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BACKGROUND: Postural instability and gait difficulties (PIGD) are a significant cause of mobility loss and lower quality of life in Parkinson's disease (PD). When PD progresses, patients may experience falls and freezing of gait (FoG) resulting in fear of falling and increasing sedentariness. Sedentary behavior results in sarcopenia associated with other changes in body composition, especially in older patients becoming frail. Previous studies have shown gender-specific changes in body composition with aging as well as gender disparities in symptoms and progression of PD, yet the association between gender-specific body composition and PIGD symptoms such as FoG along with falls, remains unexplored. OBECTIVE: This study aimed to investigate the association between gender-specific changes in body composition, FoG and falls assessment. METHODS: 136 PD subjects underwent detailed clinical test batteries and had whole-body composition assessed using dual-energy X-ray absorptiometry (DXA). Multivariate logistic forward stepwise regression was performed to define body composition associations for FoG and falls. RESULTS: Multivariate regression analysis revealed that in males with PD, lower leg lean mass was significantly associated with the presence of FoG (OR, 0.429; 95% CI, 0.219-0.839; p=0.013) but not with falls. In females with PD, higher leg adipose mass was significantly associated with falls (OR, 4.780; 95% CI, 1.506-15.174; p=0.008) but not with FoG. CONCLUSION: These observations suggest gender specific associations between body composition and FoG vs. falls in PD. Future research should explore the impact of interventions on body composition in individuals with PD by paying specific attention to gender differences.
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Acidentes por Quedas , Composição Corporal , Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Masculino , Acidentes por Quedas/estatística & dados numéricos , Acidentes por Quedas/prevenção & controle , Feminino , Idoso , Transtornos Neurológicos da Marcha/epidemiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Fatores Sexuais , Equilíbrio Postural/fisiologia , Pessoa de Meia-Idade , Absorciometria de Fóton , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.
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BACKGROUND: Anxiety in Parkinson disease (PD) negatively impacts quality of life. While research predominantly focuses on central nervous system changes, some evidence suggests a connection between peripheral autonomic dysfunctions and PD-related anxiety. The role of the peripheral autonomic nervous system in this context may be overlooked. OBJECTIVES: This study explores the link between anxiety symptoms and cardiac sympathetic denervation in PD using 11C-meta-hydroxyephedrine ([11C]HED) PET cardiac imaging. METHODS: We studied 34 non-demented PD subjects, assessing anxiety levels through the Spielberg Anxiety State-Trait test trait section (STAI-T). Patients underwent comprehensive assessments along with [11C]HED cardiac and [11C]DTBZ brain PET. To identify subdimensions of STAI-T, we employed principal components analysis (PCA). We examined associations between the anxiety subdimensions and two measures of cardiac sympathetic denervation from [11C]HED PET. We utilized correlation and linear regression models for these analyses. RESULTS: PCA revealed two STAI-T results components: anxiety-depressive and pure anxiety subcomponents. Only pure anxiety significantly correlated with measures of cardiac sympathetic denervation (rhos -0.40, p = 0.018; 0.35, p = 0.043). Regression models confirmed a significant association, with cardiac sympathetic denervation explaining â¼20 % of pure anxiety variance, independent of sex, dopaminergic impairment, and anxiolytic treatments. DISCUSSION: This study provides preliminary evidence of peripheral autonomic nervous system abnormalities contributing to PD-related anxiety, suggesting dysregulation in peripheral autonomic functions influencing anxiety perception.
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Ansiedade , Coração , Doença de Parkinson , Tomografia por Emissão de Pósitrons , Humanos , Doença de Parkinson/complicações , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Ansiedade/etiologia , Coração/inervação , Simpatectomia , Efedrina/análogos & derivadosRESUMO
Clinical trials are increasingly focused on pre-manifest and early Alzheimer's disease (AD). Accurately predicting clinical progressions from normal to MCI or from MCI to dementia/AD versus non-progression is challenging. Accurate identification of symptomatic progressors is important to avoid unnecessary treatment and improve trial efficiency. Due to large inter-individual variability, biomarker positivity and comorbidity information are often insufficient to identify those destined to have symptomatic progressions. Using only clinical variables, we aimed to predict clinical progressions, estimating probabilities of progressions with a small set of variables selected by machine learning approaches. This work updates our previous work that was applied to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set Version 2 (V2), by using the most recent version (V3) with additional analyses. We generated a user-friendly conversion probability calculator which can be used for effectively pre-screening trial participants.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Sensibilidade e Especificidade , Aprendizado de MáquinaRESUMO
OBJECTIVES: Dopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. METHODS: PD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. RESULTS: Mean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036). CONCLUSIONS: Impaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.
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Transtornos Cognitivos/etiologia , Sensibilidades de Contraste/fisiologia , Função Executiva/fisiologia , Doença de Parkinson/complicações , Transtornos de Sensação/etiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estimulação Luminosa , Índice de Gravidade de Doença , Aprendizagem Verbal/fisiologiaRESUMO
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD. While BDNF-TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Hdh(+/Q175);p75(-/-) mice to determine if p75 represents a promising therapeutic target. In Hdh(+/Q175);p75(+/+) mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFκB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh(+/+);p75(+/+) mice; this increase was lost in Hdh(+/Q175);p75(-/-) mice. Hdh(+/Q175);p75(-/-) mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh(+/Q175);p75(+/+) and Hdh(+/+);p75(+/+) littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh(+/Q175);p75(-/-) mice compared to Hdh(+/+);p75(+/+), Hdh(+/Q175);p75(+/+), and Hdh(+/+);p75(-/-) littermates. Additionally, striatal volume declined to a greater extent in Hdh(+/Q175);p75(-/-) when compared to Hdh(+/Q175);p75(+/+) littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Hdh(+/Q175) mice.
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Corpo Estriado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Idade de Início , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Feminino , Técnicas de Introdução de Genes , Proteína Huntingtina , Doença de Huntington , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Tamanho do Órgão , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fator de Crescimento Neural/genética , Fator de Transcrição RelA/metabolismo , Proteína bcl-X/metabolismoRESUMO
RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.
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Encefalopatias/complicações , Cognição/fisiologia , Complicações do Diabetes , Substância Cinzenta/patologia , Doença de Parkinson/complicações , Idoso , Atrofia , Atenção/fisiologia , Gânglios da Base/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Estudos Transversais , Neurônios Dopaminérgicos/patologia , Função Executiva/fisiologia , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tetrabenazina/análogos & derivadosRESUMO
OBJECTIVE: To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD). BACKGROUND: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system-mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function. METHODS: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I-III) without dementia and 15 control subjects underwent a clinical assessment and [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [(11)C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging. RESULTS: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (-12.3%) followed by the PD nonfallers (-6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (-11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers. CONCLUSIONS: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.
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Acidentes por Quedas , Acetilcolinesterase/metabolismo , Encéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Estudos Transversais , Dopamina/metabolismo , Feminino , Humanos , Hidrólise , Cinética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Substância Negra/diagnóstico por imagem , Substância Negra/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologiaRESUMO
OBJECTIVE: Tourette syndrome (TS) is a common neurodevelopmental disorder marked by tics and behavioral comorbidities. Clinical pharmacology suggests that dopaminergic signaling abnormalities are part of the pathophysiology of TS. Prior molecular imaging studies of nigrostriatal dopaminergic terminal markers report conflicting results. Our goal was to characterize the distribution of nigrostriatal dopaminergic terminals in subjects with TS. METHODS: Thirty-three adult subjects with TS were studied with PET using [11C]dihydrotetrabenazine (DTBZ), a ligand for the type 2 vesicular monoamine transporter, and with [11C] methylphenidate (MP), a ligand for the plasmalemmal dopamine transporter. Subjects were characterized with standard rating instruments for tic severity, obsessive-compulsive behaviors, and attentional deficits. RESULTS: We found no differences between subjects with TS and control subjects in DTBZ and MP binding in any striatal region. There was no correlation between binding measures and clinical variables. Ventral striatal DTBZ and MP binding distributions in subjects with TS were normal. CONCLUSIONS: We found no evidence of increased striatal dopaminergic innervation in Tourette syndrome (TS). Discrepancy between our present results and those of other studies may be explained by heterogeneity of TS.
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Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/metabolismo , Adolescente , Adulto , Ligação Competitiva/fisiologia , Radioisótopos de Carbono , Corpo Estriado/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina , Feminino , Humanos , Masculino , Metilfenidato , Pessoa de Meia-Idade , Terminações Pré-Sinápticas/metabolismo , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Tetrabenazina/análogos & derivados , Síndrome de Tourette/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/análise , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Adulto JovemRESUMO
Transgenic mice in which the tetracycline transactivator (tTA) is driven by the forebrain-specific calcium-calmodulin-dependent kinase II alpha promoter (CaMKII alpha-tTA mice) are used to study the molecular genetics of many behaviors. These mice can be crossed with other transgenic mice carrying a transgene of interest coupled to the tetracycline-responsive promoter element to produce mice with forebrain-specific expression of the transgene under investigation. The value of using CaMKII alpha-tTA mice to study behavior, however, is dependent on the CaMKII alpha-tTA mice themselves lacking a behavioral phenotype with respect to the behaviors being studied. Here we present data that suggest CaMKII alpha-tTA mice have a behavioral phenotype distinct from that of their wild-type (WT) littermates. Most strikingly, we find that CaMKII alpha-tTA mice, both those with a C57BL/6NTac genetic background (B6-tTA) and those with a 129S6B6F1/Tac hybrid genetic background (F1-tTA), exhibit decreased locomotor activity compared with WT littermates that could be misinterpreted as altered anxiety-like behavior. Despite this impairment, neither B6-tTA nor F1-tTA mice perform differently than their WT littermates in two commonly used learning and memory paradigms - Pavlovian fear conditioning and Morris water maze. Additionally, we find data regarding motor coordination and balance to be mixed: B6-tTA mice, but not F1-tTA mice, exhibit impaired performance on the accelerating rotarod and both perform as well as their WT littermates on the balance beam.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Comportamento Exploratório , Aprendizagem em Labirinto/fisiologia , Atividade Motora/genética , Regiões Promotoras Genéticas , Tetraciclina/metabolismo , Transativadores/genética , Animais , Ansiedade , Escuridão , Luz , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Processamento de Proteína Pós-Traducional , ProteômicaRESUMO
We studied the development of neuronal intranuclear inclusions (NIIs), neuropil aggregates (NAs), and expression of expanded repeat polyglutamine protein in the HdhCAG(150) knockin mouse model of Huntington's disease (HD). Diffuse nuclear localization of huntingtin protein (htt) was noted initially within striatal neurons at approximately 28 weeks, followed by the development of striatal htt immunoreactive NIIs by approximately 40 weeks. Striatal NIIs were observed initially in clusters within the matrix compartment but subsequently became diffusely distributed throughout the striatum. In the oldest animals (107 weeks), NIIs were enlarged and diffuse nuclear htt immunoreactivity reduced. Expression of ubiquitin immunoreactive NIIs paralleled but lagged behind the expression of htt immunoreactive NIIs. Abundant NIIs were found by approximately 75 weeks in layers 3 and 4 of somatosensory cortex and in layer 2 of piriform cortex. In the oldest animals, greater than 100 weeks, some NIIs were found in many brain regions. NAs were found mainly within the globus pallidus and substantia nigra, perhaps reflecting expression in striatal terminals. Cyclic AMP response element binding protein (CBP) was not localized to NIIs, arguing against gross sequestration of this transcriptionally active protein. Comparison of the relative levels of a common polyglutamine epitope in HdhCAG(150) knockin and hprtCAG(146) knockin mice shows greater expression of the polyglutamine epitope in the phenotypically less aggressive HdhCAG(150) knockin line. HdhCAG(150) knockin mice may be a model of early pathologic changes in HD.
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Corpos de Inclusão/ultraestrutura , Proteínas do Tecido Nervoso/genética , Neurônios/ultraestrutura , Neurópilo/ultraestrutura , Proteínas Nucleares/genética , Envelhecimento/metabolismo , Animais , Western Blotting , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina , Proteína Huntingtina , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Neostriado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/metabolismo , Ubiquitina/metabolismoRESUMO
Debate continues about the ethics of sham surgery controls. The most powerful argument for sham surgery controls is that rigorous experiments are needed to demonstrate safety and efficacy of surgical procedures. Without such experiments, there is danger of adopting worthless procedures in clinical practice. Opponents of sham surgery controls argue that sham surgery constitutes unacceptable violation of the rights of research subjects. Recent philosophical discussion has used two thought experiments-the transplant case and the trolley problem-to explore the circumstances under which individuals may be harmed to benefit a larger group. The transplant case is felt to exemplify circumstances that forbid harming some to benefit a larger group while the trolley problem exemplifies circumstances that permit harming some to benefit others. I argue that sham surgery controls satisfy criteria derived from the trolley problem and are morally permissible.
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Ética em Pesquisa , Direitos do Paciente , Procedimentos Cirúrgicos Operatórios/ética , Ensaios Clínicos Controlados como Assunto , Humanos , Consentimento Livre e EsclarecidoRESUMO
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
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Corpo Estriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Compostos Radiofarmacêuticos , Substância Negra/diagnóstico por imagem , Biomarcadores , Biotransformação , Barreira Hematoencefálica , Radioisótopos de Carbono/farmacocinética , Ensaios Clínicos como Assunto/métodos , Cocaína/análogos & derivados , Cocaína/farmacocinética , Corpo Estriado/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/farmacocinética , Dopamina/metabolismo , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Previsões , Humanos , Radioisótopos do Iodo/farmacocinética , Neurônios/química , Neurônios/diagnóstico por imagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Receptores Dopaminérgicos/metabolismo , Substância Negra/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Prior studies suggest differences exist among striatal projection neuron types in their vulnerability to Huntington's disease (HD). In the present study, we immunolabeled the fibers and terminals of the four main types of striatal projection neuron in their target areas for substance P, enkephalin, or glutamic acid decarboxylase (GAD), and used computer-assisted image analysis to quantify the abundance of immunolabeled terminals in a large sample of HD cases ranging from grade 0 to grade 4 [J. Neuropathol. Exp. Neurol. 44 (1985) 559], normalized to labeling in control human brains. Our goal was to characterize the relative rates of loss of the two striatopallidal projection systems (to the internal versus the external pallidal segments) and the two striatonigral projections systems (to pars compacta versus pars reticulata). The findings for GAD and the two neuropeptides were similar--the striatal projection to the external pallidal segment was the most vulnerable, showing substantial loss by grade 1. Loss of fibers in both subdivisions of the substantia nigra was also already great by grade 1. By contrast, the loss in the striatal projection system to the internal segment of globus pallidus proceeded more gradually. By grade 4 of HD, however, profound loss in all projection systems was apparent. These findings support the notion that the striatal neurons preferentially projecting to the internal pallidal segment are, in fact, less vulnerable in HD than are the other striatal projection neuron types.
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Corpo Estriado/patologia , Doença de Huntington/patologia , Vias Neurais/patologia , Neurônios/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Glutamato Descarboxilase/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Substância P/metabolismoRESUMO
BACKGROUND: Excessive striatal dopaminergic innervation is suggested to underlie Tourette syndrome (TS). Prior imaging and postmortem studies yield conflicting data. METHODS: The authors used PET with the type 2 vesicular monoamine transporter ligand [(11)C]dihydrotetrabenazine (DTBZ) to quantify striatal monoaminergic innervation in patients with TS (n = 19) and control subjects (n = 27). Compartmental modeling was used to determine blood to brain ligand transport (K(1)) and tissue to plasma distribution volume (a measure of ligand binding) during continuous infusion of DTBZ. TS data were compared with control data using predefined regions of interest and on a voxel by voxel basis. RESULTS: There were no significant differences in ligand binding or ligand transport between patients with TS and control subjects in the dorsal striatum. With voxel by voxel analysis, there was increased DTBZ binding in the right ventral striatum. CONCLUSIONS: Previously reported differences between patients with TS and control subjects in dorsal striatal dopamine terminal markers may reflect medication-induced regulation of terminal marker expression or be the result of intrinsic differences in striatal dopaminergic synaptic function. Increased right ventral striatal DTBZ binding suggests that abnormal ventral striatal dopaminergic innervation may underlie tics.
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Monoaminas Biogênicas/metabolismo , Corpo Estriado/diagnóstico por imagem , Proteínas de Membrana Transportadoras , Neuropeptídeos , Tetrabenazina/análogos & derivados , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/metabolismo , Adolescente , Adulto , Ligação Competitiva , Compartimentos de Líquidos Corporais , Radioisótopos de Carbono , Corpo Estriado/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Ligantes , Imageamento por Ressonância Magnética , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Neurônios/diagnóstico por imagem , Neurônios/metabolismo , Terminações Pré-Sinápticas/diagnóstico por imagem , Terminações Pré-Sinápticas/metabolismo , Valores de Referência , Tetrabenazina/farmacocinética , Tomografia Computadorizada de Emissão , Síndrome de Tourette/etiologia , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
Sham surgery is a controversial and rarely used component of randomised clinical trials evaluating surgical interventions. The recent use of sham surgery in trials evaluating efficacy of intracerebral fetal tissue grafts in Parkinson's disease has highlighted the ethical concerns associated with sham surgery controls. Macklin, and Dekkers and Boer argue vigorously against use of sham surgery controls. Macklin presents a broad argument against sham surgery controls while Dekkers and Boer present a narrower argument that sham surgery is unnecessary in the specific setting of fetal tissue engraftment for Parkinson's disease. I defend sham surgery controls against both these criticisms. Appropriate clinical trial design, sometimes including sham surgery, is needed to ensure that false positive trial results do not occur and endanger public safety. Results of a completed trial of fetal tissue grafting for Parkinson's disease are used to illustrate the potential benefits of, and problems associated with, sham surgery controls. Sham surgery controls, however, should be employed only when absolutely necessary. I suggest criteria for appropriate use of sham surgery controls.
Assuntos
Transplante de Tecido Encefálico/ética , Transplante de Tecido Fetal/ética , Doença de Parkinson/cirurgia , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Experimentação Humana Terapêutica/ética , Humanos , Procedimentos Neurocirúrgicos/normas , Projetos de Pesquisa , Medição de RiscoAssuntos
Tremor Essencial/história , Pessoas Famosas , Alcoolismo/história , Governo , História do Século XVIII , Humanos , Masculino , Estados UnidosRESUMO
Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.