Using Neuroimaging to Identify Novel Molecular Targets Implicated in Depression
April 11, 2022ID7688
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- 00:00Thanks for the introduction and thank
- 00:03you for inviting me to give this talk.
- 00:07My funding consists of for this
- 00:09particular set of studies and
- 00:11Nancy Taylor Foundation. The
- 00:16A&NAHI don't have conflicts of interest to
- 00:19disclose in relationship to these studies.
- 00:21These are all the people that participated
- 00:23in the work that I will show you with
- 00:26the integral person being the late Ron
- 00:29Duman who really motivated his work,
- 00:32motivated the studies that we're going
- 00:35to see now, and so the reason why I
- 00:38study depression is that about 1/5
- 00:41of the US population suffers from
- 00:43mood disorders in their lifetime.
- 00:45However, it takes weeks to months for
- 00:48the currently available treatments
- 00:49to exert their.
- 00:51Benefits and sometimes these treatments
- 00:52don't work and so it's 6 to 8 weeks later
- 00:55the clinician has to find a different
- 00:57treatment and then a different treatment,
- 01:00and so on and so forth.
- 01:01And so our goal is to identify novel
- 01:04targets that can be modified to
- 01:07lead to significant improvement in
- 01:09symptoms and significant improvements.
- 01:11About 50% improvement in
- 01:14depressive symptomatology.
- 01:16And so when I saw friend Dunham's work,
- 01:19I really wanted to follow up with synaptic
- 01:23density imaging and what Ron and George
- 01:26Organian showed was that in a animal.
- 01:29That is typical.
- 01:30They have normal number of synapses,
- 01:33synaptic spines and buttons.
- 01:35However,
- 01:35an animal that was stressed for
- 01:3821 days that you can see synaptic
- 01:42density loss pretty quickly.
- 01:45And so in human,
- 01:46the studies using electron microscopy is
- 01:49just showed you before are not possible
- 01:52because that's in postmortem tissue.
- 01:54But we can use MRI imaging to show us
- 01:57changes and volumes and connectivity
- 02:00in relationship to depression.
- 02:02And this was done in collaboration with
- 02:04Amar Center with Dustin Scheinost.
- 02:06And but there are many studies showing
- 02:08similar results and specifically
- 02:10changes in prefrontal cortical
- 02:12regions that are involved in emotional
- 02:16regulation cognitive changes.
- 02:18And so,
- 02:19in order to do this in human and vivo,
- 02:22about six or seven years ago,
- 02:25a radiolucent was developed to target SV 2,
- 02:28which is a synaptica circle glycoprotein,
- 02:32with SV2A being the most widely
- 02:34expressed and being the target
- 02:37of validated antiepileptic drugs.
- 02:39And so that's how the radio ligament
- 02:42was developed.
- 02:43And so we did our validation studies
- 02:46and have baboons showing that as
- 02:48compared to Sunopta Faizan,
- 02:50which is another protein that is
- 02:52typically used as a proxy for
- 02:55quantifying synaptic density in the brain.
- 02:58SV 2A is even more specific and is
- 03:00compared to housekeeping protein.
- 03:02We showed that SVQ a specific
- 03:05program matter regions.
- 03:07Correlation between synaptophysin
- 03:08and SNAP and SV2A was great and
- 03:11so was deemed at this radio.
- 03:13Ligament is a valid alternative
- 03:16to studying synaptophysin.
- 03:18I mean just studying synaptic
- 03:20density and thus we can potentially
- 03:22conduct studies in vivo.
- 03:24And so the first studies were
- 03:26done in animal models.
- 03:27And in the baboon that we showed you before,
- 03:30and then we moved into human.
- 03:33And so short friend of mine,
- 03:34Rich Carson,
- 03:35and a lot of people that yelled
- 03:37pet center did a lot of studies
- 03:39to show that we can quantify this
- 03:42radioligand in vivo using one
- 03:44tissue compartment modeling.
- 03:45And at this radio ligament
- 03:47house about a 5% test retest.
- 03:49So every time that we bring up
- 03:51a new radio ligand and human,
- 03:53we do studies where we scan people.
- 03:56We give them a break and we scan them again.
- 03:58And usually test retest is about 10 to 15%.
- 04:02This radioligand shows test
- 04:04retest of 5% across brain regions,
- 04:07which means that we can quantify
- 04:10even small differences in the
- 04:12brain and they will be meaningful.
- 04:15And so we conducted the first first
- 04:17evaluation and stress disorders
- 04:19who have people who are healthy,
- 04:21controls people with both severity,
- 04:23depression and people with moderate
- 04:25to high severity depression.
- 04:27And we show that as compared to
- 04:29controls in Gray and to severity
- 04:32groups in green individuals with
- 04:34high severity and blue here have
- 04:37markedly lower synaptic density
- 04:39across cortical limbic circuit.
- 04:41And here we see a figure on top is.
- 04:45Healthy controls in the middle
- 04:46are low severity groups.
- 04:48You can see that they have a lot of red,
- 04:51orange,
- 04:52yellow areas which are areas
- 04:53of high density of whatever it
- 04:56is that we're studying.
- 04:57In this case and optic density we can
- 05:00see that in the high severity group
- 05:02in the bottom we don't have many red,
- 05:04orange, yellow area,
- 05:06suggesting markedly lower synaptic density.
- 05:09And not surprisingly,
- 05:11when we evaluated depressive
- 05:13symptomatology using MD,
- 05:15we see that individuals with
- 05:17high depressive symptoms have
- 05:19markedly lower synaptic density.
- 05:22And so then we followed up with the terms
- 05:24of connectivity distribution using MRI.
- 05:27And we see that our prefrontal
- 05:29cortical region was region implicated
- 05:31the most in the clinical group,
- 05:34and so then we used.
- 05:35We looked at network dysfunction
- 05:38in individuals with depression,
- 05:39and we see that the prefrontal
- 05:42cortical regions were implicated
- 05:44as in connectivity to the posterior
- 05:47cingulate cortex.
- 05:48And this is the first time we're
- 05:51showing in vivo that synaptic density
- 05:55alterations subserve the disconnection
- 05:57in the DLPFC versus PC connectivity,
- 06:01and that this connectivity is
- 06:04related to symptom severity,
- 06:06so this has never been shown
- 06:07in a human before,
- 06:08and it's an example of how the imaging
- 06:12modalities at Yale can be used.
- 06:14We also examined cognitive functioning,
- 06:16of course,
- 06:17and we see that synaptic density
- 06:20alterations subserve some of the cognitive
- 06:23deficits that are exhibited in depression,
- 06:25specifically in memory and
- 06:28associated MRI findings,
- 06:30to memory impairments as well.
- 06:34And so,
- 06:35of course it's great to find and publish
- 06:38on deficits that we can replicate in
- 06:41human that are similar to animal work.
- 06:44But can this be a target to actually
- 06:47treat people and provide them relief?
- 06:49And so a drug that would chose
- 06:51to test was ketamine,
- 06:53which is in the NMDA antagonist,
- 06:55and as all of you I'm sure know,
- 06:57provides rapid antidepressant relief.
- 06:59And an animal work again showed by Ron
- 07:02Duman and Georgia Virginian and husband.
- 07:05Replicated by others,
- 07:06shows that one administration
- 07:08of ketamine 24 hours after
- 07:10administration or the time of
- 07:12greatest entity present response.
- 07:15So synaptic restoration and these
- 07:17animals who were stressed or
- 07:19as I call it, synaptogenesis.
- 07:21And so in human this is hard to show and
- 07:25previously has been shown by Amar imaging.
- 07:29So chatty. Madala did a study showing
- 07:31that before Academy there were
- 07:33deficits in individuals with MDD after
- 07:36administration of deficit of ketamine.
- 07:38Functional connectivity deficits were
- 07:40restored in individuals with MDD,
- 07:43but what are some of the targets that
- 07:45we can use to restore these deficits?
- 07:48Well, we think we can target synaptic
- 07:51density by measuring SV2A and I
- 07:54had asked Ron to see if we can
- 07:57measure synaptic density increases.
- 07:59Via measuring SV2 after administration
- 08:02of ketamine as well as novator compound
- 08:05which works a little bit differently and
- 08:08so Ron showed that administration of
- 08:11ketamine leads to significant increases
- 08:13in SV2A density that were comparable
- 08:16to other pre and post synaptic proteins,
- 08:19and so we can do this work and human
- 08:22and so we imaged individuals who
- 08:24are controls at the top and blue
- 08:26and individuals and Coco group.
- 08:28And as you can see we did not observe change.
- 08:30In synaptic density.
- 08:3424 hours after ketamine administration.
- 08:38However, when we looked
- 08:40at the clinical group.
- 08:42In terms of their synaptic numbers,
- 08:46so we compared to healthy controls in
- 08:49green versus normal synaptic density
- 08:52group that was depressed in blue and
- 08:55the synaptic deficit group in red.
- 08:58We see that.
- 08:59Individuals in the synaptic deficit groups
- 09:02show significant synaptogenesis after
- 09:04administration of ketamine 24 hours later.
- 09:07Importantly, the synaptogenesis
- 09:09was associated with symptom relief,
- 09:12so we're showing that
- 09:13it is not only synaptic.
- 09:16Density improvements are important
- 09:18in individuals with depression
- 09:20in terms of brain restoration,
- 09:22but also in terms of antidepressant response,
- 09:25and this is very clear from this picture,
- 09:27with a lot more red, orange, yellow areas.
- 09:30Portraying higher synaptic density
- 09:33after administration of ketamine.
- 09:35And so, to conclude,
- 09:36we showed first in vivo evidence of
- 09:39synaptic alterations and depression,
- 09:41and we're showing that the synaptic
- 09:43alteration is observing the
- 09:45functional connectivity changes that
- 09:47have been previously published.
- 09:49And the cognitive deficits that
- 09:50have been shown in depression before
- 09:53we're seeing association between
- 09:55synaptogenesis and depression relief.
- 09:57However,
- 09:57I do want to point out that the
- 09:59study was small and so larger
- 10:01studies need to be conducted.
- 10:02And thank you so much for your attention.