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OBJECTIVE: To examine participants' experiences with peer-support after lower limb loss (LLL) and the associations between the peer-support experience (perceived benefits and barriers) and mobility outcomes. DESIGN: Quantitative and qualitative descriptive study with a cross-sectional design. SETTING: National survey (distributed to 169 peer-support groups in 44 states in the US). PARTICIPANTS: The survey was completed by 82 individuals with a major lower limb amputation (53% female, 54% over 55 years of age; N=82). MAIN OUTCOME MEASURES: A 32-item survey to examine respondents' experiences in peer-support activities. Prosthetic mobility was measured using the Prosthetic Limb Users Survey of Mobility (PLUS-M). RESULTS: Two out of 3 respondents received some forms of peer-support after amputation. Among them 75% reported peer-support having a positive effect on their outlook on life, and 78% reported that information gained from peer-support was helpful. Companionship, altruistic acts, and gaining information on how to cope with amputation were the top themes of why respondents enjoyed the peer-support experience. Nearly all (94%) respondents would recommend peer-support to other people with LLL. Individuals who received peer-support exhibited a trend of greater mobility (55th vs 36th percentile on PLUS-M; P=.055). CONCLUSION: Individuals with LLL reported generally positive experiences regarding their engagement in peer-support activities. Peer-support groups are viewed as a helpful source for both information and emotional support, potentially benefiting functional and psychological recovery after amputation. Individuals who have received peer-support also exhibited greater mobility.
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Miembros Artificiales , Extremidad Inferior , Grupo Paritario , Apoyo Social , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Estados Unidos , Miembros Artificiales/psicología , Extremidad Inferior/cirugía , Anciano , Adulto , Amputación Quirúrgica/rehabilitación , Amputación Quirúrgica/psicología , Amputados/rehabilitación , Amputados/psicología , Limitación de la Movilidad , Grupos de AutoayudaRESUMEN
Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid ß-protein (Aß42) forms and novel intraneuronal Aß oligomers (AßOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aß uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aß42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aß pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aß42, far-peripheral AßOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.
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Enfermedad de Alzheimer , Masculino , Humanos , Femenino , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Proteoma/metabolismo , Proteómica , Retina/patología , Atrofia/patología , Biomarcadores/metabolismoRESUMEN
INTRODUCTION: Vascular amyloid beta (Aß) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that the retinal vascular tight junctions (TJs) were compromised and linked to disease status. METHODS: TJ components and Aß expression in capillaries and larger blood vessels were determined in post mortem retinas from 34 MCI or AD patients and 27 cognitively normal controls and correlated with neuropathology. RESULTS: Severe decreases in retinal vascular zonula occludens-1 (ZO-1) and claudin-5 correlating with abundant arteriolar Aß40 deposition were identified in MCI and AD patients. Retinal claudin-5 deficiency was closely associated with cerebral amyloid angiopathy, whereas ZO-1 defects correlated with cerebral pathology and cognitive deficits. DISCUSSION: We uncovered deficiencies in blood-retinal barrier markers for potential retinal imaging targets of AD screening and monitoring. Intense retinal arteriolar Aß40 deposition suggests a common pathogenic mechanism of failed Aß clearance via intramural periarterial drainage.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Retina , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/patología , Claudina-5/metabolismo , Uniones Estrechas/metabolismo , Uniones Estrechas/patología , Retina/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patologíaRESUMEN
Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2-10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aß release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aß42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aß. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aß within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Sinapsis/metabolismo , Sinaptosomas/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Agregación Patológica de ProteínasRESUMEN
BACKGROUND & AIMS: Given that standardized language measures alone are inadequate for identifying functionally defined developmental language disorder (fDLD), this study investigated whether non-linguistic cognitive abilities (procedural learning, motor functions, executive attention, processing speed) can increase the prediction accuracy of fDLD in children in linguistically diverse settings. METHODS & PROCEDURES: We examined non-linguistic cognitive abilities in mono- and bilingual school-aged children (ages 8-12) with and without fDLD. Typically developing (TD) children (14 monolinguals, 12 bilinguals) and children with fDLD (28 monolinguals, 12 bilinguals) completed tasks measuring motor functions, procedural learning, executive attention and processing speed. Children were assigned as fDLD based on parental or professional concerns regarding children's daily language functioning. If no concerns were present, children were assigned as TD. Standardized English scores, non-verbal IQ scores and years of maternal education were also obtained. Likelihood ratios were used to examine how well each measure separated the fDLD versus TD groups. A binary logistic regression was used to test whether combined measures enhanced the prediction of identifying fDLD status. OUTCOMES & RESULTS: A combination of linguistic and non-linguistic measures provided the best distinction between fDLD and TD for both mono- and bilingual groups. For monolingual children, the combined measures include English language scores, functional motor abilities and processing speed, whereas for bilinguals, the combined measures include English language scores and procedural learning. CONCLUSIONS & IMPLICATIONS: A combination of non-linguistic and linguistic measures significantly improved the distinction between fDLD and TD for both mono- and bilingual groups. This study supports the possibility of using non-linguistic cognitive measures to identify fDLD in linguistically diverse settings. WHAT THIS PAPER ADDS: What is already known on the subject Given that standardized English language measures may fail to identify functional language disorder, we examined whether supplementing English language measures with non-linguistic cognitive tasks could resolve the problem. Our study is based on the hypothesis that non-linguistic cognitive abilities contribute to language processing and learning. This is further supported by previous findings that children with language disorder exhibit non-linguistic cognitive deficits. What this paper adds to existing knowledge The results indicated that a combination of linguistic and non-linguistic cognitive abilities increased the prediction of functional language disorder in both mono- and bilingual children. What are the potential or actual clinical implications of this work? This study supports the possibility of using non-linguistic cognitive measures to identify the risk of language disorder in linguistically diverse settings.
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Trastornos del Desarrollo del Lenguaje , Multilingüismo , Niño , Cognición , Humanos , Lenguaje , Trastornos del Desarrollo del Lenguaje/diagnóstico , Pruebas del LenguajeRESUMEN
Apolipoprotein E (apoE) colocalizes with amyloid-ß (Aß) in Alzheimer disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and Aß are important for apoE's effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/Aß complex into synaptic terminals. Western blot analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/Aß complex was markedly increased in AD compared with aged control samples. Complex formation between apoE and Aß was confirmed by coimmunoprecipitation experiments. The apoE receptors low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early- and late-stage AD. Dual-labeling flow cytometry analysis of LRP1- and LDLR positives indicate most (approximately 65%) of LDLR and LRP1 is associated with postsynaptic density-95 (PSD-95)-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual-labeling experiments showed apoE and Aß concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic Aß was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/Aß complex and associated lipids into synaptic terminals, with subsequent Aß clearance in control synapses and accumulation in AD synapses.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteínas E/metabolismo , Corteza Cerebral/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Receptores de LDL/metabolismo , Sinapsis/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Corteza Cerebral/patología , Homólogo 4 de la Proteína Discs Large/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sinapsis/patología , Sinaptosomas/metabolismo , Sinaptosomas/patologíaRESUMEN
Pericyte loss and deficient vascular platelet-derived growth factor receptor-ß (PDGFRß) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid ß-protein (Aß) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aß deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRß in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRß loss significantly associated with increased retinal vascular Aß40 and Aß42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRß and Aß40 levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aß burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRß loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.
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Enfermedad de Alzheimer/patología , Amiloidosis/patología , Encéfalo/patología , Pericitos/patología , Retina/patología , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidosis/complicaciones , Barrera Hematoencefálica/patología , Angiopatía Amiloide Cerebral/patología , Cognición/fisiología , Femenino , Humanos , MasculinoRESUMEN
Amyloid-ß (Aß) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aß and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aß and p-tau in large populations of individual synaptic terminals. Soluble Aß oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aß was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aß oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aß-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aß drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Sinapsis/patología , Proteínas tau/análisis , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Microscopía Confocal , Fosforilación , Ratas , Ratas TransgénicasRESUMEN
The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from pre-synaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the pre-synaptic compartment in AD. Results demonstrate the abundance of tau, mainly C-terminal truncated tau, in synaptic terminals in aged control and in Alzheimer's disease (AD) samples. Tau fragments and dimers/oligomers are prominent in AD synapses. Following depolarization, tau release is potentiated in AD nerve terminals compared to aged controls. We hypothesize (i) endosomal release of the different tau peptides from AD synapses, and (ii) together with phosphorylation, fragmentation of synaptic tau exacerbates tau aggregation, synaptic dysfunction, and the spread of tau pathology in AD. Aß = amyloid-beta.
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Enfermedad de Alzheimer/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Terminales Presinápticos/metabolismo , Sinapsis/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-ß (Aß) levels. Evidence suggests physical interactions between apoE and Aß are partially responsible for these functional effects. However, the apoE/Aß complex is not a single static structure; rather, it is defined by detection methods. Thus, literature results are inconsistent and difficult to interpret. An ELISA was developed to measure soluble apoE/Aß in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/Aß and an increase in soluble Aß, specifically oligomeric Aß (oAß), are associated with APOE4 and AD. Previously, soluble Aß42 and oAß levels were greater with APOE4 compared with APOE2/APOE3 in hippocampal homogenates from EFAD transgenic mice (expressing five familial AD mutations and human apoE isoforms). In this study, soluble apoE/Aß levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/Aß levels isoform-specifically modulate soluble oAß clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/Aß levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/Aß levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total Aß42 levels decreased in AD patients compared with controls, oAß levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/Aß modulates oAß levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteínas E/metabolismo , Animales , Apolipoproteína E4/genética , Biomarcadores/metabolismo , Encéfalo/metabolismo , Estudios de Cohortes , Cruzamientos Genéticos , Ensayo de Inmunoadsorción Enzimática/métodos , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Modelos Biológicos , Modelos Genéticos , Isoformas de Proteínas , Sinaptosomas/metabolismoRESUMEN
BACKGROUND: The neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular vesicles (EVs) hold enormous diagnostic and therapeutic potential in neurodegenerative disorders including Alzheimer's disease (AD). NEW METHOD: Postmortem AD cortical samples were thawed and gently dissociated. Following filtration, myelin and red blood cell removal, cell pellets were immunolabeled with fluorescent antibodies and analyzed by flow cytometry. The cell pellet supernatant was applied to a triple sucrose cushion for brain EV isolation. RESULTS: Neuronal, astrocyte and microglial cell populations were identified. Cell integrity was demonstrated using calcein AM, which is retained by cells with esterase activity and an intact membrane. For some experiments cell pellets were fixed, permeabilized, and immunolabeled for cell-specific markers. Characterization of brain small EV fractions showed the expected size, depletion of EV negative markers, and enrichment in positive and cell-type specific markers. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: We optimized and integrated established protocols, aiming to maximize information obtained from each human autopsy brain sample. The uniqueness of our method lies in its capability to isolate cells and EVs from a single cryopreserved brain sample. Our results not only demonstrate the feasibility of isolating specific brain cell subpopulations for RNA-seq but also validate these subpopulations at the protein level. The accelerated study of EVs from human samples is crucial for a better understanding of their contribution to neuron/glial crosstalk and disease progression.
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Enfermedad de Alzheimer , Separación Celular , Corteza Cerebral , Vesículas Extracelulares , Enfermedad de Alzheimer/patología , Vesículas Extracelulares/patología , Separación Celular/métodos , Corteza Cerebral/patología , Humanos , Criopreservación , Autopsia , RNA-Seq , Neuroglía/patología , Neuronas/patologíaRESUMEN
The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid ß-protein (Aß) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aß deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.
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Enfermedad de Alzheimer , Retina , Enfermedades de la Retina , Enfermedad de Alzheimer/fisiopatología , Humanos , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/diagnóstico , Retina/fisiopatología , Animales , Tomografía de Coherencia Óptica/métodos , Péptidos beta-Amiloides/metabolismo , Vasos Retinianos/fisiopatología , Vasos Retinianos/diagnóstico por imagenRESUMEN
BACKGROUND: More limited working memory capacity and slower processing for language and cognitive tasks are characteristics of many children with language difficulties. Individual differences in processing speed have not consistently been found to predict language ability or severity of language impairment. There are conflicting views on whether working memory and processing speed are integrated or separable abilities. AIMS: To evaluate four models for the relations of individual differences in children's processing speed and working memory capacity in sentence imitation. The models considered whether working memory and processing speed are integrated or separable, as well as the effect of the number of operations required per sentence. The role of working memory as a mediator of the effect of processing speed on sentence imitation was also evaluated. METHODS & PROCEDURES: Forty-six children with varied language and reading abilities imitated sentences. Working memory was measured with the Competing Language Processing Task (CLPT), and processing speed was measured with a composite of truth-value judgment and rapid automatized naming tasks. Mixed-effects ordinal regression models evaluated the CLPT and processing speed as predictors of sentence imitation item scores. A single mediator model evaluated working memory as a mediator of the effect of processing speed on sentence imitation total scores. OUTCOMES & RESULTS: Working memory was a reliable predictor of sentence imitation accuracy, but processing speed predicted sentence imitation only as a component of a processing speed by number of operations interaction. Processing speed predicted working memory capacity, and there was evidence that working memory acted as a mediator of the effect of processing speed on sentence imitation accuracy. CONCLUSIONS & IMPLICATIONS: The findings support a refined view of working memory and processing speed as separable factors in children's sentence imitation performance. Processing speed does not independently explain sentence imitation accuracy for all sentence types, but contributes when the task requires more mental operations. Processing speed also has an indirect effect on sentence imitation by contributing to working memory capacity.
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Lenguaje Infantil , Desarrollo del Lenguaje , Trastornos del Lenguaje/fisiopatología , Memoria a Corto Plazo/fisiología , Percepción del Habla/fisiología , Adolescente , Niño , Comprensión , Femenino , Humanos , Trastornos del Lenguaje/diagnóstico , Pruebas del Lenguaje , Modelos Lineales , Masculino , Tiempo de Reacción/fisiologíaRESUMEN
To better understand early predictors of weak language and academic abilities, we identified children with and without weak abilities at age 8. We then looked back at age 2 vocabulary and word combining, and evaluated these measures as predictors of age 8 outcomes. More than 60% of children with weak oral language abilities at 8 were not late talkers at 2. However, no word combining at 2 was a significant risk factor for poor oral language, reading comprehension, and math outcomes at 8. The association of no word combining with age 8 reading comprehension and math ability was mediated by age 8 oral language ability. The findings indicate that children take different developmental pathways to weak language abilities in middle childhood. One begins with a delayed onset of language. A second begins with language measures in the typical range, but ends with language ability falling well below typical peers.
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PURPOSE: This tutorial aims to introduce school-based speech-language pathologists (SLPs) to developmental systems theory as a framework for considering interactions across functional domains, such as language, vision, and motor, for students with complex needs. METHOD: This tutorial summarizes the current literature on developmental systems theory in its application to working with students who have needs in multiple domains of functioning in addition to communication. A hypothetical case of a student, James, with cerebral palsy, cortical visual impairment, and complex communication needs, is presented to illustrate the primary tenets of the theory. RESULTS: Specific reason-based recommendations are presented that SLPs can put to practice with their own caseload in direct response to the three tenets of developmental systems theory. CONCLUSIONS: A developmental systems approach will be useful in expanding SLP knowledge of where to begin and how to best serve children with language, motor, vision, and other concomitant needs. The tenets, including sampling, context dependency, and interdependency, and the application of developmental systems theory can be instrumental in providing a way forward for SLPs struggling with the assessment and intervention of students with complex needs.
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Trastornos de la Comunicación , Patología del Habla y Lenguaje , Niño , Humanos , Estudiantes , Lenguaje , Comunicación , Análisis de Sistemas , Patología del Habla y Lenguaje/educación , HablaRESUMEN
The dentate gyrus (DG) is an integral portion of the hippocampal formation, and it is composed of three layers. Quantitative magnetic resonance (MR) imaging has the capability to map brain tissue microstructural properties which can be exploited to investigate neurodegeneration in Alzheimer's disease (AD). However, assessing subtle pathological changes within layers requires high resolution imaging and histological validation. In this study, we utilized a 16.4 Tesla scanner to acquire ex vivo multi-parameter quantitative MRI measures in human specimens across the layers of the DG. Using quantitative diffusion tensor imaging (DTI) and multi-parameter MR measurements acquired from AD (N = 4) and cognitively normal control (N = 6) tissues, we performed correlation analyses with histological measurements. Here, we found that quantitative MRI measures were significantly correlated with neurofilament and phosphorylated Tau density, suggesting sensitivity to layer-specific changes in the DG of AD tissues.
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Enfermedad de Alzheimer , Imagen de Difusión Tensora , Humanos , Imagen de Difusión Tensora/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Imagen por Resonancia Magnética/métodos , Encéfalo/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Giro Dentado/diagnóstico por imagen , Giro Dentado/patologíaRESUMEN
Amyloid-beta (Aß) is thought to play a central role in synaptic dysfunction (e.g. neurotransmitter release) and synapse loss. Glutamatergic dysfunction is involved in the pathology of Alzheimer's disease (AD) and perhaps plays a central role in age-related cognitive impairment. Yet, it is largely unknown whether Aß accumulates in excitatory boutons. To assess the possibility that glutamatergic terminals are lost in AD patients, control and AD synaptosomes were immunolabeled for the most abundant vesicular glutamate transporters (VGluT1 and VGluT2) and quantified by flow cytometry and immunoblot methods. In post-mortem parietal cortex from aged control subjects, glutamatergic boutons are fairly abundant as approximately 40% were immunoreactive for VGluT1 (37%) and VGluT2 (39%). However, the levels of these specific markers of glutamatergic synapses were not significantly different among control and AD cases. To test the hypothesis that Aß is associated with excitatory terminals, AD synaptosomes were double-labeled for Aß and for VGluT1 and VGluT2, and analyzed by flow cytometry and confocal microscopy. Our study demonstrated that Aß immunoreactivity (IR) was present in glutamatergic terminals of AD patients. Quantification of Aß and VGluT1 in a large population of glutamatergic nerve terminals was performed by flow cytometry, showing that 42% of VGluT1 synaptosomes were immunoreactive for Aß compared to 9% of VGluT1 synaptosomes lacking Aß-IR. Percentage of VGluT2 synaptosomes immunoreactive for Aß (21%) was significantly higher than VGluT2 synaptosomes lacking Aß-IR (9%). Moreover, Aß preferentially affects VGluT1 (42% positive) compared to VGluT2 terminals (21%). These data represent the first evidence of high levels of Aß in excitatory boutons in AD cortex and support the hypothesis that Aß may play a role in modulating glutamate transmission in AD terminals.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/metabolismo , Ácido Glutámico/metabolismo , Terminales Presinápticos/metabolismo , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Sinaptosomas/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
The apolipoprotein E4 allele (APOE4) contributes to Alzheimer's disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aß) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aß in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aß in individual synapses with concentration of Aß in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aß-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aß compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aß closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aß clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aß clearance and synaptic function.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Colesterol/metabolismo , Terminales Presinápticos/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Apolipoproteína E2/metabolismo , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ratas , Ratas TransgénicasRESUMEN
BACKGROUND: Physical activity has been shown to be fundamental in the prevention of numerous diseases and disorders. Achieving and maintaining physical activity levels can be particularly challenging in those with impairments, such as those experiencing a lower limb amputation. To slow the spread of the virus, COVID-19 lockdown mandates imposed by the US state governments may have inadvertent consequences on physical activity levels of those dependent on specific forms of exercise. Understanding how physical activity levels may have affected persons with limb loss can inform intervention strategies for this vulnerable population. OBJECTIVES: Examine the effects of the COVID-19 pandemic on physical activity levels in persons with limb loss. STUDY DESIGN: Mixed-method design. METHODS: A 20-item logic web-based survey and semistructured interviews were administered to individuals who were 18 years or older, spoke English, and had a history of lower limb loss. Quantitative data were analyzed using SPSS v25, whereas qualitative data were analyzed using constant comparison to formulate themes. RESULTS: There were a significant effect on the amount of physical activity minutes performed per day, a negative effect on the ability to exercise and participate in societal engagements, and a series of barriers to performing physical activity because of the pandemic. CONCLUSION: Physical activity was reduced significantly in persons with limb loss during the COVID-19 pandemic. A combination of health concerns, fitness center closures, and social distancing mandates were the primary drivers behind the decrease in activity.
Asunto(s)
Amputados , COVID-19 , Control de Enfermedades Transmisibles , Ejercicio Físico , Humanos , Pandemias/prevención & control , Estados UnidosRESUMEN
Abnormally phosphorylated tau, an indicator of Alzheimer's disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain's main noradrenaline supply. However, technical challenges in in-vivo assessments have impeded research into the role of the LC in Alzheimer's disease. We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer's disease (ADAD) with early onset, providing a unique window into the pathogenesis of Alzheimer's largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post-mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC. Our findings link LC degeneration to tau burden and memory in Alzheimer's, and highlight a role of the noradrenergic system in this neurodegenerative disease.