RESUMEN
BACKGROUND: Sleep and circadian rhythm disorders are well recognised in both AD (Alzheimer's Disease) dementia and MCI-AD (Mild Cognitive Impairment due to Alzheimer's Disease). Such abnormalities include insomnia, excessive daytime sleepiness, decreased sleep efficiency, increased sleep fragmentation and sundowning. Enhancing understanding of sleep abnormalities may unveil targets for intervention in sleep, a promising approach given hypotheses that sleep disorders may exacerbate AD pathological progression and represent a contributory factor toward impaired cognitive performance and worse quality of life. This may also permit early diagnosis of AD pathology, widely acknowledged as a pre-requisite for future disease-modifying therapies. This study aims to bridge the divide between in-laboratory polysomnographic studies which allow for rich characterisation of sleep but in an unnatural setting, and naturalistic studies typically approximating sleep through use of non-EEG wearable devices. It is also designed to record sleep patterns over a 2 month duration sufficient to capture both infradian rhythm and compensatory responses following suboptimal sleep. Finally, it harnesses an extensively phenotyped population including with AD blood biomarkers. Its principal aims are to improve characterisation of sleep and biological rhythms in individuals with AD, particularly focusing on micro-architectural measures of sleep, compensatory responses to suboptimal sleep and the relationship between sleep parameters, biological rhythms and cognitive performance. METHODS/DESIGN: This observational cohort study has two arms (AD-MCI / mild AD dementia and aged-matched healthy adults). Each participant undergoes a baseline visit for collection of demographic, physiological and neuropsychological information utilising validated questionnaires. The main study period involves 7 nights of home-based multi-channel EEG sleep recording nested within an 8-week study period involving continuous wrist-worn actigraphy, sleep diaries and regular brief cognitive tests. Measurement of sleep parameters will be at home thereby obtaining a real-world, naturalistic dataset. Cognitive testing will be repeated at 6 months to stratify participants by longitudinal disease progression. DISCUSSION: This study will generate new insights particularly in micro-architectural measures of sleep, circadian patterns and compensatory sleep responses in a population with and without AD neurodegenerative change. It aims to enhance standards of remotely based sleep research through use of a well-phenotyped population and advanced sleep measurement technology.
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Enfermedad de Alzheimer , Demencia , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Calidad de Vida , Sueño , Estudios de Cohortes , Estudios Observacionales como AsuntoRESUMEN
Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.
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Axones/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Anisotropía , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understood feature in patients with TBI. Damage to the inner ear, nerve, brainstem, cerebellum and cerebral hemispheres may all affect vestibular functioning, hence, a multi-level assessment-from reflex to perception-is required. In a previous report, postural instability was the commonest neurological feature in ambulating acute patients with TBI. During ward assessment, we also frequently observe a loss of vertigo sensation in patients with acute TBI, common inner ear conditions and a related vigorous vestibular-ocular reflex nystagmus, suggesting a 'vestibular agnosia'. Patients with vestibular agnosia were also more unbalanced; however, the link between vestibular agnosia and imbalance was confounded by the presence of inner ear conditions. We investigated the brain mechanisms of imbalance in acute TBI, its link with vestibular agnosia, and potential clinical impact, by prospective laboratory assessment of vestibular function, from reflex to perception, in patients with preserved peripheral vestibular function. Assessment included: vestibular reflex function, vestibular perception by participants' report of their passive yaw rotations in the dark, objective balance via posturography, subjective symptoms via questionnaires, and structural neuroimaging. We prospectively screened 918 acute admissions, assessed 146 and recruited 37. Compared to 37 matched controls, patients showed elevated vestibular-perceptual thresholds (patients 12.92°/s versus 3.87°/s) but normal vestibular-ocular reflex thresholds (patients 2.52°/s versus 1.78°/s). Patients with elevated vestibular-perceptual thresholds [3 standard deviations (SD) above controls' average], were designated as having vestibular agnosia, and displayed worse posturography than non-vestibular-agnosia patients, despite no difference in vestibular symptom scores. Only in patients with impaired postural control (3 SD above controls' mean), whole brain diffusion tensor voxel-wise analysis showed elevated mean diffusivity (and trend lower fractional anisotropy) in the inferior longitudinal fasciculus in the right temporal lobe that correlated with vestibular agnosia severity. Thus, impaired balance and vestibular agnosia are co-localized to the inferior longitudinal fasciculus in the right temporal lobe. Finally, a clinical audit showed a sevenfold reduction in clinician recognition of a common peripheral vestibular condition (benign paroxysmal positional vertigo) in acute patients with clinically apparent vestibular agnosia. That vestibular agnosia patients show worse balance, but without increased dizziness symptoms, explains why clinicians may miss treatable vestibular diagnoses in these patients. In conclusion, vestibular agnosia mediates imbalance in traumatic brain injury both directly via white matter tract damage in the right temporal lobe, and indirectly via reduced clinical recognition of common, treatable vestibular diagnoses.
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Agnosia/fisiopatología , Lesiones Traumáticas del Encéfalo/fisiopatología , Equilibrio Postural , Vestíbulo del Laberinto/fisiopatología , Adolescente , Adulto , Anciano , Agnosia/etiología , Agnosia/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/patología , Mareo/etiología , Mareo/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reflejo de Enderezamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injury patients we examined whether: (i) impairments in memory encoding are associated with abnormal brain activation in these networks; (ii) whether changes in this brain activity predict subsequent memory retrieval; and (iii) whether abnormal white matter integrity underpinning functional networks is associated with impaired subsequent memory. Thirty-five patients with moderate-severe traumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy control subjects underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network. Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources.
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Atención/fisiología , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/psicología , Encéfalo/fisiopatología , Trastornos de la Memoria/fisiopatología , Adulto , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/etiología , Recuerdo Mental/fisiología , Persona de Mediana Edad , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
It is well established that chronic cognitive problems after traumatic brain injury relate to diffuse axonal injury and the consequent widespread disruption of brain connectivity. However, the pattern of diffuse axonal injury varies between patients and they have a correspondingly heterogeneous profile of cognitive deficits. This heterogeneity is poorly understood, presenting a non-trivial challenge for prognostication and treatment. Prominent amongst cognitive problems are deficits in working memory and reasoning. Previous functional MRI in controls has associated these aspects of cognition with distinct, but partially overlapping, networks of brain regions. Based on this, a logical prediction is that differences in the integrity of the white matter tracts that connect these networks should predict variability in the type and severity of cognitive deficits after traumatic brain injury. We use diffusion-weighted imaging, cognitive testing and network analyses to test this prediction. We define functionally distinct subnetworks of the structural connectome by intersecting previously published functional MRI maps of the brain regions that are activated during our working memory and reasoning tasks, with a library of the white matter tracts that connect them. We examine how graph theoretic measures within these subnetworks relate to the performance of the same tasks in a cohort of 92 moderate-severe traumatic brain injury patients. Finally, we use machine learning to determine whether cognitive performance in patients can be predicted using graph theoretic measures from each subnetwork. Principal component analysis of behavioural scores confirm that reasoning and working memory form distinct components of cognitive ability, both of which are vulnerable to traumatic brain injury. Critically, impairments in these abilities after traumatic brain injury correlate in a dissociable manner with the information-processing architecture of the subnetworks that they are associated with. This dissociation is confirmed when examining degree centrality measures of the subnetworks using a canonical correlation analysis. Notably, the dissociation is prevalent across a number of node-centric measures and is asymmetrical: disruption to the working memory subnetwork relates to both working memory and reasoning performance whereas disruption to the reasoning subnetwork relates to reasoning performance selectively. Machine learning analysis further supports this finding by demonstrating that network measures predict cognitive performance in patients in the same asymmetrical manner. These results accord with hierarchical models of working memory, where reasoning is dependent on the ability to first hold task-relevant information in working memory. We propose that this finer grained information may be useful for future applications that attempt to predict long-term outcomes or develop tailored therapies.
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Lesiones Traumáticas del Encéfalo/fisiopatología , Encéfalo/fisiopatología , Memoria a Corto Plazo/fisiología , Modelos Neurológicos , Red Nerviosa/fisiopatología , Adulto , Trastornos del Conocimiento/fisiopatología , Conectoma , Imagen de Difusión Tensora , Femenino , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Solución de Problemas/fisiologíaRESUMEN
Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.
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Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Lesión Axonal Difusa/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Adulto , Anisotropía , Atrofia , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Lesión Axonal Difusa/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Pruebas Neuropsicológicas , Valor Predictivo de las Pruebas , Desempeño Psicomotor , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Non-invasive brain stimulation has been widely investigated as a potential treatment for a range of neurological and psychiatric conditions, including brain injury. However, the behavioural effects of brain stimulation are variable, for reasons that are poorly understood. This is a particular challenge for traumatic brain injury, where patterns of damage and their clinical effects are heterogeneous. Here we test the hypothesis that the response to transcranial direct current stimulation following traumatic brain injury is dependent on white matter damage within the stimulated network. We used a novel simultaneous stimulation-MRI protocol applying anodal, cathodal and sham stimulation to 24 healthy control subjects and 35 patients with moderate/severe traumatic brain injury. Stimulation was applied to the right inferior frontal gyrus/anterior insula node of the salience network, which was targeted because our previous work had shown its importance to executive function. Stimulation was applied during performance of the Stop Signal Task, which assesses response inhibition, a key component of executive function. Structural MRI was used to assess the extent of brain injury, including diffusion MRI assessment of post-traumatic axonal injury. Functional MRI, which was simultaneously acquired to delivery of stimulation, assessed the effects of stimulation on cognitive network function. Anodal stimulation improved response inhibition in control participants, an effect that was not observed in the patient group. The extent of traumatic axonal injury within the salience network strongly influenced the behavioural response to stimulation. Increasing damage to the tract connecting the stimulated right inferior frontal gyrus/anterior insula to the rest of the salience network was associated with reduced beneficial effects of stimulation. In addition, anodal stimulation normalized default mode network activation in patients with poor response inhibition, suggesting that stimulation modulates communication between the networks involved in supporting cognitive control. These results demonstrate an important principle: that white matter structure of the connections within a stimulated brain network influences the behavioural response to stimulation. This suggests that a personalized approach to non-invasive brain stimulation is likely to be necessary, with structural integrity of the targeted brain networks an important criterion for patient selection and an individualized approach to the selection of stimulation parameters.
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Lesión Axonal Difusa/fisiopatología , Lesión Axonal Difusa/terapia , Estimulación Transcraneal de Corriente Directa/métodos , Adulto , Axones/fisiología , Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/terapia , Mapeo Encefálico/métodos , Corteza Cerebral/fisiopatología , Cognición/fisiología , Función Ejecutiva/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Red Nerviosa/fisiopatología , Pruebas Neuropsicológicas , Corteza Prefrontal/metabolismo , Sustancia Blanca/fisiopatologíaRESUMEN
Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow-up period, as well as to changes in memory performance, prior to multiple comparison correction. In conclusion, traumatic brain injury results in progressive loss of brain tissue volume, which continues for many years post-injury. Atrophy is most prominent in the white matter, but is also more pronounced in cortical sulci compared to gyri. These findings suggest the Jacobian determinant provides a method of quantifying brain atrophy following a traumatic brain injury and is informative in determining the long-term neurodegenerative effects after injury. Power calculations indicate that Jacobian determinant images are an efficient surrogate marker in clinical trials of neuroprotective therapeutics.
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Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Encéfalo/patología , Progresión de la Enfermedad , Adulto , Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
Traumatic brain injury often produces executive dysfunction. This characteristic cognitive impairment often causes long-term problems with behaviour and personality. Frontal lobe injuries are associated with executive dysfunction, but it is unclear how these injuries relate to corticostriatal interactions that are known to play an important role in behavioural control. We hypothesized that executive dysfunction after traumatic brain injury would be associated with abnormal corticostriatal interactions, a question that has not previously been investigated. We used structural and functional MRI measures of connectivity to investigate this. Corticostriatal functional connectivity in healthy individuals was initially defined using a data-driven approach. A constrained independent component analysis approach was applied in 100 healthy adult dataset from the Human Connectome Project. Diffusion tractography was also performed to generate white matter tracts. The output of this analysis was used to compare corticostriatal functional connectivity and structural integrity between groups of 42 patients with traumatic brain injury and 21 age-matched controls. Subdivisions of the caudate and putamen had distinct patterns of functional connectivity. Traumatic brain injury patients showed disruption to functional connectivity between the caudate and a distributed set of cortical regions, including the anterior cingulate cortex. Cognitive impairments in the patients were mainly seen in processing speed and executive function, as well as increased levels of apathy and fatigue. Abnormalities of caudate functional connectivity correlated with these cognitive impairments, with reductions in right caudate connectivity associated with increased executive dysfunction, information processing speed and memory impairment. Structural connectivity, measured using diffusion tensor imaging between the caudate and anterior cingulate cortex was impaired and this also correlated with measures of executive dysfunction. We show for the first time that altered subcortical connectivity is associated with large-scale network disruption in traumatic brain injury and that this disruption is related to the cognitive impairments seen in these patients.
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Lesiones Traumáticas del Encéfalo/complicaciones , Núcleo Caudado/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Función Ejecutiva/fisiología , Giro del Cíngulo/diagnóstico por imagen , Adulto , Anciano , Animales , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/psicología , Mapeo Encefálico , Estudios de Casos y Controles , Conectoma , Imagen de Difusión Tensora , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Adulto JovenRESUMEN
Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.
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Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Microglía/efectos de los fármacos , Minociclina/uso terapéutico , Enfermedades Neurodegenerativas/etiología , Adulto , Anciano , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Estudios Transversales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Microglía/patología , Persona de Mediana Edad , Enfermedades Neurodegenerativas/inducido químicamente , Proteínas de Neurofilamentos/metabolismo , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Pirimidinas/farmacocinética , Estadísticas no Paramétricas , Adulto JovenRESUMEN
OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.
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Lesiones Traumáticas del Encéfalo/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Sustancia Blanca/patología , Adulto , Anisotropía , Estudios de Casos y Controles , Imagen de Difusión Tensora , Femenino , Hormona del Crecimiento/deficiencia , Humanos , Cápsula Interna/patología , Estudios Longitudinales , Masculino , Neuroimagen , Pruebas Neuropsicológicas , Músculos Paraespinales/patología , Calidad de Vida , Adulto JovenAsunto(s)
Memoria Episódica , Anciano , Envejecimiento , Encéfalo/diagnóstico por imagen , Cognición , HumanosRESUMEN
PURPOSE: PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [11C]PK-11195 limits accurate quantification. [18F]GE-180, a novel TSPO ligand, displays superior binding to [11C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [18F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. METHODS: Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [18F]GE-180. Kinetic modelling of time-activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. RESULTS: The two-tissue compartment model was the best model. The average regional delivery rate constant (K 1) was 0.01 mL cm-3 min-1 indicating low extraction across the blood-brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm-3 in the striatum to 0.38 mL cm-3 in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. CONCLUSION: A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [18F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.
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Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Carbazoles/farmacocinética , Interpretación de Imagen Asistida por Computador/métodos , Tomografía de Emisión de Positrones/métodos , Receptores de GABA/metabolismo , Adulto , Algoritmos , Simulación por Computador , Humanos , Aumento de la Imagen/métodos , Cinética , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Neurológicos , Imagen Molecular/métodos , Radiofármacos/farmacocinética , Receptores de GABA/genética , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Background: Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined. Methods: In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA-/-, Aicda-/-, CD19-/- and JH -/-) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy). Results: Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively. Conclusions: Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.
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Modelos Animales de Enfermedad , Citometría de Flujo , Intestino Delgado , Animales , Ratones , Citometría de Flujo/métodos , Intestino Delgado/inmunología , Intestino Delgado/patología , Ratones Noqueados , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Ratones Endogámicos C57BL , Linfocitos B/inmunología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/patologíaRESUMEN
Background: Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined. Methods: In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA -/- , Aicda -/- , CD19 -/- and J H -/- ) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy). Results: Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively. Conclusions: Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.
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BACKGROUND: Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. METHODS: Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. RESULTS: Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (ß = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. CONCLUSION: In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. DATA ACCESS STATEMENT: Data for this study are available from the corresponding author upon reasonable request.
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Enfermedades de los Pequeños Vasos Cerebrales , Fatiga , Inflamación , Tomografía de Emisión de Positrones , Humanos , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Masculino , Femenino , Anciano , Fatiga/etiología , Persona de Mediana Edad , Imagen por Resonancia Magnética , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Isoquinolinas , Enfermedades Neuroinflamatorias/complicacionesRESUMEN
BACKGROUND: Sleep disturbances are a potentially modifiable risk factor for neurodegenerative dementia secondary to Alzheimer disease (AD) and Lewy body disease (LBD). Therefore, we need to identify the best methods to study sleep in this population. OBJECTIVE: This study will assess the feasibility and acceptability of various wearable devices, smart devices, and remote study tasks in sleep and cognition research for people with AD and LBD. METHODS: We will deliver a feasibility and acceptability study alongside a prospective observational cohort study assessing sleep and cognition longitudinally in the home environment. Adults aged older than 50 years who were diagnosed with mild to moderate dementia or mild cognitive impairment (MCI) due to probable AD or LBD and age-matched controls will be eligible. Exclusion criteria include lack of capacity to consent to research, other causes of MCI or dementia, and clinically significant sleep disorders. Participants will complete a cognitive assessment and questionnaires with a researcher and receive training and instructions for at-home study tasks across 8 weeks. At-home study tasks include remote sleep assessments using wearable devices (electroencephalography headband and actigraphy watch), app-based sleep diaries, online cognitive assessments, and saliva samples for melatonin- and cortisol-derived circadian markers. Feasibility outcomes will be assessed relating to recruitment and retention, data completeness, data quality, and support required. Feedback on acceptability and usability will be collected throughout the study period and end-of-study interviews will be analyzed using thematic analysis. RESULTS: Recruitment started in February 2022. Data collection is ongoing, with final data expected in February 2024 and data analysis and publication of findings scheduled for the summer of 2024. CONCLUSIONS: This study will allow us to assess if remote testing using smart devices and wearable technology is a viable alternative to traditional sleep measurements, such as polysomnography and questionnaires, in older adults with and without MCI or dementia due to AD or LBD. Understanding participant experience and the barriers and facilitators to technology use for research purposes and remote research in this population will assist with the development of, recruitment to, and retention within future research projects studying sleep and cognition outside of the clinic or laboratory. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52652.
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BACKGROUND AND OBJECTIVES: Apathy is one of the most common symptoms following stroke and is often associated with worse functional outcome and poor quality of life (QoL). The trajectory of apathy symptoms has been previously described, and different trajectories have been identified. We determined group and individual changes in apathy symptomatology from the acute phase until 1 year after stroke. We also examined the association of apathy and depression with disability and QoL 1 year after stroke. METHODS: We measured apathy in a cohort of ischemic stroke survivors at 4 time points from 0 to 12 months after stroke. The Apathy Evaluation Scale (AES) and Dimensional Apathy Scale (DAS) were administered at each time point. Where possible we obtained apathy measured from carers. Depression was assessed with the Geriatric Depression Scale (GDS). Disability and QoL were assessed with the modified Rankin Scale (mRS) and 36-Item Short Form Survey (SF-36). We examined the cross-sectional and individual trajectory of apathy symptoms in each dimension and looked at associations of apathy and depression soon after stroke with mRS and SF-36 at 1 year. RESULTS: Of 200 participants enrolled, 165 completed apathy measures at 12 months. Patient-rated apathy scores increased in both tests at the group level (AES: χ2(3) = 9.86, p = 0.019; DAS: χ2(3) = 8.49, p = 0.037) and individual level (AES: ß = 0.13, p = 0.002; DAS ß = 0.13, p = 0.005; DAS: executive ß = 0.08, p < 0.001). By contrast, carer-rated apathy did not significantly increase (AES: χ2(3) = 0.75, p = 0.862; DAS: χ2(3) = 2.45, p = 0.484). Apathy scores were associated with worse mRS and SF-36, although most associations were no longer significant when controlling for depression. GDS was associated with worse mRS and SF-36 after controlling for covariates and apathy (mRS: ß = 0.08, p = 0.006; SF-36 Mental Component Summary: ß = -1.53, p < 0.001; SF-36 Physical Component Summary: ß = -0.57, p = 0.016). DISCUSSION: Self-reported apathy progressively increases after stroke, especially in the executive dimension. Apathy is associated with worse QoL and greater disability, although some of these associations might be mediated by depression.
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Apatía , Accidente Cerebrovascular , Humanos , Anciano , Calidad de Vida , Estudios Transversales , Escalas de Valoración Psiquiátrica , Accidente Cerebrovascular/complicacionesRESUMEN
BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.
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BACKGROUND: Fatigue is a common and disabling symptom following stroke, but its underlying mechanisms are unknown. Associations with a number of imaging features have been proposed. AIMS: We aimed to assess whether neuroimaging parameters could better inform our understanding of possible causes of post-stroke fatigue (PSF) through systematic review and meta-analysis. METHODS: Using a predefined protocol registered with PROSPERO (ID: CRD42022303168), we searched EMBASE, MEDLINE, PubMed, and PsycInfo for studies assessing PSF and computerized tomography (CT), magnetic resonance (MR), positron emission tomography (PET) imaging, or diffusion tensor imaging (DTI). We extracted neuroimaging parameters and narratively analyzed study results to assess any association with PSF. Where there were 3+ similar studies, we carried out a meta-analysis using inverse-variance random-effects model to estimate the total association of each neuroimaging parameter on PSF. The risk of bias was assessed using the Newcastle and Ottawa Scale. RESULTS: We identified 46 studies (N = 6543); in many studies, associations with fatigue were secondary or subanalyses (28.3%). Imaging parameters were assessed across eight variables: lesion lateralization, lesion location, lesion volume, brain atrophy, infarct number, cerebral microbleeds, white matter hyperintensities (WMHs), and network measures. Most variables showed no conclusive evidence for any association with fatigue. Meta-analysis, where possible, showed no association of the following with PSF; left lesion lateralization (OR: 0.88, 95% CI (0.64, 1. 22) (p = 0.45)), infratentorial lesion location (OR: 1.83, 95% CI (0.63, 5.32) (p = 0.27)), and WMH (OR: 1.21, 95% CI (0.84, 1.75) (p = 0.29)). Many studies assessed lesion location with mixed findings; only one used voxel-symptom lesion-mapping (VSLM). Some small studies suggested an association between altered functional brain networks, namely frontal, fronto-striato-thalamic, and sensory processing networks, with PSF. CONCLUSION: There was little evidence for the association between any neuroimaging parameters and PSF. Future studies should utilize advanced imaging techniques to fully understand the role of lesion location in PSF, while the role of altered brain networks in mediating PSF merits further research.