RESUMEN
Progressive supranuclear palsy syndrome (PSP-S) results from neurodegeneration within a network of brainstem, subcortical, frontal and parietal cortical brain regions. It is unclear how network dysfunction progresses and relates to longitudinal atrophy and clinical decline. In this study, we evaluated patients with PSP-S (n = 12) and healthy control subjects (n = 20) at baseline and 6 months later. Subjects underwent structural MRI and task-free functional MRI (tf-fMRI) scans and clinical evaluations at both time points. At baseline, voxel based morphometry (VBM) revealed that patients with mild-to-moderate clinical symptoms showed structural atrophy in subcortex and brainstem, prefrontal cortex (PFC; supplementary motor area, paracingulate, dorsal and ventral medial PFC), and parietal cortex (precuneus). Tf-fMRI functional connectivity (FC) was examined in a rostral midbrain tegmentum (rMT)-anchored intrinsic connectivity network that is compromised in PSP-S. In healthy controls, this network contained a medial parietal module, a prefrontal-paralimbic module, and a subcortical-brainstem module. Baseline FC deficits in PSP-S were most severe in rMT network integrative hubs in the prefrontal-paralimbic and subcortical-brainstem modules. Longitudinally, patients with PSP-S had declining intermodular FC between the subcortical-brainstem and parietal modules, while progressive atrophy was observed in subcortical-brainstem regions (midbrain, pallidum) and posterior frontal (perirolandic) cortex. This suggested that later-stage subcortical-posterior cortical change may follow an earlier-stage subcortical-anterior cortical disease process. Clinically, patients with more severe baseline impairment showed greater subsequent prefrontal-parietal cortical FC declines and posterior frontal atrophy rates, while patients with more rapid longitudinal clinical decline showed coupled prefrontal-paralimbic FC decline. VBM and FC can augment disease monitoring in PSP-S by tracking the disease through stages while detecting changes that accompany heterogeneous clinical progression.
Asunto(s)
Encéfalo/patología , Vías Nerviosas/patología , Parálisis Supranuclear Progresiva/patología , Anciano , Atrofia/patología , Atrofia/fisiopatología , Encéfalo/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiopatología , Parálisis Supranuclear Progresiva/fisiopatologíaRESUMEN
INTRODUCTION: Longitudinal imaging of neurodegenerative disorders is a potentially powerful biomarker for use in clinical trials. In Alzheimer's disease, studies have demonstrated that empirically derived regions of interest (ROIs) can provide more reliable measurement of disease progression compared with anatomically defined ROIs. METHODS: We set out to derive ROIs with optimal effect size for quantifying longitudinal change in a hypothetical clinical trial by comparing atrophy rates in 44 patients with behavioral variant of frontotemporal dementia (bvFTD), 30 with the semantic variant primary progressive aphasia (svPPA), and 26 with the nonfluent variant PPA (nfvPPA) to atrophy in 97 cognitively healthy controls. RESULTS: The regions identified for each variant were generally what would be expected from prior studies of frontotemporal lobar degeneration (FTLD). Sample size estimates for detecting a 40% reduction in annual rate of ROI atrophy varied substantially across groups, being 103 per arm in bvFTD, 31 in nfvPPA, and 10 in svPPA, but in all groups were less than those estimated for a priori ROIs and clinical measures. The variability in location of peak regions of atrophy across individuals was highest in bvFTD and lowest in svPPA, likely relating to the differences in effect size. CONCLUSIONS: These findings suggest that, while cross-validated maps of change can improve sensitivity to change in FTLD compared with a priori regions, the reliability of these maps differs considerably across syndromes. Future studies can utilize these maps to design clinical trials, and should try to identify factors accounting for the variability in patterns of atrophy across individuals, particularly those with bvFTD.
Asunto(s)
Degeneración Lobar Frontotemporal/diagnóstico por imagen , Anciano , Afasia Progresiva Primaria/diagnóstico por imagen , Afasia Progresiva Primaria/fisiopatología , Atrofia , Progresión de la Enfermedad , Femenino , Degeneración Lobar Frontotemporal/fisiopatología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios RetrospectivosRESUMEN
OBJECTIVE: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. METHODS: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. RESULTS: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. CONCLUSIONS: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.
Asunto(s)
Ganglios Basales/patología , Corteza Cerebral/patología , Parálisis Supranuclear Progresiva/complicaciones , Anciano , Atrofia/diagnóstico por imagen , Atrofia/patología , Ganglios Basales/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Parálisis Supranuclear Progresiva/diagnóstico por imagenRESUMEN
Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures.
Asunto(s)
Afasia Progresiva Primaria/patología , Afasia Progresiva Primaria/fisiopatología , Encéfalo/patología , Lenguaje , Vías Nerviosas/fisiología , Anciano , Afasia Progresiva Primaria/diagnóstico por imagen , Atrofia/etiología , Atrofia/patología , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Vías Nerviosas/diagnóstico por imagen , Pruebas Neuropsicológicas , Medición de la Producción del Habla , Estadística como AsuntoRESUMEN
Current research is investigating the potential utility of longitudinal measurement of brain structure as a marker of drug effect in clinical trials for neurodegenerative disease. Recent studies in Alzheimer's disease (AD) have shown that measurement of change in empirically derived regions of interest (ROIs) allows more reliable measurement of change over time compared with regions chosen a-priori based on known effects of AD on brain anatomy. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify an empirical ROI that maximizes the effect size for the annual rate of brain atrophy in FTLD compared with healthy age matched controls, and to estimate the effect size and associated power estimates for a theoretical study that would use change within this ROI as an outcome measure. Eighty six patients with FTLD were studied, including 43 who were imaged twice at 1.5 T and 43 at 3 T, along with 105 controls (37 imaged at 1.5 T and 67 at 3 T). Empirically-derived maps of change were generated separately for each field strength and included the bilateral insula, dorsolateral, medial and orbital frontal, basal ganglia and lateral and inferior temporal regions. The extent of regions included in the 3 T map was larger than that in the 1.5 T map. At both field strengths, the effect sizes for imaging were larger than for any clinical measures. At 3 T, the effect size for longitudinal change measured within the empirically derived ROI was larger than the effect sizes derived from frontal lobe, temporal lobe or whole brain ROIs. The effect size derived from the data-driven 1.5 T map was smaller than at 3 T, and was not larger than the effect size derived from a-priori ROIs. It was estimated that measurement of longitudinal change using 1.5 T MR systems requires approximately a 3-fold increase in sample size to obtain effect sizes equivalent to those seen at 3 T. While the results should be confirmed in additional datasets, these results indicate that empirically derived ROIs can reduce the number of subjects needed for a longitudinal study of drug effects in FTLD compared with a-priori ROIs. Field strength may have a significant impact on the utility of imaging for measuring longitudinal change.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Degeneración Lobar Frontotemporal/patología , Anciano , Atrofia , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Procesamiento de Señales Asistido por ComputadorRESUMEN
IMPORTANCE: We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. OBJECTIVE: To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy-at initial presentation and at 1-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included. MAIN OUTCOMES AND MEASURES: Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA-4-repeat-tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally. RESULTS: Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms. CONCLUSIONS AND RELEVANCE: In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.
Asunto(s)
Afasia Progresiva Primaria/complicaciones , Ganglios Basales/patología , Corteza Cerebral/patología , Enfermedades Neurodegenerativas/complicaciones , Parálisis Supranuclear Progresiva/complicaciones , Anciano , Afasia Progresiva Primaria/diagnóstico por imagen , Atrofia/patología , Autopsia , Ganglios Basales/diagnóstico por imagen , Estudios de Casos y Controles , Corteza Cerebral/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Estudios Transversales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Lenguaje , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Pruebas Neuropsicológicas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Parálisis Supranuclear Progresiva/diagnóstico por imagenRESUMEN
BACKGROUND: Although principles based in motor learning, rehabilitation, and human-computer interfaces can guide the design of effective interactive systems for rehabilitation, a unified approach that connects these key principles into an integrated design, and can form a methodology that can be generalized to interactive stroke rehabilitation, is presently unavailable. RESULTS: This paper integrates phenomenological approaches to interaction and embodied knowledge with rehabilitation practices and theories to achieve the basis for a methodology that can support effective adaptive, interactive rehabilitation. Our resulting methodology provides guidelines for the development of an action representation, quantification of action, and the design of interactive feedback. As Part I of a two-part series, this paper presents key principles of the unified approach. Part II then describes the application of this approach within the implementation of the Adaptive Mixed Reality Rehabilitation (AMRR) system for stroke rehabilitation. CONCLUSIONS: The accompanying principles for composing novel mixed reality environments for stroke rehabilitation can advance the design and implementation of effective mixed reality systems for the clinical setting, and ultimately be adapted for home-based application. They furthermore can be applied to other rehabilitation needs beyond stroke.
Asunto(s)
Aprendizaje/fisiología , Modalidades de Fisioterapia , Desempeño Psicomotor/fisiología , Rehabilitación de Accidente Cerebrovascular , Interfaz Usuario-Computador , Biorretroalimentación Psicológica/instrumentación , Biorretroalimentación Psicológica/métodos , Guías como Asunto , HumanosRESUMEN
This paper presents results from a clinical study of stroke survivors using an adaptive, mixed-reality rehabilitation (AMRR) system for reach and grasp therapy. The AMRR therapy provides audio and visual feedback on the therapy task, based on detailed motion capture, that places the movement in an abstract, artistic context. This type of environment promotes the generalizability of movement strategies, which is shown through kinematic improvements on an untrained reaching task and higher clinical scale scores, in addition to kinematic improvements in the trained task.
Asunto(s)
Actividad Motora/fisiología , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular/fisiopatología , Sobrevivientes , Anciano , Anciano de 80 o más Años , Fenómenos Biomecánicos/fisiología , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis y Desempeño de TareasRESUMEN
This paper presents a novel mixed reality rehabilitation system used to help improve the reaching movements of people who have hemiparesis from stroke. The system provides real-time, multimodal, customizable, and adaptive feedback generated from the movement patterns of the subject's affected arm and torso during reaching to grasp. The feedback is provided via innovative visual and musical forms that present a stimulating, enriched environment in which to train the subjects and promote multimodal sensory-motor integration. A pilot study was conducted to test the system function, adaptation protocol and its feasibility for stroke rehabilitation. Three chronic stroke survivors underwent training using our system for six 75-min sessions over two weeks. After this relatively short time, all three subjects showed significant improvements in the movement parameters that were targeted during training. Improvements included faster and smoother reaches, increased joint coordination and reduced compensatory use of the torso and shoulder. The system was accepted by the subjects and shows promise as a useful tool for physical and occupational therapists to enhance stroke rehabilitation.
Asunto(s)
Inteligencia Artificial , Biorretroalimentación Psicológica/métodos , Programas Informáticos , Rehabilitación de Accidente Cerebrovascular , Terapia Asistida por Computador/métodos , Interfaz Usuario-Computador , Anciano , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
We present the Systematic Test for Assessing Reaching Times (START), an interactive device for measuring reaction and movement times. START uses randomly lighted buttons to elicit reaches to a variety of target locations with a standardized setup. A magnetized wristband and reed switch monitor the hand rest position while capacitive touch sensors embedded in the buttons sense successful target reaches. A microcontroller measures reaching times at tens of milliseconds resolution. START can easily translate to the clinic because it is portable, easy to use and inexpensive to construct. We designed START for use with stroke patients and are using START to assess the progress of upper extremity rehabilitation of stroke survivors. It can be modified to fit a number of other motor control or cognitive tasks.