Introduction
Neuroinflammation is associated with increased expression of the 18-kDa translocator
protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), which
is present on the mitochondria of activated microglia, astroglia and macrophages.
TSPO positron emission tomography (PET) ligands have been used in neuroinflammation
research for over 20 years. The first-generation tracer 11C-PK11195 has some limitations
including low signal-to-noise ratio making more subtle neuroinflammation difficult
to detect in brain tissue. More recently, second- and third-generation TSPO-specific
radiotracers have been developed to overcome these hurdles and have proven useful
in assessment of neuroinflammation in a variety of neurological and psychiatric conditions.
However, one drawback of the newer ligands is the need to genotype for rs6971 polymorphisms
prior to imaging. The polymorphism determines radiotracer uptake since low-affinity
binders (Thr/Thr) have to be excluded, and statistical analyses require adjustments
depending on whether participants are mixed (Ala/Thr) or high affinity (Ala/Ala) binders.
This month’s journal club examines four papers utilising TSPO PET imaging in HIV,
traumatic brain injury, multiple sclerosis (MS) and HTLV-1-associated myelopathy (HAM),
respectively. This imaging modality is used variously in these four studies to explore
questions regarding disease pathogenesis, response to treatment, and clinicopathological
correlates.
Neuroinflammation in treated HIV-positive individuals: a TSPO PET study
Despite the advent of combined antiretroviral therapy and the consequent effective
control of HIV RNA in both the serum and CSF, many HIV-positive patients still develop
HIV-associated brain disease, including cognitive impairment. It has been suggested
that inflammation continues in the brain, despite undetectable viral loads, and that
this inflammation is responsible for the gradually accruing cognitive deficits evident
in many treated HIV patients.
One of the hypotheses regarding the mechanism of chronic immune activation in treated
HIV patients relates to the concept of microbial translocation: the passage of gut
flora into the bloodstream due to early CD4 T cell depletion in the gastrointestinal
tract in the first few weeks of HIV infection, causing a breach in the mucosal immune
system. The consequent presence of microbes in the systemic circulation (without overt
bacteraemia) is postulated to be causative in the subsequent chronic inflammatory
state in treated HIV patients.
This cross-sectional, case–control study explored the presence of microglial activation
in cognitively healthy HIV-positive patients on suppressive antiretroviral therapy,
correlating this with brain structure and function, peripheral chemokines and markers
of microbial translocation. Twelve treated HIV patients and ten controls underwent
[11C]PBR28 PET CT scans, volumetric and diffusion MR imaging, cognitive testing, measurement
of CSF chemokines and HIV RNA, as well as PCR of plasma ribosomal 16s rRNA (a marker
of microbial translocation).
Microglial activation, as measured by TSPO PET, was globally higher in treated HIV
patients compared to controls. TSPO uptake was greatest in the subcortical grey matter,
the basal ganglia in particular. Increased TSPO binding correlated with poorer performance
in verbal learning and memory domains on cognitive testing. Increased TSPO binding
and white matter mean diffusivity (MD) on diffusion imaging also correlated positively.
Markers of microbial translocation correlated with increased TSPO binding, leading
the authors to postulate that this phenomenon may be a causative factor in brain inflammation
in treated HIV positive patients.
Comment This study lends weight to the hypothesis that chronic immune activation continues
in HIV patients despite apparently effective antiretroviral treatment and that the
consequent inflammation may be responsible for HIV-associated neurocognitive impairment.
Nevertheless, these patients were by definition asymptomatic, so any relatively poorer
performance on cognitive testing was, therefore, subclinical. A longitudinal study
might be better placed to tackle the issue of causality.
Although this paper contributes to our understanding of pathophysiology in treated
HIV patients, a study comparing TSPO uptake in asymptomatic HIV patients and those
with HIV-associated cognitive impairment would be more likely to determine whether
this imaging modality will prove clinically useful in this arena.
Vera J et al (2016) Neurology 86(15):1425–1432.
Imaging of glial cell activation and white matter integrity in brains of active and
recently retired National Football League players
In traumatic brain injury, it is thought that single and repeated insults can lead
to prolonged immune activation. This study aimed to explore whether microglial activation
is ongoing in the years following sports-related concussive and sub-concussive injuries.
Ten young former and four active National Football League (NFL) players were recruited,
in parallel with 16 controls, to undergo [11C]DPA-713 TSPO imaging alongside structural
and diffusion MRI and neuropsychological testing. Mean time since last concussion
was 7 years (range 1–21).
TSPO imaging revealed increased microglial activation in the NFL players in 8 of 12
regions measured, including the supramarginal gyri, mesial temporal lobes and left
temporal pole. There was also reduced fractional anisotropy on DTI in six of ten regions
measured, reflective of likely altered white matter integrity. There were no volumetric
differences on structural MR, nor were there any differences in neuropsychological
parameters.
Comment Although none of the players in this study have developed cognitive impairment
at this stage in their lives, there is some evidence that collision sport professionals
are more likely to develop cognitive, affective and behavioural changes later in life.
Microglial activation as measured with TSPO PET may be one possible mechanism of this;
however, a longitudinal study might be better placed to answer this question.
The authors hypothesise that microglial activation pathways may be therapeutic targets
for preventative interventions before the clinical effects of recurrent head injury
manifest. Given that microglia have reparative functions as well as deleterious, this
is unlikely to be a straightforward undertaking. Another confounding factor when considering
therapeutic targets is the poor specificity of TSPO radioligands for microglia since
they also bind activated astroglia and macrophages.
Coughlin JM et al (2017) JAMA Neurol 74(1):67–74.
Evaluation of the effect of fingolimod treatment on microglial activation using serial
PET imaging in multiple sclerosis
TSPO PET has been used extensively in MS research. As might be expected, radiotracer
uptake is increased in regions that correspond to T2 lesions on MRI. Interestingly,
there is also increased tracer uptake in the normal appearing white matter (NAWM)
and grey matter (GM), both in relapsing remitting MS and in progressive disease compared
with healthy controls.
This study used 11C-(R)-PK11195 PET scans and MRI to evaluate the effect of fingolimod
on neuroinflammation in patients with relapsing remitting MS switching from another
disease-modifying treatment. Ten patients underwent scans at baseline and 6 months.
Seven of these also had intermediate scans at 2 months. Eight controls were imaged
for comparison.
Baseline scans, as expected from previous studies, revealed higher TSPO binding in
the T2 lesions, NAWM and grey matter compared with controls. After 6 months on fingolimod,
TSPO binding was 12.31% lower (p = 0.040) in the T2 lesions compared with baseline,
but not in the NAWM or GM. Interestingly, TSPO binding in the NAWM and GM at 2 months
was slightly (but not significantly) higher in the majority of patients compared to
baseline.
Comment MRI has limited utility in monitoring response to treatment in MS, so this
is one area where TSPO imaging could soon change clinical practice, both in the management
of individual patients and in the development of novel disease-modifying treatments,
whether for relapsing remitting or progressive disease. Despite the unfavourable signal-to-noise
ratio with 11C-(R)-PK11195, significant differences were still seen in TSPO binding.
Unlike novel TSPO radioligands, genetic polymorphisms do not affect binding affinity
of 11C-(R)-PK11195—an important practical consideration if TSPO imaging is to be useful
in clinical practice.
Suckersdorff M et al (2017) J Nucl Med ppjnumed.116.183020-32.
Evidence of brain inflammation in patients with human T-lymphotropic virus type 1-associated
myelopathy (HAM): a multimodal imaging study using 11C-PBR28 PET, MR T1-weighted and
diffusion-weighted imaging
More than 10 million people worldwide are infected with HTLV-1 of whom 2–4% develop
HAM. Clinically, the myelopathy manifests predominantly in the thoracic cord; however,
MRI and histological studies have revealed that brain inflammation is often present
too, albeit subclinically. The pathogenesis is thought to be a bystander effect of
the cellular immune response to HTLV-1-infected lymphocytes that enter the central
nervous system. At present the only available treatments have limited efficacy.
This pilot study examined the brains of five HAM patients and two asymptomatic HTLV-1
carriers. Historic healthy control data were also available for analysis. All participants
underwent [11C]PBR28 PET, MRI (T1-weighted and diffusion sequences) and clinical assessment
(including cognitive testing and objective gait measures). There were no consistent
abnormalities on neuropsychology. All participants were identified as high-affinity
binders on TSPO genotyping.
Global TSPO binding was significantly higher in HAM patients compared to asymptomatic
carriers. Binding was also regionally increased in the thalamus. The two HAM subjects
with severe disease had highest tracer uptake, followed by those with moderate and
mild disease in decreasing order. Thalamic and brainstem GM volumes were reduced in
HAM compared to healthy controls and correlated with disease severity, while thalamic
mean diffusivity was increased in HAM-severe patients compared with controls.
Comment Despite such a small number of study participants, the differences demonstrated
here are significant. The correlation of brain inflammation in HAM with measures of
clinical severity suggests that TSPO PET could play an important role in future therapeutic
research in HTLV. It might even prove useful in monitoring individual disease activity,
though genetic polymorphisms determining affinity binding may prove to be significant
hurdles. Research of TSPO ligand uptake in the cord may also be worth pursuing.
Dimber R et al (2016) J Nucl Med 15(12):1905–1912.