Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It

Commentary

Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein.

Gershen LD, Zanotti-Fregonara P, Dustin IH, Liow JS, Hirvonen J, Kreisl WC, Jenko KJ, Inati SK, Fujita M, Morse CL, Brouwer C, Hong JS, Pike VW, Zaqqhbi SS, Innis RB, Theodore WH. JAMA Neurol 2015;72:882–888.

IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomo-graphic (PET) imaging study using carbon 11 ([¹¹C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [¹¹C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [¹¹C]PBR28 and another TSPO radioligand, [¹¹C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [¹¹C]PBR28, and 8 patients and 7 controls were scanned with [¹¹C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [¹¹C]PBR28 distribution volume (V _T) corrected for free fraction (ƒP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [¹¹C]PBR28 and [¹¹C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [¹¹C]PBR28 V _T to ƒP ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%–42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%–32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [¹¹C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [¹¹C]PBR28 was increased significantly in thalamus. Relative [¹¹C]PBR28 and [¹¹11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([¹¹C]PBR28: 2%–6%; [¹¹C]DPA-713: 4%–9%). Asymmetry of [¹¹C]DPA-713 was greater than that of [¹¹C] PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE: Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.

Recently, neuroinflammation has been big news and a target of intense investigation for many diseases of the central nervous system, including Alzheimer's disease, multiple sclerosis, and stroke. In each case, neuroinflammation is thought to contribute to the pathology; therefore, anti-inflammatory therapy has been contemplated as a potential intervention. The same has been true in epilepsy. Several studies have suggested that seizures initiate an inflammatory cascade, leading to upregulation of reactive astrocytes, and microglial cells, and production of cytokines such as Interleukin-1β Interleukin-6, and tumor necrosis factor (TNF)-α (1). This type of inflammation is called “innate” inflammation, to differentiate it from inflammation that can be present as part of the underlying etiology of some epilepsies, such as autoimmune diseases and brain infections. In contrast, innate inflammation is thought to be triggered by any etiology that can produce seizures and results, in part, from the seizures themselves. As noted by Theodore and colleagues in this article, this inflammatory cascade could then lead to brain hyperexcitability through a number of pathways, triggering more seizures and leading to a perpetuating cycle of excitation, seizures, and inflammation. Drugs that block this cycle could potentially represent a novel therapeutic intervention for treatment resistant epilepsy. In fact, at least one intervention—an interleukin-converting enzyme (ICE) inhibitor that blocks production of IL-1β (VX-765)—was tried in two proof-of-concept studies that enrolled patients with highly drug-resistant epilepsy (2). The results were promising but not definitive, and it was clear that the intervention did not benefit everyone. It is certainly possible that some epilepsy etiologies produce higher degrees of inflammation than others, and therefore contribute more or less to the epileptic diathesis. Activated microglia and astrocytes and production of inflammatory mediators have been identified in association with a number of specific pathologies including mesial temporal sclerosis, cortical dysplasia, and tubers in patients with tuberous sclerosis (3–5). Less is known about other pathologies and about nonlesional epilepsy. It is also possible that inflammation could be more or less active at different times in the course of epilepsy, could burn out over time, and that anti-inflammatory therapies might only be useful at some times but not at others. Animal models of epilepsy have clearly demonstrated the development of an innate inflammatory process over the course of epileptogenesis, but these experiments focus on the early course of the epileptic focus, whereas in the clinic, patients often present years or decades into their disease progression (6).

As new therapies emerge that target inflammation, it becomes critically important to be able to identify individuals in whom inflammation contributes to seizure diathesis and, therefore, might benefit from an anti-inflammatory intervention. To date, this has proven challenging: Elevated serum and CSF cytokine levels have not been identified consistently enough to be useful (1). Previous attempts at finding a neuro-imaging technique to identify neuroinflammation have proven frustrating at best. In this article, Theodore and colleagues report a clear signal of neuroinflammation in patients with temporal lobe epilepsy compared to controls, as detected by PET scans that use carbon 11 ([¹¹C])-labeled PBR28 as a tracer—confirming previous work by the same author (7)—as well as with a novel ligand, [C]DPA-713. Since these tracers bind to TPSO (translocator protein 18 kDa), known to be over-expressed by activated microglia and reactive astrocytes, the presence of increased tracer uptake highly suggests that there is active ongoing brain inflammation in relevant brain regions (hippocampus and temporal lobe, ipsilateral > contralateral to focus, and bilateral thalamus).

How does this help us? For one, it goes a long way in confirming the presence of active inflammation in a living human being. This makes the consideration of an anti-inflammatory intervention even more tantalizing. The results also suggest a potential utility of the tracers for localizing epileptic foci. Twelve patients with TLE showed asymmetries that were > 2 standard deviations above the control mean, with greater inflammation ipsilateral to the seizure focus. This suggests that the tracer might be useful to localize side (and perhaps region) of epileptigenicity in preparation for epilepsy surgery. However, sensitivity and specificity still need to be evaluated, and it is not as yet known whether this technique would provide additive information over and above the current standard.

One limitation of the study is that it only evaluated patients with temporal lobe epilepsy, most of whom had mesial temporal sclerosis. If this is truly a localizing technique, it would be far more useful if it could identify a focus in patients with nonlesional/extratemporal epilepsy, where localization is much more difficult. Recent studies suggest that in the future, these patients will represent our surgical challenge, far more than TLE (8). One case study suggested that PK11195 (a less specific TPSO tracer) uptake was localizing in a patient with extratemporal epilepsy resulting from a cortical dysplasia (9).

Another issue that will need to be explored is whether changes in uptake of these novel TPSO tracers is static or dynamic. The ideal tracer would not only identify inflammation but also show a return to normal levels as inflammation resolves, providing evidence of therapeutic success. To date, there is no evidence of how or whether tracer uptake would change as inflammation is targeted. There was no difference in uptake in patients based on seizure frequency, despite the fact that previous preclinical and human tissue research has suggested that inflammation is rapidly induced by epileptic seizures (1). This might suggest a lack of sensitivity to change.

In summary, the availability of a human in vivo measure of epilepsy associated neuroinflammation may be the necessary advance that leads to effective therapeutic targeting of this potentially critically important cause of brain hyperexcitability, which in turn could potentially improve outcomes in patients who are currently treatment resistant. More research is needed, including imaging of nonlesional and extratemporal epilepsy, and correlation between PET studies using TPSO tracers and subsequent examination of tissue resected during epilepsy surgery.