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Functional movement disorder (FMD) is a common manifestation of functional neurological disorder. FMD can occur alongside other neurological conditions, but especially in patients with established Parkinson's disease (PD). An interesting observation emerging across cohort studies and case series is that FMD can precede the diagnosis of PD, suggesting that FMD may itself be a prodromal symptom of neurodegeneration. Such a notion would have significant clinical implications for the assessment and management of people with FMD, particularly with respect to decisions around the use of auxiliary investigations, counselling, and follow-up. In this Viewpoint we review the evidence concerning the temporal relationship between FMD and PD. We discuss the potential explanations and mechanisms for FMD as a prodromal symptom of PD, and highlight clinical considerations and important outstanding questions in the field. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Neuroimaging studies in rapid eye movement sleep behavior disorder (RBD) can inform fundamental questions about the pathogenesis of Parkinson's disease (PD). Across modalities, functional magnetic resonance imaging (fMRI) may be better suited to identify changes between neural networks in the earliest stages of Lewy body diseases when structural changes may be subtle or absent. This review synthesizes the findings from all fMRI studies of RBD to gain further insight into the pathophysiology and progression of Lewy body diseases. A total of 32 studies were identified using a systematic review conducted according to PRISMA guidelines between January 2000 to February 2024 for original fMRI studies in patients with either isolated RBD (iRBD) or RBD secondary to PD. Common functional alterations were detectable in iRBD patients compared with healthy controls across brainstem nuclei, basal ganglia, frontal and occipital lobes, and whole brain network measures. Patients with established PD and RBD demonstrated decreased functional connectivity across the whole brain and brainstem nuclei, but increased functional connectivity in the cerebellum and frontal lobe compared with those PD patients without RBD. Finally, longitudinal changes in resting state functional connectivity were found to track with disease progression. Currently, fMRI studies in RBD have demonstrated early signatures of neurodegeneration across both motor and non-motor pathways. Although more work is needed, such findings have the potential to inform our understanding of disease, help to distinguish between prodromal PD and prodromal dementia with Lewy bodies, and support the development of fMRI-based outcome measures of phenoconversion and progression in future disease modifying trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.
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Enfermedad de Alzheimer , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Masculino , Humanos , Femenino , Sinucleinopatías/diagnóstico por imagen , Sinucleinopatías/genética , Enfermedad de Alzheimer/patología , Adelgazamiento de la Corteza Cerebral/patología , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Trastorno de la Conducta del Sueño REM/genética , Trastorno de la Conducta del Sueño REM/complicaciones , Mitocondrias/metabolismo , Atrofia/patologíaRESUMEN
Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.
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Excitabilidad Cortical , Corteza Motora , Enfermedad de Parkinson , Humanos , Anciano , Corteza Motora/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagenRESUMEN
Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.
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Enfermedades Neurodegenerativas , Priones , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Anciano , Atrofia/patología , Encéfalo/patología , Adelgazamiento de la Corteza Cerebral , Femenino , Expresión Génica , Humanos , Masculino , Enfermedades Neurodegenerativas/patología , Priones/metabolismo , Trastorno de la Conducta del Sueño REM/metabolismo , Sinucleinopatías/diagnóstico por imagen , Sinucleinopatías/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Postoperative delirium is an important complication of surgery and is associated with poor long-term cognitive outcomes, although the neural basis underlying this relationship is poorly understood. Neuroimaging studies and network-based approaches play an important role in our understanding of the mechanism by which delirium relates to longitudinal cognitive decline. A recent resting state functional MRI study is reviewed, which shows reduced global connectivity up to 3 months after delirium, supporting recent models of delirium and opening the door for applying this approach to understanding the complex inter-relationship between delirium and dementia.
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Disfunción Cognitiva , Delirio , Delirio del Despertar , Humanos , Cognición , Disfunción Cognitiva/etiología , Neuroimagen , Complicaciones PosoperatoriasRESUMEN
OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.
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Cognición , Enfermedad por Cuerpos de Lewy/fisiopatología , Enfermedad de Parkinson/fisiopatología , Trastorno de la Conducta del Sueño REM/fisiopatología , Anciano , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Polisomnografía , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Sinucleinopatías/diagnóstico por imagen , Sinucleinopatías/fisiopatologíaRESUMEN
Depression and anxiety are commonly associated with synucleinopathies. Mood disturbances have also been reported in patients with idiopathic REM sleep behaviour disorder (iRBD) and are difficult to treat due to exacerbation of sleep symptoms with standard antidepressants. Despite this, detailed prevalence studies of mood symptomatology and contributors to mood disturbances in iRBD are limited. Mood, sleep, autonomic, cognitive and motor symptoms were assessed in 49 well-characterized patients with iRBD using a variety of clinical scales. Spearman correlations, factor analysis and multiple linear regression were used to uncover associations between mood and non-motor and motor symptoms. The prevalence of significant depression was 17.0% and that of anxiety was 14.6% in the iRBD cohort. Age and disease duration were not correlated with these affective symptoms in iRBD patients. We found depression was significantly predicted by the presence and severity of motor, sleep and cognitive symptoms. Anxiety was predicted by the severity of nocturnal and daytime sleep-related symptoms, cognitive symptoms and autonomic symptoms, with a differential effect depending on the questionnaire used. Depression and anxiety are common in iRBD patients and can be significantly explained by specific sets of non-motor and motor symptoms. These associations provide insight into the underlying pathophysiology and emphasize the importance of a holistic approach to mood disturbance in this population, which may circumvent the reliance on pharmacotherapy that can exacerbate dream enactment behaviour.
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Trastornos del Humor/epidemiología , Trastorno de la Conducta del Sueño REM/fisiopatología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y CuestionariosRESUMEN
Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson's disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.
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Nivel de Alerta , Atención , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Enfermedad por Cuerpos de Lewy/fisiopatología , Periodicidad , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/psicología , Imagen de Difusión por Resonancia Magnética , Electroencefalografía , Potenciales Evocados Auditivos , Neuroimagen Funcional , Humanos , Enfermedad por Cuerpos de Lewy/psicología , Espectroscopía de Resonancia Magnética , Pruebas Neuropsicológicas , Polisomnografía , Trastorno de la Conducta del Sueño REM/fisiopatología , Trastornos del Sueño-Vigilia/fisiopatología , Encuestas y Cuestionarios , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Two established small-group learning paradigms in medical education include Case-based learning (CBL) and Team-based learning (TBL). Characteristics common to both pedagogies include the use of an authentic clinical case, active small-group learning, activation of existing knowledge and application of newly acquired knowledge. However, there are also variances between the two teaching methods, and a paucity of studies that consider how these approaches fit with curriculum design principles. In this paper we explore student and facilitator perceptions of the two teaching methods within a medical curriculum, using Experience based learning (ExBL) as a conceptual lens. METHODS: A total of 34/255 (13%) Year 2 medical students completed four CBLs during the 2019 Renal and Urology teaching block, concurrent to their usual curriculum activities, which included weekly TBLs. Questionnaires were distributed to all students (n = 34) and CBL facilitators (n = 13). In addition, all students were invited to attend focus groups. Data were analysed using descriptive statistics and thematic analysis. RESULTS: In total, 23/34 (71%) of students and 11/13 (85%) of facilitators completed the questionnaires. Twelve students (35%) participated in focus groups. Findings indicate their experience in CBL to be positive, with many favourable aspects that built on and complemented their TBL experience that provided an emphasis on the basic sciences. The learning environment was enriched by the CBL framework that allowed application of knowledge to solve clinical problems within the small groups with consistent facilitator guidance and feedback, their capacity to focus discussion, and associated efficiencies in learning. CONCLUSION: While the TBL model was integral in developing students' knowledge and understanding of basic science concepts, the CBL model was integral in developing students' clinical reasoning skills. The strengths of CBL relative to TBL included the development of authentic clinical reasoning skills and guided facilitation of small group discussion. Our findings suggest that delivery of a medical curriculum may be enhanced through increased vertical integration, applying TBL in earlier phases of the medical program where the focus is on basic science principles, with CBL becoming more relevant as students move towards clinical immersion.
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Estudiantes de Medicina , Curriculum , Retroalimentación , Procesos de Grupo , Humanos , Aprendizaje Basado en ProblemasRESUMEN
Dual-task gait can be a useful biomarker for cognitive decline and a sensitive predictor of future neurodegeneration in certain clinical populations, such as patients with idiopathic rapid eye movement sleep behavior disorder. OBJECTIVES: The objective of this cross-sectional study was to determine the neural signature of dual-tasking deficits in idiopathic rapid eye movement sleep behavior disorder using a validated gait paradigm. METHODS: Fifty-eight participants (28 controls; 30 idiopathic rapid eye movement sleep behavior disorder patients) were recruited; 52 participants had functional MRI scans as they performed a validated dual-task virtual reality gait paradigm using foot pedals. Forty-one participants completed single- and dual-task "overground walking" on a pressure sensor carpet. RESULTS: Idiopathic rapid eye movement sleep behavior disorder patients showed deficits in dual-tasking (i.e., greater mean step time) compared to controls during "overground walking." Functional MRI revealed that idiopathic rapid eye movement sleep behavior disorder patients had reduced blood-oxygen-level-dependent signal change in the dorsal caudate nucleus, and significantly different corticostriatal functional connectivity patterns from controls, when dual-tasking in high versus low cognitive load. While controls showed greater connectivity between frontoparietal and motor networks, idiopathic rapid eye movement sleep behavior disorder patients exhibited less change in this connectivity as a function of cognitive load. CONCLUSIONS: These findings demonstrate evidence of dual-task gait deficits in idiopathic rapid eye movement sleep behavior disorder patients, underpinned by disrupted corticostriatal connectivity. Minimal differences in the level of functional connectivity between dual-tasking conditions of high and low cognitive load suggest that idiopathic rapid eye movement sleep behavior disorder patients recruit cognitive networks to control gait even when the cognitive demands are low. This may indicate a compensatory strategy for early cognitive decline in idiopathic rapid eye movement sleep behavior disorder. © 2020 International Parkinson and Movement Disorder Society.
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Disfunción Cognitiva , Trastorno de la Conducta del Sueño REM , Estudios Transversales , Marcha , Humanos , CaminataRESUMEN
The vast majority of patients with idiopathic rapid eye movement sleep behaviour disorder will develop a neurodegenerative α-synuclein-related condition, such as Parkinson's disease or dementia with Lewy bodies. The pathology underlying dream enactment overlaps anatomically with the brainstem regions that regulate circadian core body temperature. Previously, nocturnal core body temperature regulation has been shown to be impaired in Parkinson's disease. However, no study to date has investigated nocturnal core body temperature changes in patients with idiopathic rapid eye movement sleep behaviour disorder, which may prove to be an early objective biomarker for α-synucleinopathies. Ten healthy controls, 15 patients with idiopathic rapid eye movement sleep behaviour disorder, 31 patients with Parkinson's disease and six patients with dementia with Lewy bodies underwent clinical assessment and nocturnal polysomnography with core body temperature monitoring. A validated cosinor method was utilised for core body temperature analysis. No differences in mesor, nadir or time of nadir were observed between groups. However, when compared with healthy controls, the amplitude of the nocturnal core body temperature (mesor minus nadir) was significantly reduced in patients with idiopathic rapid eye movement sleep behaviour disorder, Parkinson's disease with concurrent rapid eye movement sleep behaviour disorder and dementia with Lewy bodies (p < 0.001, p = 0.043 and p = 0.017, respectively). Importantly, this relationship was not seen in those patients with Parkinson's disease without rapid eye movement sleep behaviour disorder. In addition, there was a significant negative correlation between amplitude of the core body temperature and self-reported rapid eye movement sleep behaviour disorder symptoms. Changes in thermoregulatory circadian rhythm may be specifically associated with the pathology underlying rapid eye movement sleep behaviour disorder rather than simply that of α-synucleinopathy. These findings implicate thermoregulatory dysfunction as a potential early biomarker for development of rapid eye movement sleep behaviour disorder-associated neurodegeneration, and suggest that subpopulations with differing pathological underpinnings might exist in Parkinson's disease.
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Biomarcadores/química , Temperatura Corporal/fisiología , Enfermedades Neurodegenerativas/diagnóstico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Cognitive fluctuations (CFs) are a core diagnostic feature of dementia with Lewy bodies (DLB). Detection of CF is still mostly based on subjective reports from the patient or informant; more quantitative measures are likely to improve the accuracy for the diagnosis of DLB. The purpose of the current study is to test whether performance on the Sustained Attention Response Task (SART) could distinguish those patients with DLB with and without CF. Twenty-four patients with DLB were tested on the SART and performance was related to scores on the Clinical Assessment of Fluctuations (CAFs) and One Day Fluctuation Assessment Scale (ODFAS). The number of "misses" made was a significant predictor of their fluctuation severity, attentional performance, disorganized thinking, and language production ratings on the ODFAS. However, measures on the SART did not correlate with measures on the CAF scale. In conclusion, these findings suggest that SART is a feasible measure of sustained attention in this population and has clinical and diagnostic relevance to the measurement of CF, particularly those aspects measured by the ODFAS.
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Atención/fisiología , Trastornos del Conocimiento/etiología , Cognición/fisiología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/psicología , Anciano , Trastornos del Conocimiento/psicología , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Masculino , Pruebas Neuropsicológicas , Tiempo de Reacción/fisiología , Análisis y Desempeño de TareasRESUMEN
Parkinson's disease is primarily characterized by diminished dopaminergic function; however, the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson's disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinson's disease, both ON and OFF dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson's disease OFF state was associated with greater network-level integration than in the ON state. The extent of integration in the OFF state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted OFF state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e. premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic OFF state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic OFF state. Our findings provide a mechanistic basis for understanding the Parkinson's disease OFF state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson's disease.
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Dopamina/metabolismo , Vías Nerviosas/fisiopatología , Enfermedad de Parkinson/fisiopatología , Anciano , Encéfalo/patología , Mapeo Encefálico/métodos , Conectoma/métodos , Dopamina/fisiología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismoRESUMEN
Freezing of gait (FOG) in Parkinson's disease (PD) is frequently triggered upon passing through narrow spaces such as doorways. However, despite being common the neural mechanisms underlying this phenomenon are poorly understood. In our study, 19 patients who routinely experience FOG performed a previously validated virtual reality (VR) gait paradigm where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their "ON" and "OFF" medication states. Task performance in conjunction with blood oxygenation level dependent (BOLD) signal changes between "ON" and "OFF" states were compared within each patient. Specifically, as they passed through a doorway in the VR environment patients demonstrated significantly longer "footstep" latencies in the OFF state compared to the ON state. As seen clinically in FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. Functional magnetic resonance imaging revealed that footstep prolongation on passing through doorways was associated with selective hypoactivation in the presupplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses revealed that increased latency in response to doorways was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the "hyperdirect" pathway in the generation of this phenomenon.
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Encéfalo/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Red Nerviosa/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Anciano , Encéfalo/fisiopatología , Femenino , Trastornos Neurológicos de la Marcha/epidemiología , Trastornos Neurológicos de la Marcha/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/fisiopatología , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
BACKGROUND: Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. METHODS: A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. RESULTS: Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. CONCLUSIONS: This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.
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Trastornos Neurológicos de la Marcha/etiología , Trastorno de la Conducta del Sueño REM/complicaciones , Vértigo/etiología , Adulto , Anciano , Cognición , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Polisomnografía , Equilibrio Postural , Desempeño PsicomotorRESUMEN
BACKGROUND: Leucine-rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine-rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine-rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine-rich repeat kinase 2 inhibitor clinical trials. METHODS: Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated ex vivo with a leucine-rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine-rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme-linked immunosorbent assay. RESULTS: Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine-rich repeat kinase 2 inhibitor treatment. Leucine-rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine-rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine-rich repeat kinase 2 levels. Immune-cell levels of leucine-rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels. CONCLUSIONS: Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine-rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine-rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine-rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine-rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society.
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Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Leucocitos Mononucleares/metabolismo , Neutrófilos/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Humanos , Indazoles/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Pirimidinas/farmacologíaRESUMEN
There is emerging evidence indicating that color discrimination impairments can predict the development of Lewy body dementia in patients with rapid eye movement sleep behavior disorder, Parkinson disease, and in patients with mild cognitive impairment. Despite this clear relationship, color vision deficits are not seen uniformly in patients with dementia with Lewy bodies (DLB), suggesting a more nuanced association with the underlying neuropathology. Visual hallucinations represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. In this study, we examined the relationship between color vision impairment and visual hallucinations, along with other clinical and neuropsychological features in 24 well-characterized patients with DLB alongside 25 healthy controls. Color discrimination impairment was seen in 16 (67%) of 24 DLB participants with a higher error score relative to controls (P = .001). We demonstrate for the first time a strong association between color discrimination errors on the Farnsworth-Munsell 100 hue test and both the presence and severity of hallucinatory symptoms in DLB based on clinician-derived (P = .008) and questionnaire-derived (P = .03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial difficulties measured by the clock-drawing task (P = .02) but not to global measures of cognition, motor severity, age, or disease duration in our cohort. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations, and visuospatial function. Our results suggest that color discrimination does not simply relate to dementia but rather indexes higher order perceptual deficits that may predict visual hallucinations in Lewy body disorders and share a common pathophysiological substrate.
Asunto(s)
Percepción de Color/fisiología , Discriminación en Psicología/fisiología , Alucinaciones/etiología , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad de Parkinson/complicaciones , Anciano , Femenino , Alucinaciones/patología , Humanos , MasculinoRESUMEN
Freezing of gait is a complex, heterogeneous, and highly variable phenomenon whose pathophysiology and neural signature remains enigmatic. Evidence suggests that freezing is associated with impairments across cognitive, motor and affective domains; however, most research to date has focused on investigating one axis of freezing of gait in isolation. This has led to inconsistent findings and a range of different pathophysiological models of freezing of gait, due in large part to the tendency for studies to investigate freezing of gait as a homogeneous entity. To investigate the neural mechanisms of this heterogeneity, we used an established virtual reality paradigm to elicit freezing behaviour in 41 Parkinson's disease patients with freezing of gait and examined individual differences in the component processes (i.e. cognitive, motor and affective function) that underlie freezing of gait in conjunction with task-based functional MRI. First, we combined three unique components of the freezing phenotype: impaired set-shifting ability, step time variability, and self-reported anxiety and depression in a principal components analysis to estimate the severity of freezing behaviour with a multivariate approach. By combining these measures, we were then able to interrogate the pattern of task-based functional connectivity associated with freezing (compared to normal foot tapping) in a sub-cohort of 20 participants who experienced sufficient amounts of freezing during task functional MRI. Specifically, we used the first principal component from our behavioural analysis to classify patterns of functional connectivity into those that were associated with: (i) increased severity; (ii) increased compensation; or (iii) those that were independent of freezing severity. Coupling between the cognitive and limbic networks was associated with 'worse freezing severity', whereas anti-coupling between the putamen and the cognitive and limbic networks was related to 'increased compensation'. Additionally, anti-coupling between cognitive cortical regions and the caudate nucleus were 'independent of freezing severity' and thus may represent common neural underpinnings of freezing that are unaffected by heterogenous factors. Finally, we related these connectivity patterns to each of the individual components (cognitive, motor, affective) in turn, thus exposing latent heterogeneity in the freezing phenotype, while also identifying critical functional network signatures that may represent potential targets for novel therapeutic intervention. In conclusion, our findings provide confirmatory evidence for systems-level impairments in the pathophysiology of freezing of gait and further advance our understanding of the whole-brain deficits that mediate symptom expression in Parkinson's disease.
Asunto(s)
Encéfalo/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Anciano , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Oxígeno/sangre , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Encuestas y Cuestionarios , Interfaz Usuario-ComputadorRESUMEN
BACKGROUND: Recent trends in faculty development demonstrate a shift from short term to long-term programs; formal to informal learning in the workplace; individual to group settings; and from individual support to institutional support. The purpose of this study was to develop and evaluate a one-year Clinical Teaching Fellowship (CTF) program designed to equip early career medical practitioners and basic scientists with necessary skills to facilitate Team-based learning (TBL). METHODS: The CTF program provided formal training, a choice of informal professional development activities, and practical co-teaching opportunities in TBL. Of the 40 registrants, 31 (78%) completed the program. Data were collected via questionnaire and focus group. Data were analysed using descriptive statistics and framework analysis. RESULTS: Participants considered the CTF program as relevant to their needs and useful to their career. Learning was enriched through the combination of training, practical teaching experience alongside senior clinical teachers, the multi-disciplinary context of training and co-teaching in TBLs; and the sense of community. Competing clinical responsibilities made it difficult to attend training and TBL teaching. CONCLUSIONS: The CTF program provided a longitudinal faculty development framework promoting preparation, practice and development of teaching skills. Securing institutional support to invest in the growth and development of early career teachers is essential to sustained innovation and excellence in teaching.