Article

Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later. Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm(3) greater ventricular (p = 0.013), 110 mm(3) smaller hippocampal (p = 0.013), 519 mm(3) smaller occipital (p = 0.009), and 532 mm(3) smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. Conclusions: Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Additionally, studies have found that the bloodbrain barrier in humans becomes more permeable with increasing age for other immune cells [4]. In 2017, a study found an association between elevated inflammatory markers in the blood during mid-life and brain volume in late-life [7]. This finding highlights that elevated inflammation in the body might affect the neuroinflammation and cognitive decline in the pathology of dementia [7]. ...
... In 2017, a study found an association between elevated inflammatory markers in the blood during mid-life and brain volume in late-life [7]. This finding highlights that elevated inflammation in the body might affect the neuroinflammation and cognitive decline in the pathology of dementia [7]. ...
... This indicates that peripheral activation of the immune system can affect the brain. The ARIC study from 2017 found an association between inflammation during mid-life and the brain volume in late-life [7], indicating that elevated inflammatory markers in the body may affect neuroinflammation and cognitive aging [7]. ...
Article
Background: The critical role of inflammatory processes in the pathogenesis of dementia has recently been established. Objective: The aim of this study was to investigate the association between inflammatory bowel disease (IBD) and dementia risk in patients followed in general practices in Germany. Methods: This study included patients aged over 60 with an initial diagnosis of IBD (Crohn's Disease (CD), ulcerative colitis (UC)) who were followed in 1,159 German general practices between January 1995 and December 2014. IBD patients were matched to healthy patients using propensity scores based on age, gender, index year, insurance type and comorbidities. Kaplan-Meier curves were used to study the development of dementia in patients with or without IBD within up to 15 years of the index date. Cox proportional hazard regression models were used to estimate the relationship between IBD and dementia. Results: The study included 3,850 patients with and 3,850 patients without IBD and revealed a higher cumulative incidence of dementia in IBD patients than in non-IBD patients after the follow-up period. The cumulative incidence of dementia differed within IBD subtypes; it was significantly higher in UC patients than in CD patients. Cox proportional hazard models showed that IBD is associated with a 1.22-fold increase in the risk (95% CI: 1,07-1,39) of developing dementia. UC patients had a 1.25-fold higher risk of developing dementia (95% CI: 1.07-1.46). CD is not significantly associated with an increased risk of dementia (HR: 1.17, 95% CI: 0.93-1.47). Conclusion: A positive association between IBD and dementia was found in patients followed in general practices in Germany.
... Alzheimer's disease (AD) pathology is characterized by extracellular amyloid plaques [1], neuronal and synaptic loss [2,3], intraneuronal neurofibrillary tangles [4], cortical thinning in the temporal, orbitofrontal, and parietal regions [5], and chronic inflammation [6]. New evidence suggests an association of inflammatory markers at midlife with worst performance on a word-recall test and lower brain volume in pathology-affected regions in AD [7]. Moreover, a recent study analyzing data from the Alzheimer's Disease Neuroimaging Initiative cohort has revealed, in a model that supplements the hypothetical version of Jack et al. [8], that inflammatory changes precede amyloid-beta (Ab) and tau accumulation in the presymptomatic phase of the disease [9]. ...
... Recent evidence has revealed that inflammation might be a key player in prodromal AD [7,9,26]. Among the numerous actors implicated in the inflammatory process in AD, TLR4 has been identified as an important link between AD pathological processes and the downstream release of proinflammatory cytokines in both mouse models of AD [11,12,14,27] and in human diseased brains [28]. ...
Article
Introduction: A coding variant in the TLR4 receptor (rs4986790), previously associated with longevity and Alzheimer's disease (AD) risk reduction, was examined in a population isolate (Québec Founder Population [QFP]) and in presymptomatic individuals with a parental history of AD (Pre-Symptomatic Evaluation of Novel or Experimental Treatment for Alzheimer's Disease [PREVENT-AD]). Methods: Genotyping was performed using the Illumina HumanHap 550k (QFP) and the Illumina Omni2.5 beadchips (PREVENT-AD). Cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Whole-brain cortical thickness data were analyzed using CIVET 1.12. Cerebrospinal fluid concentrations of cytokines were obtained by using Milliplex. Results: The minor allele of the rs4986790 polymorphism (G) is associated with a reduced risk of developing AD in the QFP, as well as higher visuospatial and constructional abilities, higher cortical thickness in visual-related regions, and stable cerebrospinal fluid IL-1β levels in the PREVENT-AD cohort. Discussion: The rs4986790 G coding variant in the TLR4 gene appears to reduce AD risk through the modulation of IL-1β synthesis and secretion in the presymptomatic phase of the disease.
... As this reaction does not differ significantly between neurodegenerative diseases it was initially thought to be common to various disease processes, however, increasing evidence seems to show that neuro-inflammation in itself is pathogenic (Heneka et al., 2015;Heppner et al., 2015;Metcalfe and Figueiredo-Pereira, 2010). There is a strong correlation between peripheral inflammation and cognitive deficits (Walker et al., 2017). Systemic infections have long been associated with cognitive impairment with one study showing 60% of elderly patients admitted with infection related delirium going on to develop dementia at a 3 year follow up compared to 18.5% of elderly patients without delirium (Rockwood, 1999). ...
... Compromises in blood brain barrier integrity secondary to inflammation have been observed in cardiovascular disease, obesity and type 2 diabetes mellitus, all risk factors for developing Alzheimer's (Gustafson et al., 2007;Hawkins et al., 2006;Pooja Naik et al., 2014). More recently Walker et al., in a longitudinal study spanning 20 years, showed that higher levels of circulating inflammatory markers in midlife is associated with cognitive deficits as well as smaller brain volumes later in life, particularly in regions associated with Alzheimer's pathology such as the hippocampus (Walker et al., 2019(Walker et al., , 2017. ...
Thesis
Neuroinflammation is becoming increasingly recognised as key to the pathogenesis of Alzheimer’s disease and tauopthies. Epidemiological studies report a delay in the onset of Alzheimer’s in subjects using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit enzymes in the cyclooxygenase-2 (COX-2) pathway which play a key role in synthesising prostaglandin E2 (PGE2) from arachidonic acid. PGE2 has been implicated in preclinical stages of Alzheimer’s disease, where elevated levels of PGE2 in the cerebrospinal fluid can be found, as well as aberrant amyloid processing in experimental models of disease. PGE2 signals via 4 E-prostanoid (EP) receptors, EP1-EP4, all G-protein coupled receptors (GPCR). The EP3 receptor, the most abundant PGE2 receptor in the brain, is unique in that it is alternatively spliced giving rise to species specific isoforms. One of the EP3 receptor isoforms, EP3Re, is human specific and an incidental finding within a project to investigate its distribution in brain, suggested that it could be associated with tau tangles. The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. Further work will be required to fully clarify the specificity of the interaction and understand the mechanism behind this and if targeting inflammatory EP3Re signalling has the potential to affect tau pathology in disease.
... To correct for these distortions, the diffusion weighted data were nonlinearly registered to the T1-weighted anatomical reference scan using the BrainSuite program, 20 which also produced fractional anisotropy (FA) and MD images in each subject's T1-weighted space after fitting diffusion tensors to the data by way of a weighted least-squares scheme. 16,21 DTI measures of FA and MD were used to assess microstructural integrity of lobar and deep WM regions. MD was used to assess microstructural integrity of the temporal lobe GM areas. ...
... To exclude edge voxels that were primarily cerebrospinal fluid, an upper cutoff of MD < 0.002 mm 2 /s was applied. 21 We grouped the atlas regions into four regions of interest: ...
Article
Full-text available
Introduction: As hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain. Methods: A total of 1086 dementia-free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population-based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016-2017) and magnetic resonance imaging of the brain (2011-2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts. Results: Hearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus. Conclusion: Our results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes.
... Previous evidence has suggested that neurotransmitter disturbances, especially acetylcholine deficiency and dopamine excess, could be one main reason for the development of delirium [5,6]. Additionally, hospitalization per se seems to contribute to neurocognitive brain changes [7] by promoting systemic inflammation that has been related to smaller brain volume [8], blood-brain barrier dysfunction [9], and changes in cerebral metabolism [10]. ...
... A growing number of randomized trials have examined whether physical exercise has a beneficial effect on perception and cognition in older adults, but further research is needed to determine which exercise modality is the best for obtaining cognitive gains and to explore physiological and neuromuscular changes to understand the relationship between exercise and cognition in older patients [41]. Although hospitalization per se seems to contribute to neurocognitive brain changes by promoting systemic inflammation [7,8] and short-term exercise training appears to induce an anti-inflammatory response in acutely hospitalized older patients [42], no cognitive differences were obtained between the physical exercise intervention and usual care during hospitalization in this study. Furthermore, to the authors' knowledge, this is the first meta-analysis to point toward the beneficial effects of inpatient physical exercise programs, including multidomain interventions that included physical rehabilitation, for improving cognitive function in acutely hospitalized older adults after hospital discharge. ...
Article
Background: Acute care hospitalization increases the likelihood of developing cognitive impairment and delirium in older adults. Objective: To summarize evidence about the effectiveness of exercise and physical rehabilitation interventions on the incidence of delirium and cognitive impairment in acutely hospitalized older patients. Methods: Relevant articles were systematically searched (PubMed, Web of Science, and CINHAL databases) until 26 August 2021. Randomized and nonrandomized controlled trials of in-hospital physical exercise interventions and rehabilitation programs compared to usual care performed for older patients (> 65 years) hospitalized for an acute medical condition were selected. The primary endpoints were changes in the incidence of delirium and cognition during acute hospitalization. The secondary endpoints included functional independence, psychological measures, well-being status, length of hospital stay, transfer after discharge, fall occurrence, hospital readmissions, and mortality rate. The endpoints were evaluated at different time points (at admission, at discharge, and after discharge). Results: Eleven studies from 8 trials (n = 3,646) were included. The methodological quality of the studies was mostly high. None of the studies reported any adverse events related to the intervention. Early rehabilitation improved cognitive function at 3 months postdischarge (Hedge's g = 0.33, 95% confidence interval [CI] 0.19 to 0.46, p < 0.001). No between-group differences were found for incident delirium and cognitive impairment during hospitalization (all p > 0.05). Conclusion: In-hospital physical exercise and early rehabilitation programs seem to be safe and effective interventions for enhancing cognitive function after discharge in older patients hospitalized for an acute medical condition. However, no potential benefits were obtained over usual hospital care for the incidence of delirium.
... Additionally, heightened blood inflammatory markers measured during middle adulthood have been associated with https://doi.org/10.1016/j.bbi.2020.01.006 Received 3 September 2019; Received in revised form 13 December 2019; Accepted 6 January 2020 accelerated memory decline and late-life structural abnormities in brain regions vulnerable to AD (Walker et al., 2019a,b;Walker et al., 2017). Similarly, recent work within our cohort indicates that elevated levels of blood inflammatory cytokines among cognitively normal participants is also associated with increased risk of progression to MCI (Gross et al., 2019). ...
... Although we did not find support for this hypothesis with regard to cortical amyloid burden, it is possible that inflammation promotes other aspects of AD pathology, such as tau hyperphosphorylation or synaptic dysfunction, which may also emerge and progress along select large-scale functional networks (Chavan et al., 2012;Jones et al., 2017;Popp et al., 2017;Varma et al., 2017). In support of this notion, previous work has demonstrated a relationship between inflammatory markers, subsequent region-specific atrophy and FDG PET neurometabolic changes which overlap neuroanatomically with hubs of Default network connectivity (Schmidt et al., 2016;Walker et al., 2017;Warren et al., 2018). An alternative hypothesis is that inflammation may simply serve as a byproduct of, or a compensatory mechanism in response to, an AD-related pathological process which selectively influence Default Abbreviations: BMI, body mass index; IL-6, interleukin 6; MMSE, Mini-Mental State Examination; No., number; SD, standard deviation; sTNFR1, soluble tumor necrosis factor-alpha receptor-1; y, years. ...
Article
Background: Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer's disease, but inflammation's effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status. Methods: Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden. Results: Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β=-0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (β=-0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks). Conclusion: Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.
... The onset of systemic inflammatory responses has been demonstrated decades before memory impairment and subsequent neurodegeneration in AD [32]. Moreover, higher levels of serum inflammatory cytokines are observed in individuals who after 20 years demonstrated memory decline and decreased brain volume [33]. Such observations suggest that systemic inflammatory responses play an important early role in AD pathology before amyloid deposition and microglia activation in the brain [2,14,15]. ...
... Systemic inflammation is operative in AD patients before the onset of memory impairment. This suggests an important role of peripheral immune activation in disease [15,32,33]. Aβ drains to the peripheral cervical lymph nodes [53] where APCs process and present Aβ peptides to peripheral T cells engaging MHC-I or -II, which initiates peripheral adaptive immune activation [2,11,54]. ...
Article
Full-text available
Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA b (MHCII-IA b –KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical Abstract
... Previous studies, both cross-sectional and longitudinal, showed that higher levels of inflammatory cytokines are associated with a decrease in cognitive function [43][44][45][46][47][48][49]. The relationship between higher levels of IL-6 and increased risk of dementia was presented in a meta-analysis [50]. ...
Article
Full-text available
Background: The ageing process causes a number of changes in the human immune and endocrine systems. The aim of this study was to assess the relationship between cognitive, emotional and functional skills as well lifestyle, versus selected biochemical indicators of the ageing process. Methods: The cross-sectional study was conducted in a group of 121 people aged 60-90 residing in the Lesser Poland voivodship. The study used standardized research tools including the Barthel scale, Instrumental Activities of Daily Living (IADL) scale, Mini-Mental State Examination (MMSE), Life Orientation Test (LOT-R) and inventory of health behaviors (IHB). In addition, the concentration of IL-6 and melatonin in the blood plasma was determined. Results: We determined the correlation between the level of IL-6 in a group of people over 75 years of age (requiring medical care), and results of the IADL scale. There was also a correlation between melatonin levels and the MMSE results in a group of people aged 60-75 who did not require constant medical care. Conclusions: IL-6 can be treated as a predictor of functional skills of people over 75 years of age, and melatonin can be perceived as a factor for recognizing cognitive impairment in elderly people who do not require constant medical assistance.
... For example, a prospective cohort study revealed that an increase in inflammatory markers during midlife is associated with memory decline and reduced brain volume 20 years after inflammatory marker measurement. 88,89 Moreover, AD patients and persons with mild cognitive impairment are characterized by elevated proinflammatory cytokine levels and inflammatory signals in their blood. 35 Interesting in the light of the viral infection hypothesis is the nested case-control study performed by Dunn and co-workers. ...
Article
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which only symptomatic medication is available, except for the recently FDA-approved aducanumab. This lack of effective treatment urges us to investigate alternative paths that might contribute to disease development. In light of the recent SARS-CoV-2 pandemic and the disturbing neurological complications seen in some patients, it is desirable to (re)investigate the viability of the viral infection theory claiming that a microbe could affect AD initiation and/or progression. Here, we review the most important evidence for this theory with a special focus on two viruses, namely HSV-1 and SARS-CoV-2. Moreover, we discuss the possible involvement of extracellular vesicles (EVs). This overview will contribute to a more rational approach of potential treatment strategies for AD patients. Teaser: The recent SARS-CoV-2 pandemic and the disturbing neurological complications in a significant number of COVID-19 patients brought the viral infection theory as a possible cause for AD back into the spotlight. Here, we give a vision on the latest evidence for this theory.
... The severity of cognitive decline-evaluated through performance assessments including the Mini Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination Revised (ACE-R)-was found to be inversely proportional to serum levels of inflammatory markers . Longitudinal clinical studies further implicate early chronic peripheral inflammation in the preponderance of neurodegenerative disease: individuals with higher levels of pro-inflammatory cytokines in midlife are at a significantly higher risk for cognitive decline as they age (Walker et al., 2019b)-those who maintained aberrant levels for multiple decades were found to be especially prone to debilitating neurodegeneration via reduced brain volume and abnormal white matter microstructural integrity (Walker et al., 2017(Walker et al., , 2018. Altogether, these data posit a putatively temporal relationship between chronic, systemic immune activation and cognitive deterioration and suggest that inflammation-which may occur decades before the onset of AD symptoms-exacerbates or directly mediates neurodegeneration. ...
Article
Full-text available
Late-onset Alzheimer's Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic Aβ plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies ultimately incite the propagation of a disease-associated subset of microglia—the principle immune cells of the brain—characterized by preferentially pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been identified as one of the cardinal pathophysiological driving features of AD; however, despite a number of works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis and relation to the inception of cognitive impairment remain obscure. Moreover, the limited clinical success of treatments targeting specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative, more holistic approaches for ameliorating AD outcomes. Accumulating evidence suggests significant interplay between peripheral immune activity and blood-brain barrier permeability, microglial activation and proliferation, and AD-related cognitive decline. In this work, we review a narrow but significant subset of chronic peripheral inflammatory conditions, describe how these pathologies are associated with the preponderance of neuroinflammation, and posit that we may exploit peripheral immune processes to design interventional, preventative therapies for LOAD. We then provide a comprehensive overview of notable treatment paradigms that have demonstrated considerable merit toward treating these disorders.
... Although not in line with our original hypotheses, these results do align with some findings from previous publications. For example, results from the ARIC study indicated that FVIII might have another role in brain morphology that is not specifically related to white matter lesion development; for instance, multiple midlife systemic inflammatory markers (including FVIII) were associated with brain volume late in life [31]. Another recent publication from the same cohort examined the relationship between an "inflammation composite score" that included factor VIII in middle-aged individuals and 20-year cognitive decline [32]. ...
Article
Full-text available
Objective To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time. Methods Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function. Results After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99–1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87–1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment. Interpretation The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.
... [10] In several studies, systemic inflammation has been linked with smaller brain volumes, poorer episodic memory, and progressive cognitive decline. [11,12] Based on the above studies, several clinical studies have shown that PUD was associated with an increased risk of dementia. In a nationwide study of Taiwan, patients with HP infection were 1.60-fold (95% confidence interval [CI] = 1.32-1.95) ...
Article
Full-text available
Studies have shown that peptic ulcer disease (PUD) increases the risk of dementia via the mechanism of systemic inflammation. We examined the association between PUD and the risk of dementia using a population-based national sample cohort from South Korea.Using the national cohort study from the Korean National Health Insurance Service, we extracted data for patients with dementia (n = 11,434) and for 1:4 matched control participants (n = 45,736) and then analyzed the previous histories of PUD from 2002 to 2013 using conditional logistic regression analyses. The controls were matched to the patients according to age, sex, income, region of residence, and past medical history. Subgroup analyses were performed based on age and sex.There was no statistically significant difference in the incidence of PUD between the dementia and control groups (18.0% vs 17.4%, P = .107). The adjusted odds ratio (OR) for PUD was 0.92 (95% confidence interval [CI] = 0.88-0.97, P = .002). In the subgroup analysis based on age, the adjusted ORs for PUD were 0.93 (95% CI = 0.88-0.99) in the <80-year-old group and 0.90 (95% CI = 0.82-1.00) in the ≥80-year-old group (each P < .05). In the subgroup analysis based on sex, the adjusted ORs for PUD were 0.89 (95% CI = 0.81-0.97; P < .05) in men and 0.94 (95% CI = 0.89-1.00; P = .06) in women.PUD does not increase the risk of dementia at any age or in either sex after adjusting for age and the history of hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, stroke, and depression.
... Sie erhöhen zudem das Risiko für eine vaskuläre Demenz durch eine Häufung von thromboembolischen und vaskulären Ereignissen [44]. In einer Längsschnittstudie konnte gezeigt werden, dass chronische Entzündungsprozesse im mittleren Lebensalter mehr als 20 Jahre später quantitativ mit einer Verminderung des Gehirnvolumens verbunden sind [45]. Bei entzündlichen Darmerkrankungen lassen sich diese Prozesse auf Veränderungen des Darm-Mikrobioms, auf eine vermehrte Durchlässigkeit der Darmschranke und auf das vermehrte Auftreten entzündungsfördernder Bakterienbestandteile und Bakterienmetabolite im Blut zurückführen [46]. ...
Article
ZUSAMMENFASSUNG Hintergrund Unter dem Darm-Mikrobiom versteht man die Summe der Genome der Mikrobiota des menschlichen Darms. Die Bedeutung des Darm-Mikrobiota für Entwicklung, Verlauf und Behandlung der Alzheimer-Demenz hat in den vergangenen Jahren zunehmendes Interesse gefunden, sodass mittlerweile zahlreiche Untersuchungen zu diesem Thema publiziert wurden. Ziel Darstellung des aktuellen Stands der Forschung zur Bedeutung des Darm-Mikrobioms für Entwicklung, Verlauf und Behandlung der Alzheimer-Demenz. Ergebnisse und Diskussion Bei Patienten mit Alzheimer-Demenz wurden Veränderungen des Mikrobioms beschrieben, insbesondere eine Abnahme der Diversität sowie eine Zunahme bzw. Abnahme bestimmter Stämme und Klassen von Bakterien. Ähnliche Veränderungen fanden sich bei Diabetes mellitus und Übergewicht, bekannten Risikofaktoren für die Alzheimer-Demenz, sowie mit zunehmendem Lebensalter. Schließlich sind auch entzündliche Darmerkrankungen mit einem erhöhten Risiko für die Entwicklung einer Alzheimer-Demenz verbunden. Es gibt verschiedene Mechanismen, über die das Darm-Mikrobiom die Krankheitsprozesse, die der Alzheimer-Demenz zugrunde liegen, beeinflussen kann. Am besten belegt erscheint die Verstärkung von Entzündungsprozessen durch eine vermehrte Durchlässigkeit der Darmbarriere für entzündungsfördernde Bakterienmetabolite und -bestandteile. Diese Zusammenhänge haben schon Therapieversuche ausgelöst, die insbesondere mit Pro- und Präbiotika auf eine Modifikation des Darm-Mikrobioms abzielen.
... Circulating IL-6 and CRP levels are elevated in obese humans and rodents, and weight loss reduces IL-6 expression in both white adipose depots and plasma [102]. A recent systematic review investigating the relationship between high circulating IL-6 levels and global cognitive decline concluded that there is a positive association between these variables [103] and a large neuro-imaging study showed that increased mid-life inflammatory marker expression in plasma were associated with reduced hippocampal and increased ventricular volumes in late-life [104]. High CRP levels have been associated with reduced global cognitive performance [105] and poor verbal fluency [106]. ...
Article
Poor diet and obesity are associated with cognitive impairment throughout adulthood, and increased dementia risk in aging. Here we review the current literature interrogating the mechanisms by which diets high in fat, or fat and sugar lead to cognitive impairment, focusing on changes to gut microbiome composition, inflammatory signalling and blood-brain barrier integrity. Preclinical studies indicate weight gain is not necessary for diet-induced cognitive impairment. Rather, gut microbiome composition, and systemic and central inflammatory processes appear to contribute to diet-induced cognitive impairment. While both obese humans and rodents exhibit reduced blood-brain barrier integrity, cognitive impairments precede these changes, suggesting other mechanisms may underly diet-induced cognitive changes. Other potential candidates include hormone, glucoregulatory and cardiovascular changes. Poor diet and obesity act through multiple mechanisms to affect cognitive health and the challenge for future research is to identify key processes that can be reversed to improve cognition and quality of life.
... Evidently, at discharge, one-third of COVID-19 patients exhibit cognitive impairment and motor deficits [113]. The pronounced systemic inflammation apparent in SARS-CoV-2 infection [41], and the fact that systemic inflammation promotes cognitive decline and neurodegenerative disease [114][115][116], suggests that COVID-19 survivors will likely experience long-term neurodegeneration. Furthermore, chronic ventilation is highly associated with persistent cognitive decline, executive dysfunction, and reduced quality of life (reviewed in [117]). ...
Article
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite pulmonary impairments being the most prevalent, extra-pulmonary manifestations of COVID-19 are abundant. Confirmed COVID-19 cases have now surpassed 57.8 million worldwide as of 22 November 2020. With estimated case fatality rates (number of deaths from COVID-19 divided by number of confirmed COVID-19 cases) varying between 1 and 7%, there will be a large population of recovered COVID-19 patients that may acquire a multitude of long-term health consequences. While the multi-organ manifestations of COVID-19 are now well-documented, the potential long-term implications of these manifestations remain to be uncovered. In this review, we turn to previous similar coronaviruses (i.e. SARS-CoV-1 and Middle East respiratory syndrome coronavirus [MERS-CoV]) in combination with known health implications of SARS-CoV-2 infection to predict potential long-term effects of COVID-19, including pulmonary, cardiovascular, hematologic, renal, central nervous system, gastrointestinal, and psychosocial manifestations, in addition to the well-known post-intensive care syndrome. It is necessary to monitor COVID-19 patients after discharge to understand the breadth and severity of long-term effects. This can be accomplished by repurposing or initiating large cohort studies to not only focus on the long-term consequences of SARS-CoV-2 infection, but also on acquired immune function as well as ethno-racial group and household income disparities in COVID-19 cases and hospitalizations. The future for COVID-19 survivors remains uncertain, and if this virus circulates among us for years to come, long-term effects may accumulate exponentially.
... The idea of an important role of neuroinflammation in cognitive deficits is consistent with recent studies showing that inflammatory Casp1 inhibitors, elimination of Casp1 gene expression by knock down or siRNAs, or elimination of Casp1-activating inflammasome pathways, reverse inflammation and cognitive deficits in AD mice models [15,22,47,51]. This hypothesis is also supported by the association of peripheral inflammatory markers with brain atrophy and decreased cognition in aged individuals [53]. These results suggest that the effect of MB was related to inhibition of Casp6. ...
Article
Full-text available
Abstract Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.
... Next, to reduce dimensionality and strengthen the robustness of analyses, we derived more global measures of systemic inflammation, as was done previously for Alzheimer's Disease (17). To do so, we first multiplied the Z scores of the negative blood APRs serum albumin, iron, and transferrin by −1 (since the levels of these proteins decrease in response to inflammation) after adjusting for confounding factors as described in the Methods. ...
Article
Full-text available
Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS.Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression.Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS.Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.
... Similarly, the biological underpinnings of the sex differences in cognitive status and deterioration remain to be elucidated. Comorbidities such as cardiovascular and cerebrovascular disease 35 , synaptic biology 36 , brainderived neurotrophic factor levels 37 , and systemic 38 and brain [39][40][41] immune responses are all affected by sex and could contribute to the observed effects, but no studies have investigated the role of these factors in the observed sex-related differences in cognitive function and decline. ...
Article
Although Alzheimer disease (AD) is recognized as a public health priority by the WHO 1 and is expected to affect 90 million people worldwide by 2050 (ref. 2), the condition remains incurable and all clinical trials in AD conducted in the past decade have failed. Heterogeneity of disease manifestation and progression among patients has been identified as a critical issue in the current approach to developing new therapies for AD 3,4. Therefore, characterization of genetic, demographic and phenotypic traits that predict disease onset, prognosis and treatment response (exemplified by work in the oncology field 5,6) is of growing interest in AD research. Phenotypic 7,8 and genetic 9 factors have been proposed as characteristics that can guide patient selection, stratification and clustering for AD diagnosis and treatment. However, whether demographic variables such as sex should be considered in relation to AD phenotypic variability is unclear. Differences in brain structure 10,11 and function 12 between men and women are emerging, as are effects of sex on the manifestation and progression of neurological conditions, such as ischaemic stroke 13 , Parkinson disease 14 and migraine 15. In a longitudinal study of >2,000 patients with Parkinson disease, sex accounted for 2.6% of the predictive information provided by a seven-factor clinical-genetic risk score for cognitive decline 16. However, current discussion of sex differences in AD primarily focuses on epidemiological aspects (Box 1), with very little attention given to the role of sex in the clinical and neuropathological manifestations. To address this knowledge gap, this Review-written on behalf of the Women's Brain Project and the Alzheimer Precision Medicine Initiative (APMI; Supplementary Box 1)-provides the first comprehensive overview of sex-related differences in the phenotypes of sporadic AD. The aims of the Review are to raise awareness of published evidence, to propose measures to increase the number and quality of studies in this field, and to highlight the importance of considering sex in preclinical and clinical studies in the context of a multi-variate, precision medicine approach for AD 17. Detailed discussion of sex differences in AD epidemiology is available elsewhere 18-21. In this Review, we focus on sex differences in clinical manifestations, biomarker profiles, risk factors and treatment of patients with AD. Abstract | Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review , we critically discuss the evidence for sex-related differences in AD symptomatology , progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy , suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment. *
... Because there has been a widespread assumption that "inflammatory" processes exert a deleterious influence on AD symptom development (see Section 4.3 below), we had expected higher levels of these four markers to be associated with increasing symptom severity, but we found the opposite to be true. This observation appears to converge with other evidence that some enhanced immune responses can be beneficial for individuals who are older [64] or who have established AD dementia [65]. Therefore, the described functions of the predictive markers may suggest that immune activation occurs as a response to insults such as AD pathology, presumably involving activation and recruitment of immune cells. ...
Article
Full-text available
Introduction: We sought biological pathways that explained discordance between Alzheimer's disease (AD) pathology and symptoms. Methods: In 306 Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 participants across the AD clinical spectrum, we investigated association between cognitive outcomes and 23 cerebrospinal fluid (CSF) analytes associated with abnormalities in the AD biomarkers amyloid β1-42 and total-tau. In a 200-person "training" set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS-Cog11 scores. In the remaining 106 participants ("validation" set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator-derived models and a related protein marker summary score as predictors of ADAS-Cog11, ADNI diagnostic category, and longitudinal cognitive trajectory. Results: AD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD-related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune-activation group portended better outcomes. Discussion: CSF markers of vascular, lipid-metabolic and immune-related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.
... Since systemic inflammation has been identified as a risk factor for persisting cognitive deficits in humans (Iwashyna et al, 2010;Semmler et al, 2013;Walker et al, 2017) and likewise for the development of neurodegenerative diseases such as AD (Widmann & Heneka, 2014), we tested whether a single peripheral immune stimulus would affect neuropathological changes such as Ab pathology and neuroinflammation in a murine AD model. ...
Article
Full-text available
Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.
... Several mechanisms may explain our findings. First, obesity is a state of chronic inflammation, and inflammation has been related to brain aging [55]. Inflammation is also implicated in the development of diabetes mellitus and insulin resistance, each of which affect insulin and glucose transport across the blood-brain barrier. ...
Article
Background: Adiposity may increase risk for dementia and Alzheimer's disease (AD), but mechanisms are unclear. Objective: To examine associations between measures of adiposity with AD-signature region cortical thickness and hippocampal volume. Methods: We used data from the Northern Manhattan Study, a clinically stroke-free cohort of mostly Hispanic participants. Exposures of interest included body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC), and adiponectin concentration, measured at study entry. AD-signature region cortical thickness and hippocampal volume were obtained using Freesurfer. We estimated associations using multivariable linear regression, adjusting for sociodemographics and health behaviors. We re-examined estimates after adjustment for APOEɛ4 allele status or carotid intima-media thickness (cIMT), among those cognitively unimpaired, and after weighting for inverse probability of selection into the MRI sub-study. We also repeated analyses for cortical thickness in non-AD signature regions. Results: The sample (N = 947, 63% women, 66% Hispanic/Latino, 26% obese) had a mean (SD) age = 63 (8) years. Greater BMI and WC (both z-scored) were associated with thinner AD-signature region cortex (also z-scored) (BMI: β [95% CI] = -0.09 [-0.18, -0.01], WC: β [95% CI] = -0.11 [-0.20, -0.02]). We did not find evidence that adiposity was related to hippocampal volume. Results were consistent after adjustment for APOEɛ4 allele status or cIMT, after weighting for selection, among those cognitively unimpaired, and for non-AD signature region cortical thickness. Conclusion: Greater BMI and WC were related to cortical thinning within and outside the AD-signature region, suggesting a global effect not specific to AD.
... 43 Inflammation is a key factor involved in AD development and has been associated with decreased volume in AD-signature regions. 44 On the other hand, conscientiousness is closely related to good health-related behaviors and decreased incidence of vascular diseases, such as diabetes and hypertension. [45][46][47] Therefore, individuals with low conscientiousness are more likely to have poor general health, which in turn contributes to brain damage that results in aggravated neurodegeneration. ...
Article
Aim: It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD-related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid-beta (Aβ) burden, AD-signature regional neurodegeneration, and white matter hyperintensities (WMH) in non-demented middle- and old-aged adults. Methods: A total of 397 non-demented participants underwent comprehensive clinical and neuropsychological assessments, 11 C-labelled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. Additionally, the NEO Five-Factor Inventory was administered to both the participants and their informants to measure neuroticism and conscientiousness. Results: Neither neuroticism nor conscientiousness was associated with cerebral Aβ deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD-signature region cortical thickness (AD-CT). In regard of the direct and indirect effect of each personality on AD-CT, only the direct effects were found, whereas indirect effects via Aβ deposition or WMH were not. Conclusions: The present findings suggest that amyloid-independent regional neurodegeneration might underlie relationships of neuroticism and conscientiousness with AD. This article is protected by copyright. All rights reserved.
... First, being overweight is associated with low-grade inflammation, and some proinflammation cytokines produced by adipose tissues may affect cognition (35). Second, some circulating pro-inflammatory markers such as IL-6 and CRP will likely increase in these subjects and result in global cognitive decline and hippocampal atrophy (36)(37)(38)(39). Third, overweight status will aggravate the central tissue injury in the central nervous system by decreasing the gene expression of IL-10 and increasing gene expression of nitric oxide synthase-2 in the human frontal cortex (40). ...
Article
Full-text available
Purpose: To determine the association between overweight and high-sensitivity C-reactive protein (hs-CRP) with the odds of cognitive impairment as well as its subtypes based on the Asymptomatic Polyvascular Abnormalities Community (APAC) study in China. Materials and methods: We conducted a cross-sectional analysis of the follow-up data of 2012 from the APAC study. The Chinese version of the MMSE was used as a cognitive screener, and an MMSE score <24 is generally accepted as indicating cognitive impairment. Multivariable logistic regression was used to estimate the interactions of hs-CRP levels with body mass index (BMI) on the effects of cognitive impairment and its subtypes. Results: Three thousand eight hundred seventy-five participants aged 40–90 years (median age 51.64 y) were enrolled in this study, and 1,788 (46.1%) were overweight. Before and after adjusting for confounders, such as age, sex, BMI, education, current smoking, drinking, physical activity, hypertension, hyperlipidemia, diabetes, and hs-CRP, elevated hs-CRP levels were associated with cognitive impairment in normal-weight participants (crude OR: 2.08, 95%CI: 1.28–3.37, p = 0.003; adjusted OR: 2.06, 95%CI: 1.03–4.10, p = 0.04), but not in overweight participants. There was no statistically significant evidence for the interaction between hs-CRP and BMI on any cognitive sub-item. Conclusion: Elevated hs-CRP levels increase the odds of cognitive impairment in normal-weight participants, but not in overweight participants.
... The considerable systemic inflammation in COVID-19, causes generalized endothelitis and disruption of the blood-brain barrier (BBB) [141,142]. Moreover, it is known that systemic hyper-inflammation is a leading cause of neurodegeneration and cognitive decline [143,144]. The latter requires longitudinal follow-up and studies on the pathogenesis and preventive measures, considering the already significant burden of neurodegenerative ailments such as Alzheimer's and Parkinson's disease, to prevent a delayed pandemic of new neurodegenerative conditions [10,137]. ...
Preprint
Full-text available
Introduction: Despite more than one year passed since the first cases of SARS-CoV-2 were reported, there is still no consensus on the definition and clinical management of post-acute-COVID-19. The condition has heterogeneously been named as Chronic COVID syndrome, Post COVID-19 Syndrome, post-acute sequela of SARS-CoV-2 (PASC), and the more familiar long COVID. Method: In order to capture all relevant published studies, we undertook a multi-step search with no language restriction. The following four-step search strategy was utilized: First, a preliminary (limited) search was conducted on January 20, 2021, in Google Scholar and PubMed to identify the appropriate keywords. Then, on January 30, 2021, we adopted a search strategy of electronic databases from Cochrane Library, PsycINFO, PubMed, Embase, Scopus, and Web of sciences, using those keywords. Then, after duplicate removal, we screened all titles, abstracts, and full texts. This resulted in 66 eligible studies. Subsequently, after a forward and backward search of their references and citations an additional 54 publications were found, resulting in a total of 120 publications that formed the basis of the present analysis. The titles, abstracts, and full-texts of non-English articles were translated using Google Translate for further evaluation. We conducted our scoping review based on the PRISMA-ScR Checklist.Results: We found only one randomized clinical trial in our search. Of the 67 original studies, 22 were cohort and 28 were cross-sectional studies totaling 74.6% of the original studies. Of the total of 120 publications, 59 (49.1%) focused on signs and symptoms, 28 (23.3%) were focused on management, and 13 (10.8%) focused on pathophysiology. Ten (9%) publications focused on imaging studies. Ninety-one percent of the original investigations came from high and upper-middle-income countries, highlighting the scarcity of reports originating from low-income and lower-middle-income countries.Conclusion: The predominant symptoms among those with the so-called “Long COVID” were: fatigue, breathlessness, arthralgia, sleep difficulties, and chest pain. Recent reports also point to the risk of long-term sequela with cutaneous, respiratory, cardiovascular, musculoskeletal, mental health, neurologic, and renal involvement in those who survive the acute phase of the illness. The ambiguity and controversies in its definition have impaired proper recognition and management of those requiring additional support following the resolution of the acute phase of this infection. This has resulted in long-standing distress for the patients and their families. Our findings highlight the need for a multidisciplinary approach, support, and rehabilitation for these patients in terms of long-term mental and physical health.
... Infections trigger the release of proinflammatory cytokines resulting in systemic inflammation, with such inflammation associated with cognitive decline and dementia. 21,22 Our finding of a larger effect on dementia risk of infections resulting in hospitalisation, such as pneumonia and sepsis, supports the role for notion of more severe infections having a stronger association with dementia risk. Severe infections are more likely to lead to systemic inflammation and are more prevalent in patients with diabetes due to immune dysfunction, probably caused by hyperglycaemia. ...
Article
Full-text available
Background Common infections have been associated with dementia risk; however, evidence is scarce. We aimed to investigate the association between common infections and dementia in adults (≥65 years) in a UK population-based cohort study. Methods We did a historical cohort study of individuals who were 65 years and older with no history of dementia or cognitive impairment using the Clinical Practice Research Datalink linked to Hospital Episode Statistics between Jan 1, 2004, and Dec 31, 2018. Multivariable Cox proportional hazard regression models were used to estimate the association between time-updated previous common infections (sepsis, pneumonia, other lower respiratory tract infections, urinary tract infections, and skin and soft tissue infections) and incident dementia diagnosis. We also tested for effect modification by diabetes since it is an independent risk factor for dementia and co-occurs with infection. Findings Between Jan 1, 2004, and Dec 31, 2018, our study included 989 800 individuals (median age 68·6 years [IQR 65·0–77·0]; 537 602 [54·3%] women) of whom 402 204 (40·6%) were diagnosed with at least one infection and 56 802 (5·7%) had incident dementia during a median follow-up of 5·2 years (IQR 2·3–9·0). Dementia risk increased in those with any infection (adjusted hazard ratio [HR] 1·53 [95% CI 1·50–1·55]) compared with those without infection. HRs were highest for sepsis (HR 2·08 [1·89–2·29]) and pneumonia (HR 1·88 [1·77–1·99]) and for infections leading to hospital admission (1·99 [1·94–2·04]). HRs were also higher in individuals with diabetes compared with those without diabetes. Interpretation Common infections, particularly those resulting in hospitalisation, were associated with an increased risk of dementia persisting over the long term. Whether reducing infections lowers the risk of subsequent dementia warrants evaluation. Funding Alzheimer's Society, Wellcome Trust, and the Royal Society.
... Previous research has demonstrated that postmenopausal women have higher levels of tumour necrosis factor-α (a pro-inflammatory cytokine) than premenopausal women, which persists after adjustments for age and measures of fat mass (Sites et al., 2002). Furthermore, increases in inflammation around midlife has been associated with smaller hippocampal volumes (Walker et al., 2017), which may in part, account for menopause predisposing women to experience poorer brain health outcomes. ...
Thesis
Full-text available
Maintaining a healthy brain has been recognised as an important health challenge facing women, given global estimates indicate almost twice as many women die of dementia than men. In part, this is due to their increased longevity, however, this does not explain all of the difference. Other contributors include different exposure to risk factors as well as sex-related physiological differences. This thesis focused on the latter, specifically in relation to possible impacts of menopause, as this stage of life has been suggested to involve particular risks to brain health. To address this question, five studies were conducted to precisely characterise and quantify (1) changes in fat mass during menopause; (2) lipid profile differences during menopause; (3) heterogeneity of menopause nomenclature used in peer-reviewed literature; (4) changes in fat mass and the brain; and (5) menstruation history (including menopausal status and age at menopause) and the brain. Moreover, an important conceptual and theoretical question embedded throughout this thesis has been to determine how much of the observed effects were attributable to ageing, rather than a possible effect of menopause. This has been a significant challenge, given menopause and ageing co-occur. The first two studies revealed that fat mass was higher in postmenopausal compared to premenopausal women across most measures, with the exception of leg fat which decreased, indicative of a potential change in fat mass distribution after menopause. However, the change in fat mass quantity was predominantly attributable to increasing age with menopause having no detectable additional influence. Furthermore, lipoproteins were significantly higher in postmenopausal women than premenopausal women, with the exception of high-density lipoprotein, which was not significantly different between groups. Measures of ageing explained some, but not all of the differences in lipid levels. The third study found a significant amount of heterogeneity associated with the definition of "premenopause", compared with "postmenopause". The fourth study demonstrated that those who suffered from overweight or obesity had smaller hippocampal volumes than those who maintained a normal weight. Furthermore, those who suffered from overweight or obesity in the past, but currently had a normal level of fat mass also had a smaller hippocampus than those who had always maintained a normal weight. The fifth study revealed an association between menopause and the brain, beyond typical ageing effects. Notably, postmenopausal women had larger brain volumes than premenopausal women but also experience greater decreases in total brain volume, but not hippocampal volume, over time. In addition, delayed age of menopause was negatively associated with brain volume. The findings from this thesis have demonstrated an association between menopause and the brain, which cannot be uniquely explained by ageing. Specifically, although menopause alone was not found to be negatively associated brain health, it was associated with somewhat poorer brain health when considered concurrently with other changes around menopause. Moreover, when considering that women tend to gain abdominal fat around menopause, as well as develop an unfavourable lipid profile, and given extensive evidence in the literature that higher abdominal fat and lipid levels are associated with a greater risk of cerebro-vascular disease and dementia, hypothesising a link between menopause and poorer brain health seems warranted but will require further confirmation in future research. As a whole, the findings from this thesis paint an optimistic picture for women's health, since the risk factors identified and linked with deleterious brain health outcomes are modifiable. If adequate support is available at a health policy, clinical and community level, these specific risks to brain health may be reduced or prevented.
... The considerable systemic inflammation in COVID-19, causes generalized endothelitis and disruption of the blood-brain barrier (BBB) [141,142]. Moreover, it is known that systemic hyper-inflammation is a leading cause of neurodegeneration and cognitive decline [143,144]. The latter requires longitudinal follow-up and studies on the pathogenesis and preventive measures, considering the already significant burden of neurodegenerative ailments such as Alzheimer's and Parkinson's disease, to prevent a delayed pandemic of new neurodegenerative conditions [10,137]. ...
Article
Full-text available
PurposeTo find out what is known from literature about Long COVID until January 30, 2021.Methods We undertook a four-step search with no language restriction. A preliminary search was made to identify the keywords. A search strategy of all electronic databases resulted in 66 eligible studies. A forward and backward search of the references and citations resulted in additional 54 publications. Non-English language articles were translated using Google Translate. We conducted our scoping review based on the PRISMA-ScR Checklist.ResultsOf 120 papers, we found only one randomized clinical trial. Of the 67 original studies, 22 were cohort, and 28 were cross-sectional studies. Of the total 120 publications, 49.1% focused on signs and symptoms, 23.3% on management, and 10.8% on pathophysiology. Ten publications focused on imaging studies. The results are also presented extensively in a narrative synthesis in separated sections (nomenclature, diagnosis, pathophysiology, risk factors, signs/symptoms, management).Conclusions The controversies in its definition have impaired proper recognition and management. The predominant symptoms were: fatigue, breathlessness, arthralgia, sleep difficulties, and chest pain. Recent reports also point to the risk of long-term sequela with cutaneous, respiratory, cardiovascular, musculoskeletal, mental health, neurologic, and renal involvement in those who survive the acute phase of the illness.
... Sie erhöhen zudem das Risiko für eine vaskuläre Demenz durch eine Häufung von thromboembolischen und vaskulären Ereignissen [44]. In einer Längsschnittstudie konnte gezeigt werden, dass chronische Entzündungsprozesse im mittleren Lebensalter mehr als zwanzig Jahre später quantitativ mit einer Verminderung des Gehirnvolumens verbunden sind [45]. Bei entzündlichen Darmerkrankungen lassen sich diese Prozesse auf Veränderungen des Darm-Mikrobioms, auf eine vermehrte Durchlässigkeit der Darmschranke und auf das vermehrtes Auftreten entzündungsfördernder Bakterienbestandteile und Bakterienmetabolite im Blut zurückführen [46]. ...
Preprint
Full-text available
Background: The gut microbiome is the sum of the genomes of the microbiota of the human gut. The impact of the intestinal microbiota on the development, course and treatment of Alzheimer's dementia has attracted increasing interest in recent years, so that meanwhile numerous studies on this topic have been published. Objective: To outline the actual state of research on the impact of the gut microbiome for the development, course and treatment of Alzheimer’s dementia. Results and Discussion: Changes of the gut microbiome have been described in patients with Alzheimer's dementia, in particular a reduction of diversity and an increase or decrease in certain phyla and genera of bacteria. Similar changes were found in diabetes mellitus and obesity, known risk factors for Alzheimer's dementia, and with increasing age. Furthermore, inflammatory bowel disease is associated with an increased risk of developing Alzheimer's dementia. There are various mechanisms through which the gut microbiome can influence the disease processes underlying Alzheimer's dementia. The intensification of inflammatory processes through increased permeability of the intestinal barrier for pro-inflammatory bacterial metabolites and components appears to be best documented. These connections have already stimulated various attempts for therapy, which aim to modify the intestinal microbiome in particular with probiotics and prebiotics.
... Furthermore, neuroinflammation plays an important role in different types of dementia (6,14). A prospective study has shown an association between systemic inflammation in midlife and brain volume loss in late-life, suggesting that elevated inflammatory markers in vivo may cause neuroinflammation and thus have a pathogenic effect on cognitive aging and neurodegeneration (15). These studies indicate that there may be a common pathogenic pathway or causal relationship between IBD and dementia. ...
Article
Full-text available
Background Mounting evidence suggests that there may be a causal relationship or common pathogenic pathway between inflammatory bowel disease (IBD) and dementia. However, inconsistent results have emerged from epidemiological studies. We therefore conducted this review to clarify the relationship between IBD and dementia. Methods We systematically searched PubMed, Web of Science, Embase, and Cochrane library to identify all studies exploring the relationship between IBD and dementia published as of September 2021. Risk estimates were pooled using both fixed and random-effects models. Results Six studies involving 2,334,472 subjects were included. Pooled results suggested that the risk of developing dementia significantly increased after IBD diagnosis (HR = 1.27, 95% CI: 1.10–1.47, P = 0.001), which did not vary by age, gender, dementia subtype, or IBD subtype. Whereas, the dementia incidence before IBD diagnosis and the comorbidity rate of dementia in IBD patients were similar to those without IBD (HR = 0.92, 95% CI: 0.68–1.25; 0.82, 95% CI: 0.64–1.06, respectively). However, current evidence was insufficient to establish a causal relationship. Conclusion This study shows an unidirectional association between IBD and dementia; patients with IBD have an increased risk of dementia, and it may be beneficial to develop individualized dementia screening strategies for this population. Future research needs to further investigate whether effective therapies of IBD can reduce this risk and pathophysiological mechanisms of the association.
... A composite score based on five inflammatory markers was proposed by Walker et al. [458]. In their study relating inflammation to late-life brain volume, inflammation was assessed by APPs albumin, fibrinogen, factor VII, van Willebrand factor (a factor preventing bleeding, but also being associated with several diseases including CVD) and leukocyte count, by averaging standardized z-scores. ...
Article
Full-text available
Many chronic conditions such as cancer, chronic obstructive pulmonary disease, type-2 diabetes, obesity, peripheral/coronary artery disease and auto-immune diseases are associated with low-grade inflammation. Closely related to inflammation is oxidative stress (OS), which can be either causal or secondary to inflammation. While a low level of OS is physiological, chronically increased OS is deleterious. Therefore, valid biomarkers of these signalling pathways may enable detection and following progression of OS/inflammation as well as to evaluate treatment efficacy. Such biomarkers should be stable and obtainable through non-invasive methods and their determination should be affordable and easy. The most frequently used inflammatory markers include acute-phase proteins, essentially CRP, serum amyloid A, fibrinogen and procalcitonin, and cytokines, predominantly TNFα, interleukins 1β, 6, 8, 10 and 12 and their receptors and IFNγ. Some cytokines appear to be disease-specific. Conversely, OS—being ubiquitous—and its biomarkers appear less disease or tissue-specific. These include lipid peroxidation products, e.g., F2-isoprostanes and malondialdehyde, DNA breakdown products (e.g., 8-OH-dG), protein adducts (e.g., carbonylated proteins), or antioxidant status. More novel markers include also –omics related ones, as well as non-invasive, questionnaire-based measures, such as the dietary inflammatory-index (DII), but their link to biological responses may be variable. Nevertheless, many of these markers have been clearly related to a number of diseases. However, their use in clinical practice is often limited, due to lacking analytical or clinical validation, or technical challenges. In this review, we strive to highlight frequently employed and useful markers of inflammation-related OS, including novel promising markers.
... In particular, the number of minor allele homozygous subjects was relatively small. The enlargement of lateral ventricle volume is known to be a consequence of multiple risk factors rather than a single cause, such as dietary cholesterol (Schreurs et al. 2013) and systemic inflammation (Walker et al. 2017). ...
Article
Full-text available
The enlargement of ventricular volume is a general trend in the elderly, especially in patients with Alzheimer’s disease (AD). Multiple susceptibility loci have been reported to have an increased risk for AD and the morphology of brain structures are affected by the variations in the risk loci. Therefore, we hypothesized that genes contributed significantly to the ventricular surface, and the changes of ventricular surface were associated with the impairment of cognitive functions. After the quality controls (QC) and genotyping, a lateral ventricular segmentation method was employed to obtain the surface features of lateral ventricle. We evaluated the influence of 18 selected AD susceptibility loci on both volume and surface morphology across 410 subjects from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Correlations were conducted between radial distance (RD) and Montreal Cognitive Assessment (MoCA) subscales. Only the C allele at the rs744373 loci in BIN1 gene significantly accelerated the atrophy of lateral ventricle, including the anterior horn, body, and temporal horn of left lateral ventricle. No significant effect on lateral ventricle was found at other loci. Our results revealed that most regions of the bilateral ventricular surface were significantly negatively correlated with cognitive scores, particularly in delayed recall. Besides, small areas of surface were negatively correlated with language, orientation, and visuospatial scores. Together, our results indicated that the genetic variation affected the localized areas of lateral ventricular surface, and supported that lateral ventricle was an important brain structure associated with cognition in the elderly.
... It has been reported that high levels of pro-inflammatory markers in the blood and other tissues are more often detected in older individuals [40] and that they may promote neurodegenerative events that can contribute to AD [41]. In the ARIC study, the relationship between plasma inflammatory markers during midlife and neurodegeneration 20 years later was investigated [42]. It was found that participants with elevated midlife inflammatory markers had smaller hippocampal volume and a faster cognitive decline [43]. ...
Article
Full-text available
Background Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer’s disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) ( N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) ( N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (Aβ42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated. Trial registration ClinicalTrials.gov NCT01041989 . Registered on 4 January 2010—retrospectively registered
Article
This study aimed to evaluate the effect of sleep duration on brain structures in the presence versus absence of sleep apnea in middle-aged and older individuals. The study investigated a population-based sample of 2,560 individuals, aged 49-80 years. The presence of sleep apnea and self-reported sleep duration were examined in relation to gray matter volume (GMV) in total and lobar brain regions. We identified ranges of sleep duration associated with maximal GMV using quadratic regression and bootstrap sampling. A significant quadratic association between sleep duration and GMV was observed in total and lobar brain regions of men with sleep apnea. In the fully adjusted model, optimal sleep durations associated with peak GMV between brain regions ranged from 6.7 to 7.0 hours. Shorter and longer sleep durations were associated with lower GMV in total and 4 sub-regions of the brain in men with sleep apnea.
Article
Background Chronic inflammatory conditions have been linked to dementia, but little is known about the role of atopic eczema, a inflammatory condition recently recognized to be common among older adults. Objective To determine whether active atopic eczema is associated with incident dementia. Methods Longitudinal cohort study of 1,767,667 individuals ages 60 to 99 years registered with The Health Improvement Network (THIN), a primary care cohort in the UK. Atopic eczema and dementia diagnoses were identified using medical record codes. Results The incidence rate of dementia diagnoses was 57/10,000 person-years among those with atopic eczema during follow-up (12.1% of the population), as compared to 44/10,000 person-years in the control group. This translated to a 27% increased risk of (HR 1.27, 95%CI 1.23-1.30) in adjusted Cox proportional hazard models. Similar associations were observed in subgroup analyses of vascular dementia and Alzheimer’s disease. The association persisted after additionally adjusting for systemic corticosteroid use (HR 1.29, 95% CI 1.26-1.33) and potential mediators (HR 1.19, 95%CI 1.16-1.22). More severe eczema was associated with a higher risk of dementia. Limitations Lack of detailed severity data. Conclusions Atopic eczema was associated with a small but increased risk of incident dementia. The association increased with atopic eczema severity.
Article
Aging is the primary risk factor for cardiovascular diseases (CVD), the leading cause of death in developed and developing societies. Much of this age-associated increase in CVD risk is due to arterial dysfunction, characterized by stiffening of the large elastic arteries and endothelial dysfunction. Aerobic exercise is an evidence-based healthy lifestyle strategy for improving arterial function with aging, in part, by suppressing oxidative stress and chronic inflammation. Here, we summarize the effects of exercise on arterial function and aging, highlighting recent advancements regarding estrogen-deficient postmenopausal women, cerebrovascular function and healthy lifestyle-inspired interventions that work through similar mechanisms as aerobic exercise.
Article
Human and animal studies suggest that inflammation occurring outside the central nervous system (systemic inflammation) may play a key role in promoting neurodegeneration, Alzheimer’s disease pathology, and cognitive decline in older adults. Systemic inflammation, which is marked by increased blood levels of circulating proinflammatory cytokines and chemokines, may occur as a result of events such as infection, chronic disease, and physical and psychological stress, but may also occur outside the context of these conditions as a result of subclinical processes such as cellular senescence. Proinflammatory cytokines within the body can promote a proinflammatory environment in the central nervous system by crossing the blood-brain barrier, signaling through endothelial cells or circumventricular organs, and by stimulating the vagus nerve, which signals the detection of inflammatory proteins via direct afferent connections to the brain stem. Through each of these routes, systemic inflammation is believed to induce reactive, proinflammatory microglia and astrocytic phenotypes which can promote tau hyperphosphorylation, β-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites. Together, these molecular changes are believed initiate or exacerbate neurodegenerative processes that can eventually lead to cognitive decline and dementia in vulnerable older adults.
Article
Background: Little is known about whether non-alcoholic fatty liver disease (NAFLD) is associated with dementia as well as the role of serum pro-inflammatory cytokines in the association. We aimed to investigate the interrelationships of NAFLD, serum cytokines, and dementias among rural-dwelling older adults. Methods: This population-based cross-sectional study included 5,129 participants (age ≥60 years; 61.79% women) who were living in rural communities and examined in March-September 2018. NAFLD was defined through transabdominal ultrasound examination in the absence of hepatitis B or excessive alcohol consumption. Serum cytokines were measured in a subsample (n=1,686). Dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were diagnosed following international criteria. Data were analyzed with logistic regression and mediation models. Results: Of the 5,129 participants, 455 (8.87%) were detected with moderate-to-severe NAFLD and 292 (5.69%) were diagnosed with dementia (188 with AD and 96 with VaD). The multivariable-adjusted odds ratios (ORs) associated with moderate-to-severe (vs. no-to-mild) NAFLD were 2.22 (95% confidence interval, 1.41-3.49) for all-cause dementia, 1.88 (1.01-3.50) for AD, and 2.62 (1.33-5.17) for VaD. In the cytokine subsample, controlling for multiple potential confounders, moderate-to-severe NAFLD was significantly associated with higher levels of serum monocyte chemotactic protein-1 (MCP-1), interleukin-17A (IL-17A), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) (P<0.05). The mediation analysis showed that IL-6 mediated 12.56% of the association between NAFLD and VaD. Conclusions: Moderate-to-severe NAFLD is associated with dementia and AD, especially with VaD, among rural-dwelling Chinese older adults, in which the association with VaD is partly mediated by serum inflammatory cytokines.
Article
Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.
Article
The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F 1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F 1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated ( F 2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.
Article
Full-text available
Therapeutic plasma exchange, consisting of removing blood plasma and exchanging it with donated blood products, has been proposed for treating Alzheimer's disease (AD) to remove senescent or toxic factors. In preclinical studies, administration of plasma from young healthy mice to AD transgenic mice improved cognitive deficits without affecting brain amyloid plaques. Initial encouraging results have been collected in a double‐blind, placebo‐controlled study in nine AD patients receiving young plasma. In a 14‐month double‐blind, placebo‐controlled study in 322 AD patients, multiple infusions with plasma enriched with albumin with or without immunoglobulins slowed cognitive, functional, and clinical decline, especially in moderately affected patients. Clinical trials of plasma fractions containing hypothetically beneficial proteins are also under way. These initial positive clinical results need to be confirmed in larger and more rigorous controlled studies in which the possible benefits of plasma exchange approaches can be weighed against the intrinsic side effects of repetitive infusion procedures.
Article
The physiological effects of exercise vary as a function of frequency and length. However, research on the duration-dependent effects of exercise has focused primarily on young adults and less is known about the influence of exercise duration in the aged. The current study compared the effects of short-term and long-term running wheel access on hippocampal neurogenesis and neuroimmune markers in aged (19-23 months) male C57BL/6J mice. Aged mice were given 24-hour access to a running wheel for 14 days (short-term) or 51 days (long-term). Groups of non-running aged and young (5 months) mice served as comparison groups to detect age-related differences and effects of exercise. Long-term, but not short-term, exercise increased hippocampal neurogenesis as assessed by number of doublecortin (DCX) positive cells in the granular cell layer. Assessment of cytokines, receptors, and glial-activation markers showed the expected age-related increase compared to young controls. In the aged, exercise as a function of duration regulated select aspects of the neuroimmune profile. For instance, hippocampal expression of interleukin (IL)-10 was increased only following long-term exercise. While in contrast brain levels of IL-6 were reduced by both short- and long-term exercise. Additional findings showed that exercise does not modulate all aspects of age-related neuroinflammation and/or may have differential effects in hippocampal compared to brain samples. Overall, the data indicate that increasing exercise duration produces more robust effects on immune modulation and hippocampal neurogenesis.
Article
Accumulating research suggests that stressful life events, especially those that threaten close intimate bonds, are associated with an increased risk of dementia. Grieving the loss of a spouse, whether in the form of caregiving or after the death, ranks among 'life's most significant stressors’, evoking intense psychological and physiological distress. Despite numerous studies reporting elevated dementia risk or poorer cognition among spousal caregivers and widow(er)s compared to controls, no review has summarized findings across cognitive outcomes (i.e., dementia incidence, cognitive impairment rates, cognitive performance) or proposed a theoretical model for understanding the links between partner loss and abnormal cognitive decline. The current systematic review summarizes findings across 64 empirical studies. Overall, both cross-sectional and longitudinal studies revealed an adverse association between partner loss and cognitive outcomes. In turn, we propose a biopsychosocial model of cognitive decline that explains how caregiving and bereavement may position some to develop cognitive impairment or Alzheimer's disease and related dementias. More longitudinal studies that focus on the biopsychosocial context of caregivers and widow(er)s are needed.
Article
Inflammation has been implicated in physical frailty, but its role in sensory impairment is unclear. Given that olfactory impairment predicts dementia and mortality, determining the role of the immune system in olfactory dysfunction would provide insights mechanisms of neurosensory decline. We analyzed data from the National Social Life, Health and Aging Project, a representative sample of home-dwelling older US adults. Plasma levels of 18 cytokines were measured using standard protocols (Luminex xMAP). Olfactory function was assessed with validated tools (n-butanol sensitivity and odor identification, each via Sniffin' Sticks). We tested the association between cytokine profiles and olfactory function using multivariate ordinal logistic regression, adjusting for age, gender, race/ethnicity, education level, cognitive function, smoking status, and comorbidity. Older adults with the IL-1Rahigh-IL-4low-IL-13low cytokine profile had worse n-butanol odor sensitivity (OR=1.61, 95% CI 1.19 - 2.17) and worse odor identification (OR=1.42, 95% CI 1.11 - 1.80). Proinflammatory, Th1 or Th2 cytokine profiles were not associated with olfactory function. Moreover, accounting for physical frailty did not alter the main findings. In conclusion, we identified a plasma cytokine signature - IL-1Rahigh - IL-4low - IL-13low - that is associated with olfactory dysfunction in older US adults. These data implicate systemic inflammation in age-related olfactory dysfunction and support a role for immune mechanisms in this process, a concept that warrants additional scrutiny.
Article
Full-text available
Background The association between inflammatory bowel disease (IBD) and dementia remains uncertain. We aim to investigate whether IBD is associated with higher dementia risk. Methods Using multivariable Cox regression models, we analyzed the onset of all-cause dementia among 497,775 participants, including 5778 IBD patients in the UK Biobank as primary analysis. In secondary analysis, we further examined the difference in brain structure and cognitive function changes between IBD and non-IBD individuals. The diagnosis of IBD and dementia was confirmed with combination of primary care data, hospital inpatient data, death registry, and self-report data. Brain structure was measured by brain MRI as anatomic and tissue-specific volumes; cognitive function was tested in terms of reaction, visual episodic memory, verbal-numerical reasoning, and prospective memory. Results During a mean follow-up of 11.58 years, 100 and 6709 incident all-cause dementia with or without IBD were documented, respectively. In multivariable Cox regression model, hazard ratio for incident dementia among IBD patients was 1.14 (95% confidence interval [CI], 0.94-1.39; P=.182) comparing with non-IBD participants; no statistically significant difference was observed in their brain MRI measures of anatomic and tissue-specific volumes, whereas IBD patients had a significantly increased reaction time (β=12.32; 95% CI, 1.97, 22.67; P = .020). Results of subgroup and sensitivity analyses were consistent with the main analysis. Conclusions Our study does not support a significant association between IBD and dementia. Further studies with better design and longer follow-up are needed to elucidate the association.
Article
Background/objective Inflammation is implicated in cognitive decline; however, there is a paucity of data for African American populations and for sex-specific associations. Design Prospective cohort study. Setting Genetic Epidemiology Network of Arteriopathy/Genetics of Microangiopathic Brain Injury studies. Participants African-American sibships (N = 1010). Measurements Neurocognitive tests assessed global cognition and four cognitive domains: processing speed, memory, language, and executive function at two time points over seven years. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor receptor (TNFR)-1 and TNFR2 were measured at study baseline. Linear mixed models were used to investigate the association between inflammation markers and cognitive decline. Results Among men, a one SD increase in CRP was associated with an increased rate of decline over 7 years in global cognitive Z-score (adjusted difference in slopes = −0.31, p = 0.006) and in processing speed Z-score (adjusted difference in slopes = −0.10, p = 0.02), but not declines in memory, language, or executive function Z-scores. Also among men, a one SD increase in IL-6 was associated with an increased decline rate in global cognitive Z-score (adjusted difference in slopes = −0.33, p = 0.002) and in processing speed Z-score (adjusted difference in slopes = −0.12, p = 0.007). There was no difference in decline rates by CRP or IL-6 level in adjusted analyses among women for any cognitive scores. Among men and women combined, a one SD increase in baseline sTNFR1 was associated with a faster rate of decline in memory Z-score (adjusted difference in slopes = −0.09, p = 0.02). Baseline sTNFR2 levels did not significantly predict rate of cognitive decline in any cognitive domains. Conclusions Circulating markers of CRP and IL-6 may be differential risk factors for men and women in relation to cognitive decline. A novel inflammation marker, sTNFR1, may be a useful predictor of memory decline in older adults.
Article
Full-text available
Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase.
Article
Objective: Elevated inflammation is associated with worse late-life cognitive functioning and brain health. Our goal was to examine the relationship between inflammation trajectories and white matter integrity in midlife. Methods: Participants were 508 adults from the Coronary Artery Risk Development in Young Adults Study (CARDIA; 51% female). Latent class analysis was used to identify inflammation trajectories based on repeated measures of the inflammatory marker C-reactive protein (CRP) over the 18 years before brain magnetic resonance imaging (MRI). Outcomes were brain MRI measures of total and region-specific white matter volume and integrity at a mean age of 50.6±3.4 years. Linear regression was used to examine if inflammation trajectories were associated with brain MRI outcomes, adjusting for potential confounds in all models and for disease and health behaviors in follow-up models. Results: Lower-stable (38%), moderate-increasing (7%), and consistently-higher (54%), trajectories emerged. Compared to the lower-stable group, the moderate-increasing group showed lower white matter volume (β = -0.18, 95% CI -0.29, -0.06) and worse white matter integrity as indexed by lower fractional anisotropy (FA; β = -0.37, 95% CI -0.70, -0.04) and higher mean diffusivity (β = 0.44, 95% CI 0.11, 0.78) in the whole brain. The consistently-higher group showed lower whole-brain FA (β = -0.20, -0.38, -0.03). In exploratory analyses, the moderate-increasing group showed lower white matter volume, lower FA and higher MD in the frontal, temporal, and parietal lobes compared to the lower-stable group. The consistently-higher group showed lower white matter volume in the parietal lobe and lower FA in the frontal, temporal, and parietal lobes, but similar MD, compared to the lower-stable group. Findings for the moderate-increasing, but not the consistently-higher, group were robust to adjustment for disease and lifestyle factors. Conclusion: Increasing or high inflammation trajectories from early to mid adulthood are associated with worse brain health, as indexed by lower white matter volume and/or worse white matter integrity.
Article
Full-text available
Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in it. The present review discusses the effects of obesity, chronic peripheral inflammation and obesity-associated metabolic and endocrine perturbations, including insulin resistance, dyslipidemia and increased glucocorticoid levels, on microglial function.
Article
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. Aging is the most significant risk factor for late-onset AD. The age-associated changes in the immune system are termed immunosenescence. A close connection between immunosenescence and AD is increasingly recognized. This article provides an overview of immunosenescence and evidence for its role in the pathogenesis of AD and possible mechanisms as well as the outlook for drug development.
Article
Objective: To examine the association between systemic inflammation measured during midlife and 20-year cognitive decline. Methods: Within the Atherosclerosis Risk in Communities cohort study, inflammatory biomarkers were measured during middle adulthood. We created an inflammation composite score using 4 blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); we measured C-reactive protein (CRP) at visit 2. Cognition was assessed over 3 visits spanning 20 years using measures of memory, executive function, and language. Results: A total of 12,336 participants (baseline age 56.8 [5.7], 21% black, 56% women) were included. After adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of -0.035 SD (95% confidence interval: -0.062 to -0.007) on the cognitive composite score. We found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (-0.038 SD, 95% confidence interval: -0.057 to -0.019). Participants with a midlife inflammation composite score in the top quartile had a 7.8% steeper cognitive decline, compared to participants in the lowest quartile; CRP in the top quartile was associated with an 11.6% steeper cognitive decline. In cognitive domain-specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory. Results were similar after adjusting for attrition using inverse probability weighting. Conclusions: Our findings highlight what may be an early pathogenic role for systemic inflammation as a driver of cognitive decline in the decades leading up to older adulthood.
Article
Full-text available
Background: Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. Methods: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for CD68 (phagocytosis), HLA-DR (antigen presenting function), Iba1 (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fc??receptor I). Results: The presence of dementia was associated positively with CD68 (P<0.001), MSR-A (P=0.010) and CD64 (P=0.007), and negatively with Iba1 (P<0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination, was associated positively with Iba1 (P<0.001) and negatively with CD68 (P=0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. APOE ?2 allele was associated with expression of Iba1 (P=0.001) and MSR-A (P<0.001) and APOE ?4 with CD68, HLA-DR and CD64 (P<0.001). Conclusion: Our findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to A? and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.
Article
Full-text available
Background Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. Methods Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). Results The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). Conclusions Our findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer’s pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.
Article
Full-text available
Introduction We examined prevalence of mild cognitive impairment (MCI) and dementia in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive study. Methods Beginning in June, 2011, we invited all surviving ARIC participants to undergo cognitive, neurologic, and brain imaging assessments to diagnose MCI or dementia and assign an etiology for the cognitive disorder. Results Of 10,713 surviving ARIC participants (age range, 69–88 years), we ascertained cognitive diagnoses in 6471 in person, 1966 by telephone interviews (participant or informant), and the remainder by medical record review. The prevalence of dementia was 9.0% and MCI 21%. Alzheimer's disease (AD) was the primary or secondary etiology in 76% of dementia and 75% of MCI participants. Cerebrovascular disease was the primary or secondary etiology in 46% of dementia and 32% of MCI participants. Discussion MCI and dementia were common among survivors from the original ARIC cohort. Nearly 30% of the ARIC cohort received diagnoses of either dementia or MCI, and for the majority of these individuals, the etiologic basis was attributed to AD.
Article
Full-text available
Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.
Article
Full-text available
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.
Article
Full-text available
Background Alzheimer’s disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain’s innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease. Methods The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. Results We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. Conclusion Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.
Article
Full-text available
C-reactive protein is a marker of inflammation and vascular disease. It also seems to be associated with an increased risk of dementia. To better understand potential underlying mechanisms, we assessed microstructural brain integrity and cognitive performance relative to serum levels of high-sensitivity C-reactive protein (hs-CRP). We cross-sectionally examined 447 community-dwelling and stroke-free individuals from the Systematic Evaluation and Alteration of Risk Factors for Cognitive Health (SEARCH) Health Study (mean age 63 years, 248 female). High-field MRI was performed in 321 of these subjects. Imaging measures included fluid-attenuated inversion recovery sequences for assessment of white matter hyperintensities, automated quantification of brain parenchyma volumes, and diffusion tensor imaging for calculation of global and regional white matter integrity, quantified by fractional anisotropy (FA). Psychometric analyses covered verbal memory, word fluency, and executive functions. Higher levels of hs-CRP were associated with worse performance in executive function after adjustment for age, gender, education, and cardiovascular risk factors in multiple regression analysis (beta = -0.095, p = 0.02). Moreover, higher hs-CRP was related to reduced global fractional anisotropy (beta = -0.237, p < 0.001), as well as regional FA scores of the frontal lobes (beta = -0.246, p < 0.001), the corona radiata (beta = -0.222, p < 0.001), and the corpus callosum (beta = -0.141, p = 0.016), in particular the genu (beta = -0.174, p = 0.004). We did not observe a significant association of hs-CRP with measures of white matter hyperintensities or brain atrophy. These data suggest that low-grade inflammation as assessed by high-sensitivity C-reactive protein is associated with cerebral microstructural disintegration that predominantly affects frontal pathways and corresponding executive function.
Article
Full-text available
Recent epidemiologic studies found that there is a strong association of hemostatic factors with ischemic heart disease. The Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability (IIV) Study was conducted to estimate the various components of variation in hemostasis factors measured in the ARIC Study and to estimate the measures of repeatability of these factors. A total of 39 subjects (16 men, 23 women) were studied. Each had blood collected three times, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person (biologic) variability, and processing and assay variability were estimated. Then the reliability coefficient R was estimated as the proportion of total variance accounted for by between-person variance. The reliability coefficient can be interpreted as the correlation between measures made at repeat visits. Among the various analytes, the reliability coefficients were quite high for activated partial thromboplastin time and plasma factor VIII (R = 0.92, 0.86, respectively). Low repeatability was obtained for antithrombin III activity and protein C (R = 0.42, 0.56, respectively). The lack of repeatability for these variables derives mostly from the processing (field center and laboratory) variation. Other analytes--fibrinogen, plasma factor VII, and von Willebrand factor--were intermediate in repeatability. In comparing the analyte-specific high-level to low-level groups, no substantial difference of within-person plus method coefficient of variation between the two groups was found for any analyte except for factor VIII, whereas the corresponding variance components for most analytes were higher for the higher analyte level. Reliability coefficients from this ARIC IIV study are generally higher than those found in other studies, and this is related to the relative variations in populations studied and to the time between measurements.
Article
Full-text available
Low-density lipoprotein (LDL) cholesterol concentrations are most commonly estimated by the formula LDL cholesterol = total cholesterol - [triglycerides (TG)/5 + high-density lipoprotein cholesterol], although alternative factors such as TG/6 have also been used. Using standardized, automated, enzymatic lipid assays, we analyzed 4797 plasma samples from normal and dyslipidemic adults, to compare LDL cholesterol concentrations obtained after ultracentrifugation with those calculated by several such methods (i.e., TG/4-TG/8). or TG concentrations less than or equal to 0.50 g/L, TG/4 agreed best with the direct assay; for TG of 0.51-2.00 g/L, TG/4.5 was best; and for TG of 2.01-4.00 g/L, TG/5 was best. Differences in estimated values were generally small, however. At TG greater than 4.00 g/L, none of the factors tested allowed a reliable estimate of LDL cholesterol. When TG were less than or equal to 4.00 g/L, 86% of estimated LDL cholesterol values were properly classified according to National Cholesterol Education Program cutpoints when the factor TG/5 was used. We conclude that a convenient direct method for measuring LDL cholesterol is needed but, until one is available, use of the factor TG/5 will assure that most individuals with TG less than or equal to 4.00 g/L, as measured in a standardized laboratory, can be reasonably well classified for risk of coronary artery disease.
Article
Full-text available
Although hemostatic factors contribute to acute coronary syndromes and atherogenesis, few studies have prospectively evaluated the association between multiple hemostatic factors and coronary heart disease incidence. The Atherosclerosis Risk in Communities Study recruited 14,477 adults from 45 to 64 years of age who were initially free of coronary heart disease. Coronary disease risk factors and several plasma hemostatic factors were measured, and incidence of coronary heart disease was ascertained during an average follow-up of 5.2 years. Age-, race-, and field center-adjusted relative risks of coronary heart disease were significantly elevated (P < or = .05) per higher value of fibrinogen (relative risk: men, 1.76; women, 1.54), white blood cell count (men, 1.68; women, 2.23), factor VIII coagulant activity (women, 1.25), and von Willebrand factor antigen (men, 1.20; women, 1.18). Adjustment for other risk factors attenuated these associations for fibrinogen (adjusted relative risk: men, 1.48; women, 1.21), and it eliminated the white blood cell count, factor VIII, and von Willebrand factor associations, consistent with the other risk factors either confounding or partly operating through their effects on the hemostatic variables. Adjusted standardized relative risks of total mortality, ranging from 1.13 to 1.37, were also elevated (P < .05) in relation to these four factors. There was no association of coronary disease incidence with factor VII, protein C, antithrombin III, or platelet count. Elevated levels of fibrinogen, white blood cell count, factor VIII, and von Willebrand factor are risk factors and may play causative roles in coronary heart disease. However, their measurement in healthy adults appears to add little to prediction of coronary events beyond that of more established risk factors.
Article
Full-text available
A large number of changes, distant from the site or sites of inflammation and involving many organ systems, may accompany inflammation. In 1930 interest was focused on these changes by the discovery of C-reactive protein (so named because it reacted with the pneumococcal C-polysaccharide) in the plasma of patients during the acute phase of pneumococcal pneumonia.1 Accordingly, these systemic changes have since been referred to as the acute-phase response,2 even though they accompany both acute and chronic inflammatory disorders. New acute-phase phenomena continue to be recognized, and the mechanisms mediating them are becoming better understood. This review summarizes much of . . .
Article
Full-text available
To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer's Disease Research Center. MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown. Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998. Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (> or =6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance. Data point to a role for midlife vascular risk factors in the development of MCI in late life.
Article
Full-text available
Evidence exists that the incidence of Alzheimer disease (AD), as well as risk attributable to specific genetic factors such as apolipoprotein E (APOE) genotype, may vary considerably among ethnic groups. Family studies of probands with AD offer an opportunity to evaluate lifetime risk of dementia among relatives of these probands. To compare lifetime dementia risk estimates among relatives of white and African American probands with probable or definite AD. Risk analysis using data collected by questionnaire and supplemental records between May 1991 and March 2001 at 17 medical centers contributing to the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. A total of 17 639 first-degree biological relatives and 2474 spouses of 2339 white AD probands, and 2281 first-degree biological relatives and 257 spouses of 255 African American AD probands. Cumulative risk of dementia by age 85 years, stratified by ethnicity and sex of relatives and by APOE genotype of probands. Cumulative risk of dementia in first-degree biological relatives of African American AD probands by age 85 years was 43.7% (SE, 3.1%), and the corresponding risk in first-degree biological relatives of white AD probands was 26.9% (SE, 0.8%), yielding a relative risk (RR) of 1.6 (95% confidence interval [CI], 1.4-1.9; P<.001). The risk in spouses of African American AD probands of 18.5% (SE, 8.4%) was also higher than the risk in white spouses of 10.4% (SE, 1.7%) but did not reach statistical significance (RR, 1.8; 95% CI, 0.5-6.0; P =.34), likely due to the smaller sample size of African Americans. The proportional increase in risk of dementia among white first-degree biological relatives compared with white spouses of 2.6 (95% CI, 2.1-3.2) was similar to that of 2.4 (95% CI, 1.3-4.4) in African American first-degree biological relatives compared with African American spouses. Female first-degree biological relatives of probands had a higher risk of developing dementia than did their male counterparts, among whites (31.2% vs 20.4%; RR, 1.5; 95% CI, 1.3-1.7; P<.001) as well as among African Americans, although this was not significant among African Americans (46.7% vs 40.1%; RR, 1.2; 95% CI, 0.9-1.7, P =.30). The patterns of risk among first-degree biological relatives stratified by APOE genotype of the probands were similar in white families and African American families. First-degree relatives of African Americans with AD have a higher cumulative risk of dementia than do those of whites with AD. However, in this study, the additional risk of dementia conferred by being a first-degree relative, by being female, or by the probability of having an APOE epsilon4 allele appeared similar in African American and white families. These data provide estimates of dementia risk that can be used to offer counseling to family members of patients with AD.
Article
Full-text available
Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.
Article
Full-text available
To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). Interpretation: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.
Article
Full-text available
There is now a large body of evidence linking inflammation to Alzheimer's disease (AD). This association manifests itself neuropathologically in the presence of activated microglia and astrocytes around neuritic plaques and increased levels of inflammatory mediators in the brains of AD patients. It is considered that amyloid-beta peptide (Abeta), which is derived from the processing of the longer amyloid precursor protein (APP), could be the most important stimulator of this response, and therefore determining the role of the different secretases involved in its generation is essential for a better understanding of the regulation of inflammation in AD. The finding that certain non-steroidal anti-inflammatory drugs (NSAIDs) can affect the processing of APP by inhibiting beta- and gamma-secretases, together with recent revelations that these enzymes may be regulated by inflammation, suggest that they could be an interesting target for anti-inflammatory drugs. In this review we will discuss some of these issues and the role of the secretases in inflammation, independent of their effect on Abeta formation.
Article
Atherosclerosis Risk in Communities (ARIC) is a new prospective study to investigate the etiology of atherosclerosis and its clinical sequelae and variation in cardiovascular risk factors, medical care, and disease by race, sex, place, and time. in each of four US communities—Forsyth County, North Carolina, Jackson, Mississippi, suburbs of Minneapolis, Minnesota, and Washington County, Maryland—4, 000 adults aged 45–64 years will be examined twice, three years apart. ARIC has coordinating, ultrasound, pulmonary, and electrocardiographic centers and three central laboratories. Three cohorts represent the ethnic mix of their communities; the Jackson cohort, its black population. Examinations include ultrasound scanning of carotid and popliteal arteries; lipids, lipoprotelns, and apolipoproteins assayed in the Lipid Laboratory; and coagulation, inhibition, and platelet and fibrinolytic actmty assayed in the Hemostasis Laboratory. Surveil lance for coronary heart disease will involve review of hospitalizations and deaths among community residents aged 35–74 years. ARIC aims to study atheroscle rosis by direct observation of the disease and by use of modem biochemistry.
Article
Objectives: To quantify associations between inflammatory biomarkers and hippocampal volume (HV) and to examine effect modification according to sex, race, and age. Design: Cross-sectional analyses using generalized estimating equations to account for familial clustering; standardized β-coefficients adjusted for age, sex, race, and education. Setting: Community cohorts in Jackson, Mississippi and Rochester, Minnesota. Participants: The Genetic Epidemiology Network of Arteriopathy study. Measurements: C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors 1 (sTNFR-1) and 2 (sTNFR-2) from peripheral blood were measured in a sample of 773 non-Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV. Results: In the full sample, higher sTNFR-1 and sTNFR-2 were associated with smaller HV. Each standard deviation (SD) increase in sTNFR-1 was associated with 59.1 mm(3) (95% confidence interval (CI) = -101.4 to -16.7 mm(3) ) smaller HV and each SD increase in sTNFR-2 associated with 48.8 mm(3) (95% CI = -92.2 to -5.3 mm(3) ) smaller HV. Relationships were stronger for sTNFR-2 in men (HV = -116.6 mm(3) for each SD increase, 95% CI = -201.0 to -32.1) than women (HV = -26.0 per SD increase, 95% CI = -72.4-20.5) and sTNFR-1 in non-Hispanic whites (HV = -84.7 mm(3) per SD increase, 95% CI = -142.2 to -27.1) than African Americans (HV = -14.1 mm(3) per SD increase, 95% CI = -78.3-50.1). Associations between IL-6 or CRP and HV were not supported. Conclusion: Higher levels of sTNFRs were associated cross-sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late-life cognitive impairment.
Article
Ageing is characterized by chronically elevated inflammatory markers (IMs). Peripheral IM levels have been found in negative correlations with brain structural measures including global and lobar volumes and the hippocampus. This study investigated the relationship between 10 peripheral IMs and voxel-based gray matter (GM) volumes in nondemented older adults (n = 463). Two proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1β) and 2 vascular IMs (vascular cellular adhesion molecule-1 and plasminogen activator inhibitor-1) were negatively correlated with regional GM volumes. TNF-α and interleukin-1β were both significantly correlated with GM volumes in the left occipitotemporal area, left superior occipital gyrus, and left inferior parietal lobule; TNF-α was also significantly correlated with the bilateral medial prefrontal cortices and approached significance for the correlations with the bilateral hippocampi. Significant GM correlations with vascular cellular adhesion molecule-1 were located in the bilateral anterior cingulate cortices, and with plasminogen activator inhibitor-1 in the cerebellum and right hippocampus. The neuroanatomical correlation patterns of 2 proinflammatory cytokines and 2 vascular IMs might be reflective of the effects of neurodegenerative and vascular pathological processes in the ageing brain.
Article
The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Total of 1906 nondemented participants (59% women; 25% African-American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process. © 2015 American Heart Association, Inc.
Article
Type 2 diabetes is associated with dementia risk, but evidence is limited for possible associations of diabetes and prediabetes with cognitive decline. To determine whether diabetes in midlife is associated with 20-year cognitive decline and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c) levels. Prospective cohort study. The community-based ARIC (Atherosclerosis Risk in Communities) study. 13 351 black and white adults aged 48 to 67 years at baseline (1990 to 1992). Diabetes was defined by self-reported physician diagnosis or medication use or HbA1c level of 6.5% or greater. Undiagnosed diabetes, prediabetes, and glucose control in persons with diagnosed diabetes were defined by clinical categories of HbA1c level. Delayed word recall, digit symbol substitution, and word fluency tests were used to assess cognitive performance and were summarized with a global Z score. Diabetes in midlife was associated with a 19% greater cognitive decline over 20 years (adjusted global Z-score difference, -0.15 [;95% CI, -0.22 to -0.08];) compared with no diabetes. Cognitive decline was significantly greater among persons with prediabetes (HbA1c level of 5.7% to 6.4%) than among those with an HbA1c level less than 5.7%. Participants with poorly controlled diabetes (HbA1c level ≥7.0%) had greater decline than those whose diabetes was controlled (adjusted global Z-score difference, -0.16; P = 0.071). Longer-duration diabetes was also associated with greater late-life cognitive decline (P for trend < 0.001). Rates of decline did not differ significantly between white and black persons (P for interaction = 0.44). Single HbA1c measurement at baseline, 1 test per cognitive domain, and potential geographic confounding of race comparisons. Diabetes prevention and glucose control in midlife may protect against late-life cognitive decline. National Institutes of Health.
Article
Importance Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age.Objective To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance.Design, Setting, and Participants The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up.Exposures Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures.Main Outcomes and Measures Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition.Results During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, −0.100 to −0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, −0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (−0.050 [95% CI, −0.003 to −0.097] vs −0.079 [95% CI, −0.156 to −0.002] global z score points). Having a JNC-8–specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (−0.044 [95% CI, −0.085 to −0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20–mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, −0.074 to −0.022) points in global cognitive z score in whites but not in African Americans (decline, −0.020 [95% CI, −0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations.Conclusions and Relevance Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.
Article
Accurate assessment of cognitive impairment requires comparison of cognitive performance in individuals to performance in a comparable healthy normative population. Few prior studies have included a large number of black participants and few have excluded participants from the normative sample with subclinical/latent neurological disease or dementia. This study provides age, race, and education-specific normative data for 8 cognitive tests derived from 320 black and 392 white participants aged 61 to 82 years (mean 71 y) in the Atherosclerosis Risk in Communities (ARIC) study without clinical or subclinical/latent neurological disease. Normative data are provided for the Delayed Word Recall Test, Logical Memory Parts I and II, the Word Fluency Test, Animal Naming, the Trail Making Test Parts A and B and the Digit Symbol Substitution Test. Age, race, and education-specific mean and -1.5 SD scores are given in tabular form and graphically, as well as regression-based equations to derive adjusted score cut-points. These robust normative data should enhance comparison across studies of cognitive aging, where these measures are widely used, and improve interpretation of performance on these tests for the diagnosis of cognitive impairment not only within the ARIC cohort, but also among older blacks and whites with similar demographics.