NeuroscienceFlorbetapir-PET β-amyloid imaging and associated neuropsychological trajectories in survivors of critical illness: A case series
Introduction
Over 5 million people are admitted to intensive care units (ICUs) in North America annually. A key concern among survivors is whether they will experience cognitive impairment, a condition that impacts up to half of all ICU survivors [1]. Currently, 6 million Americans have Alzheimer's disease (AD) [2], and it may be that the global burden of dementia needs to be recalculated due to “at risk” ICU survivors.
Data suggest that a significant percentage of patients will experience marked cognitive impairment after critical illness [3], [4], [5], [6], [7], yet questions exist about its natural history and mechanisms. Memory and executive deficits [4], [8] are prominent in those with Post-Intensive Care Syndrome (PICS) [9], [10] patients, and hippocampal atrophy, common in AD, occurs in at least some individuals [11], [12], [13]. Inflammation, a hallmark of critical illness, is linked to the development of dementia [14], [15]. It seems plausible to posit that an AD process may be uncovered or stimulated during critical illness [16], [17].
One key feature of those with AD is the accumulation of amyloid-beta (Aβ) oligomers in the brain, widely believed to be causally linked to synaptic loss and neurodegeneration [18], [19], [20], [21]. Known as the amyloid hypothesis [21], [22], [23], [24], this is the dominant framework for understanding AD, although some experts view it with skepticism [25], [26] as therapeutic studies targeting amyloid have been negative [27]. The presence of a pathological amount of amyloid is currently viewed as diagnostic for AD [28], although amyloid may exist in elderly individuals who do not have cognitive impairments [29]. In the current study, we evaluated the presence of amyloid using a novel in-vivo method via the amyloid tracer, florbetapir F18 (also known as F18 -AV-45), which demonstrates high affinity binding to amyloid plaques [30]. Early amyloid PET studies show that florbetapir binds to amyloid in AD patients, with minimal binding in cognitively healthy individuals [31]. Strong correspondence between florbetapir and amyloid plaque burden has been shown in post-mortem studies [32]. We chose to focus on amyloid as a possible mechanism as we believed it could compellingly explain the existence of phenotypes of impairment that resemble AD in patients after critical illness, recognizing that there are many other candidate mechanisms (including those of a vascular nature) that could be explored.
In this paper, we describe the results of a pilot case series assessing the presence of brain amyloid with florbetapir F18 PET in a convenience sample ICU survivors up to 6 years after ICU discharge, using a quantitative measurement of florbetapir cortical uptake known as Standard Uptake Value ratio (SUVr). We compared our findings with findings pertaining to neuropsychological trajectories. We hypothesized that: 1) levels of amyloid suggestive of AD would be more prevalent than expected in these patients with previously undocumented cognitive impairment/dementia; and 2) that clinically significant amyloid would exist in the patients with cognitive trajectories marked by decline over time.
Section snippets
Materials and methods
This investigation was conducted between the dates of 5/2/2012 and 12/3/2015. IRB approval was obtained before study initiation and the initiation of consent.
Demographics
A total of 14 patients participated in amyloid imaging (Table 1). Patients were between 40 and 81 years (mean 56, SD ± 12). A total of 57% [8] had > 12 years of education and none had pre-existing cognitive impairment (see Table 1 data and footnote). Patients were uniformly severely ill and experienced a median delirium duration of 4 days.
Amyloid imaging findings
A total of 2 patients, both geriatric (74 and 81), demonstrated the presence of amyloid, demonstrating SUVr scores of 1.18 and 1.30 (SUVr scores > 1.10 are
Discussion
In a case series of 14 adult ICU survivors who received amyloid imaging via a florbetapir F18 PET scan, 2 (14%) were amyloid positive (their amyloid status prior to the onset of critical illness is unknown) and cognitively impaired and remained so. Four other patients were cognitively impaired, yet amyloid negative. These data are hypothesis generating in that there may be contributory mechanisms undergirding cognitive decline in ICU survivors which are distinct from those frequently implicated
Conclusion
Data from this small case series demonstrated that in our small sample of individuals across the age range, few individuals were amyloid positive, while nearly half of all patients displayed sustained cognitive impairment. In general, amyloid accumulation did not appear to be implicated in the cognitive impairment of a majority of our patients. Future investigations should prospectively utilize novel imaging modalities – including amyloid and tau imaging via PET – with substantially larger
Conflicts of interest and sources of funding
This was an investigator-initiated investigation (IIT) conceived of, designed, and carried out by the ICU Delirium and Cognitive Impairment Study Group (JCJ, RK, and EWE). Avid Radiopharmaceuticals, Inc., a subsidiary of Eli Lilly and Company, provided the F18 tracer by which to conduct the PET scans. The tracer was created by Avid in Atlanta on the morning of each investigational PET study day and driven to Nashville for its administration that afternoon. Avid provided no other funds for this
References (38)
- et al.
Amyloid deposition as the central event in the aetiology of Alzheimer's disease
Trends Pharmacol Sci
(1991) The molecular pathology of Alzheimer's disease
Neuron
(1991)- et al.
Variation in critical care services across North America and Western Europe
Crit Care Med
(2008) - et al.
Epidemiology of Alzheimer disease
Nat Rev Neurol
(2011) - et al.
Six-month neuropsychological outcome of medical intensive care unit patients
Crit Care Med
(2003) - et al.
Long-term cognitive impairment after critical illness
N Engl J Med
(2013) - et al.
Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome
Am J Respir Crit Care Med
(1999) - et al.
Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study
Crit Care
(2014) - et al.
Delirium as a predictor of long-term cognitive impairment in survivors of critical illness
Crit Care Med
(2010) - et al.
Cognitive dysfunction in ICU patients: risk factors, predictors, and rehabilitation interventions
Crit Care Med
(2013)
Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference
Crit Care Med
Implementation of the Pain, Agitation, and Delirium Clinical Practice Guidelines and promoting patient mobility to prevent post-intensive care syndrome
Crit Care Med
The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study
Crit Care Med
The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study
Crit Care Med
Brain autopsy findings in intensive care unit patients previously suffering from delirium: a pilot study
J Crit Care
Systemic inflammation and delirium: important co-factors in the progression of dementia
Biochem Soc Trans
Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model
Science
Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer's disease?
Nat Rev Neurosci
PET imaging of brain amyloid in dementia: a review
Int J Geriatr Psychiatry
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