USING PET TO UNDERSTAND NEUROIMMUNE-RELATED BRAIN HEALTH

Transcript

• 00:00Alright, everyone. We're gonna resume
• 00:02our second part,
• 00:04of this,
• 00:06Dean workshop.
• 00:07We have the next session
• 00:09is two talks by,
• 00:11we entitled
• 00:12Imaging Success Stories,
• 00:14of two heavy users who
• 00:16really have,
• 00:17made a career using imaging.
• 00:20And I'm delighted to introduce
• 00:21them. I'll start with doctor
• 00:23Kelly Cosgrove who received her
• 00:24PhD
• 00:25in clinical psychology from Minnesota,
• 00:28Complete her internship at South
• 00:29Carolina,
• 00:31before coming to psychiatry
• 00:32here, for a post doc
• 00:34at Yale.
• 00:35She's a professor of psychiatry,
• 00:36neuroscience, and radiology and biomedical
• 00:38imaging.
• 00:39And her research focuses on
• 00:40using neuroimaging techniques
• 00:42to understand and inform treatment
• 00:44of psychiatric disorders. Kenny?
• 00:53Hi. Can you guys hear
• 00:54me? Okay. So I'm gonna
• 00:56talk about two studies
• 00:58that we've done using PET
• 00:59to image the neuroimmune system
• 01:01that I think really highlight
• 01:02how important brain PET is.
• 01:05I'm gonna specifically talk about
• 01:07measuring microglia
• 01:08and how that has helped
• 01:10inform our understanding
• 01:11of the neurobiology of post
• 01:12traumatic stress disorder or PTSD.
• 01:16So for some background,
• 01:17microglia
• 01:18are the immune cells of
• 01:20the brain, sometimes referred to
• 01:22as the brain's resonant macrophages.
• 01:24And they're important for healthy
• 01:26brain function, in particular for
• 01:28synaptic function and synaptic plasticity.
• 01:31And when they're in their
• 01:32so called resting state, they
• 01:34have a cell body, and
• 01:35they have all these processes
• 01:36that protrude.
• 01:37And those processes are constantly
• 01:39surveying and maintaining the brain's
• 01:41environment.
• 01:42When there's an immune stimulus,
• 01:45the microglia become activated, they
• 01:47increase in number or proliferate,
• 01:50and they can change shape,
• 01:51ultimately becoming more amoeboid, which
• 01:53helps them engulf debris.
• 01:56And then that in a
• 01:57healthy system, that would reset.
• 01:59And so healthy microglia are
• 02:01associated with healthy neurons. But
• 02:03if there's chronic activation, there's
• 02:05dysfunction in the system, and
• 02:07then that's associated with poor
• 02:08neuronal outcomes,
• 02:10including neurodegeneration.
• 02:13And we can measure a
• 02:14marker of microglia in the
• 02:16brain.
• 02:17The protein that we measure
• 02:18is translocator
• 02:20protein or TSPO.
• 02:22It's found on mitochondria, and
• 02:24it's present predominantly in microglia.
• 02:26The radio tracer that binds
• 02:28to TSPO is carbon eleven
• 02:30labeled PBR twenty eight. And
• 02:32the radio tracer has been
• 02:33used,
• 02:34to study a variety of
• 02:35immune related
• 02:36disorders, including Alzheimer's. So you
• 02:39can see in the picture,
• 02:40these are axial slices of
• 02:41a human brain, and there's
• 02:43low levels of the radiotracer
• 02:45in the healthy control, but
• 02:46much higher concentration of the
• 02:48radiotracer
• 02:49throughout the brain in the
• 02:50person with Alzheimer's disease, indicating
• 02:52higher levels of microglia or
• 02:54what we might call neuroinflammation.
• 02:57And so we use these
• 02:59techniques to study the neuroimmune
• 03:01system in people with PTSD,
• 03:04and we were interested in
• 03:05that because there was a
• 03:06large literature suggesting
• 03:08a heightened inflammatory
• 03:09profile
• 03:10in people with PTSD.
• 03:12So PTSD is diagnosed when
• 03:14somebody has a life threatening
• 03:16traumatic event, and then they
• 03:17develop symptoms that cluster around
• 03:19threat and loss, like,
• 03:22flashbacks, nightmares. There's increased arousal
• 03:24and, typically, mood symptoms.
• 03:26And these symptoms are significantly
• 03:28interfering with their life. So
• 03:30a person under chronic stress
• 03:32with higher levels of immune
• 03:33markers
• 03:34in blood,
• 03:36For example, there's a lot
• 03:37of studies that have shown
• 03:39higher levels of peripheral c
• 03:40reactive protein or CRP,
• 03:43which is a nonspecific immune
• 03:44marker. And the higher the
• 03:46levels of CRP, the worse
• 03:48the PTSD.
• 03:50A lot of studies have
• 03:51also shown higher levels of
• 03:53pro inflammatory cytokines, and these
• 03:55are the signaling proteins that
• 03:56regulate the immune response.
• 03:59And this is supported by
• 04:00preclinical studies. So in rodents
• 04:02with PTSD like behaviors,
• 04:04there's elevated pro inflammatory markers
• 04:07in brain.
• 04:08And so, all this was
• 04:09the basis, served as the
• 04:10basis for advocating testing of
• 04:12anti inflammatory medications,
• 04:14but we didn't know if
• 04:15there was no inflammation in
• 04:17PTSD. And it's important to
• 04:18understand what's happening in the
• 04:20brain to inform treatment of
• 04:21psychiatric disorders.
• 04:24And I think this is
• 04:25where PET is really helpful.
• 04:27So we used the radio
• 04:29tracer in PET to image
• 04:30people with and without PTSD.
• 04:32And based on all the
• 04:33existing literature,
• 04:34we confidently
• 04:36hypothesized that we were gonna
• 04:37find elevated levels of microglia
• 04:39and neuroinflammation,
• 04:41and we found the opposite.
• 04:43So we found that microglia
• 04:45levels were lower in people
• 04:46with PTSD.
• 04:47So
• 04:48the green circles are controls.
• 04:50The pink triangles are people
• 04:52with PTSD.
• 04:54Lower levels across these brain
• 04:55regions that are known to
• 04:56be important in PTSD,
• 04:59specifically
• 05:00insula and ventromedial prefrontal cortex.
• 05:03And importantly,
• 05:04this was correlated with clinical
• 05:06outcomes
• 05:07so that the lower the
• 05:08TSPO or microglial levels, the
• 05:10worse the PTSD symptoms.
• 05:14We confirmed in our sample
• 05:16the previous finding about c
• 05:18reactive reactive protein. So in
• 05:19our sample, the people with
• 05:21PTSD
• 05:22did have higher levels of,
• 05:24peripheral CRP,
• 05:26and that was associated with
• 05:27worse symptoms.
• 05:29But then the higher levels
• 05:31of CRP in the periphery
• 05:32were associated with lower levels
• 05:34of TSPO,
• 05:35so high
• 05:36peripheral
• 05:37inflammatory markers being associated with
• 05:39a microglial deficit.
• 05:43And this was unexpected,
• 05:44suggesting a dysregulated
• 05:46or a disconnected immune system,
• 05:48but this is also just
• 05:50one scan, one point in
• 05:51time. And we're also interested
• 05:53in learning about neuroimmune function.
• 05:55So what's the response to
• 05:57an immune stressor?
• 05:59And we had previously developed
• 06:00a paradigm
• 06:02to measure neuroimmune function in
• 06:04response to a lipopolysaccharide
• 06:07or LPS injection. So LPS
• 06:09is a bacteria that when
• 06:10given to a person or
• 06:12animal,
• 06:13elicits a very robust, reliable
• 06:15immune response.
• 06:16It's kind of like a
• 06:17you can think of it
• 06:18kind of like a vaccine
• 06:19response in that people get
• 06:21they get a little bit
• 06:22sick. They get flu like
• 06:23symptoms, but it's transient. So
• 06:25it dissipates, and it, they're
• 06:26back to normal by the
• 06:27end of our study day.
• 06:29And our study day is
• 06:31people come in, they get
• 06:31the baseline PET scan, we
• 06:33give LPS,
• 06:34and then we do a
• 06:35second PET scan. And so
• 06:37we can measure the microglial
• 06:39increase or activation
• 06:41by measuring the increase in
• 06:42TSPO from scan one to
• 06:44scan two. And so that's
• 06:45what you see in the
• 06:46black,
• 06:47bar graph. It's a percent
• 06:49increase in TSPO levels from
• 06:51scan one to scan two.
• 06:53And it's across the brain.
• 06:54We see this increase of
• 06:55an average of almost fifty
• 06:57percent
• 06:58across regions, which is a
• 06:59really big signal for a
• 07:00PET study. You can clearly
• 07:02see that in the picture
• 07:03as well.
• 07:05And we measure cytokines and
• 07:07sickness symptoms over the course
• 07:08of the day. So
• 07:10the cytokines listed there increase
• 07:12after the LPS injection.
• 07:14They peak around two to
• 07:16three hours, which is when
• 07:17we do our second PET
• 07:18scan.
• 07:19And there's increases
• 07:20in things like fatigue and
• 07:21sickness and then reductions in
• 07:23things like energy
• 07:24and desire to socialize. And
• 07:26you can see that those
• 07:27are back to baseline by
• 07:28the end of the study.
• 07:30And this is good. This
• 07:31is a healthy response if
• 07:33you are exposed to something
• 07:34like LPS. You want,
• 07:36to have a really nice
• 07:37robust immune response.
• 07:39So we had a subset
• 07:40of people from our first
• 07:41study with PTSD,
• 07:43participate in this paradigm. So
• 07:45have their baseline scan and
• 07:47then stay for LPS in
• 07:49a second PET scan.
• 07:52And we were not as
• 07:53surprised with this finding that
• 07:55there was a suppressed neuroimmune
• 07:56response in PTSD,
• 07:59significantly
• 08:00lower
• 08:02magnitude
• 08:03of neuroimmune response to the
• 08:05LPS injection.
• 08:06So the healthy controls are
• 08:08in blue. People with PTSD
• 08:10are in red,
• 08:12significantly suppressed response across these
• 08:14different brain regions.
• 08:16And this also was correlated
• 08:17with clinical outcomes
• 08:20so that the people that
• 08:21had the most suppressed or
• 08:23the most blunted neuroimmune response,
• 08:26had reported the worst anhedonia,
• 08:29anhedonic symptoms.
• 08:31We measured
• 08:32cytokine responses to the LPS.
• 08:36Interestingly, there weren't really very
• 08:38many group differences,
• 08:41except with one exception.
• 08:42And the exception is a
• 08:44g c GM CSF, which
• 08:46is spelled out there.
• 08:48And you can see the
• 08:49blue, control, red, PTSD. There's
• 08:52a much more blunted response
• 08:53in the PTSD group than
• 08:55the control group.
• 08:56And it made sense because
• 08:58this is a cytokine that's
• 08:59important for the initiation of
• 09:01the immune response.
• 09:02So you have sort of
• 09:03a blunted,
• 09:05immune response in the periphery
• 09:06associated with the blunted,
• 09:09response in the brain. And
• 09:10because these were originally
• 09:12unexpected findings, we did a
• 09:14little bit of,
• 09:16digging, and we collaborated with
• 09:18doctor Matt Jurginty, who has
• 09:21post mortem brain tissue,
• 09:23from people with PTSD, from
• 09:25a PTSD brain bank. And
• 09:26so then he can look
• 09:27at some of these same
• 09:28markers that we look at
• 09:30with PEP.
• 09:31And if you look at
• 09:32the pink
• 09:33bar graph, what this is
• 09:35showing is that in
• 09:37people with PTSD, there's a
• 09:39significantly
• 09:40lower expression of TSPO,
• 09:43in PTSD
• 09:44relative to the control group.
• 09:46And this was more apparent
• 09:47in the females in this
• 09:49sample.
• 09:50And the other side shows
• 09:52that he looked at numbers
• 09:54of microglia, and this is
• 09:55dorsal lateral prefrontal cortex,
• 09:58and found that in the
• 09:59PTSD group, there was significantly
• 10:01fewer micro glia, compared to
• 10:03the control group. And so
• 10:04this was just sort of
• 10:05a nice extra confirmation of
• 10:07our finding that what we
• 10:09think we have found is
• 10:10a microglial
• 10:11or a neuroimmune
• 10:13deficit
• 10:14in this,
• 10:15disorder.
• 10:17And and so we think
• 10:19that instead of having this
• 10:20sort of overly activated microglia
• 10:23and neuroinflammation,
• 10:24that over time, the microglia
• 10:26are sort of burning out
• 10:27or becoming dystrophic or senescent.
• 10:30And then when they're in
• 10:31this state, they can't they
• 10:33can't support healthy brain function.
• 10:35They can't support healthy synaptic
• 10:37function or synaptic plasticity,
• 10:39and that this may be
• 10:40contributing to symptom severity or
• 10:42sort of contributing to the
• 10:43maintenance of PTSD.
• 10:45And that changes how we
• 10:46think about treating it because
• 10:47instead of sort of trying
• 10:49to tamp down the inflammation,
• 10:50we wanna think about how
• 10:52can we rescue the deficit.
• 10:54And we're working on some
• 10:56ideas about that. I would
• 10:57be happy to hear if
• 10:58anybody has any ideas as
• 11:00well.
• 11:01And I just wanna highlight
• 11:02the importance of pet, right?
• 11:04Because our hypothesis was based
• 11:05on peripheral findings in people
• 11:08and in from the preclinical
• 11:10literature, and we assumed that
• 11:12that would hold.
• 11:13And I think there's lots
• 11:15of areas,
• 11:16particularly in neuroscience, where a
• 11:17lot of our understanding comes
• 11:18from the preclinical literature.
• 11:21And it's very important to
• 11:22have techniques such as PET
• 11:24where we can translate those
• 11:25findings
• 11:26and measure brain chemistry in
• 11:27people who are living with
• 11:28the disorder that we're interested
• 11:30in treating.
• 11:32There are limitations of the
• 11:34radio tracer that we used.
• 11:36We are working with the
• 11:37Pet Center and lots of
• 11:38other people in the field
• 11:39are working on developing radio
• 11:41tracers,
• 11:42that label different proteins in
• 11:45the neuroimmune system. And so
• 11:46these are just some examples
• 11:48from a review paper of
• 11:50targets that we have tracers
• 11:52for or that we are
• 11:54in develop developing tracers for.
• 11:59We have used these techniques
• 12:01and apply them to other
• 12:02psychiatric disorders,
• 12:04and many other people have
• 12:05used these techniques and apply
• 12:06them to other psychiatric disorders
• 12:08in
• 12:09the department.
• 12:10We have really interesting findings
• 12:11in people with alcohol use
• 12:13disorder, and we have a
• 12:14poster later if you are
• 12:15interested in hearing about that.
• 12:18And then I would just
• 12:19like to thank our funding
• 12:21sources, participants,
• 12:23and these are some of
• 12:24the individuals who really helped
• 12:26lead, the studies that I
• 12:28talked about today.