based interventions are potentially effective in improving other PD symptoms and can be extended to atypical parkinsonism.
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Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Estimulação Acústica , Marcha/fisiologia , Encéfalo , Modalidades de FisioterapiaRESUMO
Rapid eye movement sleep behavior disorder (RBD) is a common condition found in more than 50% of the patients with Parkinson's disease (PD). Molecular imaging shows that PD with RBD (PD-RBD+) have lower striatal dopamine transporter activity within the caudate and putamen relative to PD without RBD (PD-RBD-). However, the characterization of the extra-striatal dopamine within the mesocortical and mesolimbic pathways remains unknown. We aim to elucidate this with PET imaging in 15 PD-RBD+ and 15 PD-RBD- patients, while having 15 age-matched healthy controls (HC). Each participant underwent a single PET scan with [11 C]FLB-457 to detect the D2 receptor availability within the extra-striatal regions of interest (ROI), including the prefrontal, temporal, and limbic areas. [11 C]FLB-457 retention was expressed as the nondisplaceable binding potential. Our results reveal that relative to HC, PD-RBD+ and PD-RBD- patients have lower levels of D2 receptor availability within the uncus parahippocampus, superior, lateral, and inferior temporal cortex. PD-RBD+ showed steep decline in D2 receptors within the left uncus parahippocampus with increasing disease severity, but this was not observed for PD-RBD- patients. Findings imply that extra-striatal dopaminergic system may play a role in contributing to symptomatic progress in PD patients with RBD. However, validation with more advanced PD patients are needed.
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Dopamina/metabolismo , Doença de Parkinson/metabolismo , Transtorno do Comportamento do Sono REM/metabolismo , Idoso , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Giro Para-Hipocampal , Doença de Parkinson/fisiopatologia , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismoRESUMO
Research in basic and clinical neuroscience of music conducted over the past decades has begun to uncover music's high potential as a tool for rehabilitation. Advances in our understanding of how music engages parallel brain networks underpinning sensory and motor processes, arousal, reward, and affective regulation, have laid a sound neuroscientific foundation for the development of theory-driven music interventions that have been systematically tested in clinical settings. Of particular significance in the context of motor rehabilitation is the notion that musical rhythms can entrain movement patterns in patients with movement-related disorders, serving as a continuous time reference that can help regulate movement timing and pace. To date, a significant number of clinical and experimental studies have tested the application of rhythm- and music-based interventions to improve motor functions following central nervous injury and/or degeneration. The goal of this review is to appraise the current state of knowledge on the effectiveness of music and rhythm to modulate movement spatiotemporal patterns and restore motor function. By organizing and providing a critical appraisal of a large body of research, we hope to provide a revised framework for future research on the effectiveness of rhythm- and music-based interventions to restore and (re)train motor function.
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Cognitive decline in Parkinson's disease (PD) is a common sequela of the disorder that has a large impact on patient well-being. Its physiological etiology, however, remains elusive. Our study used graph theory analysis to investigate the large-scale topological patterns of the extrastriatal dopamine D2 receptor network. We used positron emission tomography with [11 C]FLB-457 to measure the binding potential of cortical dopamine D2 receptors in two networks: the meso-cortical dopamine network and the meso-limbic dopamine network. We also investigated the application of partial volume effect correction (PVEC) in conjunction with graph theory analysis. Three groups were investigated in this study divided according to their cognitive status as measured by the Montreal Cognitive Assessment score, with a score ≤25 considered cognitively impaired: (a) healthy controls (n = 13, 11 female), (b) cognitively unimpaired PD patients (PD-CU, n = 13, 5 female), and (c) PD patients with mild cognitive impairment (PD-MCI, n = 17, 4 female). In the meso-cortical network, we observed increased small-worldness, normalized clustering, and local efficiency in the PD-CU group compared to the PD-MCI group, as well as a hub shift in the PD-MCI group. Compensatory reorganization of the meso-cortical dopamine D2 receptor network may be responsible for some of the cognitive preservation observed in PD-CU. These results were found without PVEC applied and PVEC proved detrimental to the graph theory analysis. Overall, our findings demonstrate how graph theory analysis can be used to detect subtle changes in the brain that would otherwise be missed by regional comparisons of receptor density.
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Encéfalo/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Doença de Parkinson/fisiopatologia , Receptores de Dopamina D2/fisiologia , Idoso , Mapeamento Encefálico , Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismoRESUMO
Activated microglia have been reported to play an important role in Parkinson's disease (PD). A more rapid cognitive decline has been associated with deposits of ß-amyloid. In this study, the aim was to evaluate the role of brain ß-amyloid and its relationship with activated microglia in PD patients with normal and impaired cognition. We studied 17 PD patients with normal cognition (PDn), 12 PD patients with mild cognitive impairment (PD-MCI), and 12 healthy controls (HCs) with [11C] Pittsburgh compound B (PIB) to assess the impact of ß-amyloid deposition in the brain on microglial activation evaluated using the translocator protein 18-kDa (TSPO) radioligand [18F]-FEPPA. [11C] PIB distribution volume ratio was measured in cortical and subcortical regions. [18F]-FEPPA total distribution volume values were compared for each brain region between groups to evaluate the effect of PIB positivity while adjusting for the TSPO rs6971 polymorphism. Factorial analysis of variance revealed a significant main effect of PIB positivity in the frontal lobe (F(1, 34) = 7.1, p = 0.012). Besides the frontal (p = 0.006) and temporal lobe (p = 0.001), the striatum (p = 0.018), the precuneus (p = 0.019), and the dorsolateral prefrontal cortex (p = 0.010) showed significant group × PIB positivity interaction effects. In these regions, PD-MCIs had significantly higher FEPPA VT if PIB-positive. Our results indicate an interaction between amyloid-ß deposition and microglial activation in PD. Further investigations are necessary to evaluate if amyloid deposits cause neuroinflammation and further neurodegeneration or if increased microglia activation develops as a protective response.
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Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/complicações , Inflamação/patologia , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Idoso , Anilidas , Feminino , Humanos , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Piridinas , Distribuição TecidualRESUMO
Modern music therapy, starting around the middle of the twentieth century was primarily conceived to promote emotional well-being and to facilitate social group association and integration. Therefore, it was rooted mostly in social science concepts. More recently, music as therapy began to move decidedly toward perspectives of neuroscience. This has been facilitated by the advent of neuroimaging techniques that help uncover the therapeutic mechanisms for non-musical goals in the brain processes underlying music perception, cognition, and production. In this paper, we focus on executive function (EF) and attentional processes (AP) that are central for cognitive rehabilitation efforts. To this end, we summarize existing behavioral as well as neuroimaging and neurophysiological studies in musicians, non-musicians, and clinical populations. Musical improvisation and instrumental playing may have some potential for EF/AP stimulation and neurorehabilitation. However, more neuroimaging studies are needed to investigate the neural mechanisms for the active musical performance. Furthermore, more randomized clinical trials combined with neuroimaging techniques are warranted to demonstrate the specific efficacy and neuroplasticity induced by music-based interventions.
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Dopaminergic signaling within the striatum is crucial for motor planning and mental function. Neurons within the striatum contain two dopamine D2 receptor isoforms-D2 long and D2 short. The amount of expression for these receptor isoforms is affected by the genotype within two single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C > A), found in the DRD2 gene. However, it is unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system. We aim to elucidate this with PET imaging in healthy young adults using [11C]-(+)-PHNO. Participants were genotyped for the DRD2 rs2283265 SNP and a total of 20 enrolled: 9 with CC, 6 with CA, and 5 with AA genotype. The main effect of genotype on [11C]-(+)-PHNO binding was tested and we found significant group effect within the ventral striatum. Specifically, CC and CA carriers had higher binding in this region compared to AA carriers. There were no observed differences between genotypes in other regions within the basal ganglia. Our preliminary results implicate that the polymorphism genotype affects the dopaminergic signaling by controlling either the quantity of D2 receptors, D2 affinity, or a combination thereof within the ventral striatum.
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Receptores de Dopamina D2/genética , Estriado Ventral/metabolismo , Adulto , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Auditory-motor entrainment using rhythmic auditory stimulation (RAS) has been shown to improve motor control in healthy persons and persons with neurologic motor disorders such as Parkinson's disease and stroke. Neuroimaging studies have shown the modulation of corticostriatal activity in response to RAS. However, the underlying neurochemical mechanisms for auditory-motor entrainment are unknown. The current study aimed to investigate RAS-induced dopamine (DA) responses in basal ganglia (BG) during finger tapping tasks combined with [11C]-(+)-PHNO-PET in eight right-handed young healthy participants. Each participant underwent two PET scans with and without RAS. Binding potential relative to the non-displaceable compartment (BPND) values were derived using the simplified reference tissue method. The task performance was measured using absolute tapping period error and its standard deviation. We found that the presence of RAS significantly improved the task performance compared to the absence of RAS, demonstrated by reductions in the absolute tapping period error (p = 0.007) and its variability (p = 0.006). We also found that (1) the presence of RAS reduced the BG BPND variability (p = 0.013) and (2) the absence of RAS resulted in a greater DA response in the left ventral striatum (VS) compared to the presence of RAS (p = 0.003), These suggest that the absence of external cueing may require more DA response in the left VS associated with more motivational and sustained attentional efforts to perform the task. Additionally, we demonstrated significant age effects on D2/3 R availability in BG: increasing age was associated with reduced D2/3 R availability in the left putamen without RAS (p = 0.026) as well as in the right VS with RAS (p = 0.02). This is the first study to demonstrate the relationships among RAS, DA response/D2/3 R availability, motor responses and age, providing the groundwork for future studies to explore mechanisms for auditory-motor entrainment in healthy elderly and patients with dopamine-based movement disorders.
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To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.
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Neurônios Dopaminérgicos/metabolismo , Globo Pálido/metabolismo , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Substância Negra/diagnóstico por imagemRESUMO
Parkinson's disease (PD) is characterized primarily by a dysfunctional basal ganglia (BG) system, producing motor and non-motor symptoms. A significant number of studies have demonstrated that rhythmic auditory stimulation can improve gait and other motor behaviors in PD that are not well managed by the conventional therapy. As music, being highly complex stimulus, can modulate brain activity/function in distributed areas of brain, the therapeutic properties of music potentially extend to alleviate non-motor symptoms of PD. Despite the clinical, behavioral evidence and promises of rhythm and music based interventions, the neural substrates underlying the effectiveness are poorly understood. The goal of this review is to appraise the current state of knowledge in order to direct further neuroimaging studies that help to determine the therapeutic effects of rhythm and music based interventions for motor and non-motor symptoms of PD.
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Encéfalo/fisiologia , Musicoterapia/tendências , Rede Nervosa/fisiologia , Reabilitação Neurológica/tendências , Doença de Parkinson/terapia , Periodicidade , Estimulação Acústica/métodos , Estimulação Acústica/tendências , Previsões , Marcha/fisiologia , Humanos , Música/psicologia , Musicoterapia/métodos , Reabilitação Neurológica/métodos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologiaRESUMO
This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451.
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Carbolinas/farmacocinética , Meios de Contraste/farmacocinética , Melaninas/metabolismo , Doença de Parkinson/patologia , Substância Negra/metabolismo , Paralisia Supranuclear Progressiva/patologia , Idoso , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Substância Negra/diagnóstico por imagem , Substância Negra/efeitos dos fármacos , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
PURPOSE: The input function (IF) is a core element in the quantification of Translocator protein 18 kDa with positron emission tomography (PET), as no suitable reference region with negligible binding has been identified. Arterial blood sampling is indeed needed to create the IF (ASIF). In the present manuscript we study individualization of a population based input function (PBIF) with a single arterial manual sample to estimate total distribution volume (VT) for [18F]FEPPA and to replicate previously published clinical studies in which the ASIF was used. METHODS: The data of 3 previous [18F]FEPPA studies (39 of healthy controls (HC), 16 patients with Parkinson's disease (PD) and 18 with Alzheimer's disease (AD)) was reanalyzed with the new approach. PBIF was used with the Logan graphical analysis (GA) neglecting the vascular contribution to estimate VT. Time of linearization of the GA was determined with the maximum error criteria. The optimal calibration of the PBIF was determined based on the area under the curve (AUC) of the IF and the agreement range of VT between methods. The shape of the IF between groups was studied while taking into account genotyping of the polymorphism (rs6971). RESULTS: PBIF scaled with a single value of activity due to unmetabolized radioligand in arterial plasma, calculated as the average of a sample taken at 60 min and a sample taken at 90 min post-injection, yielded a good interval of agreement between methods and optimized the area under the curve of IF. In HC, gray matter VTs estimated by PBIF highly correlated with those using the standard method (r2 = 0.82, p = 0.0001). Bland-Altman plots revealed PBIF slightly underestimates (~1 mL/cm3) VT calculated by ASIF (including a vascular contribution). It was verified that the AUC of the ASIF were independent of genotype and disease (HC, PD, and AD). Previous clinical results were replicated using PBIF but with lower statistical power. CONCLUSION: A single arterial blood sample taken 75 minute post-injection contains enough information to individualize the IF in the groups of subjects studied; however, the higher variability produced requires an increase in sample size to reach the same effect size.
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Doença de Alzheimer/metabolismo , Anilidas/administração & dosagem , Artérias/metabolismo , Doença de Parkinson/metabolismo , Piridinas/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de GABA/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Artérias/diagnóstico por imagem , Estudos de Viabilidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodosRESUMO
Progressive supranuclear palsy is a rare form of atypical Parkinsonism that differs neuropathologically from other parkinsonian disorders. While many parkinsonian disorders such as Parkinson's disease, Lewy body dementia, and multiple system atrophy are classified as synucleinopathies, progressive supranuclear palsy is coined a tauopathy due to the aggregation of pathological tau in the brain. [18F]AV-1451 (also known as [18F]-T807) is a positron emission tomography radiotracer that binds to paired helical filaments of tau in Alzheimer's disease. We investigated whether [18F]AV-1451 could be used as biomarker for the diagnosis and disease progression monitoring in progressive supranuclear palsy. Six progressive supranuclear palsy, six Parkinson's disease, and 10 age-matched healthy controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio from 60 to 90 min post-injection was calculated in each region of interest, using the cerebellar cortex as a reference region. No significant differences in standardized uptake value ratios were detected in our progressive supranuclear palsy group compared to the two control groups. [18F]AV-1451 may bind selectivity to the paired helical filaments in Alzheimer's disease, which differ from the straight conformation of tau filaments in progressive supranuclear palsy.
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Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Agregação Patológica de Proteínas/diagnóstico por imagem , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Proteínas tau/metabolismo , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Carbolinas/metabolismo , Estudos de Casos e Controles , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/metabolismo , Paralisia Supranuclear Progressiva/patologiaRESUMO
BACKGROUND: Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. METHODS: Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. RESULTS: Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). CONCLUSIONS: Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.
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Anilidas/farmacocinética , Radioisótopos de Flúor/farmacocinética , Microglia/efeitos dos fármacos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Piridinas/farmacocinética , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Tomografia por Emissão de Pósitrons , Receptores de GABA/genética , Índice de Gravidade de DoençaRESUMO
The recent application of graph theory to brain networks promises to shed light on complex diseases such as Parkinson's disease (PD). This study aimed to investigate functional changes in sensorimotor and cognitive networks in Parkinsonian patients, with a focus on inter- and intra-connectivity organization in the disease-associated nodal and hub regions using the graph theoretical analyses. Resting-state functional MRI data of a total of 65 participants, including 23 healthy controls (HCs) and 42 patients, were investigated in 120 nodes for local efficiency, betweenness centrality, and degree. Hub regions were identified in the HC and patient groups. We found nodal and hub changes in patients compared with HCs, including the right pre-supplementary motor area (SMA), left anterior insula, bilateral mid-insula, bilateral dorsolateral prefrontal cortex (DLPFC), and right caudate nucleus. In general, nodal regions within the sensorimotor network (i.e., right pre-SMA and right mid-insula) displayed weakened connectivity, with the former node associated with more severe bradykinesia, and impaired integration with default mode network regions. The left mid-insula also lost its hub properties in patients. Within the executive networks, the left anterior insular cortex lost its hub properties in patients, while a new hub region was identified in the right caudate nucleus, paralleled by an increased level of inter- and intra-connectivity in the bilateral DLPFC possibly representing compensatory mechanisms. These findings highlight the diffuse changes in nodal organization and regional hub disruption accounting for the distributed abnormalities across brain networks and the clinical manifestations of PD.
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This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [18F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson's disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (VT) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [18F]-FEPPA VT values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.
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Corpo Estriado/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Microglia/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Idoso , Corpo Estriado/metabolismo , Feminino , Genótipo , Humanos , Inflamação/genética , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Neuroimagem , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Polimorfismo Genético , CintilografiaRESUMO
OBJECTIVE: Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. METHODS: We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. RESULTS: Memory-impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. INTERPRETATION: Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Transtornos da Memória/metabolismo , Rede Nervosa/metabolismo , Giro Para-Hipocampal/metabolismo , Doença de Parkinson/metabolismo , Idoso , Neurônios Dopaminérgicos/diagnóstico por imagem , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico por imagem , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Giro Para-Hipocampal/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/fisiologia , Receptores de Dopamina D2/metabolismoRESUMO
Generally, rewards that are received sooner are often preferred over future rewards, and the time between the choice and the reception of the reward is an important factor that influences our decisions, a phenomenon called delay discounting (DD). In DD, the medial prefrontal cortex (MePFC) and striatal dopamine neurotransmission both play an important role. We used repetitive transcranial magnetic stimulation (rTMS) to transiently activate the MePFC to evaluate its behavioral effect on the DD paradigm, and subsequently to measure its effect on striatal dopamine. Twenty-four right-handed young healthy subjects (11 females; age: 22.1±2.9 years) underwent DD following 10 Hz-rTMS of the MePFC and vertex stimulation (control condition). Thereafter, 11 subjects (5 females; age: 22.2±2.87 years) completed the PET study at rest using [(11)C]-(+)-PHNO following 10 Hz-rTMS of the MePFC and vertex. Modulation of the MePFC excitability influenced the subjective level of DD for delayed rewards and interfered with synaptic dopamine level in the striatum. The present study yielded findings that might reconcile the role of these areas in inter-temporal decision making and dopamine modulation, suggesting that the subjective sense of time and value of reward are critically controlled by these important regions.