Regulatory objectivity in action: Mild cognitive impairment and the collective production of uncertainty

In this paper, we investigate recent changes in the definition and approach to Alzheimer’s disease brought about by growing clinical, therapeutic and regulatory interest in the prodromal or preclinical aspects of this condition. In the last decade, there has been an increased interest in the biomolecular and epidemiological characterization of pre-clinical dementia. It is argued that early diagnosis of dementia, and particularly of Alzheimer‘s disease, will facilitate the prevention of dementing processes and lower the prevalence of the condition in the general population. The search for a diagnostic category or biomarker that would serve this purpose is an ongoing but problematic endeavour for research and clinical communities in this area. In this paper, we explore how clinical and research actors, in collaboration with regulatory institutions and pharmaceutical companies, come to frame these domains as uncertainties and how they re-deploy uncertainty in the ‘collective production’ of new diagnostic conventions and bioclinical standards. While drawing as background on ethnographic, documentary and interview data, the paper proposes an in-depth, contextual analysis of the proceedings of an international meeting organized by the Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration to discuss whether or not a particular diagnostic convention — mild cognitive impairment — exists and how best it ought to be studied. Based on this analysis we argue that the deployment of uncertainty is reflexively implicated in bioclinical collectives’ search for rules and conventions, and furthermore that the collective production of uncertainty is central to the ‘knowledge machinery’ of regulatory objectivity

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults

Introduction Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer’s disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults. Methods A large sample of 139 CU older adults (mean age (range) = 85.4 (82–95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations. Results At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions. Discussion In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment