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BACKGROUND AND PURPOSE: Various blood biomarkers reflecting brain amyloid-ß (Aß) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. METHODS: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aß40, Aß42, Aß42/Aß40 and the amplified plasmonic exosome (APEX) Aß42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aß+) participants. RESULTS: Compared to Simoa biomarkers, APEX-Aß42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aß42 and 48.6% for Simoa-Aß42/Aß40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aß42 pre-screening does not increase the required number of initial participants. CONCLUSIONS: With its high diagnostic performance, APEX is an ideal candidate for Aß+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aß+ participants whilst halving recruitment costs.
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Enfermedad de Alzheimer , Exosomas , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides , Biomarcadores , Humanos , Inmunoensayo , Fragmentos de PéptidosRESUMEN
Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.
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Enfermedad de Alzheimer/genética , Herencia Multifactorial/genética , Caracteres Sexuales , Anciano , Progresión de la Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-ß protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Herencia Multifactorial/genética , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genéticaRESUMEN
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.
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Enfermedad de Alzheimer/genética , Enfermedades Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteínas E/genética , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. CONCLUSIONS: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.
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Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Anciano , Humanos , Persona de Mediana EdadRESUMEN
[This corrects the article DOI: 10.1371/journal.pmed.1002487.].
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Purpose To evaluate whether patients with neurofibromatosis type 1 (NF1)-a multisystem neurodevelopmental disorder with myriad imaging manifestations, including focal transient myelin vacuolization within the deep gray nuclei, brainstem, and cerebellum-exhibit differences in cortical and subcortical structures, particularly in subcortical regions where these abnormalities manifest. Materials and Methods In this retrospective study, by using clinically obtained three-dimensional T1-weighted MR images and established image analysis methods, 10 intracranial volume-corrected subcortical and 34 cortical regions of interest (ROIs) were quantitatively assessed in 32 patients with NF1 and 245 age- and sex-matched healthy control subjects. By using linear models, ROI cortical thicknesses and volumes were compared between patients with NF1 and control subjects, as a function of age. With hierarchic cluster analysis and partial correlations, differences in the pattern of association between cortical and subcortical ROI volumes in patients with NF1 and control subjects were also evaluated. Results Patients with NF1 exhibited larger subcortical volumes and thicker cortices of select regions, particularly the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami, and occipital cortices. For the thalami and pallida and 22 cortical ROIs in patients with NF1, a significant inverse association between volume and age was found, suggesting that volumes decrease with increasing age. Moreover, compared with those in control subjects, ROIs in patients with NF1 exhibited a distinct pattern of clustering and partial correlations. Discussion Neurofibromatosis type 1 is characterized by larger subcortical volumes and thicker cortices of select structures. Most apparent within the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami and occipital cortices, these neurofibromatosis type 1-associated volumetric changes may, in part, be age dependent. © RSNA, 2018 Online supplemental material is available for this article.
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Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/patología , Niño , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE É4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE É4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488.
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Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Medición de Riesgo , Factores de RiesgoRESUMEN
There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Tomografía de Emisión de Positrones , Pronóstico , Análisis de SupervivenciaRESUMEN
Aging is often accompanied by changes in brain anatomy and cerebrovascular health. However, the specific relationship between declines in regional cortical volumes and loss of cerebral arterial elasticity is less clear, as only global or very localized estimates of cerebrovascular health have been available. Here we employed a novel tomographic optical method (pulse-DOT) to derive local estimates of cerebral arterial elasticity and compared regional volumetric estimates (obtained with FreeSurfer) with optical arterial elasticity estimates from the same regions in 47 healthy adults (aged 18-75). Between-subject analyses revealed a global correlation between cortical volume and cortical arterial elasticity, which was a significant mediator of the association between age and cortical volume. Crucially, a novel within-subject analysis highlighted the spatial association between regional variability in cortical volumes and arterial elasticity in the same regions. This association strengthened with age. Gains in the predictability of cortical volumes from arterial elasticity data were obtained by sharpening the resolution up to individual cortical regions. These results indicate that some of the variance of sub-clinical age-related brain atrophy is associated with differences in the status of cerebral arteries, and can help explain the unique patterns of brain atrophy found within each individual.
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Envejecimiento/patología , Encéfalo/patología , Arterias Cerebrales/patología , Rigidez Vascular , Adolescente , Adulto , Anciano , Atrofia/patología , Encéfalo/irrigación sanguínea , Elasticidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Persona de Mediana Edad , Tomografía Óptica , Adulto JovenRESUMEN
BACKGROUND: White matter hyperintensities (WMHs) represent diffuse small vessel disease implicating the cardiac, systemic, and cerebral vasculatures. As the brain may be the end-organ of cumulative vascular disease, and higher education is protective of both cardiovascular and brain health, we aim to clarify their intertwining relationships. METHODS: We evaluated participants (mean age = 64) from the UK Biobank with neuroimaging measures of WMHs, left ventricular ejection fraction (LVEF) quantified using cardiovascular MRI, and arterial stiffness index (ASI) quantified using finger photoplethysmography. We used multiple regression to evaluate the basic, independent, and interactive relationships of LVEF status (n = 27,512) and ASI (n = 33,584) with WMHs. Moderated mediation analysis was used to determine whether the relationship between LVEF status and WMH was mediated by ASI and moderated by education. RESULTS: Abnormal LVEF (ß = -0.082, p < 0.001) and higher ASI (ß = 0.02, p < 0.001) were associated with greater WMHs separately and independently, but not interactively. Moderated mediation analyses revealed that the relationship between abnormal LVEF and WMH was mediated by ASI, for individuals with lower education (ß = -0.004, p < 0.001). Abnormal LVEF was associated with lower cortical thickness in 16 predominantly frontotemporal and select parietal regions (FDR, q < 0.05). CONCLUSIONS: Cardiovascular dysfunction is associated with regional cerebral atrophy and may precipitate cerebrovascular disease via stiffening of systemic vasculatures, particularly for individuals with lower education. Integrative approaches to study biophysiological vascular systems can elucidate the complex interplay between biological and social determinants of brain and cerebrovascular health.
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Trastornos Cerebrovasculares , Rigidez Vascular , Humanos , Rigidez Vascular/fisiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Trastornos Cerebrovasculares/fisiopatología , Trastornos Cerebrovasculares/diagnóstico por imagen , Función Ventricular Izquierda/fisiología , Volumen Sistólico/fisiología , Reino Unido/epidemiología , Imagen por Resonancia Magnética/métodosRESUMEN
Higher resting heart rate variability (HRV)-an index of more flexible response to environmental stressors, including noxious stimuli-has been linked to reduced perception of experimentally induced pain. However, as stress responses are adapted to one's chronic environments, we propose that chronic exposure to threats captured by one's subjective socioeconomic status (SSS) may shape different adaptations that produce distinct pain responses linked to higher resting HRV. Specifically, lower SSS individuals with more threat exposures may prioritize threat detection by upregulating sensitivity to stressors, such as acute pain. Therefore, higher HRV would predict greater perceived acute pain among lower SSS individuals. In contrast, higher SSS individuals with less threat exposures may instead prioritize affective regulation by downregulating sensitivity to stressors, producing lower pain perception with higher HRV. We examined this stress response moderation by SSS in 164 healthy young adults exposed to experimental pain via the cold pressor test (CPT). Resting HRV, indexed by the root-mean-square of successive differences in heart rate, and self-reported SSS were measured at rest. Pain perception indexed by self-reported pain and pain tolerance indexed by hand-immersion time during the CPT were assessed. Results revealed that among higher SSS individuals, higher resting HRV predicted lower pain reports and subsequently greater pain tolerance during the CPT. Conversely, among lower SSS individuals, higher resting HRV predicted higher pain reports and subsequently lower pain tolerance. These findings provide preliminary evidence that environmental stress exposures linked to one's SSS may shape unique biological adaptations that predict distinct pain responses. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-023-00234-w.
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[This corrects the article DOI: 10.1007/s42761-023-00234-w.].
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BACKGROUND: Cartilage defects are debilitating injuries that can reduce quality of life in patients. However, the poor regenerative properties of cartilage mean that cartilage repair remains challenging, and many methods have arisen to address that. Autologous matrix-induced chondrogenesis (AMIC®) is a popular technique to manage cartilage defects. Recent advances have allowed AMIC® to be done arthroscopically, instead of a mini-open arthrotomy approach. This systematic review and meta-analysis aims to investigate whether the arthroscopic approach to AMIC® provides better clinical outcomes than does the mini-open approach, in hopes of delineating a gold standard in cartilage repair. METHODS: With reference to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search of the following databases (PubMed, Embase, Scopus, and Cochrane Library) was performed on 26th October 2022 using a combination of the following search terms: "autologous matrix induced", "chondrogenesis", and "knee". A total of 390 studies were identified, of which, 24 studies were included in our final analysis. RESULTS: The arthroscopic approach achieves lower Visual Analogue Scale for pain scores. The International Knee documentation Committee) score and Knee Injury and Osteoarthritis Outcome Score were comparable between arthroscopic and open approaches. The open approach achieves a higher Magnetic Resonance Observation of Cartilage Repair Tissue score. Incidence of reported postoperative complications of revision surgery and knee stiffness was higher for the open approach than for the arthroscopic approach, whereas deep vein thrombosis was higher in the arthroscopic approach. CONCLUSION: The AMIC® repair outcomes indicate that the arthroscopic approach does not hold a distinct advantage over the open approach. The choice of approach should consider surgeon expertise, location of lesion, and patient-specific factors. LEVEL OF EVIDENCE: Systematic review and meta-analysis; Level III.
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Enfermedades de los Cartílagos , Cartílago Articular , Humanos , Cartílago Articular/cirugía , Cartílago Articular/lesiones , Condrogénesis , Calidad de Vida , Enfermedades de los Cartílagos/cirugía , Articulación de la Rodilla/cirugíaRESUMEN
There is increasing recognition that socioeconomic inequalities contribute to disparities in brain and cognitive health in older adults. However, whether neighborhood socioeconomic status (SES) buffers individuals with low individual SES against neurodegeneration, cerebrovascular disease, and poorer cognitive function is not well understood. Here, we evaluated whether neighborhood deprivation (Townsend deprivation index) interacted with individual SES (composite household income and education levels) on hippocampus volume, regional cortical thickness, white matter hyperintensities, and cognition in 19,638 individuals (mean age = 54.8) from the UK Biobank. We found that individuals with low individual SES had the smallest hippocampal volumes, greatest white matter hyperintensity burden, and poorest cognition if they were living in high deprivation neighborhoods but that these deleterious effects on brain and cognitive function were attenuated if they were living in low deprivation neighborhoods (p for interactions < .05). While neighborhood deprivation did not interact with individual SES to influence regional cortical thickness, higher neighborhood deprivation was independently associated with lower cortical thickness in 16 regions (false discovery rate q < .05). Across multiple brain indices and cognitive function analyses, we found converging evidence suggesting that low neighborhood deprivation may have a neuroprotective effect against neurodegeneration, cerebrovascular pathology, and cognitive impairment, particularly in vulnerable individuals with low household income and education levels.
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Sustancia Blanca , Humanos , Anciano , Clase Social , Hipocampo , Cognición , EncéfaloRESUMEN
BACKGROUND: The mainstay of surgical management of perforated peptic ulcer is omental patch repair. Advances in minimally invasive techniques have shown feasibility of laparoscopic omental patch repair (LOPR). Laparoscopic omental patch repair is limited by learning curve (LC), but there is a lack of reporting of LC in LOPR. This study aims to compare outcomes following LOPR versus open omental patch repair (OOPR) with reporting of LC. METHODS: PubMed, Embase, The Cochrane Library, and Scopus were systematically searched from inception till January 2022 for randomized controlled trials (RCTs) and non-RCTs comparing LOPR and OOPR in perforated peptic ulcer. Exclusion criteria were primary repair without use of omental patch repair. Primary outcomes were 30-day mortality, postoperative leak, and LC analysis. RESULTS: There were a total of 29 studies including 5,311 patients (LOPR, n = 1,687; OOPR, n = 3,624), with 4 RCTs with 238 patients (LOPR, n = 118; OOPR, n = 120). Majority of ulcers were located in the duodenum (57.0%) followed by stomach (30.7%). Mean ulcer size ranged from 5 to 16.2 mm in LOPR and 4.7 to 15.8 mm in OOPR. Laparoscopic omental patch repair was associated with lower 30-day mortality (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.35-0.92; p = 0.02), overall morbidity (OR, 0.31; 95% CI, 0.18-0.53; p < 0.0001), surgical site infection (OR, 0.27; 95% CI, 0.18-0.42; p < 0.00001), and length of stay (mean difference, -2.84 days; 95% CI, -3.63 to -2.06; p < 0.00001). Postoperative leakage (OR, 1.06; 95% CI, 0.43-2.61; p = 0.90) was comparable between LOPR and OOPR. Only three studies analyzed the proportion of consultants to trainees; LOPR was performed mainly by consultants (range, 82.4-91.4%), while OOPR was mainly performed by trainees (range, 52.8-96.8%). One study showed that consultants who performed open conversion had shorter operating time compared with chief residents (85 vs. 186.6 minutes, p < 0.003). CONCLUSION: Laparoscopic omental patch repair has lower mortality, overall morbidity, length of stay, intraoperative blood loss, and postoperative pain compared with OOPR. More prospective studies should be conducted to evaluate LC in LOPR. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level IV.
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Laparoscopía , Úlcera Péptica Perforada , Humanos , Resultado del Tratamiento , Dolor Postoperatorio , Úlcera Péptica Perforada/cirugía , Laparoscopía/métodos , Duodeno , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Tiempo de InternaciónRESUMEN
How beta-amyloid accumulation influences brain atrophy in Alzheimer's disease remains contentious with conflicting findings. We aimed to elucidate the correlations of regional longitudinal atrophy with cross-sectional regional and global amyloid in individuals with mild cognitive impairment and no cognitive impairment. We hypothesized that greater cortical thinning over time correlated with greater amyloid deposition, particularly within Alzheimer's disease characteristic regions in mild cognitive impairment, and weaker or no correlations in those with no cognitive impairment. 45 patients with mild cognitive impairment and 12 controls underwent a cross-sectional [11C]-Pittsburgh Compound B PET and two retrospective longitudinal structural imaging (follow-up: 23.65 ± 2.04 months) to assess global/regional amyloid and regional cortical thickness, respectively. Separate linear mixed models were constructed to evaluate relationships of either global or regional amyloid with regional cortical thinning longitudinally. In patients with mild cognitive impairment, regional amyloid in the right banks of the superior temporal sulcus was associated with longitudinal cortical thinning in the right medial orbitofrontal cortex (P = 0.04 after False Discovery Rate correction). In the mild cognitive impairment group, greater right banks amyloid burden and less cortical thickness in the right medial orbitofrontal cortex showed greater visual and verbal memory decline over time, which was not observed in controls. Global amyloid was not associated with longitudinal cortical thinning in any locations in either group. Our findings indicate an increasing influence of amyloid on neurodegeneration and memory along the preclinical to prodromal spectrum. Future multimodal studies that include additional biomarkers will be well-suited to delineate the interplay between various pathological processes and amyloid and memory decline, as well as clarify their additive or independent effects along the disease deterioration.
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White matter hyperintensities (WMH) and ß-amyloid (Aß) accumulation have both been linked to neurodegeneration in Alzheimer's disease (AD). However, the independent effects of global WMH and regional Aß on the corresponding regional cortical thickness have not been investigated. Here, we evaluated 280 cognitively normal (CN), 450 mild cognitive impairment (MCI), and 63 individuals with AD dementia separately. In CN individuals, only WMH was associated with lower cortical thickness in fronto-temporal regions, independent of regional Aß deposition in the corresponding cortical regions. In MCI individuals, the spatial pattern of independent WMH associations was predominantly in temporal and cingulate regions, while independent regional Aß associations were now evident in temporal regions. No regional interactions were found. In non-demented individuals and MCI individuals alone, we found that global WMH, composite regional Aß burden and cortical thickness in AD-associated regions all independently predicted progression to AD dementia. Our findings suggest that the independent effects of global WMH and regional Aß on regional cortical thickness are spatially different, converging in temporal regions in MCI individuals.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Sustancia Blanca , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
Comorbid neuropsychiatric symptoms are commonly found in individuals with dementia and is likely influenced by a combination of neurodegenerative and cerebrovascular pathophysiology. We evaluated the associations of a validated composite MRI-based quantitative measure of both neurodegeneration (hippocampus volume and cortical thickness of AD-specific regions) and cerebrovascular disease (CeVD; white matter hyperintensities and infarcts) with neuropsychiatric subsyndromes, and their interactions on cognition in a community-based sample across the disease spectrum (N = 773). Lower composite MRI scores corresponding to greater comorbid neurodegeneration and CeVD burden were associated with hyperactivity (OR = 1.48) and apathy (OR = 1.90) subsyndromes. Lower MRI scores with concomitant hyperactivity was associated with greater cognitive impairment, especially in patients who were at least moderately impaired, while the interaction with apathy was not dependent on disease stage. These MRI scores interaction models resulted in a better fit than models consisting of neurodegeneration or CeVD alone. Integrating multiple biomarkers with specific, disease stage-dependent neuropsychiatric subsyndromes may provide a more holistic risk profile to facilitate the identification of individuals at the highest risk of disease progression.