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BACKGROUND: Gait variability is a common feature in neurodegenerative diseases and has been linked to cognitive impairment. Despite this link, the influence of specific cognitive domains, such as memory, visual spatial skills, executive function, and verbal function on gait variability is not well-understood. OBJECTIVE: To investigate the predictive value of these specific cognitive domains on gait variability in people with mild cognitive impairment (MCI) and dementia during preferred and dual task walking. METHOD: One hundred and two participants with either MCI or dementia underwent a comprehensive cognitive assessment and completed preferred and dual-task walking trials on a pressure-sensing walkway. Gait variability was assessed using the PKMAS software. Lower extremity function was evaluated with a self-reported validated scale. RESULTS: Our findings indicate that only visual spatial abilities had a moderate predictive value on gait variability [F (1, 78) = 17.30, p < 0.01, r = 0.43], both in preferred pace walking (70% direct effect) and dual-task walking (90% direct effect) (p's < 0.05). Additionally, lower extremity functional skills had a significant indirect effect (30%) on gait variability in preferred walking contexts. CONCLUSION: For individuals diagnosed with MCI or dementia, increased gait variability may be driven by deficits in visual spatial processing. An increased understanding of the role of visual spatial processing in gait variability can aid in the assessment and management of individuals with MCI or dementia, potentially leading to targeted interventions to improve mobility and safety.
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Disfunção Cognitiva , Demência , Humanos , Disfunção Cognitiva/fisiopatologia , Masculino , Feminino , Idoso , Demência/fisiopatologia , Idoso de 80 Anos ou mais , Marcha/fisiologia , Função Executiva/fisiologia , Desempenho Psicomotor/fisiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Caminhada/fisiologiaRESUMO
OBJECTIVE: Multiple sclerosis (MS) is a debilitating neurological disease associated with a variety of psychological, cognitive, and motoric symptoms. Walking is among the most important functions compromised by MS. Dual-task walking (DTW), an everyday activity in which people walk and engage in a concurrent, discrete task, has been assessed in MS, but little is known about how it relates to other MS symptoms. Self-awareness theory suggests that DTW may be a function of the interactions among psychological, cognitive, and motor processes. METHOD: Cognitive testing, self-report assessments for depression and falls self-efficacy (FSE), and walk evaluations [DTW and single-task walk (STW)] were assessed in seventy-three people with MS in a clinical care setting. Specifically, we assessed whether psychological factors (depression and FSE) that alter subjective evaluations regarding one's abilities would moderate the relationships between physical and cognitive abilities and DTW performance. RESULTS: DTW speed is related to diverse physical and cognitive predictors. In support of self-awareness theory, FSE moderated the relationship between STW and DTW speeds such that lower FSE attenuated the strength of the relationship between them. DTW costs - the change in speed normalized by STW speed - did not relate to cognitive and motor predictors. DTW costs did relate to depressive symptoms, and depressive symptoms moderated the effect of information processing on DTW costs. CONCLUSIONS: Findings indicate that an interplay of physical ability and psychological factors - like depression and FSE - may enhance understanding of walking performance under complex, real-world, DTW contexts.
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Marcha , Esclerose Múltipla , Humanos , Depressão/etiologia , Esclerose Múltipla/psicologia , Autoeficácia , Caminhada/psicologia , CogniçãoRESUMO
Compound 1c, 5-chloro-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2,3-dihydro-1H-inden-1-one was previously reported from our laboratory showing high affinity binding to the 5-HT7 receptor (Ki = 0.5 nM). However, compound 1c racemizes readily upon enantiomeric separation. To prevent racemization, we have redesigned and synthesized methyl and carboxyethyl analogs, compounds 2 and 3 respectively, whose binding affinities were similar to those of compound 1c. Compounds 2 and 3 cannot undergo racemization since tautomerism was no longer possible and thus, compound 2 was selected for enantiomeric separation and further evaluation. Upon enantiomeric separation, the levorotatory enantiomer, (-)2 or 2a demonstrated a higher affinity (Ki = 1.2 nM) than the (+)2 or 2b enantiomer (Ki = 93 nM) and a ß-arrestin biased functional selectivity for the 5-HT7 receptor. Although 2a showed about 8 times less activity than 5-HT in the Gs pathway, it showed over 31 times higher activity than 5-HT in the ß-arrestin pathway. This constitutes a significant ß-arrestin pathway preference and shows 2a to be more potent and more efficacious than the recently published ß-arrestin biased 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine, the N-debenzylated analog of JNJ18038683 (Compound 7).
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Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D2 & D3 receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D4 and 5-HT1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D2 receptor subtype but with moderate binding affinity at the D3 and D4 receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D2 receptor subtype in reversing apomorphine-induced climbing behavior.
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Antipsicóticos/farmacologia , Apomorfina/antagonistas & inibidores , Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Apomorfina/farmacologia , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
This study investigated the cytotoxic effects of gemcitabine-loaded solid lipid nanoparticle (Gem-SLN) on the patient-derived primary pancreatic cancer cell lines (PPCL-46) and MiaPaCa-2. Different SLN formulations were prepared from glyceryl monostearate (GMS), polysorbate 80 (Tween® 80) and poloxamer 188 (Pol 188) as surfactants using a cold homogenization method. Gem-SLN was characterized for particle size and charge distribution, entrapment efficiency and loading capacity. Fourier Transform Infra-Red (FTIR) spectroscopy was used to verify Gem and SLN interaction while differential scanning calorimetry (DSC) was used to acquire thermodynamic information on Gem-SLN. Cytotoxicity studies was conducted on PPCL-46 cells and Mia-PaCa-2 cells. Among the different Gem-SLN formulations prepared, Gem-SLN15 was selected based on entrapment efficiency (EE) of Gem, loading efficiency of Gem, cytotoxicity and rate of Gem release. Growth inhibition of Gem-SLN15-treated PPCL-46 culture (IC50 (2D) =27± 5 µM; IC50 (3D) = 66 ± 2 µM) was remarkably higher than gemcitabine hydrochloride (GemHCl)-treated PPCL-46 culture (IC50 (2D) =126±3 µM; IC50 (3D) =241±3 µM). Similar trend of higher Gem-SLN15 inhibition in MiaPaCa-2 culture was found (IC50 (2D) =56±16 µM; IC50 (3D) =127±4 µM) compared with GemHCl-treated Mia-PaCa-2 culture (IC50 (2D) =188±46 µM; IC50 (3D) =254±52 µM). The anticancer activity of Gem-SLN15 was significantly more effective than GemHCl in PPCL-46 compared to Mia-PaCa-2 cancer cells. Schematic diagram for preparation of Gem-SLN through cold homogenization and methods for characterization and in-vitro studies.
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Extracellular ß-amyloid (Aß) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimer's disease and related neurodegenerative dementias could serve to monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to investigate the effects of Aß and inflammatory interleukin-6 (IL6), alone or in combination, on in vivo tissue microstructure in the TgCRND8 mouse model of Alzheimer's-type Aß deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1â¯T. Images were processed using the diffusion tensor imaging (DTI) model or the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern in white matter (WM) and hippocampus consistent with radial and longitudinal diffusivity deficits along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean, axial and radial diffusivity, and increased orientation dispersion (ODI) and intracellular volume fraction (ICVF) measured in WM and hippocampus. IL6 produced a 'protective-like' effect on WM FA in TgCRND8 mice, observed as an increased FA that counteracted a reduction in FA observed with endogenous Aß production and accumulation. In addition, we found that ICVF and ODI had an inverse relationship with the functional connectome clustering coefficient. The relationship between NODDI and graph theory metrics suggests that currently unknown microstructure alterations in WM and hippocampus are associated with diminished functional network organization in the brain.
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Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Hipocampo , Interleucina-6/metabolismo , Rede Nervosa , Neuritos/ultraestrutura , Substância Branca , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Camundongos Transgênicos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/patologiaRESUMO
In previous structure-activity relationship studies to identify new and selective 5-HT7 receptor (5-HT7 R) ligands, we identified the chiral compound, 5-chloro-2-{2-[3,4-dihydroisoquinoline-2(1H)-yl]ethyl}-2-methyl-2,3-dihydro-1H-inden-1-one (SYA 40247), with high-affinity binding to the 5-HT7 R. Thus, it was of interest to separate the enantiomers in order to evaluate their affinity at the 5-HT7 R. To achieve this separation, a normal-phase analytical method using HPLC-PDA and a 4.6 × 250 mm Chiralpak AD-H column was developed. Optimized isocratic conditions of 1.00 mL/min 95:5:0.1 v/v/v hexane-ethanol-diethylamine and a 254 nm analysis wavelength yielded a 6.07 min baseline separation. The method was scaled up to a 10 × 250 mm Chiralpak AD-H column, allowing 3 mg of racemate to be separated with a single injection, and 6 mg for an overlapping double injection in the same run. The separated enantiomers were reinjected into the analytical HPLC system, peak identities confirmed by retention time and PDA UV spectra, and the enantiomeric purities determined to be 100% for peak 1 and 100% for peak 2. A Jasco P-1020 polarimeter was used to determine the specific rotation [α] of the enantiomers of peaks 1 and 2, which were -86.2 and +93.3 (deg mL)/(g dm) respectively. No racemization was observed, and the enantiomeric purity remained at 100% for each peak.
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Amilose/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Indenos/química , Indenos/isolamento & purificação , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Fenilcarbamatos/química , Amilose/química , Isoquinolinas/análise , Ligantes , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , EstereoisomerismoRESUMO
Progression markers of Parkinson's disease are crucial for successful therapeutic development. Recently, a diffusion magnetic resonance imaging analysis technique using a bitensor model was introduced allowing the estimation of the fractional volume of free water within a voxel, which is expected to increase in neurodegenerative disorders such as Parkinson's disease. Prior work demonstrated that free water in the posterior substantia nigra was elevated in Parkinson's disease compared to controls across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in controls at a single site. Here, the goal was to validate free water in the posterior substantia nigra as a progression marker in Parkinson's disease, and describe the pattern of progression of free water in patients with a 4-year follow-up tested in a multicentre international longitudinal study of de novo Parkinson's disease (http://www.ppmi-info.org/). The analyses examined: (i) 1-year changes in free water in 103 de novo patients with Parkinson's disease and 49 controls; (ii) 2- and 4-year changes in free water in a subset of 46 patients with Parkinson's disease imaged at baseline, 12, 24, and 48 months; (iii) whether 1- and 2-year changes in free water predict 4-year changes in the Hoehn and Yahr scale; and (iv) the relationship between 4-year changes in free water and striatal binding ratio in a subgroup of Parkinson's disease who had undergone both diffusion and dopamine transporter imaging. Results demonstrated that: (i) free water level in the posterior substantia nigra increased over 1 year in de novo Parkinson's disease but not in controls; (ii) free water kept increasing over 4 years in Parkinson's disease; (iii) sex and baseline free water predicted 4-year changes in free water; (iv) free water increases over 1 and 2 years were related to worsening on the Hoehn and Yahr scale over 4 years; and (v) the 4-year increase in free water was associated with the 4-year decrease in striatal binding ratio in the putamen. Importantly, all longitudinal results were consistent across sites. In summary, this study demonstrates an increase over 1 year in free water in the posterior substantia nigra in a large cohort of de novo patients with Parkinson's disease from a multi-site cohort study and no change in healthy controls, and further demonstrates an increase of free water in Parkinson's disease over the course of 4 years. A key finding was that results are consistent across sites and the 1-year and 2-year increase in free water in the posterior substantia nigra predicts subsequent long-term progression on the Hoehn and Yahr staging system. Collectively, these findings demonstrate that free water in the posterior substantia nigra is a valid, progression imaging marker of Parkinson's disease, which may be used in clinical trials of disease-modifying therapies.
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Progressão da Doença , Doença de Parkinson/metabolismo , Água/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Corpo Estriado/metabolismo , Imagem de Difusão por Ressonância Magnética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neuroimagem , Substância Negra/metabolismoRESUMO
Increased beta oscillations over sensorimotor cortex are antikinetic. Motor- and pain-related processes separately suppress beta oscillations over sensorimotor cortex leading to the prediction that ongoing pain should facilitate movement. In the current study, we used a paradigm in which voluntary movements were executed during an ongoing pain-eliciting stimulus to test the hypothesis that a pain-related suppression of beta oscillations would facilitate the initiation of a subsequent voluntary movement. Using kinematic measures, electromyography, and high-density electroencephalography, we demonstrate that ongoing pain leads to shorter reaction times without affecting the kinematics or accuracy of movement. Reaction time was positively correlated with beta power prior to movement in contralateral premotor areas. Our findings corroborate the view that beta-band oscillations are antikinetic and provide new evidence that pain primes the motor system for action. Our observations provide the first evidence that a pain-related suppression of beta oscillations over contralateral premotor areas leads to shorter reaction times for voluntary movement.
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Córtex Motor/fisiologia , Movimento/fisiologia , Dor/fisiopatologia , Fenômenos Biomecânicos , Mapeamento Encefálico , Eletroencefalografia , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia , Processamento de Sinais Assistido por Computador , Adulto JovemRESUMO
Accurate motor performance may depend on the scaling of distinct oscillatory activity within the motor cortex and effective neural communication between the motor cortex and other brain areas. Oscillatory activity within the beta-band (13-30Hz) has been suggested to provide distinct functional roles for attention and sensorimotor control, yet it remains unclear how beta-band and other oscillatory activity within and between cortical regions is coordinated to enhance motor performance. We explore this open issue by simultaneously measuring high-density cortical activity and elbow flexor and extensor neuromuscular activity during ballistic movements, and manipulating error using high and low visual gain across three target distances. Compared with low visual gain, high visual gain decreased movement errors at each distance. Group analyses in 3D source-space revealed increased theta-, alpha-, and beta-band desynchronization of the contralateral motor cortex and medial parietal cortex in high visual gain conditions and this corresponded to reduced movement error. Dynamic causal modeling was used to compute connectivity between motor cortex and parietal cortex. Analyses revealed that gain affected the directionally-specific connectivity across broadband frequencies from parietal to sensorimotor cortex but not from sensorimotor cortex to parietal cortex. These new findings provide support for the interpretation that broad-band oscillations in theta, alpha, and beta frequency bands within sensorimotor and parietal cortex coordinate to facilitate accurate upper limb movement. SUMMARY STATEMENT: Our findings establish a link between sensorimotor oscillations in the context of online motor performance in common source space across subjects. Specifically, the extent and distinct role of medial parietal cortex to sensorimotor beta connectivity and local domain broadband activity combine in a time and frequency manner to assist ballistic movements. These findings can serve as a model to examine whether similar source space EEG dynamics exhibit different time-frequency changes in individuals with neurological disorders that cause movement errors.
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Ritmo beta/fisiologia , Eletroencefalografia/métodos , Atividade Motora/fisiologia , Lobo Parietal/fisiologia , Desempenho Psicomotor/fisiologia , Córtex Sensório-Motor/fisiologia , Adulto , Eletromiografia , Retroalimentação Sensorial/fisiologia , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Cervical dystonia (CD) is the most common type of focal dystonia, causing abnormal movements of the neck and head. In this study, we used noninvasive imaging to investigate the motor system of patients with CD and uncover the neural correlates of dystonic symptoms. Furthermore, we examined whether a commonly prescribed anticholinergic medication in CD has an effect on the dystonia-related brain abnormalities. Participants included 16 patients with CD and 16 healthy age-matched controls. We collected functional MRI scans during a force task previously shown to extensively engage the motor system, and diffusion and T1-weighted MRI scans from which we calculated free-water and brain tissue densities. The dystonia group was also scanned ca. 2 h after a 2-mg dose of trihexyphenidyl. Severity of dystonia was assessed pre- and post-drug using the Burke-Fahn-Marsden Dystonia Rating Scale. Motor-related activity in CD was altered relative to controls in the primary somatosensory cortex, cerebellum, dorsal premotor and posterior parietal cortices, and occipital cortex. Most importantly, a regression model showed that increased severity of symptoms was associated with decreased functional activity of the somatosensory cortex and increased activity of the cerebellum. Structural imaging measures did not differ between CD and controls. The single dose of trihexyphenidyl altered the fMRI signal in the somatosensory cortex but not in the cerebellum. Symptom severity was not significantly reduced post-treatment. Findings show widespread changes in functional brain activity in CD and most importantly that dystonic symptoms relate to disrupted activity in the somatosensory cortex and cerebellum. Hum Brain Mapp 38:4563-4573, 2017. © 2017 Wiley Periodicals, Inc.
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Cerebelo/efeitos da radiação , Atividade Motora/fisiologia , Córtex Sensório-Motor/fisiopatologia , Torcicolo/fisiopatologia , Antidiscinéticos/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Mapeamento Encefálico , Cerebelo/diagnóstico por imagem , Cerebelo/efeitos dos fármacos , Cerebelo/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Vias Neurais/diagnóstico por imagem , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Fármacos Neuromusculares/uso terapêutico , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/efeitos dos fármacos , Índice de Gravidade de Doença , Torcicolo/diagnóstico por imagem , Torcicolo/tratamento farmacológico , Triexifenidil/uso terapêuticoRESUMO
BACKGROUND: Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP. METHODS: The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures. RESULTS: In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water-corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity. The direction of correlations between single-tensor mean diffusivity and free-water values and clinical scores was similar at each site. CONCLUSIONS: Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. © 2017 International Parkinson and Movement Disorder Society.
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Imagem de Tensor de Difusão , Processamento de Imagem Assistida por Computador , Doença de Parkinson/diagnóstico por imagem , Substância Negra/diagnóstico por imagem , Água , Idoso , Análise de Variância , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Estatística como Assunto , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.
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Imagem de Difusão por Ressonância Magnética/métodos , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Água/metabolismo , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/metabolismoRESUMO
The Parkinson's Disease Biomarkers Program (PDBP) is a multi-site study designed to identify Parkinson's disease (PD) biomarkers that can be used to improve the understanding of PD pathophysiology and to develop tools that provide novel measures to evaluate PD clinical trials. The PDBP consortium comprises numerous individual projects of which two are specifically geared to the development of brain imaging markers for diagnosis, progression, and prognosis of PD or related disorders. All study data from PD patients, atypical Parkinsonian patients, patients with essential tremor, and healthy controls collected from the sites are integrated in the PDBP database and will be publically available. All subjects are asked to submit blood samples, and undergo a battery of clinical evaluations that cover motor, cognitive, and other background information. In addition, a subset of subjects contributed cerebrospinal fluid samples. A restricted access, web-based Data Management Resource facilitates rapid sharing of data and biosamples across the entire PD research community. The PDBP consortium is a useful resource for research and collaboration aimed at the discovery of biomarkers and their use in understanding the pathophysiology of PD.
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Biomarcadores , Encéfalo/patologia , Bases de Dados Factuais , Neuroimagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Progressão da Doença , Tremor Essencial/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Internet , Neuroimagem/normas , Doença de Parkinson/psicologia , PrognósticoRESUMO
Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wild-type (WT) controls using resting-state functional magnetic resonance imaging (MRI) and an independent component analysis. In addition, using diffusion MRI we examined how structural integrity across the basal ganglia and cerebellum directly relates to impairments in functional connectivity. Compared to WT mice, Dyt1 KI mice revealed increased functional connectivity across the striatum, thalamus, and somatosensory cortex; and reduced functional connectivity in the motor and cerebellar cortices. Further, Dyt1 KI mice demonstrated elevated free-water (FW) in the striatum and cerebellum compared to WT mice, and increased FW was correlated with impairments in functional connectivity across basal ganglia, cerebellum, and sensorimotor cortex. The current study provides the first in vivo MRI-based evidence in support of the hypothesis that the deletion of a 3-base pair (ΔGAG) sequence in the Dyt1 gene encoding torsinA has network level effects on in vivo functional connectivity and microstructural integrity across the sensorimotor cortex, basal ganglia, and cerebellum.
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Cerebelo/patologia , Distonia/genética , Imageamento por Ressonância Magnética , Chaperonas Moleculares/genética , Rede Nervosa/patologia , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Heterozigoto , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos KnockoutRESUMO
Rasagiline is a monoamine oxidase type B inhibitor that possesses no amphetamine-like properties, and provides symptomatic relief in early and late stages of Parkinson's disease (PD). Data in animal models of PD suggest that chronic administration of rasagiline is associated with structural changes in the substantia nigra, and raise the question whether the structure and function of the basal ganglia could be different in PD patients treated chronically with rasagiline as compared with PD patients not treated with rasagiline. Here, we performed a retrospective cross-sectional magnetic resonance imaging (MRI) study at 3 T that investigated nigrostriatal function and structure in PD patients who had taken rasagiline before testing (â¼8 months), PD who had not taken rasagiline before testing, and age-matched controls. The two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. We evaluated percent signal change in the posterior putamen during force production using functional MRI, free-water in the posterior substantia nigra using diffusion MRI, and performance on a bimanual coordination task using a pegboard test. All patients were tested after overnight withdrawal from antiparkinsonian medication. The rasagiline group had greater percent signal change in the posterior putamen, less free-water in the posterior substantia nigra, and better performance on the coordination task than the group not taking rasagiline. These findings point to a possible chronic effect of rasagiline on the structure and function of the basal ganglia in PD. Hum Brain Mapp 37:2894-2903, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Indanos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Idoso , Mapeamento Encefálico , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Água/análiseRESUMO
Diseases of the CNS are often complex and involve multiple receptor systems and thus, the treatment options for these diseases must focus on targeting the multiple receptors implicated in the various disorders. Schizophrenia and depression are examples of such diseases and their pharmacotherapy thus depends on agents which target multiple receptors including the dopamine, serotonin and even cholinergic receptors at the same time. In our previous campaign to find multi-receptor ligands, we have identified the benzothiazole 1a as an initial lead molecule. In the current work, we have expanded the structure affinity relationship (SAFIR) of 1a resulting in the identification of a partially restrained butyrophenone 3j as a potent and selective dual 5-HT1A and 5-HT7 receptor ligand. It is expected that compound 3j may serve as a new lead for further development in our search for newer and novel ligands with the potential to treat diseases of CNS origin.
Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/químicaRESUMO
5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.
Assuntos
Isoquinolinas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ligantes , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.
Assuntos
Receptores de Dopamina D2/metabolismo , Animais , Dopaminérgicos/metabolismo , Humanos , Ligantes , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson's disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinson's disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinson's disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinson's disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinson's disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinson's disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinson's disease, increases with progression of Parkinson's disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.