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The goal of the Biostatistics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been to ensure that sound study designs and statistical methods are used to meet the overall goals of ADNI. We have supported the creation of a well-validated and well-curated longitudinal database of clinical and biomarker information on ADNI participants and helped to make this accessible and usable for researchers. We have developed a statistical methodology for characterizing the trajectories of clinical and biomarker change for ADNI participants across the spectrum from cognitively normal to dementia, including multivariate patterns and evidence for heterogeneity in cognitive aging. We have applied these methods and adapted them to improve clinical trial design. ADNI-4 will offer us a chance to help extend these efforts to a more diverse cohort with an even richer panel of biomarker data to support better knowledge of and treatment for Alzheimer's disease and related dementias. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Biostatistics Core provides study design and analytic support to ADNI investigators. Core members develop and apply novel statistical methodology to work with ADNI data and support clinical trial design. The Core contributes to the standardization, validation, and harmonization of biomarker data. The Core serves as a resource to the wider research community to address questions related to the data and study as a whole.
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INTRODUCTION: Well-chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity. METHODS: We suggest measures that operationalize these criteria and describe a general approach that can be used for inference-based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Ventricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group. DISCUSSION: The methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers. HIGHLIGHTS: A framework for comparison of biomarkers on pre-defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures' performance in clinical validity varies more for dementia than for MCI.
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Introduction: There is a dearth of research on cognitive aging and dementia in Asian Americans, particularly in Vietnamese Americans, the fourth largest Asian subgroup in the United States. Methods: The Vietnamese Insights into Cognitive Aging Program (VIP) investigates early life adversity and war-related trauma and their associations with cognitive health in a community-based sample of older Vietnamese Americans in Northern California (i.e., Sacramento and Santa Clara counties). Baseline measurements include a comprehensive neuropsychological battery, including measures of global cognition along with executive function, semantic memory, and episodic memory. Data also include measures of functioning, early life adversity and trauma exposure, and psychosocial and traditional cardiovascular disease risk factors. Cognitive assessments will be repeated twice over the course of the data collection period, approximately 12- and 24- months post-baseline. Blood samples collected during Wave 2 will be assayed for biochemical risk factors. Results: Baseline assessments were conducted from January 2022 to November 2023, with N = 548 Vietnamese Americans; mean age ± SD was 73 ± 5.31 years and 55% of participants were women. There were significant differences in social factors by site, with Santa Clara participants having higher education (some college or higher: Sacramento, ≈25%; Santa Clara: ≈48%) and marginally higher incomes compared to Sacramento participants. A higher percentage of Santa Clara participants reported speaking English well or very well (24%) compared to Sacramento participants (13%), although the majority of the entire sample (81%) reported speaking some to no English (response options: not at all; some/a little bit; well/very well). Discussion: This longitudinal study providea a unique opportunity to more fully delineate psychosocial factors that contribute to dementia disparities in diverse and under-engaged populations. Future work will examine cognition, the prevalence of mild cognitive impairment and dementia, and other health outcomes, while controlling for site differences in all analyses. Highlights: Vietnamese Insights into Cognitive Aging Program (VIP) is a new study.VIP has detailed early life and health data on 548 older Vietnamese Americans.History of war and trauma may contribute to Alzheimer's disease and related dementias (ADRD)-related burden.VIP may provide insight into ADRD burden in other understudied groups.
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BACKGROUND: Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD. METHODS: Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization). RESULTS: Over a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model. CONCLUSIONS: The present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.
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Adaptação Psicológica , Cognição , Deficiências do Desenvolvimento , Deficiência Intelectual , Humanos , Masculino , Criança , Adolescente , Feminino , Adaptação Psicológica/fisiologia , Adulto Jovem , Adulto , Cognição/fisiologia , Estudos Longitudinais , Atividades Cotidianas , Socialização , Síndrome de Down/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologiaRESUMO
Introduction: The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. Methods: In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. Results: LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). Discussion: These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.
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High-density lipoproteins (HDLs) are key regulators of cellular cholesterol homeostasis but are functionally altered in many chronic diseases. The factors that cause HDL functional loss in chronic disease are not fully understood. It is also unknown what roles antioxidant carotenoids play in protecting HDL against functional loss. The aim of this study was to measure how various disease-associated chemical factors including exposure to (1) Cu2+ ions, (2) hypochlorous acid (HOCL), (3) hydrogen peroxide (H2O2), (4) sialidase, (5) glycosidase, (6) high glucose, (7) high fructose, and (8) acidic pH, and the carotenoid antioxidants (9) lutein and (10) zeaxanthin affect HDL functionality. We hypothesized that some of the modifications would have stronger impacts on HDL particle structure and function than others and that lutein and zeaxanthin would improve HDL function. HDL samples were isolated from generally healthy human plasma and incubated with the corresponding treatments listed above. Cholesterol efflux capacity (CEC), lecithin-cholesterol acyl transferase (LCAT) activity, and paraoxonase-1 (PON1) activity were measured in order to determine changes in HDL functionality. Median HDL particle diameter was increased by acidic pH treatment and reduced by HOCl, high glucose, high fructose, N-glycosidase, and lutein treatments. Acidic pH, oxidation, and fructosylation all reduced HDL CEC, whereas lutein, zeaxanthin, and sialidase treatment improved HDL CEC. LCAT activity was reduced by acidic pH, oxidation, high fructose treatments, and lutein. PON1 activity was reduced by sialidase, glycosidase, H2O2, and fructose and improved by zeaxanthin and lutein treatment. These results show that exposure to oxidizing agents, high fructose, and low pH directly impairs HDL functionality related to cholesterol efflux and particle maturation, whereas deglycosylation impairs HDL antioxidant capacity. On the other hand, the antioxidants lutein and zeaxanthin improve or preserve both HDL cholesterol efflux and antioxidant activity but have no effect on particle maturation.
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Previous studies have reported alterations in cortical thickness in autism. However, few have included enough autistic females to determine if there are sex specific differences in cortical structure in autism. This longitudinal study aimed to investigate autistic sex differences in cortical thickness and trajectory of cortical thinning across childhood. Participants included 290 autistic (88 females) and 139 nonautistic (60 females) individuals assessed at up to 4 timepoints spanning ~2-13 years of age (918 total MRI timepoints). Estimates of cortical thickness in early and late childhood as well as the trajectory of cortical thinning were modeled using spatiotemporal linear mixed effects models of age-by-sex-by-diagnosis. Additionally, the spatial correspondence between cortical maps of sex-by-diagnosis differences and neurotypical sex differences were evaluated. Relative to their nonautistic peers, autistic females had more extensive cortical differences than autistic males. These differences involved multiple functional networks, and were mainly characterized by thicker cortex at ~3 years of age and faster cortical thinning in autistic females. Cortical regions in which autistic alterations were different between the sexes significantly overlapped with regions that differed by sex in neurotypical development. Autistic females and males demonstrated some shared differences in cortical thickness and rate of cortical thinning across childhood relative to their nonautistic peers, however these areas were relatively small compared to the widespread differences observed across the sexes. These results support evidence of sex-specific neurobiology in autism and suggest that processes that regulate sex differentiation in the neurotypical brain contribute to sex differences in the etiology of autism.
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Acute intoxication with high levels of organophosphate (OP) cholinesterase inhibitors can cause cholinergic crisis, which is associated with acute, life-threatening parasympathomimetic symptoms, respiratory depression and seizures that can rapidly progress to status epilepticus (SE). Clinical and experimental data demonstrate that individuals who survive these acute neurotoxic effects often develop significant chronic morbidity, including behavioral deficits. The pathogenic mechanism(s) that link acute OP intoxication to chronic neurological deficits remain speculative. Cellular senescence has been linked to behavioral deficits associated with aging and neurodegenerative disease, but whether acute OP intoxication triggers cellular senescence in the brain has not been investigated. Here, we test this hypothesis in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats were administered DFP (4 mg/kg, s.c.). Control animals were administered an equal volume (300 µL) of sterile phosphate-buffered saline (s.c.). Both groups were subsequently injected with atropine sulfate (2 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.). DFP triggered seizure activity within minutes that rapidly progressed to SE, as determined using behavioral seizure criteria. Brains were collected from animals at 1, 3, and 6 months post-exposure for immunohistochemical analyses of p16, a biomarker of cellular senescence. While there was no immunohistochemical evidence of cellular senescence at 1-month post-exposure, at 3- and 6-months post-exposure, p16 immunoreactivity was significantly increased in the CA3 and dentate gyrus of the hippocampus, amygdala, piriform cortex and thalamus, but not the CA1 region of the hippocampus or the somatosensory cortex. Co-localization of p16 immunoreactivity with cell-specific biomarkers, specifically, NeuN, GFAP, S100ß, IBA1 and CD31, revealed that p16 expression in the brain of DFP animals is neuron-specific. The spatial distribution of p16-immunopositive cells overlapped with expression of senescence associated ß-galactosidase and with degenerating neurons identified by FluoroJade-C (FJC) staining. The co-occurrence of p16 and FJC was positively correlated. This study implicates cellular senescence as a novel pathogenic mechanism underlying the chronic neurological deficits observed in individuals who survive OP-induced cholinergic crisis.
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BACKGROUND: Kinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort. METHODS: 18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer's disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ([Formula: see text] was also calculated from the multi-reference tissue model (MRTM). RESULTS: Amyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with [Formula: see text] analysis. [Formula: see text]and VT from kinetic models were correlated (r² = 0.46, P < 2[Formula: see text] with a stronger positive correlation observed in amyloid-positive participants, indicating reliable model fits with the IDIFs. VT from 2TCM was highly correlated ([Formula: see text]= 0.65, P < 2[Formula: see text]) with Logan graphical VT estimation. CONCLUSION: Non-invasive quantification of amyloid binding from total-body 18F-florbetaben PET data is feasible using aorta IDIFs with high agreement between kinetic distribution volume parameters compared to [Formula: see text]in amyloid-positive and amyloid-negative older individuals.
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Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
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This study aimed to compare the breastfeeding (BF) duration of the younger siblings of children with ASD in an enriched-likelihood cohort for autism spectrum disorder (ASD), and to determine whether longer BF duration was associated with differences in neurodevelopmental outcomes in this cohort. Information on BF practices was collected via surveys in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. Developmental evaluations, including the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, were conducted by expert clinicians. Participants' neurodevelopmental outcome was classified by an algorithm into three groups: typical development, ASD, and non-typical development. The median duration of BF was 10.70 months (interquartile range of 12.07 months). There were no significant differences in the distribution of duration of BF among the three neurodevelopmental outcome categories. Children in this enriched-likelihood cohort who were breastfed for > 12 months had significantly higher scores on cognitive testing compared to those who were breastfed for 0-3 months. There was no significant difference in ASD symptomatology or ASD risk based on BF duration.
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Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.
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Lesões Encefálicas , Estado Epiléptico , Ratos , Animais , Diazepam/farmacologia , Midazolam/farmacologia , Midazolam/uso terapêutico , Isoflurofato/farmacologia , Organofosfatos , Doenças Neuroinflamatórias , Neuroproteção , Ratos Sprague-Dawley , Encéfalo/metabolismo , Benzodiazepinas/farmacologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Proteínas de Transporte/metabolismo , Imageamento por Ressonância Magnética , Lesões Encefálicas/metabolismo , Atrofia/patologiaRESUMO
RATIONALE: Children with new-onset epilepsies often exhibit co-morbidities including cognitive dysfunction, which adversely affects academic performance. Application of unsupervised machine learning techniques has demonstrated the presence of discrete cognitive phenotypes at or near the time of diagnosis, but there is limited knowledge of their longitudinal trajectories. Here we investigate longitudinally the presence and progression of cognitive phenotypes and academic status in youth with new-onset seizures as sibling controls. METHODS: 282 subjects (6-16 years) were recruited within 6 weeks of their first recognized seizure along with 167 unaffected siblings. Each child underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months later. Factor analysis of the neuropsychological tests revealed four underlying domains - language, processing speed, executive function, and verbal memory. Latent trajectory analysis of the mean factor scores over 36 months identified clusters with prototypical cognitive trajectories. RESULTS: Three unique phenotypic groups with distinct cognitive trajectories over the 36-month period were identified: Resilient, Average, and Impaired phenotypes. The Resilient phenotype exhibited the highest neuropsychological factor scores and academic performance that were all similar to controls; while the Impaired phenotype showed the polar opposite with the worst performances across all test metrics. These findings remained significant and stable over 36 months. Multivariate logistic regression indicated that age of onset, EEG, neurological examination, and sociodemographic disadvantage were associated with phenotype classification. CONCLUSIONS: This study demonstrates the presence of diverse latent cognitive trajectory phenotypes over 36 months in youth with new-onset seizures that are associated with a stable neuropsychological and academic performance longitudinally.
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Testes Neuropsicológicos , Fenótipo , Convulsões , Humanos , Masculino , Feminino , Criança , Adolescente , Convulsões/psicologia , Convulsões/diagnóstico , Estudos Longitudinais , Função Executiva/fisiologia , Eletroencefalografia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Cognição/fisiologiaRESUMO
Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.
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Lesões Encefálicas , Intoxicação por Organofosfatos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Isoflurofato/toxicidade , Organofosfatos , Inibidores da Colinesterase/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Intoxicação por Organofosfatos/patologia , Lesões Encefálicas/induzido quimicamente , Encéfalo , Midazolam/farmacologiaRESUMO
PURPOSE: Past research shows that parentally responsive behavior toward the child positively influences language development in both neurotypical children and children with intellectual and developmental disabilities, including those with fragile X syndrome (FXS); however, most studies have focused exclusively on the mother-child relationship. The current study examined relationships between parent behavior (i.e., responsivity and behavior management) and child language performance in both mother-child and father-child interactions, as well as relationships between child characteristics and both parent behavior and child language. METHOD: Participants were 23 families of young boys with FXS between 3 and 7 years of age. Mothers and fathers independently completed questionnaires assessing child characteristics and separately engaged in 12-min play-based interactions with their child via telehealth. One parent also completed a comprehensive interview assessing child adaptive behavior. Video recordings of the parent-child interactions were transcribed and coded for parent and child behavior, and measures of parent and child language were obtained from the transcripts. RESULTS: Mothers and fathers used similar rates of responsive behaviors during parent-child interactions, and parental responsivity was positively associated with some aspects of child language performance (i.e., talkativeness and lexical diversity). Parental behavior, however, was not associated with syntactic complexity. Older children and children with higher levels of adaptive behavior had parents who used higher rates of responsive behaviors. Fathers used higher rates of behavior management strategies compared to mothers, and this type of parent behavior was not associated with child language. CONCLUSION: Overall, this study provides evidence that interventions focused on increasing parental responsiveness would be beneficial for families of children with FXS and that these interventions should be delivered early given the association between responsivity and child age. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25229939.
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Síndrome do Cromossomo X Frágil , Masculino , Feminino , Criança , Humanos , Adolescente , Pais , Relações Pais-Filho , Mães , Relações Mãe-Filho , Comunicação , PaiRESUMO
OBJECTIVE: Little is known about caregiving across the spectrum of cognitive impairment [mild cognitive impairment (MCI) to dementia] and how early life and sociocultural factors affect caregiver health. In this study, we characterized differences between caregivers of those with MCI versus those with dementia. METHODS: A total of 158 caregivers were enrolled in this cross-sectional study, most of whom were dementia caregivers (65%). Caregivers completed questionnaires on depressive symptoms, self-rated health (SRH), perceived burden and stress, as well as psychosocial and demographic measures. RESULTS: Caregivers of those with MCI reported fewer depressive symptoms and lower stress and burden compared with dementia caregivers. In adjusted analyses caregivers with greater stress reported more depressive symptoms. For SRH, at lower stress levels, having a sibling die before age 18 (ie, early life adversity) was associated with poorer SRH; at higher stress levels, having early life adversity was associated with better SRH. At lower burden levels, more live births were associated with worse SRH; at higher burden levels, more live births were associated with better SRH. CONCLUSIONS: Early life factors are relevant for caregivers of those with cognitive impairment and targeted prevention and early intervention may be helpful in alleviating caregiver burden and stress.
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Disfunção Cognitiva , Demência , Humanos , Adolescente , Cuidadores/psicologia , Estudos Transversais , Efeitos Psicossociais da Doença , Disfunção Cognitiva/psicologia , Demência/psicologia , Qualidade de Vida/psicologiaRESUMO
INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cognição , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , FemininoRESUMO
Background: Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living (DSM-5). Individuals with IDD often present with an intellectual disability in addition to a developmental disability such as autism or Down syndrome. Those with IDD may present with deficits in intellectual functioning as well as adaptive functioning that interfere with independence and living skills. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two-year period. Methods: Eligible participants for this multisite longitudinal study included those who were between 6 and 26 years at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID. Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid, Crystallized, Composite) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization). Results: Over a two-year period, change in cognition (both Crystalized and Composite) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model. Conclusions: The present study demonstrated that developmental improvements in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in Daily Living Skills on the VABS-3 emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of the NIHTB-CB in IDD, and important empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.
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The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides , Neuroimagem/métodos , Biomarcadores , Progressão da Doença , Proteínas tau , Disfunção Cognitiva/diagnóstico por imagemRESUMO
Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.