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OBJECTIVES: On average, adults racialized as non-Hispanic Black and Hispanic sleep more poorly than adults racialized as non-Hispanic White (hereafter, Black, Hispanic, White), but associations between factors that may moderate sleep-memory associations in these groups, such as neighborhood conditions, are unclear. Poorer neighborhood conditions (e.g. lower neighborhood cohesion) may be negatively associated with sleep quality and multiplicatively influence sleep-memory associations. We hypothesized lower ratings of neighborhood conditions would be associated with poorer sleep quality and moderate the association between sleep quality and episodic memory, especially in Black and Hispanic adults, who are disproportionately situated in poor neighborhood conditions. DESIGN: Seven-hundred-thirty-six adults across the adult lifespan (27-89 years) were recruited from the northern Manhattan community as a part of the Offspring Study of Racial and Ethnic Disparities in Alzheimer's disease. Sleep quality was assessed using a modified version of the Pittsburgh Sleep Quality Index, and episodic memory was evaluated with the Buschke Selective Reminding Test. With multiple regression models, we measured associations between perceived neighborhood conditions and sleep quality and the interaction between sleep quality and neighborhood conditions on episodic memory stratified by racial/ethnic and gender identity groups. RESULTS: Overall, poorer neighborhood conditions were associated with poorer sleep quality. In Black and Hispanic women, the sleep-memory association was moderated by neighborhood conditions. With more favorable neighborhood conditions, Black women showed an association between higher sleep quality and higher memory performance, and Hispanic women showed a protective effect of neighborhood (higher memory even when sleep quality was poor). CONCLUSION: Poorer neighborhood experiences may contribute to poorer sleep quality across groups. In Black and Hispanic women, the association between sleep quality and episodic memory performance was dependent upon neighborhood conditions. These findings may inform tailored, structural level sleep interventions, aimed to improve neighborhood experiences and thereby sleep quality and episodic memory.
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Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with CSF/PET biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/Aß42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.
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BACKGROUND: Although related, the precise mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are unclear. Platelets are mediators of CVD risk and thrombosis and prior studies suggested associations of OSA and platelet activity. The aim of this study is to assess the link between OSA, platelet activity, and CVD-related risk factors. METHODS AND RESULTS: We studied the association of OSA-measures and platelet aggregation in participants dually enrolled in the SHHS (Sleep Heart and Health Study) and FHS (Framingham Heart Study). We applied linear regression models with adjustment for demographic and clinical covariates and explored interactions with OSA and CVD-related factors, including age, sex, body mass index, hypertension, OSA diagnosis (apnea-hypopnea index 4%≥5), and aspirin use. Our final sample was of 482 participants (60 years [14.00], 50.4% female). No associations were observed between apnea-hypopnea index 4% and platelet aggregation in the main sample. Stratified analysis revealed an association in aspirin users (n=65) for our primary exposure (apnea-hypopnea index 4%, ß=0.523; P<0.001; n=65), and secondary exposures: hypoxic burden (ß=0.358; P<0.001), minimum saturation (ß=-0.519; P=0.026), and oxygen desaturation index 3% (ß=74.672; P=0.002). No associations were detected in nonaspirin users (n=417). CONCLUSIONS: No associations were detected between OSA and platelet aggregation in a community sample. Our finding that OSA associates with increased platelet aggregation in the aspirin group, most of whom use it for primary prevention of CVD, suggests that platelet aggregation may mediate the adverse impact of OSA on vascular health in individuals with existing CVD risk, supporting further investigation.
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Enfermedades Cardiovasculares , Factores de Riesgo de Enfermedad Cardiaca , Agregación Plaquetaria , Apnea Obstructiva del Sueño , Humanos , Femenino , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/complicaciones , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/diagnóstico , Agregación Plaquetaria/efectos de los fármacos , Anciano , Medición de Riesgo , Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). METHODS: Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. RESULTS: Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (ß = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (ß = .13, SE: .07, P = .047), past memory (ß = .13, SE: .06, P = .039) and functional abilities (ß = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (ß = -.27, SE: .13, P = .039), MoCA (ß = -.80 SE: .34, P = .032), Trails A (ß = 2.75, SE: .89, P = .002), Trails B (ß = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (ß = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.
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Importance: Understanding the heterogeneity of neuropsychiatric symptoms (NPSs) and associated brain abnormalities is essential for effective management and treatment of dementia. Objective: To identify dementia subtypes with distinct functional connectivity associated with neuropsychiatric subsyndromes. Design, Setting, and Participants: Using data from the Open Access Series of Imaging Studies-3 (OASIS-3; recruitment began in 2005) and Alzheimer Disease Neuroimaging Initiative (ADNI; recruitment began in 2004) databases, this cross-sectional study analyzed resting-state functional magnetic resonance imaging (fMRI) scans, clinical assessments, and neuropsychological measures of participants aged 42 to 95 years. The fMRI data were processed from July 2022 to February 2024, with secondary analysis conducted from August 2022 to March 2024. Participants without medical conditions or medical contraindications for MRI were recruited. Main Outcomes and Measures: A multivariate sparse canonical correlation analysis was conducted to identify functional connectivity-informed NPS subsyndromes, including behavioral and anxiety subsyndromes. Subsequently, a clustering analysis was performed on obtained latent connectivity profiles to reveal neurophysiological subtypes, and differences in abnormal connectivity and phenotypic profiles between subtypes were examined. Results: Among 1098 participants in OASIS-3, 177 individuals who had fMRI and at least 1 NPS at baseline were included (78 female [44.1%]; median [IQR] age, 72 [67-78] years) as a discovery dataset. There were 2 neuropsychiatric subsyndromes identified: behavioral (r = 0.22; P = .002; P for permutation = .007) and anxiety (r = 0.19; P = .01; P for permutation = .006) subsyndromes from connectivity NPS-associated latent features. The behavioral subsyndrome was characterized by connections predominantly involving the default mode (within-network contribution by summed correlation coefficients = 54) and somatomotor (within-network contribution = 58) networks and NPSs involving nighttime behavior disturbance (R = -0.29; P < .001), agitation (R = -0.28; P = .001), and apathy (R = -0.23; P = .007). The anxiety subsyndrome mainly consisted of connections involving the visual network (within-network contribution = 53) and anxiety-related NPSs (R = 0.36; P < .001). By clustering individuals along these 2 subsyndrome-associated connectivity latent features, 3 subtypes were found (subtype 1: 45 participants; subtype 2: 43 participants; subtype 3: 66 participants). Patients with dementia of subtype 3 exhibited similar brain connectivity and cognitive behavior patterns to those of healthy individuals. However, patients with dementia of subtypes 1 and 2 had different dysfunctional connectivity profiles involving the frontoparietal control network (FPC) and somatomotor network (the difference by summed z values was 230 within the SMN and 173 between the SMN and FPC for subtype 1 and 473 between the SMN and visual network for subtype 2) compared with those of healthy individuals. These dysfunctional connectivity patterns were associated with differences in baseline dementia severity (eg, the median [IQR] of the total score of NPSs was 2 [2-7] for subtype 3 vs 6 [3-8] for subtype 1; P = .04 and 5.5 [3-11] for subtype 2; P = .03) and longitudinal progression of cognitive impairment and behavioral dysfunction (eg, the overall interaction association between time and subtypes to orientation was F = 4.88; P = .008; using the time × subtype 3 interaction item as the reference level: ß = 0.05; t = 2.6 for time × subtype 2; P = .01). These findings were further validated using a replication dataset of 193 participants (127 female [65.8%]; median [IQR] age, 74 [69-77] years) consisting of 154 newly released participants from OASIS-3 and 39 participants from ADNI. Conclusions and Relevance: These findings may provide a novel framework to disentangle the neuropsychiatric and brain functional heterogeneity of dementia, offering a promising avenue to improve clinical management and facilitate the timely development of targeted interventions for patients with dementia.
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Encéfalo , Demencia , Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Estudios Transversales , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Demencia/fisiopatología , Demencia/diagnóstico por imagen , Demencia/psicología , Adulto , Pruebas Neuropsicológicas/estadística & datos numéricos , Conectoma/métodosRESUMEN
Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3â hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.
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Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; pâ=â0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEÉ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.
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Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Proteínas tau/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Anciano , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Tiazoles , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Biomarcadores/sangre , CarbolinasRESUMEN
INTRODUCTION: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS: We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. HIGHLIGHTS: We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.
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Antidepresivos , Demencia , Trastorno Depresivo Mayor , Veteranos , Humanos , Femenino , Estudios Retrospectivos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Masculino , Persona de Mediana Edad , Veteranos/estadística & datos numéricos , Antidepresivos/uso terapéutico , Antidepresivos/efectos adversos , Estados Unidos/epidemiología , Demencia/epidemiología , Modelos de Riesgos Proporcionales , Factores de Riesgo , AncianoRESUMEN
BACKGROUND: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-ß42 (Aß42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aß-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aß42 (ß = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (ß = 26.812, p = 0.019) and p-tau (ß = 3.441, p = 0.015), but not Aß42. In the NYU cohort alone, subjects classified as Aß + (n = 38) displayed a stronger association between the NLR and t-tau (ß = 100.476, p = 0.037) compared to Aß- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS: We report associations between the NLR and Aß42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
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Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-ß42 (Aß42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aß-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aß42 (ß=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (ß = 26.812, p = 0.019) and p-tau (ß = 3.441, p = 0.015), but not Aß42. In the NYU cohort alone, subjects classified as Aß+ (n = 38) displayed a stronger association between the NLR and t-tau (ß = 100.476, p = 0.037) compared to Aß- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions: We report associations between the NLR and Aß42 in the older ADNI cohort, and between the NLR and t-tau and p-tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.
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Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Trastornos del Sueño-Vigilia , Accidente Cerebrovascular , Humanos , Enfermedad de Alzheimer/complicaciones , American Heart Association , Sueño , Encéfalo/patología , Accidente Cerebrovascular/complicaciones , Trastornos del Sueño-Vigilia/complicacionesRESUMEN
BACKGROUND: Dementia is highly heterogeneous, with pronounced individual differences in neuropsychiatric symptoms (NPS) and neuroimaging findings. Understanding the heterogeneity of NPS and associated brain abnormalities is essential for effective management and treatment of dementia. METHODS: Using large-scale neuroimaging data from the Open Access Series of Imaging Studies (OASIS-3), we conducted a multivariate sparse canonical correlation analysis to identify functional connectivity-informed symptom dimensions. Subsequently, we performed a clustering analysis on the obtained latent connectivity profiles to reveal neurophysiological subtypes and examined differences in abnormal connectivity and phenotypic profiles between subtypes. RESULTS: We identified two reliable neuropsychiatric subsyndromes - behavioral and anxiety in the connectivity-NPS linked latent space. The behavioral subsyndrome was characterized by the connections predominantly involving the default mode and somatomotor networks and neuropsychiatric symptoms involving nighttime behavior disturbance, agitation, and apathy. The anxiety subsyndrome was mainly contributed by connections involving the visual network and the anxiety neuropsychiatric symptom. By clustering individuals along these two subsyndromes-linked connectivity latent features, we uncovered three subtypes encompassing both dementia patients and healthy controls. Dementia in one subtype exhibited similar brain connectivity and cognitive-behavior patterns to healthy individuals. However, dementia in the other two subtypes showed different dysfunctional connectivity profiles involving the default mode, frontoparietal control, somatomotor, and ventral attention networks, compared to healthy individuals. These dysfunctional connectivity patterns were associated with differences in baseline dementia severity and longitudinal progression of cognitive impairment and behavioral dysfunction. CONCLUSIONS: Our findings shed valuable insights into disentangling the neuropsychiatric and brain functional heterogeneity of dementia, offering a promising avenue to improve clinical management and facilitate the development of timely and targeted interventions for dementia patients.
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BACKGROUND: Alzheimer's disease's (AD) prevalence is projected to increase as the population ages and current treatments are minimally effective. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates into the cerebral cortex, stimulates the mitochondrial respiratory chain, and increases cerebral blood flow. Preliminary data suggests t-PBM may be efficacious in improving cognition in people with early AD and amnestic mild cognitive impairment (aMCI). METHODS: In this randomized, double-blind, placebo-controlled study with aMCI and early AD participants, we will test the efficacy, safety, and impact on cognition of 24 sessions of t-PBM delivered over 8 weeks. Brain mechanisms of t-PBM in this population will be explored by testing whether the baseline tau burden (measured with 18F-MK6240), or changes in mitochondrial function over 8 weeks (assessed with 31P-MRSI), moderates the changes observed in cognitive functions after t-PBM therapy. We will also use changes in the fMRI Blood-Oxygenation-Level-Dependent (BOLD) signal after a single treatment to demonstrate t-PBM-dependent increases in prefrontal cortex blood flow. CONCLUSION: This study will test whether t-PBM, a low-cost, accessible, and user-friendly intervention, has the potential to improve cognition and function in an aMCI and early AD population.
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Obesity and components of the metabolic syndrome (MetS) are associated with differences in brain structure and function and in general and food-related cognition in adults. Here, we review evidence for similar phenomena in children and adolescents, with a focus on the implications of extant research for possible underlying mechanisms and potential interventions for obesity and MetS in youth. Current evidence is limited by a relative reliance on small cross-sectional studies. However, we find that youth with obesity and MetS or MetS components show differences in brain structure, including alterations in grey matter volume and cortical thickness across brain regions subserving reward, cognitive control and other functions, as well as in white matter integrity and volume. Children with obesity and MetS components also show some evidence for hyperresponsivity of food reward regions and hyporesponsivity of cognitive control circuits during food-related tasks, altered brain responses to food tastes, and altered resting-state connectivity including between cognitive control and reward processing networks. Potential mechanisms for these findings include neuroinflammation, impaired vascular reactivity, and effects of diet and obesity on myelination and dopamine function. Future observational research using longitudinal measures, improved sampling strategies and study designs, and rigorous statistical methods, promises to further illuminate dynamic relationships and causal mechanisms. Intervention studies targeted at modifiable biological and behavioural factors associated with paediatric obesity and MetS can further inform mechanisms, as well as test whether brain and behaviour can be altered for beneficial outcomes.
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Síndrome Metabólico , Obesidad Infantil , Adolescente , Niño , Humanos , Encéfalo/diagnóstico por imagen , Cognición , Estudios Transversales , Imagen por Resonancia Magnética , Síndrome Metabólico/complicaciones , Obesidad Infantil/complicacionesRESUMEN
The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-ß 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein É4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein É4, female É4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein É4 and biomarkers showed that female É4 carriers tended to exhibit lower CSF amyloid-ß 42/amyloid-ß 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein É4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.
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STUDY OBJECTIVES: Phenotyping using polysomnography (PUP) is an algorithmic method to quantify physiologic mechanisms underlying obstructive sleep apnea (OSA): loop gain (LG1), arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp). The consecutive-night test-retest reliability and agreement of PUP-derived estimates are unknown. From a cohort of elderly (age ≥55 years), largely non-sleepy, community-dwelling volunteers who underwent in-lab polysomnography (PSG) on 2 consecutive nights, we determined the test-retest reliability and agreement of PUP-estimated physiologic factors. METHODS: Participants who had an apnea-hypopnea index (AHI3A) of at least 15 events per hour on the first night were included. PUP analyses were performed on each of the two PSGs from each participant. Physiologic factor estimates were derived from NREM sleep and compared across nights using intraclass correlation coefficients for reliability and smallest real differences (SRD) for agreement. RESULTS: Two PSGs from each of 43 participants (86 total) were analyzed. A first-night effect was evident with increased sleep time and stability and decreased OSA severity on the second night. LG1, ArTH, and Vpassive demonstrated good reliability (ICC > 0.80). Vcomp had modest reliability (ICC = 0.67). For all physiologic factors, SRD values were approximately 20% or more of the observed ranges, suggesting limited agreement of longitudinal measurements for a given individual. CONCLUSIONS: For NREM sleep in cognitively normal elderly individuals with OSA, PUP-estimated LG1, ArTH, and Vpassive demonstrated consistent relative ranking of individuals (good reliability) on short-term repeat measurement. For all physiologic factors, longitudinal measurements demonstrated substantial intraindividual variability across nights (limited agreement).
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Nivel de Alerta , Apnea Obstructiva del Sueño , Anciano , Humanos , Persona de Mediana Edad , Polisomnografía , Reproducibilidad de los Resultados , Vida Independiente , Apnea Obstructiva del Sueño/diagnósticoRESUMEN
Background: Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). Methods: We measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. Results: Most regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. Conclusions: Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.
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Background and objectives: Obesity is a risk factor for cognitive decline. Probable mechanisms involve inflammation and cerebrovascular dysfunction, leading to diminished cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). The hippocampus, crucially involved in memory processing and thus relevant to many types of dementia, poses a challenge in studies of perfusion and CVR, due to its location, small size, and complex shape. We examined the relationships between body mass index (BMI) and hippocampal resting CBF and CVR to carbon dioxide (CVRCO2) in a group of cognitively normal middle-aged and older adults. Methods: Our study was a retrospective analysis of prospectively collected data. Subjects were enrolled for studies assessing the role of hippocampal hemodynamics as a biomarker for AD among cognitively healthy elderly individuals (age > 50). Participants without cognitive impairment, stroke, and active substance abuse were recruited between January 2008 and November 2017 at the NYU Grossman School of Medicine, former Center for Brain Health. All subjects underwent medical, psychiatric, and neurological assessments, blood tests, and MRI examinations. To estimate CVR, we increased their carbon dioxide levels using a rebreathing protocol. Relationships between BMI and brain measures were tested using linear regression. Results: Our group (n = 331) consisted of 60.4% women (age 68.8 ± 7.5 years; education 16.8 ± 2.2 years) and 39.6% men (age 70.4 ± 6.4 years; education 16.9 ± 2.4 years). Approximately 22% of them (n = 73) were obese. BMI was inversely associated with CVRCO2 (ß = -0.12, unstandardized B = -0.06, 95% CI -0.11, -0.004). A similar relationship was observed after excluding subjects with diabetes and insulin resistance (ß = -0.15, unstandardized B = -0.08, 95% CI -0.16, -0.000). In the entire group, BMI was more strongly related to hippocampal CVRCO2 in women (ß = -0.20, unstandardized B = -0.08, 95% CI -0.13, -0.02). Discussion: These findings lend support to the notion that obesity is a risk factor for hippocampal hemodynamic impairment and suggest targeting obesity as an important prevention strategy. Prospective studies assessing the effects of weight loss on brain hemodynamic measures and inflammation are warranted.
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There is emerging evidence that obstructive sleep apnea (OSA) is a risk factor for preclinical Alzheimer's disease (AD). An American Thoracic Society workshop was convened that included clinicians, basic scientists, and epidemiologists with expertise in OSA, cognition, and dementia, with the overall objectives of summarizing the state of knowledge in the field, identifying important research gaps, and identifying potential directions for future research. Although currently available cognitive screening tests may allow for identification of cognitive impairment in patients with OSA, they should be interpreted with caution. Neuroimaging in OSA can provide surrogate measures of disease chronicity, but it has methodological limitations. Most data on the impact of OSA treatment on cognition are for continuous positive airway pressure (CPAP), with limited data for other treatments. The cognitive domains improving with CPAP show considerable heterogeneity across studies. OSA can negatively influence risk, manifestations, and possibly progression of AD and other forms of dementia. Sleep-dependent memory tasks need greater incorporation into OSA testing, with better delineation of sleep fragmentation versus intermittent hypoxia effects. Plasma biomarkers may prove to be sensitive, feasible, and scalable biomarkers for use in clinical trials. There is strong biological plausibility, but insufficient data, to prove bidirectional causality of the associations between OSA and aging pathology. Engaging, recruiting, and retaining diverse populations in health care and research may help to decrease racial and ethnic disparities in OSA and AD. Key recommendations from the workshop include research aimed at underlying mechanisms; longer-term longitudinal studies with objective assessment of OSA, sensitive cognitive markers, and sleep-dependent cognitive tasks; and pragmatic study designs for interventional studies that control for other factors that may impact cognitive outcomes and use novel biomarkers.