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1.
N Engl J Med ; 387(5): 408-420, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35921450

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/imunologia
2.
Mult Scler ; 27(14): 2240-2253, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33821693

RESUMO

BACKGROUND: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVE: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients. METHODS: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60. RESULTS: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable. CONCLUSION: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Estudos Prospectivos
3.
BMC Neurol ; 21(1): 459, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814867

RESUMO

BACKGROUND: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson's disease (PD). Depending on the stage of progression, approximately 5-15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood. METHODS: The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis. RESULTS: In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]). CONCLUSION: A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03318523 . Date submitted: October 19, 2017. First Posted: October 24, 2017.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Doença de Parkinson , Biomarcadores , Dopamina , Humanos , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único
4.
J Neurosci ; 35(8): 3663-75, 2015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25716864

RESUMO

The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.


Assuntos
Encéfalo/irrigação sanguínea , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Modelos Cardiovasculares , Animais , Encéfalo/fisiologia , Corantes Fluorescentes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley
5.
Neuroimage ; 104: 146-55, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25300201

RESUMO

There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41±3mmHg) and hypercapnia (50±4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of -42.3% in the straight sinus, -39.9% in the internal cerebral veins, and approximately -50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation.


Assuntos
Veias Cerebrais/metabolismo , Hipercapnia/sangue , Consumo de Oxigênio/fisiologia , Adulto , Mapeamento Encefálico , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacologia , Artérias Cerebrais/anatomia & histologia , Artérias Cerebrais/metabolismo , Veias Cerebrais/anatomia & histologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Córtex Pré-Frontal/metabolismo , Marcadores de Spin , Adulto Jovem
6.
Brain Inj ; 29(3): 403-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25384127

RESUMO

PRIMARY OBJECTIVE: To use breath-hold functional magnetic resonance imaging (fMRI) to localize the brain regions with impaired cerebrovascular reactivity (CVR) in a female patient diagnosed with mild traumatic brain injury (mTBI). The extent of impaired CVR was evaluated 2 months after concussion. Follow-up scan was performed 1 year post-mTBI using the same breath-hold fMRI technique. RESEARCH DESIGN: Case report. METHODS AND PROCEDURES: fMRI blood oxygenation dependent level (BOLD) signals were measured under breath-hold challenge in a female mTBI patient 2 months after concussion followed by a second fMRI with breath-hold challenge 1 year later. CVR was expressed as the percentage change of BOLD signals per unit time of breath-hold. MAIN OUTCOMES: In comparison with CVR measurement of normal control subjects, statistical maps of CVR revealed substantial neurovascular deficits and hemispheric asymmetry within grey and white matter in the initial breath-hold fMRI scan. Follow-up breath-hold fMRI performed 1 year post-mTBI demonstrated normalization of CVR accompanied with symptomatic recovery. CONCLUSIONS: CVR may serve as an imaging biomarker to detect subtle deficits in both grey and white matter for individual diagnosis of mTBI. The findings encourage further investigation of hypercapnic fMRI as a diagnostic tool for mTBI.


Assuntos
Lesões Encefálicas/fisiopatologia , Hipercapnia/patologia , Imageamento por Ressonância Magnética , Biomarcadores , Lesões Encefálicas/patologia , Suspensão da Respiração , Circulação Cerebrovascular , Feminino , Humanos , Hipercapnia/sangue , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Oxigênio/sangue , Recuperação de Função Fisiológica , Fatores de Tempo
7.
Neuroimage ; 102 Pt 2: 729-35, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25196509

RESUMO

Calibrated functional magnetic resonance imaging (fMRI) is a widely used method to investigate brain function in terms of physiological quantities such as the cerebral metabolic rate of oxygen (CMRO2). The first and one of the most common methods of fMRI calibration is hypercapnic calibration. This is achieved via simultaneous measures of the blood-oxygenation-level dependent (BOLD) and the arterial spin labeling (ASL) signals during a functional task that evokes regional changes in CMRO2. A subsequent acquisition is then required during which the subject inhales carbon dioxide for short periods of time. A calibration constant, typically labeled M, is then estimated from the hypercapnic data and is subsequently used together with the BOLD-ASL recordings to compute evoked changes in CMRO2 during the functional task. The computation of M assumes a constant CMRO2 during the CO2 inhalation, an assumption that has been questioned since the origin of calibrated fMRI. In this study we used diffuse optical tomography (DOT) together with BOLD and ASL--an alternative calibration method that does not require any gas manipulation and therefore no constant CMRO2 assumption--to cross-validate the estimation of M obtained from a traditional hypercapnic calibration. We found a high correlation between the M values (R=0.87, p<0.01) estimated using these two approaches. The findings serve to validate the hypercapnic fMRI calibration technique and suggest that the inter-subject variability routinely obtained for M is reproducible with an alternative method and might therefore reflect inter-subject physiological variability.


Assuntos
Encéfalo/metabolismo , Hipercapnia/diagnóstico , Imageamento por Ressonância Magnética , Imagem Multimodal , Neuroimagem , Tomografia Óptica , Adulto , Calibragem , Humanos , Hipercapnia/metabolismo , Masculino , Oxigênio/sangue
8.
Psychother Psychosom ; 83(6): 364-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25323387

RESUMO

BACKGROUND: Psychodynamic psychotherapy has been used to treat depression for more than a century. However, not all patients respond equally well, and there are few reliable predictors of treatment outcome. METHODS: We used resting (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) scans immediately before and after a structured, open trial of brief psychodynamic psychotherapy (n = 16) in conjunction with therapy process ratings and clinical outcome measures to identify neural correlates of treatment response. RESULTS: Pretreatment glucose metabolism within the right posterior insula correlated with depression severity. Reductions in depression scores correlated with a pre- to posttreatment reduction in right insular metabolism, which in turn correlated with higher objective measures of patient insight obtained from videotaped therapy sessions. Pretreatment metabolism in the right precuneus was significantly higher in patients who completed treatment and correlated with psychological mindedness. CONCLUSIONS: Resting brain metabolism predicted both clinical course and relevant psychotherapeutic process during short-term psychodynamic psychotherapy for depression.


Assuntos
Transtorno Depressivo Maior/terapia , Psicoterapia Breve , Adulto , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Masculino , Neuroimagem , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
9.
J Neurol ; 271(5): 2547-2559, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38282082

RESUMO

This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.


Assuntos
Esclerose Lateral Amiotrófica , Progressão da Doença , Imageamento por Ressonância Magnética , Humanos , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Índice de Gravidade de Doença , Estudos Longitudinais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia
10.
Neurology ; 102(5): e209137, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38315945

RESUMO

BACKGROUND AND OBJECTIVES: Sensitive, reliable, and scalable biomarkers are needed to accelerate the development of therapies for Parkinson disease (PD). In this study, we evaluate the biomarkers of early PD diagnosis, disease progression, and treatment effect collected in the SPARK. METHODS: Cinpanemab is a human-derived monoclonal antibody binding preferentially to aggregated forms of extracellular α-synuclein. SPARK was a randomized, double-blind, placebo-controlled, phase 2 multicenter trial evaluating 3 cinpanemab doses administered intravenously every 4 weeks for 52 weeks with an active treatment dose-blind extension period for up to 112 weeks. SPARK enrolled 357 participants diagnosed with PD within 3 years, aged 40-80 years, ≤2.5 on the modified Hoehn and Yahr scale, and with evidence of striatal dopaminergic deficit. The primary outcome was change from baseline in the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale total score. Secondary and exploratory biomarker outcomes evaluated change from baseline at week 52 relative to placebo. Dopamine transporter SPECT and MRI were used to quantify changes in the nigrostriatal dopamine pathway and regional atrophy. CSF and plasma samples were used to assess change in total α-synuclein levels, α-synuclein seeding, and neurofilament light chain levels. SPARK was conducted from January 2018 to April 2021 and terminated due to lack of efficacy. RESULTS: Approximately 3.8% (15/398) of SPECT-imaged participants did not have evidence of dopaminergic deficit and were screen-failed. Binary classification of α-synuclein seeding designated 93% (110/118) of the enrolled CSF subgroup as positive for α-synuclein seeds at baseline. Clinical disease progression was observed, with no statistically significant difference in cinpanemab groups compared with that in placebo. Ninety-nine percent of participants with positive α-synuclein seeding remained positive through week 52. No statistically significant changes from baseline were observed between treatment groups and placebo across biomarker measures. Broadly, there was minimal annual change with high interindividual variability across biomarkers-with striatal binding ratios of the ipsilateral putamen showing the greatest mean change/SD over time. DISCUSSION: Biomarker results indicated enrollment of the intended population with early PD, but there was no significant correlation with disease progression or clear evidence of a cinpanemab treatment effect on biomarker measures. Suitable biomarkers for evaluating disease severity and progression in early PD trials are still needed. TRIAL REGISTRATION INFORMATION: NCT03318523 (clinicaltrials.gov/ct2/show/NCT03318523); Submitted October 24, 2017; First patient enrolled January 2018.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína , Antiparkinsonianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Dopamina/metabolismo , Biomarcadores , Progressão da Doença , Método Duplo-Cego
11.
NPJ Parkinsons Dis ; 8(1): 139, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271084

RESUMO

MRI was suggested as a promising method for the diagnosis and assessment of Parkinson's Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T2* with radiomics analysis for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants [NM-carriers (NMC) and NM-non-carriers (NMNC)], underwent MRI and DAT-SPECT. Imaging-based metrics included 48 neuromelanin and T2* radiomics features and DAT-SPECT specific-binding-ratios (SBR), were extracted from several brain regions. Imaging values were assessed for their correlations with age, differences between groups, and correlations with the MDS-likelihood-ratio (LR) score. Several machine learning classifiers were evaluated for group classification. A total of 127 participants were included: 46 patients with PD (62.3 ± 10.0 years) [15:LRRK2-PD, 16:GBA-PD, and 15:idiopathic-PD (iPD)], 47 NMC (51.5 ± 8.3 years) [24:LRRK2-NMC and 23:GBA-NMC], and 34 NMNC (53.5 ± 10.6 years). No significant correlations were detected between imaging parameters and age. Thirteen MRI-based parameters and radiomics features demonstrated significant differences between PD and NMNC groups. Support-Vector-Machine (SVM) classifier achieved the highest performance (AUC = 0.77). Significant correlations were detected between LR scores and two radiomic features. The classifier successfully identified two out of three NMC who converted to PD. Genotype-related differences were detected based on radiomic features. SBR values showed high sensitivity in all analyses. In conclusion, neuromelanin and T2* MRI demonstrated differences between groups and can be used for the assessment of individuals at-risk in cases when DAT-SPECT can't be performed. Combining neuromelanin and T2*-MRI provides insights into the pathophysiology underlying PD, and suggests that iron accumulation precedes neuromelanin depletion during the prodromal phase.

12.
J Neurophysiol ; 103(1): 297-321, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19889849

RESUMO

Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.


Assuntos
Encéfalo/fisiologia , Imageamento por Ressonância Magnética/métodos , Processamento de Sinais Assistido por Computador , Adolescente , Adulto , Atenção/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/irrigação sanguínea , Bases de Dados como Assunto , Fixação Ocular/fisiologia , Humanos , Modelos Neurológicos , Atividade Motora/fisiologia , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Oxigênio/sangue , Respiração , Descanso/fisiologia , Fatores de Tempo , Percepção Visual/fisiologia , Adulto Jovem
13.
PLoS One ; 15(9): e0238946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956397

RESUMO

BACKGROUND: The origin of low frequency cerebral hemodynamic fluctuations (CHF) in the resting state remains unknown. Breath-by breath O2-CO2 exchange ratio (bER) has been reported to correlate with the cerebrovascular response to brief breath hold challenge at the frequency range of 0.008-0.03Hz in healthy adults. bER is defined as the ratio of the change in the partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration. In this study, we aimed to investigate the contribution of respiratory gas exchange (RGE) metrics (bER, ΔPO2 and ΔPCO2) to low frequency CHF during spontaneous breathing. METHODS: Twenty-two healthy adults were included. We used transcranial Doppler sonography to evaluate CHF by measuring the changes in cerebral blood flow velocity (ΔCBFv) in bilateral middle cerebral arteries. The regional CHF were mapped with blood oxygenation level dependent (ΔBOLD) signal changes using functional magnetic resonance imaging. Temporal features and frequency characteristics of RGE metrics during spontaneous breathing were examined, and the simultaneous measurements of RGE metrics and CHF (ΔCBFv and ΔBOLD) were studied for their correlation. RESULTS: We found that the time courses of ΔPO2 and ΔPCO2 were interdependent but not redundant. The oscillations of RGE metrics were coherent with resting state CHF at the frequency range of 0.008-0.03Hz. Both bER and ΔPO2 were superior to ΔPCO2 in association with CHF while CHF could correlate more strongly with bER than with ΔPO2 in some brain regions. Brain regions with the strongest coupling between bER and ΔBOLD overlapped with many areas of default mode network including precuneus and posterior cingulate. CONCLUSION: Although the physiological mechanisms underlying the strong correlation between bER and CHF are unclear, our findings suggest the contribution of bER to low frequency resting state CHF, providing a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.


Assuntos
Circulação Cerebrovascular/fisiologia , Taxa Respiratória/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Encéfalo/fisiologia , Dióxido de Carbono/sangue , Feminino , Voluntários Saudáveis , Hemodinâmica/fisiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Artéria Cerebral Média/fisiologia , Oxigênio/sangue , Pressão Parcial , Respiração , Descanso/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Vasodilatação/fisiologia
14.
PLoS One ; 15(3): e0225915, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208415

RESUMO

BACKGROUND: Hypercapnia during breath holding is believed to be the dominant driver behind the modulation of cerebral blood flow (CBF). However, increasing evidence show that mild hypoxia and mild hypercapnia in breath hold (BH) could work synergistically to enhance CBF response. We hypothesized that breath-by-breath O2-CO2 exchange ratio (bER), defined as the ratio of the change in partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration, would be able to better correlate with the global and regional cerebral hemodynamic responses (CHR) to BH challenge. We aimed to investigate whether bER is a more useful index than end-tidal PCO2 to characterize cerebrovascular reactivity (CVR) under BH challenge. METHODS: We used transcranial Doppler ultrasound (TCD) to evaluate CHR under BH challenge by measuring cerebral blood flow velocity (CBFv) in the middle cerebral arteries. Regional changes in CHR to BH and exogenous CO2 challenges were mapped with blood oxygenation level dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). We correlated respiratory gas exchange (RGE) metrics (bER, ΔPO2, ΔPCO2, end-tidal PCO2 and PO2, and time of breaths) with CHR (CBFv and BOLD) to BH challenge. Temporal features and frequency characteristics of RGE metrics and their coherence with CHR were examined. RESULTS: CHR to brief BH epochs and free breathing were coupled with both ΔPO2 and ΔPCO2. We found that bER was superior to either ΔPO2 or ΔPCO2 alone in coupling with the changes of CBFv and BOLD signals under breath hold challenge. The regional CVR results derived by regressing BOLD signal changes on bER under BH challenge resembled those derived by regressing BOLD signal changes on end-tidal PCO2 under exogenous CO2 challenge. CONCLUSION: Our findings provide a novel insight on the potential of using bER to better quantify CVR changes under BH challenge.


Assuntos
Encéfalo , Suspensão da Respiração , Dióxido de Carbono/sangue , Circulação Cerebrovascular , Hipercapnia , Imageamento por Ressonância Magnética , Oxigênio/sangue , Ultrassonografia Doppler Transcraniana , Adulto , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Hipercapnia/sangue , Hipercapnia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pressão Parcial
15.
Mult Scler Relat Disord ; 39: 101863, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31901758

RESUMO

BACKGROUND: Natalizumab is an effective treatment for multiple sclerosis (MS) and has a well-characterized safety profile, with more than 10 years of postmarketing experience. TYGRIS was a 5-year observational cohort study designed to obtain long-term safety data in natalizumab-treated MS patients. We examined the incidence and pattern of serious adverse events (SAEs) in this large postmarketing sample of natalizumab-treated patients. METHODS: Investigators reported SAEs in natalizumab-treated patients. Malignancy incidence rates were compared with rates in the general population using external databases. RESULTS: Of 6508 enrolled patients, 4938 (75.9%) completed the study. SAEs occurring in more than 0.5% of patients included urinary tract infection (n = 50; 0.8%), pneumonia (n = 46; 0.7%), progressive multifocal leukoencephalopathy (PML; n = 44; 0.7%), and immune reconstitution inflammatory syndrome (n = 44; 0.7%). Fifty-five patients (0.9%) experienced treatment-emergent serious opportunistic infections, 44 of which were PML. Two patients with PML died. The overall malignancy incidence rate was 449.0 per 100,000 patient-years (95% confidence interval [CI], 375.1-533.1). With few exceptions, incidence rates for individual malignancies had 95% CIs encompassing incidence rates in the general population. Hepatotoxic events occurred in 6 patients; 4 patients had evidence of alternative cause or confounders. Of 96 fatal events, investigators considered 81 unrelated or unlikely to be related to treatment and 5 related or possibly related; causality was not provided for 10. CONCLUSION: Data from this large, long-term study indicate that the nature, character, and frequency of SAEs in real-world settings are consistent with natalizumab's known safety profile. (Funded by Biogen; ClinicalTrials.gov identifiers: NCT00477113 and NCT00483847.).

16.
Neuroimage ; 47(3): 961-71, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19450692

RESUMO

It is well established that pacemaker neurons in the brainstem provide automatic control of breathing for metabolic homeostasis and survival. During waking spontaneous breathing, cognitive and emotional demands can modulate the intrinsic brainstem respiratory rhythm. However the neural circuitry mediating this modulation is unknown. Studies of supra-pontine influences on the control of breathing have implicated limbic/paralimbic-bulbar circuitry, but these studies have been limited to either invasive surgical electrophysiological methods or neuroimaging during substantial respiratory provocation. Here we probed the limbic/paralimbic-bulbar circuitry for respiratory-related neural activity during unlabored spontaneous breathing at rest as well as during a challenging cognitive task (sustained random number generation). Functional magnetic resonance imaging (fMRI) with simultaneous physiological monitoring (heart rate, respiratory rate, tidal volume, end-tidal CO(2)) was acquired in 14 healthy subjects during each condition. The cognitive task produced expected increases in breathing rate, while end-tidal CO(2) and heart rate did not significantly differ between conditions. The respiratory cycle served as the input function for breath-by-breath, event-related, voxel-wise, random-effects image analyses in SPM5. Main effects analyses (cognitive task+rest) demonstrated the first evidence of coordinated neural activity associated with spontaneous breathing within the medulla, pons, midbrain, amygdala, anterior cingulate and anterior insular cortices. Between-condition paired t-tests (cognitive task>rest) demonstrated modulation within this network localized to the dorsal anterior cingulate and pontine raphe magnus nucleus. We propose that the identified limbic/paralimbic-bulbar circuitry plays a significant role in cognitive and emotional modulation of spontaneous breathing.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Potenciais Evocados/fisiologia , Vias Neurais/fisiologia , Respiração , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
17.
Depress Anxiety ; 25(6): 496-505, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17595018

RESUMO

Neuroimaging studies using angry or contemptuous human facial photographic stimuli have suggested amygdala hyper-responsivity in social anxiety disorder (SAD). We sought to determine if an angry "schematic face" (simple line drawing) would evoke exaggerated amygdalar responses in SAD patients compared with healthy control (HC) subjects. Angry, happy, and neutral schematic faces were overtly presented to matched cohorts of 11 SAD and 11 HC subjects for passive viewing, whereas brain functional magnetic resonance imaging signal was measured at 1.5 Tesla. Voxel-wise analyses were performed using a random effects model in SPM99. Compared with HC subjects, SAD patients exhibited exaggerated responses in the right amygdala for the Angry versus Neutral contrast. The findings of exaggerated amygdala responses to angry schematic faces in SAD converge with results from earlier neuroimaging studies and illustrate the potential utility of schematic faces for probing amygdala function in psychiatric disorders. One prospective advantage of schematic faces is that they may minimize confounds related to gender, age, or race effects. However, extending earlier findings in healthy subjects, schematic faces appear more effective for probing amygdala responses to arousal-based (Angry versus Neutral) as opposed to valence-based (Angry versus Happy) contrasts.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Ira/fisiologia , Expressão Facial , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Reconhecimento Visual de Modelos/fisiologia , Transtornos Fóbicos/fisiopatologia , Adulto , Mapeamento Encefálico , Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Estudos de Coortes , Emoções/fisiologia , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Rede Nervosa/fisiopatologia , Consumo de Oxigênio/fisiologia , Inventário de Personalidade/estatística & dados numéricos , Transtornos Fóbicos/diagnóstico , Transtornos Fóbicos/psicologia , Psicometria , Valores de Referência
18.
Neuroimage Clin ; 20: 572-579, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186761

RESUMO

Background: The development of therapeutic interventions for Parkinson disease (PD) is challenged by disease complexity and subjectivity of symptom evaluation. A Parkinson's Disease Related Pattern (PDRP) of glucose metabolism via fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to correlate with motor symptom scores and may aid the detection of disease-modifying therapeutic effects. Objectives: We sought to independently evaluate the potential utility of the PDRP as a biomarker for clinical trials of early-stage PD. Methods: Two machine learning approaches (Scaled Subprofile Model (SSM) and NPAIRS with Canonical Variates Analysis) were performed on FDG-PET scans from 17 healthy controls (HC) and 23 PD patients. The approaches were compared regarding discrimination of HC from PD and relationship to motor symptoms. Results: Both classifiers discriminated HC from PD (p < 0.01, p < 0.03), and classifier scores for age- and gender- matched HC and PD correlated with Hoehn & Yahr stage (R2 = 0.24, p < 0.015) and UPDRS (R2 = 0.23, p < 0.018). Metabolic patterns were highly similar, with hypometabolism in parieto-occipital and prefrontal regions and hypermetabolism in cerebellum, pons, thalamus, paracentral gyrus, and lentiform nucleus relative to whole brain, consistent with the PDRP. An additional classifier was developed using only PD subjects, resulting in scores that correlated with UPDRS (R2 = 0.25, p < 0.02) and Hoehn & Yahr stage (R2 = 0.16, p < 0.06). Conclusions: Two independent analyses performed in a cohort of mild PD patients replicated key features of the PDRP, confirming that FDG-PET and multivariate classification can provide an objective, sensitive biomarker of disease stage with the potential to detect treatment effects on PD progression.


Assuntos
Ensaios Clínicos como Assunto/métodos , Progressão da Doença , Fluordesoxiglucose F18 , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença de Parkinson/metabolismo
19.
Neurology ; 89(15): 1584-1593, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28916537

RESUMO

OBJECTIVE: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. METHODS: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule-1 (VCAM-1) binding were assessed using flow cytometry. RESULTS: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 109 vs 3.5 × 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. CONCLUSIONS: Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.


Assuntos
Fatores Imunológicos/uso terapêutico , Subpopulações de Linfócitos/imunologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Fatores Imunológicos/sangue , Integrina alfa4/sangue , Contagem de Linfócitos , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Natalizumab/sangue , Estudos Retrospectivos , Prevenção Secundária , Resultado do Tratamento , Molécula 1 de Adesão de Célula Vascular/sangue
20.
Philos Trans A Math Phys Eng Sci ; 374(2067)2016 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-27044992

RESUMO

The influence of cardiac activity on the viscoelastic properties of intracranial tissue is one of the mechanisms through which brain-heart interactions take place, and is implicated in cerebrovascular disease. Cerebrovascular disease risk is not fully explained by current risk factors, including arterial compliance. Cerebrovascular compliance is currently estimated indirectly through Doppler sonography and magnetic resonance imaging (MRI) measures of blood velocity changes. In order to meet the need for novel cerebrovascular disease risk factors, we aimed to design and validate an MRI indicator of cerebrovascular compliance based on direct endogenous measures of blood volume changes. We implemented a fast non-gated two-dimensional MRI pulse sequence based on echo-planar imaging (EPI) with ultra-short repetition time (approx. 30-50 ms), which stepped through slices every approximately 20 s. We constrained the solution of the Bloch equations for spins moving faster than a critical speed to produce an endogenous contrast primarily dependent on spin volume changes, and an approximately sixfold signal gain compared with Ernst angle acquisitions achieved by the use of a 90° flip angle. Using cardiac and respiratory peaks detected on physiological recordings, average cardiac and respiratory MRI pulse waveforms in several brain compartments were obtained at 7 Tesla, and used to derive a compliance indicator, the pulsatility volume index (pVI). The pVI, evaluated in larger cerebral arteries, displayed significant variation within and across vessels. Multi-echo EPI showed the presence of significant pulsatility effects in both S0 and [Formula: see text] signals, compatible with blood volume changes. Lastly, the pVI dynamically varied during breath-holding compared with normal breathing, as expected for a compliance indicator. In summary, we characterized and performed an initial validation of a novel MRI indicator of cerebrovascular compliance, which might prove useful to investigate brain-heart interactions in cerebrovascular disease and other disorders.


Assuntos
Imageamento por Ressonância Magnética/métodos
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