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1.
PLoS One ; 19(4): e0295749, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38558059

RESUMEN

Alzheimer's disease (AD) affects Latinos disproportionately. One of the reasons underlying this disparity may be type 2 diabetes (T2D) that is a risk factor for AD. The purpose of this study was to examine the associations of T2D and AD blood biomarkers and the differences in these associations between Mexican Americans and non-Hispanic Whites. This study was a secondary analysis of baseline data from the observational Health and Aging Brain Study: Health Disparities (HABS-HD) that investigated factors underlying health disparities in AD in Mexican Americans in comparison to non-Hispanic Whites. HABS-HD participants were excluded if they had missing data or were large outliers (z-scores >|4|) on a given AD biomarker. Fasting blood glucose and glycosylated hemoglobin (HbA1c) levels were measured from clinical labs. T2D was diagnosed by licensed clinicians. Plasma amyloid-beta 42 and 40 (Aß42/42) ratio, total tau (t-tau), and neurofilament light (NfL) were measured via ultra-sensitive Simoa assays. The sample sizes were 1,552 for Aß42/40 ratio, 1,570 for t-tau, and 1,553 for NfL. Mexican Americans were younger (66.6±8.7 vs. 69.5±8.6) and had more female (64.9% female vs. 55.1%) and fewer years of schooling (9.5±4.6 vs. 15.6±2.5) than non-Hispanic Whites. Mexican Americans differed significantly from non-Hispanic Whites in blood glucose (113.5±36.6 vs. 99.2±17.0) and HbA1c (6.33±1.4 vs. 5.51±0.6) levels, T2D diagnosis (35.3% vs. 11.1%), as well as blood Aß42/40 ratio (.051±.012 vs. .047±.011), t-tau (2.56±.95 vs. 2.33±.90), and NfL levels (16.3±9.5 vs. 20.3±10.3). Blood glucose, blood HbA1c, and T2D diagnosis were not related to Aß42/40 ratio and t-tau but explained 3.7% of the variation in NfL (p < .001). Blood glucose and T2D diagnosis were not, while HbA1c was positively (b = 2.31, p < .001, ß = 0.26), associated with NfL among Mexican Americans. In contrast, blood glucose, HbA1c, and T2D diagnosis were negatively (b = -0.09, p < .01, ß = -0.26), not (b = 0.34, p = .71, ß = 0.04), and positively (b = 3.32, p < .01, ß = 0.33) associated with NfL, respectively in non-Hispanic Whites. To conclude, blood glucose and HbA1c levels and T2D diagnosis are associated with plasma NfL levels, but not plasma Aß and t-tau levels. These associations differ in an ethnicity-specific manner and need to be further studied as a potential mechanism underlying AD disparities.


Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Femenino , Humanos , Masculino , Envejecimiento , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Biomarcadores , Glucemia , Encéfalo , Hemoglobina Glucada , Inequidades en Salud , Proteínas tau , Persona de Mediana Edad , Anciano
2.
Brain ; 147(6): 2158-2168, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38315899

RESUMEN

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.


Asunto(s)
Enfermedad de Alzheimer , Cognición , Factor A de Crecimiento Endotelial Vascular , Proteínas tau , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Masculino , Femenino , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Proteínas tau/metabolismo , Proteínas tau/sangre , Estudios Longitudinales , Anciano de 80 o más Años , Cognición/fisiología , Tomografía de Emisión de Positrones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/sangre , Biomarcadores/sangre
3.
BMC Psychiatry ; 23(1): 716, 2023 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-37794326

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. The clinical continuum of AD ranges from asymptomatic disease to mild cognitive impairment (MCI), followed by AD dementia, categorized as mild, moderate, or severe. Almost one-third of patients suspected of having MCI or mild AD dementia are referred to specialists including psychiatrists. We sought to better understand the role that psychiatrists play in the diagnosis, treatment, and management of patients with all-cause MCI or mild AD dementia. METHODS: We conducted an anonymous, online survey among physicians in the United States between February 4, 2021, and March 1, 2021. We surveyed psychiatrists, primary care physicians (PCPs), geriatricians, and neurologists who treat patients with all-cause MCI or mild AD dementia. RESULTS: A total of 301 physicians participated in the survey, 50 of whom were psychiatrists. Of their patients with all-cause MCI or mild AD dementia, psychiatrists reported personally diagnosing two-thirds (67%). Psychiatrists used various methods to diagnose MCI or mild AD dementia including mental status testing (94%), review of patient medical history (86%), and neurological exams (61%). Upon diagnosis, psychiatrists reported most commonly discussing treatments (86%), management strategies (80%), disease progression (72%), and etiology of MCI or mild AD dementia (72%) with their patients. Most psychiatrists surveyed (82%) reported receiving advanced formal training in MCI and AD dementia care, primarily via residency training (38%), continuing medical education (22%) or fellowship (18%). Additionally, almost all psychiatrists (92%) reported receiving referrals for ongoing management of patients with MCI or mild AD dementia, primarily from PCPs or neurologists. However, only 46% of psychiatrists viewed themselves as the coordinator of care for their patients with MCI or mild AD dementia. CONCLUSIONS: Many psychiatrists indicated that they were well-informed about MCI and AD dementia and have a strong interest in providing care for these patients. They can provide timely and accurate diagnosis of clinical MCI and mild AD dementia and develop optimal treatment plans for patients. Although many psychiatrists consider other physicians to be the care coordinators for patients with MCI and mild AD dementia, psychiatrists can play a key role in diagnosing and managing patients with MCI and mild AD dementia.


Alzheimer's disease (AD) is the most common cause of dementia. Symptoms of AD include a decline in memory, language, problem-solving, and other thinking abilities that affect daily life. AD may first appear as mild cognitive impairment (MCI) but eventually progresses to AD dementia which is categorized as mild, moderate, or severe based on how much symptoms interfere with patients' everyday activities. We wanted to better understand the roles of different types of doctors in the diagnosis and management of MCI and mild AD dementia. A total of 301 doctors in the United States took an online survey in 2021. Of these, 50 were psychiatrists who specialize in mental health. Psychiatrists used several methods to diagnose patients with MCI or mild AD dementia, including mental status and memory testing. At diagnosis, psychiatrists discussed various topics with their patients who have MCI or mild AD dementia, including treatment options, ways to manage the disease, cause of the disease, and its progression. After diagnosis, most psychiatrists saw their patients with MCI or mild AD dementia at least four times a year. Most psychiatrists reported having advanced training in MCI and AD dementia care. Almost all psychiatrists said other doctors refer patients to them for ongoing management. However, less than half of psychiatrists consider themselves to be the coordinator of care for their patients with MCI or mild AD dementia. As physicians with training in MCI and AD dementia care, psychiatrists can play an important role in the timely diagnosis, treatment, and management of MCI and mild AD dementia.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia , Psiquiatría , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Estudios Transversales , Demencia/diagnóstico , Demencia/terapia , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/terapia , Progresión de la Enfermedad
4.
Nat Commun ; 14(1): 5120, 2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37612284

RESUMEN

Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Apolipoproteínas , Apolipoproteínas E/genética , Cognición , Escolaridad , Genotipo
5.
Postgrad Med ; 135(5): 530-538, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37219410

RESUMEN

OBJECTIVES: Early diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia is crucial for effective disease management and optimizing patient outcomes. We sought to better understand the MCI and mild AD dementia medical journey from the perspective of patients, care partners, and physicians. METHODS: We conducted online surveys in the United States among patients/care partners and physicians in 2021. RESULTS: 103 patients with all-cause MCI or mild AD dementia aged 46-90 years, 150 care partners for someone with all-cause MCI or mild AD dementia, and 301 physicians (101 of which were primary care physicians, [PCPs]) completed surveys. Most patient/care partners reported that experiencing forgetfulness (71%) and short-term memory loss (68%) occurred before talking to a healthcare professional. Most patients (73%) followed a common medical journey, in which the initial discussion with a PCP took place 15 months after symptom onset. However, only 33% and 39% were diagnosed and treated by a PCP, respectively. Most (74%) PCPs viewed themselves as coordinators of care for their patients with MCI and mild AD dementia. Over one-third (37%) of patients/care partners viewed PCPs as the care coordinator. CONCLUSIONS: PCPs play a vital role in the timely diagnosis and treatment of MCI and mild AD dementia but often are not considered the care coordinator. For the majority of patients, the initial discussion with a PCP took place 15 months after symptom onset; therefore, it is important to educate patients/care partners and PCPs on MCI and AD risk factors, early symptom recognition, and the need for early diagnosis and treatment. PCPs could improve patient care and outcomes by building their understanding of the need for early AD diagnosis and treatment and improving the efficiency of the patient medical journey by serving as coordinators of care.


Alzheimer's disease (AD) is not a normal part of aging, but many people develop AD as they age, and it is the seventh leading cause of death in the US. AD is a neurological condition that begins as mild cognitive impairment (MCI) or mild AD dementia. To understand the medical journey of patients with MCI or mild AD dementia, we surveyed 103 patients with MCI or mild AD dementia, 150 care partners, and 301 doctors. Patients had several symptoms before talking to a doctor, including forgetfulness and short-term memory loss; most patients (64%) first discussed these symptoms with a primary care physician (PCP) on average 15 months later. However, most patients were not diagnosed or treated by a PCP for MCI or mild AD dementia. We asked patients/care partners who they believe is the coordinator of their care for MCI and mild AD dementia. Thirty-seven percent felt the PCP was the coordinator of care. Most surveyed PCPs (74%) considered themselves to be the coordinator of care for their patients with MCI or mild AD dementia. In conclusion, PCPs play a key role in the care of patients with MCI and mild AD dementia. It is important for patients and care partners to understand the symptoms of MCI and mild AD dementia, and the need to get a diagnosis and treatment soon after symptoms appear. PCPs can play an important role in early diagnosis and treatment and serve as coordinators of care for their patients with MCI and mild AD dementia.[Figure: see text].


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia , Médicos de Atención Primaria , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/psicología , Cuidadores , Progresión de la Enfermedad , Demencia/diagnóstico , Demencia/terapia , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/terapia
6.
Alzheimers Dement ; 19(5): 1938-1946, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36373344

RESUMEN

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones
7.
Pilot Feasibility Stud ; 8(1): 243, 2022 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-36461134

RESUMEN

BACKGROUND: Alzheimer's disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-ß42 and Aß40 (Aß42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). METHODS: This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20-50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aß42, Aß40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen's d, and linear mixed models. RESULTSS: The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and -0.001 (0.010) for Aß42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and -0.020 (0.279) pg/mL and -0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [-0.33, 1.19]) and t-tau in cycling (-0.35 [-0.87, 0.17]). CONCLUSIONS: Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013.

8.
Alzheimers Dement (Amst) ; 14(1): e12319, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35821672

RESUMEN

Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks. Methods: rs-fcMRI, amyloid beta (Aß) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance. Results: Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PA's effects on Aß-related cognitive decline. Discussion: Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks.

9.
Neurology ; 2022 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-35473760

RESUMEN

BACKGROUND AND OBJECTIVES: Vascular risk factors and elevated ß-amyloid (Aß) are commonly observed together among older adults. Here, we examined the interactive versus independent effects of systemic vascular risk and Aß burden on longitudinal gray matter atrophy, and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. METHODS: Participants were 196 adults (age=73.8±6.1 years) from the Harvard Aging Brain Study. Baseline Aß burden was quantified with Pittsburgh Compound-B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural magnetic resonance imaging over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aß burden as interactive versus independent predictors of gray matter atrophy, adjusting for age, sex, years of education, APOE ε4 status, intracranial volume (where appropriate), and their interactions with time. In subsequent models we adjusted for markers of white matter injury to determine whether vascular risk accelerates brain atrophy independently from diffusion- and FLAIR-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aß burden on cognitive decline. RESULTS: Higher vascular risk and elevated Aß burden interacted to predict more severe atrophy within frontal and temporal lobes, thalamus, and striatum. Higher Aß burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aß burden. DISCUSSION: We observed an interaction between elevated vascular risk and higher Aß burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer's disease.

10.
Alzheimers Dement ; 18(4): 645-653, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34160128

RESUMEN

INTRODUCTION: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aß), remains unclear. METHODS: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aß. We next examined associations between cytokine levels and neuroimaging biomarkers of Aß/tau/neurodegeneration. RESULTS: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aß (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aß (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aß. DISCUSSION: Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Péptidos beta-Amiloides , Biomarcadores , Cognición , Disfunción Cognitiva/diagnóstico por imagen , Humanos , Interleucina-12 , Tomografía de Emisión de Positrones , Proteínas tau
11.
Neurobiol Aging ; 93: 124-130, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32249013

RESUMEN

In the present study, we tested the hypothesis that higher amyloid-beta (Aß) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aß positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aß burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aß burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Índice de Masa Corporal , Encéfalo/metabolismo , Voluntarios Sanos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Tomografía de Emisión de Positrones , Riesgo
12.
Neuroimage Clin ; 26: 102052, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31711955

RESUMEN

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for ß-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/fisiopatología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Conectoma , Red Nerviosa/fisiopatología , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Red Nerviosa/diagnóstico por imagen , Tomografía de Emisión de Positrones
13.
Nat Rev Neurol ; 16(1): 30-42, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31827267

RESUMEN

The shared role of amyloid-ß (Aß) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aß generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aß clearance, creating conditions for a self-reinforcing cycle of increased vascular Aß, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aß deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aß immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aß from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Transducción de Señal/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Encéfalo/patología , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Humanos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología
14.
JAMA Neurol ; 76(10): 1203-1210, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31312836

RESUMEN

IMPORTANCE: In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease. OBJECTIVE: To examine whether physical activity moderates the association of ß-amyloid (Aß) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study. Participants were required to have baseline Aß positron emission tomography data, baseline medical data to quantify vascular risk, and longitudinal neuropsychological and structural magnetic resonance imaging data. Data were collected from April 2010 to June 2018. Data were analyzed from August to December 2018. MAIN OUTCOMES AND MEASURES: Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aß burden was measured with carbon 11-labeled Pittsburgh Compound B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median [interquartile range] follow-up, 6.0 [4.3-6.3] years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2 to 5 scans per participant; median [interquartile range] follow-up, 4.5 [3.0-5.0] years), with a focus on total gray matter volume and regional cortical thickness. Physical activity and Aß burden were examined as interactive predictors of PACC decline and volume loss in separate linear mixed models, adjusting for age, sex, education, apolipoprotein E ε4 status, and, where appropriate, intracranial volume. Secondary models adjusted for vascular risk and its interaction with Aß burden. RESULTS: Of the 182 included participants, 103 (56.6%) were female, and the mean (SD) age was 73.4 (6.2) years. In models examining PACC decline and volume loss, there was a significant interaction of physical activity with Aß burden, such that greater physical activity was associated with slower Aß-related cognitive decline (ß, 0.03; 95% CI, 0.02-0.05; P < .001) and volume loss (ß, 482.07; 95% CI, 189.40-774.74; P = .002). Adjusting for vascular risk did not alter these associations. In these models, lower vascular risk was independently associated with slower Aß-related PACC decline (ß, -0.04; 95% CI, -0.06 to -0.02; P < .001) and volume loss (ß, -483.41; 95% CI, -855.63 to -111.20; P = .01). CONCLUSIONS AND RELEVANCE: Greater physical activity and lower vascular risk independently attenuated the negative association of Aß burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.

15.
Ann Neurol ; 83(4): 718-729, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29466839

RESUMEN

OBJECTIVE: To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons. METHODS: A total of 4,015 community-based persons (28% black; 74% women; mean baseline age = 78 years) were enrolled in 1 of 4 longitudinal cohort studies, and another 2,937 in a population-based cohort. Memory scores, assessed using 2 questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and 5 cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1,350 deceased subjects with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology. RESULTS: Baseline memory complaints (n = 1,310; 33% of 4,015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032, standard error = 0.004, p < 0.0001), during a mean follow-up of 6 (standard deviation = 2) years. Persons with memory complaints had higher dementia risk (hazard ratio = 1.64, 95% confidence interval [CI] = 1.42-1.89) and odds of pathologic Alzheimer disease (odds ratio [OR] = 1.96, 95% CI = 1.51-2.54), neocortical Lewy bodies (OR = 2.47, 95% CI = 1.54-3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2,937 older persons in a population-based cohort with similar data, the population-attributable risk for incident dementia due to memory complaints was 14.0% (95% CI = 2.6-23.0), and did not vary between the black and white groups. INTERPRETATION: Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. Ann Neurol 2018;83:718-729.


Asunto(s)
Demencia/etnología , Demencia/epidemiología , Trastornos de la Memoria/etnología , Trastornos de la Memoria/epidemiología , Neuropatología , Anciano , Anciano de 80 o más Años , Población Negra , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/etiología , Estudios de Cohortes , Planificación en Salud Comunitaria , Femenino , Humanos , Incidencia , Vida Independiente , Masculino , Trastornos de la Memoria/complicaciones , Escala del Estado Mental , Pruebas Neuropsicológicas , Población Blanca
16.
Alzheimer Dis Assoc Disord ; 31(1): 41-47, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27755004

RESUMEN

We examined the relationship of diabetes and hemoglobin A1C (A1C) to 2 common causes of dementia. The study included 1228 subjects who underwent annual clinical evaluations and a brain autopsy at death, as part of a Rush longitudinal cohort study of aging. A total of 433 subjects had A1C data available. Neuropathologic evaluations documented the size and location of infarcts. Modified silver stain-based Alzheimer disease (AD) measures included global and regional scores. We used regression analyses to examine associations of diabetes and A1C with overall and regional neuropathology. Diabetes [odds ratio (OR)=0.94; 95% confidence interval (CI), 0.73-1.20) and A1C (OR=0.83; 95% CI, 0.62-1.10) were not associated with global AD pathology across the brain, nor with overall or individual measures of neuropathology in mesial temporal or neocortical regions separately (all P>0.05). Diabetes was associated with a higher odds of any infarct (OR=1.43; 95% CI, 1.07-1.90), and particularly with gross (OR=1.53; 95% CI, 1.14-2.06) but not microinfarcts (P=0.06), and subcortical (OR=1.79; 95% CI, 1.34-2.39) but not cortical infarcts (P=0.83). In summary, we found no relationship of diabetes or A1C with global or regional AD pathology, including in the mesial temporal lobe. Diabetes is associated with gross subcortical infarcts. Our results suggest that the diabetes-dementia link is based on subcortical vascular pathology and not on regional AD pathology.


Asunto(s)
Enfermedad de Alzheimer/patología , Infarto Cerebral/patología , Diabetes Mellitus/epidemiología , Hemoglobina Glucada/análisis , Anciano de 80 o más Años , Envejecimiento/patología , Encéfalo/patología , Femenino , Humanos , Estudios Longitudinales , Masculino
17.
PLoS One ; 10(10): e0135076, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26474411

RESUMEN

We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.


Asunto(s)
Proteínas del Citoesqueleto/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Pueblo Asiatico , China/etnología , Femenino , Técnicas de Genotipaje , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Factores de Riesgo , Esquizofrenia/etnología
18.
J Hered ; 102 Suppl 1: S40-6, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21846746

RESUMEN

Due to their unique population structure, purebred dogs have emerged as a key model for the study of complex genetic disorders. To evaluate the utility of a newly available high-density canine whole-genome array with >170,000 single nucleotide polymorphisms (SNPs), genome-wide association was performed on a small number of case and control dogs to determine disease susceptibility loci in canine necrotizing meningoencephalitis (NME), a disorder with known non-Mendelian inheritance that shares clinical similarities with atypical variants of multiple sclerosis in humans. Genotyping of 30 NME-affected Pug dogs and 68 healthy control Pugs identified 2 loci associated with NME, including a region within dog leukocyte antigen class II on chromosome 12 that remained significant after Bonferroni correction. Our results support the utility of this high-density SNP array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.


Asunto(s)
Enfermedades de los Perros/genética , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase I/genética , Meningoencefalitis/veterinaria , Animales , Proteínas Portadoras/genética , Perros , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos/genética , Meningoencefalitis/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
19.
Neuroimage ; 54(3): 1896-902, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20888920

RESUMEN

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/genética , Química Encefálica/genética , Glucosa/metabolismo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Cognición/fisiología , ADN/genética , ADN/aislamiento & purificación , Femenino , Fluorodesoxiglucosa F18 , Haplotipos , Heterocigoto , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Cintigrafía , Radiofármacos
20.
Hum Mol Genet ; 19(16): 3295-301, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20534741

RESUMEN

In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls.


Asunto(s)
Enfermedad de Alzheimer/genética , Clusterina/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Ensamble de Clatrina Monoméricas/genética , Receptores de Complemento 3b/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Estudios de Cohortes , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple
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