RESUMO
BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
Assuntos
Anticorpos Monoclonais Humanizados , Antiparkinsonianos , Doença de Parkinson , alfa-Sinucleína , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antiparkinsonianos/efeitos adversos , Método Duplo-Cego , Humanos , Doença de Parkinson/tratamento farmacológico , Resultado do Tratamento , alfa-Sinucleína/imunologiaRESUMO
Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.
Assuntos
Fluordesoxiglucose F18 , Neuroanatomia , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Marcha/fisiologia , Caminhada/fisiologia , Tomografia por Emissão de Pósitrons/métodos , Glucose/metabolismoRESUMO
BACKGROUND: Using 11C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11C-(R)-PK11195 and 18F-DOPA-PET underwent repeat 18F-DOPA-PET after 3 years. 18F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C-(R)-PK11195 binding at baseline was a predictor of 18F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Progressão da Doença , Microglia , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Humanos , Masculino , Transtorno do Comportamento do Sono REM/fisiopatologia , Microglia/metabolismo , Microglia/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Di-Hidroxifenilalanina/análogos & derivados , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , IsoquinolinasRESUMO
Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE-PE2I ([18F]-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [18F]FE-PE2I PET or [3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.
Assuntos
Corpo Estriado , Proteínas da Membrana Plasmática de Transporte de Dopamina , Ketamina , Ratos Sprague-Dawley , Animais , Ketamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Feminino , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/diagnóstico por imagem , Ratos , Tomografia por Emissão de Pósitrons , AutorradiografiaRESUMO
Brain network dysfunction is increasingly recognised in Alzheimer's disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aß deposition, brain connectivity and cognition. 42 participants (12 Aß-positive MCI, 14 Aß-positive AD and 16 Aß-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aß deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aß-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised ß = -0.375, p = 0.037) and network local efficiency (standardised ß = -0.468, p < 0.001), independent of cortical thickness and Aß deposition, while Aß was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aß and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer's disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias , Estudos Transversais , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismoRESUMO
BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/psicologia , Acetilcolinesterase , Donepezila , Encéfalo/diagnóstico por imagemRESUMO
Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
Assuntos
Neurônios , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Idoso , Biomarcadores/sangue , Antígeno CD11b/sangue , Antígeno CD11b/imunologia , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/imunologia , Substância Negra/diagnóstico por imagem , Substância Negra/imunologia , Substância Negra/metabolismo , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/imunologiaRESUMO
INTRODUCTION: Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS: Using dynamic susceptibility contrast magnetic resonance imaging and positron emission tomography, we examined alterations in microvascular circulation and levels of Aß deposition in two independent cohorts of APOE ε4 carriers. RESULTS: Capillary dysfunction was elevated in both prodromal and preclinical AD individuals compared to age-matched controls. Additionally, the prodromal group exhibited higher levels of capillary dysfunction compared to the preclinical group. DISCUSSION: These findings suggest that capillary dysfunction can be detected at the preclinical stage of AD and indicates a worsening of capillary dysfunction throughout the AD continuum. Understanding the interaction between capillary dysfunction and Aß could provide insights into the relationship between cardiovascular risk factors and the development of AD. HIGHLIGHTS: Alzheimer's disease (AD) is associated with disturbances in microvascular circulation. Capillary dysfunction can be detected in preclinical AD. As cognitive symptoms progress in prodromal AD, capillary dysfunction worsens. Capillary dysfunction may impede the clearance of beta-amyloid (Aß). Capillary dysfunction might contribute to the development of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level. RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Corpos de Lewy/metabolismo , Tomografia por Emissão de Pósitrons , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismoRESUMO
BACKGROUND: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. OBJECTIVE: The aim of this study was to identify neural networks of discrete gait impairments in PD. METHODS: Fifty-five participants with early-stage PD and 20 age-matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18 F]-2-fluoro-2-deoxyglucose-positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. RESULTS: In PD, we identified two metabolic gait-related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. CONCLUSIONS: We have identified two novel gait-related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Marcha , Glucose , Humanos , Levodopa/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Qualidade de VidaRESUMO
During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.
Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Transtorno do Comportamento do Sono REM/patologia , Idoso , Circulação Cerebrovascular , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-IdadeRESUMO
Previous studies have reported substantial involvement of the noradrenergic system in Parkinson's disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson's disease. We examined 93 subjects (40 healthy controls and 53 Parkinson's disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson's disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson's disease, which may eventually direct research towards potential novel treatment approaches.
Assuntos
Locus Cerúleo/diagnóstico por imagem , Locus Cerúleo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodosRESUMO
Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death. We injected 8 µg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response. While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra. Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.
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Corpo Estriado/metabolismo , Progressão da Doença , Neurônios Dopaminérgicos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Agregados Proteicos/fisiologia , alfa-Sinucleína/toxicidade , Animais , Corpo Estriado/imunologia , Corpo Estriado/patologia , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Feminino , Injeções Intraventriculares , Ratos , Ratos Sprague-Dawley , alfa-Sinucleína/administração & dosagem , alfa-Sinucleína/imunologiaRESUMO
Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. METHODS: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. RESULTS: Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. CONCLUSION: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.
Assuntos
Neurônios Adrenérgicos/patologia , Encéfalo/patologia , Doença de Parkinson/patologia , Terminações Pré-Sinápticas/patologia , Tremor/patologia , Neurônios Adrenérgicos/metabolismo , Idoso , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/farmacologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia , Reboxetina/farmacologia , Tremor/diagnóstico por imagem , Tremor/etiologiaRESUMO
BACKGROUND: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. METHODS: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age-matched controls. We measured microglial activation as 11 C-(R)-PK11195 binding potentials, and dopamine terminal integrity with 18 F-dopa influx constants. RESULTS: The 11 C-(R)-PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = -4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11 C-(R)-PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11 C-(R)-PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18 F-dopa uptake was similar to healthy controls. CONCLUSIONS: In vivo 11 C-(R)-PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Microglia/metabolismo , Mutação/genética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genéticaRESUMO
BACKGROUND: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking. OBJECTIVE: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15). METHOD: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined. RESULTS: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function. CONCLUSION: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de PósitronsRESUMO
OBJECTIVE: Imaging activated glutamate N-methyl-D-aspartate receptor ion channels (NMDAR-ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [18 F]GE-179 is a known use-dependent marker of NMDAR-ICs. We studied whether interictal [18 F]GE-179 PET would detect foci of abnormal NMDAR-IC activation in patients with refractory focal epilepsy. METHODS: Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90-min dynamic [18 F]GE-179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [18 F]GE-179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [18 F]GE-179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [18 F]GE-179 uptake. RESULTS: Interictal [18 F]GE-179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [18 F]GE-179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [18 F]GE-179 uptake showed the most abnormal EEGs. SIGNIFICANCE: Detection of multiple foci of abnormal NMDAR-IC activation in 80% of our patients with refractory focal epilepsy using interictal [18 F]GE-179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [18 F]GE-179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment-resistant focal epilepsy.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/metabolismo , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/metabolismo , Epilepsia/metabolismo , Fluordesoxiglucose F18/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons/métodos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ß-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS: Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ß-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS: Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ß-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ß-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS: Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ß-amyloid load show correlated levels of microglial activation which then later decline when the ß-amyloid load approaches AD levels. Later, as tau tangles form in ß-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/patologia , Progressão da Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Inflamação/patologia , Estudos Longitudinais , Masculino , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Proteínas tau/metabolismoRESUMO
PURPOSE: This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes. METHODS: Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking. CONCLUSION: All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.