Person:

Culley, Deborah

OBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention.

The purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects ≥ 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days (n = 1018) and 3 months (n = 946). Postoperative cognitive dysfunction was defined as a composite Z-score > 2 across tests or at least two individual test Z-scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1–2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6–2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.

Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1–3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24–48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.

This narrative review examines serum biomarkers for the diagnosis and monitoring of delirium. Serum biomarkers for delirium fall into three major groups: 1) those that are present or elevated prior to disease onset—risk markers, 2) those that rise with onset and fall with recovery—disease markers, and 3) those that rise in proportion to the consequences of disease—end products. As risk markers, we examine serum chemistries and genetic risk markers. As disease markers, we examine serum anticholinergic activity, amino acids, melatonin, cytokines, cortisol, and gene expression. As end products of delirium, we examine markers of neuronal injury. Finally, we discuss methodological and biostatistical considerations for future biomarker studies. Identifying accurate biomarkers for delirium may shed further light into its pathophysiology and on the interrelationship between delirium and dementia.

Background. Dementia and delirium have been postulated to share common pathophysiologic mechanisms; however, identification of these unifying mechanisms has remained elusive. The inhalation anesthetic isoflurane has been shown to enhance β-amyloid protein (Aβ) oligomerization and generation, to potentiate the cytotoxicity of Aβ, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Aβ fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human β-amyloid precursor protein (APP).

Methods. H4 human neuroglioma cells stably transfected to express human full-length wild-type APP were exposed to 2% isoflurane for 6 hours. The cells were harvested at the end of the treatment. Caspase-3 activation was measured with quantitative Western blotting.

Results. We found that isoflurane induces cellular apoptosis in a dose-dependent manner, and that Congo red inhibits isoflurane-induced apoptosis in H4 human neuroglioma cells overexpressing APP. Interestingly, Congo red also inhibits staurosporine-induced apoptosis.

Conclusion. The demonstration that isoflurane contributes to well-described mechanisms of Alzheimer's neuropathogenesis provides a plausible link between the acute effects of anesthesia, a well-described risk factor for delirium, and the more long-term sequelae of dementia. These findings suggest that isoflurane-induced Aβ oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.