Bordetella pertussis and vaccination: The persistence of a genetically monomorphic pathogen

Before childhood vaccination was introduced in the 1950s, pertussis or whooping cough was a major cause of infant death worldwide. Widespread vaccination of children was successful in significantly reducing morbidity and mortality. However, despite vaccination, pertussis has persisted and, in the 1990s, resurged in a number of countries with highly vaccinated populations. Indeed, pertussis has become the most prevalent vaccine-preventable disease in developed countries with estimated infection frequencies of 1–6%. Recently vaccinated children are well protected against pertussis disease and its increase is mainly seen in adolescents and adults in which disease symptoms are often mild. The etiologic agent of pertussis, Bordetella pertussis, is extremely monomorphic and its ability to persist in the face of intensive vaccination is intriguing. Numerous studies have shown that B. pertussis populations changed after the introduction of vaccination suggesting adaptation. These adaptations did not involve the acquisition of novel genes but small genetic changes, mainly SNPs, and occurred in successive steps in a period of 40 years. The earliest adaptations resulted in antigenic divergence with vaccine strains. More recently, strains emerged with increased pertussis toxin (Ptx) production. Here I argue that the resurgence of pertussis is the compound effect of pathogen adaptation and waning immunity. I propose that the removal by vaccination of naïve infants as the major source for transmission was the crucial event which has driven the changes in B. pertussis populations. This has selected for strains which are more efficiently transmitted by primed hosts in which immunity has waned. The adaptation of B. pertussis to primed hosts involved delaying an effective immune response by antigenic divergence with vaccine strains and by increasing immune suppression through higher levels of Ptx production. Higher levels of Ptx may also benefit transmission by enhancing clinical symptoms. The study of B. pertussis populations has not only increased our understanding of pathogen evolution, but also suggests way to improve pertussis vaccines, underlining the public health significance of population-based studies of pathogens.     

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease

IntroductionVascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition.Methods433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/−) and tau status (T+/−). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition.ResultsThe absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline.DiscussionOur results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.     

Brain arterial dilatation and the risk of Alzheimer's disease

IntroductionWe tested the hypothesis that brain arterial dilatation increases the risk of Alzheimer's dementia (AD).MethodsWe studied dementia-free participants in the Washington Heights-Inwood Columbia Aging Project who had a brain MRI and post-MRI dementia adjudication. We measured the axial T2-proton density diameters of the intracranial carotids and basilar diameters and used Cox models to obtain AD hazard ratios and 95% intervals.ResultsOf 953 participants (mean age 77 ± 7 y, women 64%, 71% nonwhite) followed on average for 3 ± 3 years, 76 (8%) developed AD. In a model adjusted for demographics, vascular risks, apolipoprotein E (APOE)-ε4, and white matter hyperintensities, larger carotid diameters increased the risk of AD, defined categorically as ≥ 90th percentile (HR 4.34, 1.70–11.11) or continuously (HR 1.44 per SD, 1.07–1.94).DiscussionUnderstanding the pathophysiology of the association between AD and brain arterial dilatation may reveal new clues to the vascular contributions to AD.     

Development and Validation of a Nomogram for Predicting the 6-Year Risk of Cognitive Impairment Among Chinese Older Adults

ObjectiveAlthough some people with mild cognitive impairment may not suffer from dementia lifelong, about 5% of them will progress to dementia within 1 year in community settings. However, a general tool for predicting the risk of cognitive impairment was not adequately studied among older adults.DesignProspective cohort study.SettingCommunity-living, older adults from 22 provinces in China.ParticipantsWe included 10,066 older adults aged 65 years and above (mean age, 83.2 ± 11.1 years), with normal cognition at baseline in the 2002–2008 cohort and 9354 older adults (mean age, 83.5 ± 10.8 years) in the 2008–2014 cohort of the Chinese Longitudinal Healthy Longevity Survey.MethodsWe measured cognitive function using the Chinese version of the Mini-Mental State Examination. Demographic, medical, and lifestyle information was used to develop the nomogram via a Lasso selection procedure using a Cox proportional hazards regression model. We validated the nomogram internally with 2000 bootstrap resamples and externally in a later cohort. The predictive accuracy and discriminative ability of the nomogram were measured by area-under-the-curves and calibration curves, respectively.ResultsEight factors were identified with which to construct the nomogram: age, baseline of the Mini-Mental State Examination, activities of daily living and instrumental activities of daily living score, chewing ability, visual function, history of stroke, watching TV or listening to the radio, and growing flowers or raising pets. The area-under-the-curves for internal and external validation were 0.891 and 0.867, respectively, for predicting incident cognitive impairment. The calibration curves showed good consistency between nomogram-based predictions and observations.Conclusions and ImplicationsThe nomogram-based prediction yielded consistent results in 2 separate large cohorts. This feasible prognostic nomogram constructed using readily ascertained information may assist public health practitioners or physicians to provide preventive interventions of cognitive impairment.