Current Alzheimer Research (v.12, #7)

Meet Our Editorial Board Member by Martin R. Farlow (605-605).

Brain Aging in African-Americans: The Atherosclerosis Risk in Communities (ARIC) Experience by Rebecca F. Gottesman, Myriam Fornage, David S. Knopman, Thomas H. Mosley (607-613).
Reported rates of dementia differ by race, although most studies have not focused on carefully measured outcomes, confounding by education or other demographic factors, nor have they studied other outcomes other than dementia. In this review we will discuss the experience in the Atherosclerosis Risk in Communities (ARIC) study evaluating racial disparities relating to stroke, subclinical brain infarction, leukoaraiosis, as well as cognitive change and dementia. ARIC is a biracial cohort of 15,792 participants from four U.S. communities, initially recruited in 1987-1989, and seen at a total of 5 in-person visits (most recently seen in 2011-2013) with annual follow-up phone calls. We will provide evidence from ARIC studies that disproportionate rates of vascular risk factors explain at least some of these observed disparities by race, but particular risk factors, including diabetes, may differentially affect the brain in African-American versus white participants. In addition, we will review some of the disparities by race in studies focusing on the genetics of stroke, small vessel disease, and dementia.

Stability in Cognitive Function Over 18 Years: Prevalence and Predictors among Older Mexican Americans by Bret T. Howrey, Mukaila A. Raji, Meredith M. Masel, M. Kristen Peek (614-621).
Purpose: Numerous studies have examined the association of physical, behavioral and social factors with cognitive decline in older adults. Less attention has been placed on factors associated with long-term maintenance of intact cognition even into very old age. A greater understanding of those factors can inform the development of activities for maintaining cognitive strength. Methods: Using a sample from the Hispanic Established Populations for Epidemiologic Study of the Elderly, a population-based study of non-institutionalized Mexican Americans aged 65 and older from five Southwestern states (N = 2767), latent class mixture models were developed to identify subgroups of cognitive change over time. Results: Three distinct trajectories of cognitive change were identified and characterized as stable, slow decline and rapid decline. Compared to the rapid decline group, a higher proportion of the stable cognition group were women, had high school education, were married and attended church one or more times per week. Regular church attendance had a significant positive impact in the stable group (β = 0.64, p <0.01), the slow decline group (β = 0.84, p <0.001) and the rapid decline group (β = 2.50, p <0.001). Activity limitations had a consistently negative association with cognition in the stable, slow decline and rapid decline groups (β = -0.37, p <0.001; β = -0.85, p <0.001; and β = -1.58, p <0.001 respectively). Conclusion: Substantial heterogeneity exists in rates of cognitive decline among older Mexican Americans. Interventions targeting cognitive maintenance may benefit from increased focus on factors associated with continued social engagement.

Social Determinants, Race, and Brain Health Outcomes: Findings from the Chicago Health and Aging Project by Neelum T. Aggarwal, Susan A. Everson-Rose, Denis A. Evans (622-631).
The broad spectrum of economic and cultural diversity in the U.S. population correlates with and affects the study of behavioral aspects of health. The purpose of this article is to provide a selective overview of research findings from the Chicago Health and Aging Project (CHAP), which covers a socio-demographically diverse population in Chicago, with a focus on role-related psychosocial factors and observed racial/ethnic differences in aging outcomes. CHAP is a longitudinal, epidemiological study of common chronic conditions of aging with an emphasis on medical, psychosocial, and environmental risk factors for the decline in cognitive function across the older adult lifespan. We briefly summarize the study design and methods used in the CHAP study and characterize the study population and describe the psychosocial data, noting black-white associations as they relate to three common brain health outcomes: cognitive function and Alzheimer's Disease, stroke, and subclinical vascular disease as noted on neuroimaging.

Structural MRI Predictors of Late-Life Cognition Differ Across African Americans, Hispanics, and Whites by Laura B. Zahodne, Jennifer J. Manly, Atul Narkhede, Erica Y. Griffith, Charles DeCarli, Nicole S. Schupf, Richard Mayeux, Adam M. Brickman (632-639).
Background. Structural magnetic resonance imaging (MRI) provides key biomarkers to predict onset and track progression of Alzheimer's disease (AD). However, most published reports of relationships between MRI variables and cognition in older adults include racially, ethnically, and socioeconomically homogenous samples. Racial/ethnic differences in MRI variables and cognitive performance, as well as health, socioeconomic status and psychological factors, raise the possibility that brain-behavior relationships may be stronger or weaker in different groups. The current study tested whether MRI predictors of cognition differ in African Americans and Hispanics, compared with non-Hispanic Whites.Methods. Participants were 638 non-demented older adults (29% non-Hispanic White, 36% African American, 35% Hispanic) in the Washington Heights-Inwood Columbia Aging Project. Composite scores of memory, language, speed/executive functioning, and visuospatial function were derived from a neuropsychological battery. Hippocampal volume, regional cortical thickness, infarcts, and white matter hyperintensity (WMH) volumes were quantified with FreeSurfer and in-house developed procedures. Multiple-group regression analysis, in which each cognitive composite score was regressed onto MRI variables, demographics, and cardiovascular health, tested which paths differed across groups. Results. Larger WMH volume was associated with worse language and speed/executive functioning among African Americans, but not among non-Hispanic Whites. Larger hippocampal volume was more strongly associated with better memory among non-Hispanic Whites compared with Hispanics. Cortical thickness and infarcts were similarly associated with cognition across groups.Conclusion. The main finding of this study was that certain MRI predictors of cognition differed across racial/ethnic groups. These results highlight the critical need for more diverse samples in the study of cognitive aging, as the type and relation of neurobiological substrates of cognitive functioning may be different for different groups.

What Metabolic Syndrome Contributes to Brain Outcomes in African American & Caucasian Cohorts by Melissa Lamar, Leah H. Rubin, Olusola Ajilore, Rebecca Charlton, Aifeng Zhang, Shaolin Yang, Jamie Cohen, Anand Kumar (640-647).
Metabolic syndrome (MetS), i.e., meeting criteria for any three of the following: hyperglycemia, hypertension, hypertriglyceridemia, low high-density lipoprotein and/or abdominal obesity, is associated with negative health outcomes. For example, MetS negatively impacts cognition; however, less is known about incremental MetS risk, i.e., meeting 1 or 2 as opposed to 3 or more criteria. We hypothesized incremental MetS risk would negatively contribute to cognition and relevant neuroanatomy, e.g., memory and hippocampal volumes, and that this risk extends to affective functioning. 119 non-demented/non-depressed participants (age=60.1+12.9;~50% African American) grouped by incremental MetSrisk–no (0 criteria met), low (1-2 criteria met), or high (3+ criteria met)–were compared across cognition, affect and relevant neuroanatomy using multivariable linear regressions. Exploratory analyses, stratified by race, consider the role of health disparities in disease severity of individual MetS component (e.g., actual blood pressure readings) on significant results from primary analyses. Incremental MetS risk contributed to depressive symptomatology (nolow=high) after controlling for age, race (n.s.) and IQ. Different indices of disease severity contributed to different aspects of brain structure and function by race providing empirical support for future studies of the impact distinct health disparities in vascular risk have on brain aging. MetS compromised mood, cognition and hippocampal structure with incremental risk applying to some but not all of these outcomes. Care providers may wish to monitor a broader spectrum of risk including components of MetS like blood pressure and cholesterol levels when considering brainbehavior relationships in adults from diverse populations.

Racial Differences in Gray Matter Integrity by Diffusion Tensor in Black and White Octogenarians by Ge Liu, Ben Allen, Oscar Lopez, Howard Aizenstein, Robert Boudreau, Anne Newman, Kristine Yaffe, Stephen Kritchevsky, Lenore Launer, Suzanne Satterfield, Eleanor Simonsick, Caterina Rosano (648-654).
Objective: To quantify racial differences in brain structural characteristics in white and black octogenarians, and to examine whether these characteristics contribute to cognition. Methods: Cross-sectional study of 283 adults 79-89 years old (59.4% white;42.0% women) with data on gray matter integrity via diffusion tensor imaging (mean diffusivity), gray matter atrophy (GMA), white matter hyperintensities (WMH), literacy, smoking, drinking, income, hypertension and diabetes. Participants were recruited from an ongoing epidemiological study of older adults living in the community with a range of chronic conditions, physical and cognitive function. Standardized betas (sβ) of neuroimaging markers predicting Digit Symbol Substitution Test (DSST) and Modified Mini-Mental State Examination (3MS) scores were computed in multivariable regression models stratified by race. Results: Compared to whites, blacks had lower DSST (p=0.001) and lower 3MS (p=0.006), but also lower mean diffusivity (i.e. higher gray matter microstructural integrity, p=0.032), independent of gender, income, literacy, body mass index, diabetes and drinking habits. Racial differences were not significant for WMH (p=0.062) or GMA (p=0.4). Among blacks, mean diffusivity and WMH were associated with DSST (sβ=-.209, p=0.037and -.211, p=.038, respectively) independent of each other and other covariates; among whites, mean diffusivity, but not WMH, was significantly associated with DSST and 3MS (sβ =-.277, p=.002 and -.250, p=0.029, respectively). Conclusions: In this cohort of octogenarians living in the community, blacks appeared to have higher microstructural integrity of gray matter as compared to whites. This neuroimaging marker was related to higher cognition even in the presence of WMH and other cardiovascular conditions. If confirmed, these findings suggest microstructural gray matter integrity may be a target to improve cognition, especially among blacks who survive to very old age with a range of chronic cardiovascular conditions.

Dysfunction of Endoplasmic Reticulum (ER) and Mitochondria (MT) in Alzheimer's Disease: The Role of the ER-MT Cross-Talk by Katalin Volgyi, G&#225;bor Juh&#225;sz, Zsolt Kovacs, Botond Penke (655-672).
A common feature of neurodegenerative diseases is the formation of misfolded, mostly enzyme resistant proteins. These substances may form toxic assemblies according to the current concept of the neurodegenerative diseases. Overlapping of the misfolded proteins is typical in these disorders. The formation of misfolded proteins and toxic aggregates point to a common pathway of these disorders: failure in normal protein folding in the ER as a consequence of ER-stress and mitochondrial energy production. Alzheimer's disease (AD) is a rather heterogeneous, multifactorial disorder with wide clinical heterogeneity and is classified into several subtypes. In AD the processing of the amyloid precursor protein (APP) and formation of toxic β-amyloid (Aβ) structures occur intraneuronally. Aβ affects both ER and mitochondria and disturbs Ca2+-homeostasis of the cells. Mitochondrial dysfunction is one of the main pathological events in AD. Mitochondria accumulate Aβ derived from the ER/Golgi or from the mitochondriaassociated ER-membranes (MAM). Free radicals, oxidative stress and increasing Ca2+-concentration in mitochondria cause decreased ATP production. Mitochondrial dynamic and trafficking are also altered as a result of Aβ toxicity. Synaptic mitochondria show a very high vulnerability. Depletion of Ca2+ level in the ER results in dysfunction of protein folding and evokes unfolded protein response (UPR), and affects also mitochondria. MAM may play special role in the ERmitochondria cross talk. Mitochondria themselves (using mitochondria-targeting antioxidants such as MitoQ) could be a special target for AD treatment. Another targets are the UPR cascade proteins (PERK, IRE1, ATF6) and receptors involved in Ca2+ -level stabilization of the ER (Ryr, IP3R).

Sodium Hydrosulfide Attenuates Beta-Amyloid-Induced Cognitive Deficits and Neuroinflammation via Modulation of MAPK/NF-κB Pathway in Rats by Huiyu Liu, Yuanyuan Deng, Jianmei Gao, Yuangui Liu, Wenxian li, Jingshan Shi, Qihai Gong (673-683).
Beta-amyloid (Aβ), a neurotoxic peptide, accumulates in the brain of Alzheimer's disease (AD) subjects to initiate neuroinflammation eventually leading to memory impairment. Here, we demonstrated that Aβ-injected rats exhibited cognitive impairment and neuroinflammation with a remarkable reduction of hydrogen sulfide (H2S) levels in the hippocampus compared with that in shamoperated rats. Interestingly, the expression of cystathionine-β-synthase (CBS) and 3- mercaptopyruvate-sulfurtransferase (3MST), the major enzymes responsible for endogenous H2S generation, were also significantly decreased. However, intraperitoneal (i.p.) injection of sodium hydrosulfide (NaHS, a H2S donor) dramatically attenuated cognitive impairment and neuroinflammation induced by hippocampal injection of 10 μg of Aβ1-42 in rats. Subsequently, NaHS significantly suppressed the expression of tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) in rat hippocampus following Aβ administration. Furthermore, NaHS exerted a beneficial effect on inhibition of IκB-α degradation and subsequent activation of transcription factor nuclear factor κB (NF-κB), as well as inhibition of extracellular signal-regulated kinase (ERK1/2) activity and p38 MAPK activity but not c-Jun N-terminal kinase (JNK) activity induced by Aβ. These results demonstrate that NaHS might be a potential agent for treatment of neuroinflammation-related AD.

Insulin Modulates In Vitro Secretion of Cytokines and Cytotoxins by Human Glial Cells by Lindsay J. Spielman, Manpreet Bahniwal, Jonathan P. Little, Douglas G. Walker, Andis Klegeris (684-693).
Alzheimer's disease (AD) is the most common form of dementia worldwide. Type 2 diabetes (T2D) has been implicated as a risk factor for AD. Since T2D is a peripheral inflammatory condition, and AD brains exhibit exacerbated neuroinflammation, we hypothesized that inflammatory mechanisms could contribute to the observed link between T2D and AD. Abnormal peripheral and brain insulin concentrations have been reported in both T2D and AD. The neurotrophic role of insulin has been described; however, this hormone can also regulate inflammatory responses in the periphery. Therefore we used in vitro human cell culture systems to elucidate the possible effects of insulin on neuroinflammation. We show that human astrocytes and microglia express both isoforms of the insulin receptor as well as the insulin-like growth factor (IGF)-1 receptor. They also express insulin receptor substrate (IRS)-1 and IRS-2, which are required for propagation of insulin/IGF- 1 signaling. We show that at low nanomolar concentrations, insulin could be pro-inflammatory by upregulating secretion of interleukin (IL)-6 and IL-8 from stimulated human astrocytes and secretion of IL-8 from stimulated human microglia. This effect dissipates at higher insulin concentrations. In contrast, insulin at a broader concentration range (10 pM – 1 μM) reduces the toxicity of stimulated human microglia and THP-1 monocytic cells towards SH-SY5Y neuronal cells. These data show that insulin may regulate the inflammatory status of glial cells by modulating their select functions, which in turn can influence the survival of neurons contributing to the observed link between T2D and AD.

Quantitative μPET Imaging of Cerebral Glucose Metabolism and Amyloidosis in the TASTPM Double Transgenic Mouse Model of Alzheimer's Disease by Ann-Marie Waldron, Leonie Wyffels, Jeroen Verhaeghe, Astrid Bottelbergs, Jill Richardson, Jonathan Kelley, Mark Schmidt, Sigrid Stroobants, Xavier Langlois, Steven Staelens (694-703).
Positron emission tomography studies of cerebral glucose utilization and amyloid-β deposition with fluoro-deoxy-D-glucose ([18F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [18F]-FDG and [18F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-β and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [18F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significantregional decreases in [18F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-β showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [18F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement no.115009.

A Cyclooxygenase-2 Inhibitor Reduces Vascular Wall Thickness and Ameliorates Cognitive Impairment in a Cerebral Small Vessel Diseases Rat Model by Jie Tang, Weizhong Xiao, Qinghua Li, Qiuqiong Deng, Xinquan Chu, Yang Chen, Danhong Pan, Jianhui Fu (704-710).
Cerebral small vessel disease (CSVD) is a group of diseases that originate from changes in cerebral small vessels and that cause many conditions, such as cognitive impairment. However, there is no effective therapy for these diseases. Recent studies have suggested that inflammation is associated with this disease. Cyclooxygenase-2 (cox-2) is an inflammatory mediator; however, whether a cox-2 inhibitor could protect against the CSVD progression remains unknown. In the present study, stroke-prone spontaneously hypertensive rats (SHRsp) were used as a model of CSVD, and Sprague Dawley (SD) rats served as the control. SHRsp were treated with the cox-2 inhibitor celecoxib or vehicle. The Morris water maze test was performed, and vascular morphometry and the expression of collagen I and fibronectin were examined in cerebral small vessels and cerebral tissue. The results revealed that thickened small veesel walls, increased expression of collagen I and fibronectin and impaired cognitive function in SHRsp compared with SD rats. Additionally, celecoxib significantly down-regulated the expression of collagen I and fibronectin, attenuated the increase in vascular wall thickness and ameliorates the cognitive impairment. Our study indicated that this cox-2 inhibitor may serve as a promising candidate for the pharmacological intervention of CSVD.