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OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.
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Concussão Encefálica , Militares , Humanos , Concussão Encefálica/fisiopatologia , Masculino , Adulto Jovem , Feminino , Pupila/fisiologia , Reflexo Pupilar/fisiologia , Adulto , Valor Preditivo dos Testes , Biomarcadores , Lesões Encefálicas Traumáticas/fisiopatologia , Adolescente , Recuperação de Função Fisiológica/fisiologia , Estudos de CoortesRESUMO
Importance: Many military service members and veterans report insomnia after sustaining traumatic brain injury (TBI). Limitations of first-line treatment, cognitive-behavioral therapy for insomnia (CBT-I), include availability of qualified clinicians, low completion rates, and cost. Objective: To investigate the feasibility and efficacy of internet-guided CBT-I (eCBT-I) in military service members and veterans with insomnia and a history of TBI. Design, Setting, and Participants: This randomized clinical trial of fully remote internet-based interventions and evaluations was conducted from September 1, 2020, to June 30, 2021, with 3 months of follow-up. Participants included a volunteer sample of military service members and veterans aged 18 to 64 years with a history of mild TBI/concussion and at least moderately severe insomnia defined as an insomnia severity index (ISI) score of greater than 14 and Pittsburgh Sleep Quality Index of greater than 4. Self-reported race, ethnicity, and educational level were generally representative of the US military. Data were analyzed from October 21, 2021, to April 29, 2024. Intervention: Internet-based CBT-I delivered over 6 weekly lesson modules with assigned homework activities. Main Outcomes and Measures: The prespecified primary outcome measure was change in ISI score over time. Prespecified secondary outcome measures included self-reported measures of depression symptoms, posttraumatic stress disorder (PTSD) symptoms, sleep quality, migraine impact, and fatigue. Results: Of 204 people screened, 125 were randomized 3:1 to eCBT-I vs online sleep education, and 106 completed baseline evaluations (83 men [78.3%]; mean [SD] age, 42 [12] years). Of these, 22 participants (20.8%) were Hispanic or Latino and 78 (73.6%) were White. Fifty participants completed postintervention evaluations, and 41 completed the 3-month follow-up. Baseline mean (SD) ISI scores were 19.7 (4.0) in those randomized to eCBT-I and 18.9 (5.0) in those randomized to sleep education. After intervention, mean (SD) ISI scores were 13.7 (5.6) in those randomized to eCBT-I and 16.6 (5.7) in those randomized to sleep education. The difference in the extent of reduction in ISI scores between groups was 3.5 (95% CI,-6.5 to -0.4 [P = .03]; Cohen d, -0.32 [95% CI, -0.70 to -0.04]). In the eCBT-I group, the extent of insomnia improvement correlated with the extent of depressive symptom improvement (Spearman ρ = 0.68 [P < .001]), PTSD symptoms (ρ = 0.36 [P = .04]), sleep quality (ρ = 0.54 [P = .001]), and fatigue impact (ρ = -0.58 [P < .001]) but not migraine-related disability. Conclusions and Relevance: The findings of this randomized clinical trial suggest that fully remote eCBT-I was moderately feasible and effective for self-reported insomnia and depression symptoms in military service members and veterans with a history of TBI. There is great potential benefit for eCBT-I due to low availability and cost of qualified CBT-I clinicians, although optimization of completion rates remains a challenge. Future studies may use home-based objective sleep assessments and should increase study retention. Trial Registration: ClinicalTrials.gov Identifier: NCT04377009.
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Lesões Encefálicas Traumáticas , Terapia Cognitivo-Comportamental , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/terapia , Terapia Cognitivo-Comportamental/métodos , Masculino , Adulto , Feminino , Lesões Encefálicas Traumáticas/complicações , Pessoa de Meia-Idade , Veteranos/psicologia , Veteranos/estatística & dados numéricos , Intervenção Baseada em Internet , Adulto Jovem , Militares/psicologia , Militares/estatística & dados numéricos , Internet , Resultado do Tratamento , AdolescenteRESUMO
BACKGROUND AND OBJECTIVES: The objective of this study was to determine the utility of the pupillary light reflex use as a biomarker of mild traumatic brain injury (mTBI). METHODS: This prospective cohort study was conducted at The US Military Academy at West Point. Cadets underwent a standard battery of tests including Balance Error Scoring System, Sports Concussion Assessment Tool Fifth Edition Symptom Survey, Standard Assessment of Concussion, and measure of pupillary responses. Cadets who sustained an mTBI during training events or sports were evaluated with the same battery of tests and pupillometry within 48 hours of the injury (T1), at the initiation of a graded return to activity protocol (T2), and at unrestricted return to activity (T3). RESULTS: Pupillary light reflex metrics were obtained in 1300 cadets at baseline. During the study period, 68 cadets sustained mTBIs. At T1 (<48 hours), cadets manifested significant postconcussion symptoms (Sports Concussion Assessment Tool Fifth Edition P < .001), and they had decreased cognitive performance (Standardized Assessment of Concussion P < .001) and higher balance error scores (Balance Error Scoring System P < .001) in comparison with their baseline assessment (T0). The clinical parameters showed normalization at time points T2 and T3. The pupillary responses demonstrated a pattern of significant change that returned to normal for several measures, including the difference between the constricted and initial pupillary diameter (T1 P < .001, T2 P < .05), dilation velocity (T1 P < .01, T2 P < .001), and percent of pupillary constriction (T1 P < .05). In addition, a combination of dilation velocity and maximum constriction velocity demonstrates moderate prediction ability regarding who can return to duty before or after 21 days (area under the curve = 0.71, 95% CI [0.56-0.86]). CONCLUSION: This study's findings indicate that quantitative pupillometry has the potential to assist with injury identification and prediction of symptom severity and duration.
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OBJECTIVE: Effective interventions are needed to address postconcussive symptoms. We report the results of randomized, sham-controlled trial of Cereset Research™ Standard Operating Procedures (CR-SOP), a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology previously shown to improve insomnia. METHODS: Military service members, veterans, or their spouses with persistent symptoms (Neurobehavioral Symptom Inventory [NSI] Score ≥23) after mTBI 3 months to 10 years ago, were randomized to receive 10 sessions of engineered tones linked to brainwaves (LB, intervention), or random engineered tones not linked to brainwaves (NL, sham control). The primary outcome was change in NSI, with secondary outcomes of heart rate variability and self-report measures of sleep, mood, and anxiety. RESULTS: Participants (n = 106, 22% female, mean age 37.1, 2.8 deployments, 3.8 TBIs) were randomized 1:1 to LB or NL, with no significant differences between groups at baseline. Among all study participants, the NSI declined from baseline 41.0 to 27.2 after (P < 0.0001), with gains largely sustained at 3 months (31.2) and 6 months (28.4). However, there were no significant differences between the LB (NSI declined from 39.9 at baseline to 28.2 post-intervention, 31.5 at 3 months, and 29.4 at 6 months) and NL (NSI declined from 41.5 at baseline to 26.2, 29.9, and 27.3, respectively. Similar patterns were observed for the PCL5 and PHQ-9 and there was no difference in HRV between groups. INTERPRETATION: Ten hours of acoustic stimulation while resting in a zero-gravity chair improves postconcussive symptoms. However, linking tones to brain electrical activity did not reduce symptoms more than random tones. REGISTRATION: ClinicalTrials.gov - NCT03649958.
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Síndrome Pós-Concussão , Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Feminino , Masculino , Síndrome Pós-Concussão/complicações , Estimulação Acústica , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Ansiedade/etiologia , Ansiedade/terapiaRESUMO
We studied the effect of multimodal traumatic brain injuries on daily sleep/activity patterns and related histology. Gyrencephalic ferrets wore actigraphs and received military-relevant brain injuries including shockwaves, strong rotational impact, and variable stress, which were evaluated up to 6 months post injury. Sham and Baseline animals exhibited activity patterns occurring in distinct clusters of high activity, interspersed with periods of low activity. In the Injury and Injury + Stress groups, activity clusters diminished and overall activity patterns became significantly more dispersed at 4 weeks post injury with significant sleep fragmentation. Additionally, the Injury + Stress group exhibited a significant decrease in daytime high activity up to 4 months post injury. At 4 weeks post injury, the reactive astrocyte (GFAP) immunoreactivity was significantly greater in both the injury groups compared to Sham, but did not differ at 6 months post injury. The intensity of immunoreactivity of the astrocytic endfeet that surround blood vessels (visualized with aquaporin 4; AQP4), however, differed significantly from Sham at 4 weeks post injury (in both injured groups) and at 6 months (Injury + Stress only). As the distribution of AQP4 plays a key role in the glymphatic system, we suggest that glymphatic disruption occurs in ferrets after the injuries described here.
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Concussão Encefálica , Lesões Encefálicas Traumáticas , Lesões Encefálicas , Animais , Concussão Encefálica/complicações , Furões , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , SonoRESUMO
Importance: Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective: To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants: This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures: A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results: The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs ≥14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.
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Biomarcadores/sangue , Concussão Encefálica , Volta ao Esporte/estatística & dados numéricos , Adolescente , Adulto , Atletas , Concussão Encefálica/sangue , Concussão Encefálica/classificação , Concussão Encefálica/epidemiologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudantes , Universidades , Adulto Jovem , Proteínas tau/sangueRESUMO
Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.
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Lesões Encefálicas Traumáticas/diagnóstico por imagem , Dieta , Ácidos Graxos Ômega-3/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Substância Branca/diagnóstico por imagem , Substância Branca/lesões , Animais , Teorema de Bayes , Imagem de Tensor de Difusão , Substância Cinzenta/patologia , Traumatismos Cranianos Fechados/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Trato Óptico/diagnóstico por imagem , Trato Óptico/lesões , Colículos Superiores/diagnóstico por imagem , Colículos Superiores/lesõesRESUMO
Cigarette smoking has been associated with dementia and dementia-related brain changes, notably gray matter (GM) volume atrophy. These associations are thought to reflect the co-morbidity of smoking and vascular, respiratory, and substance use/psychological conditions. However, the extent and localization of the smoking-GM relationship and the degree to which vascular, respiratory, and substance use/psychological factors influence this relationship remain unclear. In the Coronary Artery Risk Development in Young Adults CARDIA cohort (n = 698; 52% women; 40% black participants; age = 50.3 (SD = 3.5)), we examined the associations of smoking status with total GM volume and GM volume of brain regions linked to neurocognitive and addiction disorders. Linear regression models were used to adjust for vascular, respiratory, and substance use/psychological factors and to examine whether they modify the smoking-GM relationship. Compared to never-smokers, current smokers had smaller total GM volume (-8.86 cm3 (95%CI = -13.44, -4.29). Adjustment for substance use/psychological - but not vascular or respiratory - factors substantially attenuated this association (coefficients = -5.54 (95% CI = -10.32, -0.76); -8.33 (95% CI = -12.94, -3.72); -7.69 (95% CI = -6.95, -4.21), respectively). There was an interaction between smoking and alcohol use such that among alcohol non-users, smoking was not related to GM volumes and among alcohol users, those who currently smoked had -12 cm3 smaller total GM, specifically in the frontal and temporal lobes, amygdala, cingulate, and insula. Results suggest a large-magnitude association between smoking and smaller GM volume at middle age, accounting for vascular, respiratory, and substance use/psychological factors, and that the association was strongest in alcohol users. Regions suggested to be most vulnerable are those where cognition and addiction processes overlap.
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Encéfalo/patologia , Fumar Cigarros/efeitos adversos , Substância Cinzenta/patologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/patologiaRESUMO
Cigarette smoking is often associated with dementia. This association is thought to be mediated by hypoperfusion; however, how smoking behavior relates to cerebral blood flow (CBF) remains unclear. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (mean age = 50; n = 522), we examined the association between smoking behavior (status, cumulative pack-years, age at smoking initiation, and years since cessation) and CBF (arterial spin labeling) in brain lobes and regions linked to dementia. We used adjusted linear regression models and tested whether associations differed between current and former-smokers. Compared to never-smokers, former-smokers had lower CBF in the parietal and occipital lobes, cuneus, precuneus, putamen, and insula; in contrast, current-smokers did not have lower CBF. The relationship between pack-years and CBF was different between current and former-smokers (p for interaction < 0.05): Among current-smokers, higher pack-years were associated with higher occipital, temporal, cuneus, putamen, insula, hippocampus, and caudate CBF; former-smokers had lower caudate CBF with increasing pack-years. Results show links between smoking and CBF at middle-age in regions implicated in cognitive and compulsive/addictive processes. Differences between current and former smoking suggest that distinct pathological and/or compensatory mechanisms may be involved depending on the timing and history of smoking exposure.
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Circulação Cerebrovascular/fisiologia , Fumar Cigarros/fisiopatologia , Adolescente , Adulto , Comportamento , Comportamento Aditivo , Fumar Cigarros/efeitos adversos , Cognição/fisiologia , Estudos de Coortes , Comportamento Compulsivo , Feminino , Seguimentos , Humanos , Masculino , Fluxo Sanguíneo Regional/fisiologia , Fatores de Risco , Abandono do Hábito de Fumar , Adulto JovemRESUMO
Objective: We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife. Methods: In 698 community-dwelling adults (mean age 50â¯years ±3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study, WML were identified on structural MR and fractional anisotropy (FA), representing WM microstructural integrity, was derived using Diffusion Tensor Imaging. FA and WML maps were overlaid on a parcellated T1-template, based on an expert-delineated brain atlas, which included 42 WM tract ROIs. Analyses occurred in stages: 1) WML were quantified for the different tracts (i.e., frequency, volume, volume relative to tract size); 2) the interdependence of FA in normal appearing WM (NAWM) and WML was examined across tracts; 3) associations of NAWM FA and hypertension status were assessed controlling for WML volume. In the latter analysis, both overall hypertension (i.e. hypertension vs. normotension and prehypertension vs. normotension) and hypertension categorized by antihypertensive treatment status (yes/no) and blood pressure control (e.g., diastolic <90â¯mmHg, systolic <140â¯mmHg), were assessed. Results: WML were widely distributed across different WM tracts, however, WML volume was small. Mean NAWM FA was lower in participants with vs. participants without WML in given tracts. Hypertension was significantly associated with lower mean NAWM FA globally across tracts, both before and after adjustment for WML volume. Moreover, the magnitude of this association differed by treatment status and the level of control of the hypertension. Conclusions: In middle-aged adults, NAWM FA could represent a relevant marker of cerebrovascular injury when WML are minimally present.
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Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Clinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community. MATERIALS AND METHODS: Subjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison. RESULTS: In multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD. CONCLUSIONS: In middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.
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Doença de Alzheimer/sangue , Biomarcadores/sangue , Clusterina/sangue , Imageamento por Ressonância Magnética/métodos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N = 3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. © 2016 Wiley Periodicals, Inc.
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Envelhecimento , Algoritmos , Mapeamento Encefálico , Encéfalo/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Encéfalo/diagnóstico por imagem , Planejamento em Saúde Comunitária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Países Baixos/epidemiologia , Reprodutibilidade dos Testes , Fatores SexuaisRESUMO
BACKGROUND: Total brain volume is an integrated measure of health and may be an independent indicator of mortality risk independent of any one clinical or subclinical disease state. We investigate the association of brain volume to total and cause-specific mortality in a large nondemented stroke-free community-based cohort. METHODS: The analysis includes 3,543 men and women (born 1907-1935) participating in the Age, Gene, Environment Susceptibility-Reykjavik Study. Participants with a known brain-related high risk for mortality (cognitive impairment or stroke) were excluded from these analyses. Quantitative estimates of total brain volume, white matter, white matter lesions, total gray matter (GM; cortical GM and subcortical GM separately), and focal cerebral vascular disease were generated from brain magnetic resonance imaging. Brain atrophy was expressed as brain tissue volume divided by total intracranial volume, yielding a percentage. Mean follow-up duration was 7.2 (0-10) years, with 647 deaths. Cox regression was used to analyze the association of mortality to brain atrophy, adjusting for demographics, cardiovascular risk factors, and cerebral vascular disease. RESULTS: Reduced risk of mortality was significantly associated with higher total brain volume (hazard ratio, 95% confidence interval = 0.71, 0.65-0.78), white matter (0.85, 0.78-0.93), total GM (0.74, 0.68-0.81), and cortical GM (0.78, 0.70-0.87). Overall, the associations were similar for cardiovascular and noncardiovascular-related deaths. CONCLUSIONS: Independent of multiple risk factors and cerebral vascular damage, global brain volume predicts mortality in a large nondemented stroke-free community-dwelling older cohort. Total brain volume may be an integrated measure reflecting a range of health and with further investigation could be a useful clinical tool when assessing risk for mortality.
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Envelhecimento/fisiologia , Encéfalo/patologia , Mortalidade , Idoso , Idoso de 80 Anos ou mais , Atrofia , Doenças Cardiovasculares/epidemiologia , Causas de Morte , Transtornos Cerebrovasculares/epidemiologia , Demografia , Feminino , Indicadores Básicos de Saúde , Humanos , Islândia/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Modelos de Riscos Proporcionais , Fatores de Risco , Estatística como AssuntoRESUMO
Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (ß=-0.063, 95% CI: -0.106, -0.020), anterior cingulate (ß=-0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (ß=-0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (ß=-0.024, 95% CI: -0.062, 0.014) and the hippocampus (ß=-0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.
Assuntos
Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/psicologia , Rede Nervosa/fisiopatologia , Algoritmos , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Suspensão da Respiração , Circulação Cerebrovascular/fisiologia , Estudos Transversais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Dislipidemias/metabolismo , Dislipidemias/fisiopatologia , Feminino , Seguimentos , Hipocampo/irrigação sanguínea , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Fatores de RiscoRESUMO
IMPORTANCE: Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia. OBJECTIVE: To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment. DESIGN AND SETTING: Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada. PARTICIPANTS: Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period. MAIN OUTCOMES AND MEASURES: Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid ß-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18. RESULTS: In converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid ß-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076). CONCLUSIONS AND RELEVANCE: The dissociation of WMHs and cerebrospinal fluid ß-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Lesões Encefálicas/líquido cefalorraquidiano , Transtornos Cerebrovasculares/líquido cefalorraquidiano , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Leucoencefalopatias/líquido cefalorraquidiano , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD. METHODS: Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models were applied, and an inverse-probability of treatment weight estimation was used to account for time-dependent confounding between study variables. RESULTS: At any given time, population-level differences (e.g., 1-standard deviation [SD] increase) in brain glucose metabolism (-1.036; 95% confidence interval [95% CI], -1.608, -0.464) and hippocampal volume (-1.537; 95% CI, -2.399, -0.674) independently reduced mean (ADAS-Cog), whereas a 1-SD increase in whole brain volume did not (0.372; 95% CI, -0.283, 1.027). The effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume. CONCLUSIONS: Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Glicemia/metabolismo , Encéfalo/patologia , Canadá , Disfunção Cognitiva/patologia , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Fatores de Risco , Fatores Socioeconômicos , Estados UnidosRESUMO
RATIONALE: Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest. METHODS: To determine whether pre-ban FAs increase their Dco and pulmonary blood flow (Qc) during exercise, we administered a symptom-limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake (VO2) achieved by FAs. After 30 min rest, we then measured Dco and Qc at 20, 40, 60, and 80 percent of maximum observed work. RESULTS: The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and VO2 compared to those with normal resting Dco (mean±SEM; 88.7±2.9 vs. 102.5±3.1%predicted VO2; pâ=â0.001). Exercise limitation was associated with the FAs' FEV(1) (râ=â0.33; pâ=â0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean±SEM: 1.36±0.16 vs. 1.90±0.16 ml/min/mmHg per 20% increase in predicted watts; pâ=â0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in Qc was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in Qc during exercise (mean±SEM: 0.93±0.06 vs. 1.47±0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with ≥10 years of pre-ban experience (râ=â-0.32; pâ=â0.032). CONCLUSIONS: This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Circulação Pulmonar/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Idoso , Aeronaves , Estudos de Coortes , Teste de Esforço , Tolerância ao Exercício/fisiologia , Feminino , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Circulação Pulmonar/fisiologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Troca Gasosa Pulmonar/fisiologia , Fatores de TempoRESUMO
Age-related decline is common in multiple cognitive domains. ß-amyloid (Aß) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aß on cognition during aging. Using positron emission tomography (PET) imaging with the radiotracer Pittsburgh Compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Aß. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Aß and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Aß on cognitive changes in normal elderly.
Assuntos
Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Transtornos Cognitivos/diagnóstico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Compostos de Anilina , Apolipoproteína E4/genética , Área Sob a Curva , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Transtornos Cognitivos/genética , Análise Discriminante , Função Executiva , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Análise de Componente Principal , Curva ROC , Tiazóis , Aprendizagem Verbal , Adulto JovemRESUMO
BACKGROUND: Left bundle branch block (LBBB) has been proposed as a risk factor for cardiovascular morbidity and mortality. We sought to characterize the strength of these associations in a population without preexisting clinical heart disease. METHODS: The association between LBBB and new-onset congestive heart failure (CHF) or death from cardiovascular diseases was examined in 1,688 participants enrolled in the SPPARCS study who were free of known CHF or previous myocardial infarction. SPPARCS is a community-based cohort study in residents of Sonoma, California that are > 55 years. Medical history and 12-lead ECGs were obtained every 2 years for up to 6 years of follow-up. LBBB at enrollment or year 2 was considered "baseline" and assessed as a predictor of CHF and cardiovascular death ascertained at years 4 and 6. RESULTS: The prevalence of LBBB at baseline was 2.5% (n = 42). During 6 years of follow-up, 70 (4.8%) people developed new CHF. Incidence of CHF was higher in patients with LBBB than in participants without LBBB. This association persisted after controlling for potential confounders (odds ratio (OR): 2.85; 95% confidence interval (CI): 1.01 - 8.02; P = 0.047). A higher mortality from cardiovascular diseases was also found in participants with LBBB after adjusting for potential confounders (OR: 2.35, 95%CI: 1.02 - 5.41; P = 0.044). CONCLUSIONS: LBBB in the absence of a clinically detectable heart disease is associated with new-onset CHF and death from cardiovascular diseases. Further study is warranted to determine if additional diagnostic testing or earlier treatment in patients with asymptomatic LBBB can decrease cardiovascular morbidity or mortality.