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Review Article

The Role of Neuroimaging in Elucidating Delirium Pathophysiology

¹ Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
² Geriatric Research, Education, and Clinical Center (GRECC), VA Boston Healthcare System and Harvard Medical School, Boston, Massachusetts.
³ Departments of Radiology and Neurology, Massachusetts General Hospital, Boston.
⁴ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
⁵ Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
⁶ Division of Gerontology, Beth Israel Deaconess Medical Center, Harvard Medical School, and Aging Brain Center, Hebrew SeniorLife, Boston, Massachusetts.

Address correspondence to David Alsop, PhD, Department of Radiology, Ansin 226, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. E-mail: dalsop{at}bidmc.harvard.edu

	Abstract

Top Abstract Target Questions for... Imaging Studies of Delirium Newer Techniques With Potential... Future Prospects for... References

 
Understanding of delirium pathogenesis remains limited despite improved diagnosis, and elucidation of risk factors and prognosis. Major advances in neuroimaging offer the possibility of probing the mechanisms and networks involved in delirium and hence improving understanding of this often devastating syndrome. This review describes the current literature of imaging studies in delirium and related conditions, introduces some of the newer capabilities of neuroimaging with magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, and discusses how these techniques may be applied to the study of delirium. Despite considerable challenges in patient recruitment, study design, intersubject variability, and scanner and contrast agent availability, imaging offers great potential for the identification and clarification of pathogenic mechanisms of delirium and its long-term sequelae.

In this review article, we discuss the shortcomings of our current understanding of delirium and distill from this a series of target questions about the pathophysiology of delirium that might be addressable by neuroimaging studies and whose answers would provide a major advance in the understanding of delirium. We survey the existing literature on imaging studies in delirium and highlight the gaps that remain. Subsequently, we introduce a number of newer neuroimaging techniques and describe how some of these methods might be used to answer our target questions about delirium. Finally, we consider the obstacles to performing such neuroimaging studies and discuss potential solutions. This article may provide a useful framework to guide future neuroimaging studies investigating the pathophysiology of delirium.

	TARGET QUESTIONS FOR NEUROIMAGING STUDIES OF DELIRIUM

Top Abstract Target Questions for... Imaging Studies of Delirium Newer Techniques With Potential... Future Prospects for... References

 
Delirium is an acute confusional state characterized by decline in attention and cognition. It is a syndrome defined by its clinical features (1), rather than its histopathologic or molecular effects. Since delirium arises predominantly in older persons during hospitalization, where comorbidity can confound many diagnostic tests, studies of clinical populations have yielded only modest insights into the mechanisms of delirium to date. In the absence of defined mechanisms, delirium may appear to be a nonspecific syndrome of a vulnerable brain. As it has for other pathologies, neuroimaging may enable the definition of delirium as a regional pathology of the brain, as a global deficit in flow or metabolism, or as a deficiency in one or more neurotransmitter systems. Hence, the first target question is: 1. What abnormalities of brain function are responsible for the state of delirium?

While most cases of delirium may result from a final common pathway of disordered brain function, the factors that initiate delirium are typically multifactorial, including systemic illnesses, extracranial processes, or injury that need not originate in the brain. The capabilities of these diverse factors for inducing delirium must be mediated by a pathway into the brain, such as the blood–brain barrier, requiring either high permeability of the inciting factors or a compromised blood–brain barrier (2). Thus, the second target question is: 2. How do extracranial factors associated with delirium reach the brain?

Considerable progress has been made at defining risk factors for delirium, including both vulnerability and precipitating factors identified in epidemiologic studies (1). Neuroimaging may permit the investigation of brain-specific risk factors including structural abnormalities (i.e., periventricular white matter disease, atrophy), incipient dementia, amyloid deposition, and cholinergic dysfunction. The third target question is: 3. What brain-specific factors predict an elevated risk of delirium?

Delirium is associated with numerous negative outcomes including longer hospital stay, reduced cognitive function, increased institutionalization, and death. Considerable evidence indicates that delirium itself, above and beyond the precipitating factors, contributes to reduced cognitive function and may initiate or accelerate incipient dementia (1). This raises the fourth target question: 4. Does delirium result in permanent effects on the brain?

After reviewing the existing literature on neuroimaging in delirium, we will consider some of the newer neuroimaging techniques available, and how they may be used to address these four questions.

	IMAGING STUDIES OF DELIRIUM

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Structural and Lesion Studies
Several studies have used x-ray computed tomography (CT) or magnetic resonance imaging (MRI) scanning to search for lesions or other indicators of structural abnormality in the brains of patients with delirium. In one CT study (3), an increase in the incidence of abnormal brain findings (hemorrhage, hematoma, space-occupying lesion, infarct) in elderly emergency room patients with delirium was noted, but such findings were present in less than half of the delirium cases. In a different emergency room population study (4), abnormal head scans were not predictive of delirium. The authors note that serious medical disease was much more predictive of delirium incidence. These studies suggest that brain lesions visible on CT may contribute to delirium in some cases but delirium without brain lesion is more common. Incidence of delirium following antidepressant (5) or electroconvulsive therapy (6) was reported as highly correlated with the presence of basal ganglia and subcortical white matter changes.

While the evidence for a relationship between abnormal MRI or CT structural scans and the occurrence of delirium in a general population is limited, a number of case reports or small case series describe delirium in response to focal lesions. One report of delirium following an infarct in the basal forebrain that resolved following cholinesterase inhibitor administration (7) supports a cholinergic deficit as a major contributor to delirium. However, delirium has also been noted following posterior artery infarction (8), a relapsing multiple sclerosis lesion in the hippocampus (9), focal infarction of the right thalamus (10), and a lesion following cerebrovascular surgery in the right temporal lobe (11). Additionally, reversible lesions of the splenium of the corpus callosum on T2 and especially diffusion MRI have been associated with delirium (12–14). Similar lesions, and delirium-related symptoms, have been observed in high altitude cerebral edema and acute mountain sickness, where they are believed to represent vasogenic edema induced by hypoxia-associated leakage of the blood–brain barrier (15). The reason for the preferential occurrence in the corpus callosum remains unclear but may relate to unique characteristics of its vasculature. These lesion studies provide a fertile source of hypotheses for further study, but, because of limited numbers of study participants and varied recruitment and diagnostic methods, they should not be overinterpreted.

Cerebral Blood Flow Studies
Because anatomic imaging is often inconclusive in cognitive and psychiatric disorders, imaging methods sensitive to the level of activity in the brain are frequently evaluated for further characterization. Measurements of cerebral blood flow (CBF) are appealing because they can be performed with clinically available imaging systems and because blood flow is typically correlated with metabolic indicators of brain activity such as glucose utilization. Thus, these modalities may allow detection of regional or global blood flow changes that might be associated with delirium.

Single photon emission computed tomography (SPECT) measures CBF using a radioactive tracer. A substantial number of SPECT studies of delirium or related conditions have been reported (see Table 1). It should be noted that there is variation across the reports in etiology of delirium, radioactive isotope used, and processing of scans. Frequently, SPECT scans are interpreted visually by an experienced radiologist or by quantitative comparison to a control region.

One limitation of most SPECT studies is that absolute measurement of blood flow is not performed. Thus, while fairly sensitive for localized changes, SPECT studies are usually not capable of detecting global flow changes. One study performed with Xenon-enhanced CT for blood flow measurement in 10 patients during and after delirium (16) demonstrated a 42% globally decreased flow during delirium with possibly greater decreases in subcortical structures and occipital cortex compared to other brain regions. Such changes would be largely missed in relative flow studies and are consistent with delirium being, at least in part, a global brain dysfunction (17). Globally reduced blood flow could represent a causal mechanism in some cases of delirium or a marker for some of the conditions that can precipitate delirium (e.g., toxic–metabolic derangements). Evaluation of global alterations in flow would also be useful to investigate the coupling between brain function and blood flow, which might be altered in delirium, such as with cholinergic deficiency (18).

Thus, regional and global CBF studies with SPECT, or possibly other imaging modalities, can provide a sensitive means to evaluate pathophysiologic changes associated with delirium, both acutely and evolving over time. Caution must be taken in interpreting CBF studies of delirium since elderly persons are prone to vascular disease, which can affect both CBF and brain activity, and alterations of neurotransmitter activity frequently associated with delirium may directly affect vascular regulation. The use of serial scans in matched patients with and without delirium may help to address these issues.

Limitations of Existing Studies
Previous studies have not fully addressed any of the target questions we raised. While regional findings of anatomic, diffusion MRI, or CBF abnormalities were sometimes found, they lacked the specificity and reproducibility required to demonstrate a regional or neurotransmitter basis for delirium. Little additional understanding of the mechanisms for inducing delirium was achieved, and no study addressed permanent damage following delirium. In addition, neuroimaging-based risk factors for delirium were not addressed in any of these studies.

	NEWER TECHNIQUES WITH POTENTIAL FOR THE STUDY OF DELIRIUM

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Newer neuroimaging techniques may offer powerful methods to elucidate the pathophysiology of delirium and to directly address our target questions. The current literature suggests that anatomical imaging findings in delirium may be subtle or absent. Newer imaging and analysis methods may be helpful to either detect subtle anatomical changes or to provide different information with greater sensitivity to delirium. Since most of these newer techniques are not readily available for clinical assessment of delirium, making them available, at least for research studies, is an important priority.

Volumetric Analysis
Imaging studies of anatomy and brain atrophy have been greatly improved in the past decade. Improved image contrast and robustness to motion can be achieved with optimized timing, surface coil arrays, and motion correction strategies. Perhaps the biggest advance, however, has been in postprocessing (19,20). Careful statistical methods for analysis of structural images have been honed for detecting subtle changes in volume over time, as can occur in Alzheimer's disease. Less than 1% changes in brain volume can be detected within participants, and only slightly higher standard deviations occur in smaller, automatically defined regions. Such techniques could be useful to test for accelerated rates of atrophy following delirium, which would indicate permanent damage. High levels of delayed atrophy have been observed in other insults, such as brain trauma (21). Measures of brain volumes would help to address our questions about brain-specific risk factors for delirium (Question 3), since high levels of atrophy may be predictive of delirium, perhaps representing the onset of incipient dementia. In addition, detection of accelerated brain atrophy following delirium could demonstrate the nature of permanent damage from delirium (Question 4) and, if regionally specific, may provide input for defining the physiologic basis of delirium (Question 1). Because atrophy is a nonspecific indicator of degeneration, its diagnostic value will be limited unless a strong regional specificity is demonstrated.

Blood Oxygen Level Dependent (BOLD) Technique
In addition to structural imaging, MRI has made major advances in functional assessment of the brain. Perhaps most widely known is the blood oxygen level dependent (BOLD) technique for imaging of brain activity changes (22). This technique permits the imaging study of brain responses to different stimuli or task activities. While this technique generally requires a controlled and cooperative patient population, clinical studies in Alzheimer's disease (23) and other dementias (24) have been successfully performed. The magnitude of BOLD activation in temporal lobe structures during memory tasks can used to predict conversion from mild cognitive impairment to Alzheimer's disease. BOLD studies might be used as a predictor of risk or vulnerability for delirium (Question 3), or as an indicator of performance over time in long-term follow-up studies after delirium (Question 4). Because BOLD studies can detect altered brain activity in response to stimuli, they offer a different window into the delirious state than resting studies such as SPECT and PET. High requirements of patient cooperation in BOLD studies may limit the use of BOLD to studying the neural substrates of confusion and other cognitive symptoms of delirium, which could contribute to our understanding of the delirious state (Question 1).

Arterial Spin Labeling
Another MRI technique capable of imaging brain activity change is the arterial spin labeling blood flow MRI method (25). This technique measures blood flow and can provide a resting blood flow measure (26), as in the SPECT studies reviewed in the previous section, and can also quantify modulations of flow over seconds to hours (27). Arterial spin labeling can be performed as part of a standard MRI scan so that both anatomical and blood flow information can be obtained. It is particularly well suited to measuring the effect of pharmacologic challenges (28) and its use in conjunction with neurotransmitter modulators, such as scopolamine or donepezil, is intriguing for assessing the contribution of neurotransmitter function to the risk of delirium (Question 3), or for assessing long-term changes after delirium (Question 4).

Diffusion Tensor Imaging
Another exciting MRI technique is diffusion tensor imaging (29). Diffusion MRI is sensitive to the random motion of water within tissue. In acute stroke, diffusion decreases rapidly and is highly sensitive to early injury to tissue (30). Diffusion changes can be reversible, and there have been some signs of delirium-related symptoms in participants with diffusion lesions in the splenium of the corpus callosum (13). Many of the recent developments in diffusion imaging relate to measuring the directionality of diffusion in white matter (31). Diffusion is much faster along axons than perpendicular to them. Because MRI tends to measure diffusion along one direction at a time, the images appear different with the direction chosen. The direction of greatest diffusion in a region can be used to determine the direction of fiber tracts. Computerized methods can be used to define fiber tracks anatomically and potentially derive measures related to connectivity between brain regions. Additionally, a measure of the dependence of diffusion on direction, or anisotropy, has been used as an indicator of brain connectivity. Decreases in white matter integrity and connectivity have been identified with diffusion tensor imaging in Alzheimer's disease (32), schizophrenia (33), and geriatric depression (34). With its high sensitivity, diffusion tensor imaging may prove useful to identify chronic pathologic changes associated with delirium (Question 4), which may contribute to the associated longer-term cognitive impairment.

Blood–Brain Barrier Imaging
MRI can also be used to assess blood–brain barrier integrity. The blood–brain barrier plays a critical role in protecting the brain from systemic disease and dysfunction. Delirium, however, is frequently initiated by conditions outside the brain. The health of the blood–brain barrier prior to and during delirium could be an important factor in pathogenesis. Inflammatory cytokines and other potentially neurotoxic agents enter the brain when the blood–brain barrier is disrupted (35). MRI with routine paramagnetic contrast is an indicator of blood–brain barrier disruption. While aging, and most likely delirium, are not associated with sufficient contrast uptake to readily detect visually, the subtle blood–brain barrier disruption associated with aging (36), and possibly a more severe disruption associated with delirium, are potentially measurable with contrast-enhanced MRI (36–38). Quantitative analysis of serial images must be used for greatest sensitivity to small concentrations of contrast. This modality may offer important clues about the pathophysiologic initiation of delirium (Question 2).

Amyloid Imaging
Recent research in the neurochemistry of amyloid plaques has resulted in the development of the benzothiazole class of compounds, which specifically bind to individual amyloid plaques in mouse models of Alzheimer's disease (39). These compounds cross the blood–brain barrier and have now been labeled with radioisotopes for use as in vivo molecular probes. One such compound, known as Pittsburgh Compound B, has been tested in animal models of Alzheimer's disease, in human Alzheimer's disease post mortem brain tissue, in living healthy older participants, and in patients with a clinical diagnosis of Alzheimer's disease (40). Pittsburgh Compund B binds primarily to fibrillar forms of amyloid and has been found to be highest in neocortical regions, especially frontal, temporal, and parietal cortices. Interestingly, recent reports have also found evidence of neocortical Pittsburgh Compund B retention in a subset of cognitively intact older participants (41), consistent with autopsy reports of amyloid deposition in a small proportion of healthy older individuals. Amyloid PET imaging is an important modality to explore in patients exhibiting prolonged delirium, as early Alzheimer's disease pathology may be a significant contributing factor. Moreover, this modality will facilitate follow-up studies to detect increased amyloid deposition over time following a delirium episode. This technique could help to elucidate the brain-specific risk factors for delirium (Question 3), and the relationship between delirium and subsequent occurrence or acceleration of dementia (Question 4).

PET and SPECT Imaging
PET and SPECT offer a number of exciting new possibilities for the characterization of delirium. Besides more traditional glucose utilization and flow imaging, which can be used to determine the presence and severity of dementia before and after delirium, newer tracers for imaging of neurotransmitters, such as cholinergic receptor activity (42) and dopaminergic function (43), are now available. Since neurotransmitter dysfunction is likely an important part of the physiologic basis of delirium, the ability to image neurotransmitter function could be an invaluable tool for clarifying the pathophysiology of delirium (Question 1). Many of these agents require special chemistry or cyclotron facilities as well as considerable preparation time and expense, which may make studies of acute delirium impractical in the near term. Nevertheless, the potential these methods present for more sensitive physiologic characterization of delirium is promising as an area for future investigation.

	FUTURE PROSPECTS FOR NEUROIMAGING STUDIES OF DELIRIUM

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While existing and newer imaging modalities hold great promise for the study of delirium, progress is impeded by the many challenges posed by studying acutely-ill older persons with delirium (See Table 2). Some potential solutions to these challenges are indicated. One approach to avoiding these challenges is by the imaging study of animal (44) or human (45) models of delirium. Definitive clinical imaging studies of delirium are likely to require careful planning and recruitment, moderate to large sample sizes, and considerable imaging and clinical infrastructure. Advances in imaging speed and sensitivity, such as are made possible with high field strength and parallel imaging MRI, may help make studies in this clinical population more feasible. Despite their challenges, these studies will represent a major advance in understanding the pathophysiology of delirium and its long-term sequelae.

	Acknowledgments

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This work is an adaptation of a presentation at "The Interface of Delirium and Dementia," a conference organized by the Aging Brain Center, Hebrew SeniorLife, April 10, 2006, in Waltham, Massachusetts. Authors acknowledge support from the Education Core of the Massachusetts Alzheimer's Disease Research Center (P50AG005134), a conference grant from the Alzheimer's Association, the National Institute on Aging R21AG025193 (SKI) and K24AG00949 (SKI), the National Institute of Neurological Disorders and Stroke 5F32NS047431 (TGF), and the Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife.

	Footnotes

Top Abstract Target Questions for... Imaging Studies of Delirium Newer Techniques With Potential... Future Prospects for... References

 
Decision Editor: Luigi Ferrucci, MD, PhD

Received July 6, 2006

Accepted September 19, 2006

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Top Abstract Target Questions for... Imaging Studies of Delirium Newer Techniques With Potential... Future Prospects for... References

 

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