The links between traumatic brain injury and Alzheimer disease have been of great interest

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1 NEUROLOGICAL REVIEW New Perspectives on Amyloid- Dynamics After Acute Brain Injury Moving Between Experimental Approaches and Studies in the Human Brain Sandra Magnoni, MD; David L. Brody, MD, PhD The links between traumatic brain injury and Alzheimer disease have been of great interest for many years. However, the importance of amyloid- related neurodegenerative pathophysiologic processes after traumatic brain injury is still unknown. In this review, we present a brief overview of the scientific evidence regarding traumatic brain injury as a contributor toalzheimerdiseaseanddescriberecentresultsshowingsignificantchangesinbrainextracellularamyloid- dynamics in patients with severe brain injury. We then discuss the clinical significance of these findings with their implications for translational neurobiology and conclude with further directions for traumatic brain injury and Alzheimer disease research. Arch Neurol. 00;67(9): Author Affiliations: Department of Anesthesia and Intensive Care, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy (Dr Magnoni); and Department of Neurology and Hope Center for Neurological Disorders, Washington University in St Louis, Saint Louis, Missouri (Dr Brody). Moderate to severe traumatic brain injury (TBI) is a well-documented environmental risk factor for the later development of dementia of the Alzheimer type. -3 This increased risk could in principle be owing to or more of the following: () impaired cognitive reserve, () acceleration of the underlying neurodegenerative processes that normally cause this type of dementia later in life, and (3) as yet undefined factors. Direct evidence favoring impaired cognitive reserve is difficult to obtain because cognitive reserve is not well defined from a pathophysiologic perspective. However, the findings that cerebral infarction, poor social network support, and low educational attainment also increase the risk of dementia of the Alzheimer type provide some support for this concept. Evidence favoring a TBI-related acceleration of Alzheimer disease (AD) related pathophysiologic processes comes from human studies and experimental animal data. First, amyloid (A ) plaques and intra-axonal A deposits have been found in approximately one-third of patients with fatal TBI who did not have preexisting AD, Down syndrome, or clinical dementia. 5-3 A biopsy study of TBI survivors requiring decompressive temporal lobectomy has confirmed this finding,,5 suggesting it is also relevant to patients with nonfatal TBI. Second, a genetic risk factor for AD, the ε allele of the apolipoprotein E gene (ApoE; GenBank AF679), also increases the risk of adverse clinical outcomes after TBI. 6 Although ApoE has many functions, the primary role of ApoE in the development of AD may be to promote the development of A plaque pathology. 7 In a large autopsy series, 8 5% of patients with TBI who had or more ApoE allele had A plaque pathology, whereas only 0% of patients with TBI without an ApoE allele had such pathology. This finding needs to be replicated, however. Third, experimental studies in a pig model of traumatic axonal injury reliably reproduced this A plaque pathology, further strengthening the evidence for a causal role of TBI. 9,0 Traumatic axonal injury may also play a key role in patients with TBI because colocalization of A with several of the enzymes involved in cleaving the amyloid precursor protein has been detected at sites of axonal injury in human TBI autopsy samples. 3 Taken together, these results raise the possibility that TBI may increase the lev- 068

2 els of A in the brain, accelerating the A -related pathophysiologic processes believed to be a root cause of dementia of the Alzheimer type. The specific model put forward by Chen et al 0 involves coaccumulation of amyloid precursor protein with its proteolytic enzymes at sites of axonal injury, increased intracellular production of A, release of A from injured axons into the extracellular space, and deposition of A into extracellular A plaques. Ultimately, this process could play a role in the observed link between a history of brain trauma and an increased risk of developing AD. MICRODIALYSIS MEASUREMENTS OF EXTRACELLULAR A IN EXPERIMENTAL ANIMALS: REGULATION BY NEURONAL ACTIVITY Since 003, it has been possible to measure A in the cerebral interstitial fluid (ISF) of mice using intracerebral microdialysis. The extracellular space is believed to be the crucial site for A aggregation and toxicity. These early studies demonstrated the presence of A in the ISF of amyloid precursor protein transgenic mouse brains before the onset of AD-like A plaque pathology. Furthermore, they showed a reduction in A clearance rate after the onset of A deposition, likely reflecting plaqueassociated changes in amyloid metabolism. Subsequent experiments indicated that neuronal activity and more specifically synaptically coupled endocytic activity was directly correlated with extracellular A concentrations as measured by microdialysis. 3, These data were in agreement with previous findings showing that neuronal activity modulates the formation and secretion of A peptides in hippocampal slices overexpressing amyloid precursor protein. 5 Because neuronal activity is likely to be reduced in the setting of TBI, these findings raised an intriguing alternative possibility: if the same relationship between extracellular A and synaptically coupled endocytosis exists in humans, TBI could in fact decrease extracellular A owing to reductions in neuronal and synaptic activity. MICRODIALYSIS MEASUREMENTS OF EXTRACELLULAR A IN THE INJURED HUMAN BRAIN Intracerebral microdialysis can also be used in patients monitored in the intensive care unit. 6 Clinically approved, commercially available sterile microdialysis catheters can be placed at the same time that another clinically indicated intracranial neurosurgical procedure is being performed with little additional risk to the patient. Among other applications, brain microdialysis has been used clinically to detect early signs of metabolic deterioration, which may provide an early warning of impending secondary insults after acute brain injury. 7 We adapted these clinically approved microdialysis methods to allow recovery of A by adding sterile human albumin to the perfusion fluid to block nonspecific binding of A to the catheters and tubing. We then studied 8 patients with severe brain injuries who were affected by TBI or aneurysmal subarachnoid hemorrhage using these microdialysis methods. 8 Our principal hypothesis was that there would be an acute increase in extracellular A after TBI in accordance with the model of Chen et al, 0 but the results we found were more consistent with an alternative model. Specifically, there were increasing trends in brain ISF A concentrations during several hours to days in most patients, although the specific pattern of these trends was variable. Interestingly, we found that brain ISF A levels tracked the patients overall neurological status, as assessed using the Glasgow Coma Scale. In particular, brain ISF A levels increased as patients neurological status improved, remained stable in clinically stable patients, and appeared to decline when neurological status worsened (Figure ). We also measured the A -0 and A - species from pooled samples of a subset of these patients; their concentrations appeared to correlate with those of total A. Independently, Marklund et al 9 measured ISF A -0 and A - in 8 severely brain-injured patients using a similar microdialysis technique. They reported nonsignificantly higher interstitial A - levels in 3 patients with diffuse axonal injury compared with 5 patients with focal cerebral injuries. Interestingly and in concordance with our findings, a patient with rapid clinical improvement and good recovery had relatively high A levels (case in their study), whereas with persistent coma and poor outcome had undetectable levels of A (case 7 in their study). All these findings, in conjunction with the experimental microdialysis studies discussed herein, support the alternative hypothesis that extracellular A may be decreased after brain injury owing to or in conjunction with injury-related suppression of neuronal activity. In this light, previous results involving ventricular cerebrospinal fluid (CSF) measurements of A could be reinterpreted; observations of an increase in ventricular CSF A levels over time in TBI and subarachnoid hemorrhage patients could be related to recovery of neurological status rather than secondary injury cascades This may also help explain the findings that ventricular CSF from severely injured aneurysmal subarachnoid hemorrhage patients had lower A levels than ventricular CSF from otherwise healthy, neurologically intact patients with chronic hydrocephalus with suspected shunt dysfunction. 30 Suppression of neuronal activity is a likely feature of many types of acute brain injury. This finding may be a consequence of direct disruption of neuronal membranes, energy failure, sodium channel inactivation related to massive depolarization driven by glutamate release, 33 or other processes. Interestingly, in a study combining intracerebral electroencephalographic recordings and microdialysis, TBI-induced suppression of neuronal firing was associated with characteristic posttraumatic alterations of microdialysis-measured metabolic markers, such as reduced extracellular glucose levels and increased lactatepyruvate ratio. 3 In our study, we found a strong association between similar metabolic alterations and reduced levels of extracellular A ; brain ISF A levels were positively correlated with cerebral glucose levels and negatively correlated with cerebral lactate-pyruvate ratios (Figure in Brody et al 8 ). This finding indirectly suggests that reduced A is associated with suppression of neuronal firing. 069

3 A Rapid recovery GCS B Secondary insult (ischemia) GCS C Clinical fluctuations GCS D Prolonged coma (GCS = ) E Change in GCS From Baseline Figure. Brain interstitial fluid (ISF) amyloid- (A ) concentrations and neurological status. A-D, Examples of the course of changes in brain ISF A concentrations and changes in neurological status, as reflected by the Glasgow Coma Score (GCS). Changes in A appear to track (A and B), and in some cases even precede (C and D), neurological status changes. E, Correlation of change in brain ISF A from baseline with changes in neurological status across 3 patients in which serial GCS measurements could be reliably obtained (n=73 paired measurements) (Spearman r=0, P.00 overall; Spearman r=0.8, P.00 for change in GCS score ). In areas of the brain adjacent to sites of macroscopic injury, reduced neuronal activity owing to repeated waves of depression of electrocorticographic activity (cortical spreading depressions) have been documented in a large proportion of patients. 35 Electrocorticography was not performed in our study, but it is likely that similar cortical spreading depressions occurred in our patients near sites of macroscopic injury as well. We therefore predicted that patients in whom microdialysis catheters were placed close to areas of focal brain damage (eg, contusions, infarctions apparent on computed tomographic scans) would have lower A levels than patients in whom microdialysis catheters were placed in normal-appearing tissue (based on computed tomographic scans). Reanalysis of our published data with the inclusion of data from several additional patients confirmed this prediction (Figure ). Taken together, these findings are consistent with the hypothesis that brain extracellular A levels in humans are reduced after acute brain injury as a consequence of reduction of brain neuronal and synaptic activity (Figure 3A). However, we cannot completely rule out the possibility that the reduced levels of ISF A observed in the patients with TBI were a reflection of extracellular A deposition into insoluble aggregates or intracellular A retention (Figure 3B). Similar reductions in brain extracellular soluble A owing to A being retained in insoluble forms have been hypothesized to explain the reduced levels of A - seen in the lumbar CSF of patients with AD. 36 Clearly, the relationship between intracellular and extracellular A is complex. For example, Billings et al 37 found that water maze training (which may increase synaptic activity) was asso- 070

4 A Recovery: [ISF Aβ] increases Acute brain injury: ISF Aβ unknown Stabilization: [ISF Aβ] stable Secondary insults: [ISF Aβ] decreases B 000 Acute brain injury Reduced synaptic activity [ISF Aβ] reduced Brain ISF Aβ-x, pg/ml Adjacent to Macroscopic Injury Normal-Appearing Tissue Figure. Amyloid- (A ) levels adjacent to sites of macroscopic injury vs in normal-appearing tissue after traumatic brain injury. Initial interstitial fluid (ISF) A levels were significantly lower when catheters were placed adjacent to sites of macroscopic injury (n=) compared with when catheters were placed in normal-appearing tissue (n=8), as assessed by computed tomographic scans. White arrows indicate microdialysis catheter tips. P=.0, Mann-Whitney test. ciated with increased total soluble A but decreased insoluble A and oligomeric A in transgenic mice with A plaque pathology. Furthermore, it is formally possible that A levels are initially higher than normal after TBI and then increase further in concert with clinical recovery. For logistical reasons, most microdialysis catheters were placed to hours after injury, leaving the possibility that an early spike in extracellular A levels could have occurred within the first few hours of injury. Obviously, preinjury A levels cannot be assessed directly in humans. We therefore are in the process of going back to mouse models to directly address these mechanistic questions about the handling of A after TBI. Combined experimental TBI, A microdialysis, and electrophysiologic studies in transgenic mice are feasible. To date, these have revealed that extracellular A levels and electroencephalographic activity are immediately reduced in the hippocampus after controlled cortical-impact TBI. 38 These experimental results are concordant with the alternative hypothesis discussed herein. CLINICAL IMPLICATIONS AND FURTHER RESEARCH DIRECTIONS Fundamentally, there are many still-unresolved questions regarding the interaction between TBI and neurodegenerative processes related to Alzheimer disease. First, the aggregation state of the soluble extracellular A was?? Extracellular Aβ aggregation into insoluble forms Intracellular Aβ retention Figure 3. Schematic view of brain interstitial fluid (ISF) amyloid- (A ) dynamics in the setting of acute brain injury. A, Observed changes in ISF A in patients with acute severe brain injury. Preinjury A levels were unknown in patients, but after injury A levels tracked the patients global neurological status, as assessed using the Glasgow Coma Scale. In particular, brain ISF A levels increased as patients neurological status improved, remained stable in clinically stable patients, and appeared to decline when neurological status worsened. B, Hypothesized model of ISF A dynamics after acute brain injury. Soluble A levels are likely reduced after injury owing to reduction of synaptic activity. However, such reduced levels of soluble extracellular A could also reflect insoluble A aggregation in the extracellular space and/or intracellular A accumulation. not investigated in any of these experimental or clinical microdialysis studies. It is possible that minor but potentially important toxic A subspecies, such as oligomers and protofibrils, could be elevated after TBI, even if total ISF A levels are reduced. Such toxic subspecies could represent a pathophysiologic link between TBI and dementia. Microdialysis-based methods for assessing the aggregation state of A in the extracellular space of the human brain will be of great interest. Second, the relationship between traumatic axonal injury and extracellular brain A dynamics requires clarification. Advanced magnetic resonance imaging methods, such as diffusion tensor imaging, can provide much more detailed information regarding axonal integrity after TBI than standard methods, such as computed tomography or conventional magnetic resonance imaging. Combined microdialysis and diffusion tensor imaging studies could be used to address this issue. Third, the dynamics of tau-related pathophysiologic processes after TBI have not been thoroughly assessed. Tau pathology in the form of neurofibrillary tangles is another hallmark of AD and has been described in a subset of TBI patients.,5 Finally, the relationship between genetic factors and A handling after TBI should be readdressed using microdialysis-based approaches. As described herein, ApoE genotype may have a substantial effect on A deposition, but ApoE genotype effects on soluble extracellular A dynamics have not been determined. Likewise, polymorphisms in the promoter region of neprilysin, of the key A -degrading enzymes, appear to affect A deposition after TBI 39 but, again, their role in extracellular A has not been addressed, to our knowledge. 07

5 The answers to these questions will help address whether TBI in fact accelerates the neurodegenerative processes underlying AD. If so, interventions designed to block or reverse these processes could be of great benefit. For example, if toxic A subspecies are produced after TBI, microdialysis-based pharmacodynamic and pharmacokinetic studies could help assess candidate therapeutics targeting the productions or effects of these subspecies. A recent study 0 describing beneficial effects of inhibiting the secretase enzymes required for A production in experimental TBI underscores the potential for the development of such therapeutics. However, the preclinical findings of Loane et al 0 need to be interpreted cautiously because the targeted secretase enzymes have other roles and the effects of their inhibition may not be necessarily or exclusively related to A. In the broader context, such pharmacodynamic and pharmacokinetic studies in patients with TBI could help drive forward the development of therapeutics for Alzheimer disease. Although our study and that of Marklund et al 9 demonstrate that it is possible to perform A microdialysis measurements in patients with brain injuries, it has not yet been ethically or logistically possible to directly assess A dynamics in the brain of patients with AD. Intracranial procedures are commonly indicated in patients with TBI but not commonly performed in those with AD. On the other hand, if TBI does not accelerate specific AD-related pathophysiologic processes, it may be more fruitful to focus on enhancing cognitive function and cognitive reserve using general restorative and rehabilitative approaches. Furthermore, there may be other, non A -related secondary injury cascades that should be targeted to improve long-term cognitive outcomes after TBI. Microdialysis-based assessments in patients with TBI could similarly play a key role in therapeutic development. As a final note, if further verification of the link between synaptic activity and extracellular A in the human brain can be obtained, this link could potentially be useful in improving the clinical monitoring of patients with severe brain injuries. Specifically, A could serve as an independent and objective real-time measure of neuronal and synaptic activity in the local region around the catheter. Questions about the prognostic value of A -based microdialysis measurements and assay standardization issues clearly must be addressed before any such clinical monitoring could be routinely useful. Accepted for Publication: November 9, 009. Correspondence: David L. Brody, MD, PhD, 660 S Euclid Ave, Campus Box 8, Washington University in St Louis, St Louis, MO 630 (brodyd@neuro.wustl.edu). Author Contributions: Study concept and design: Magnoni and Brody. 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