Predicting Treatment Response to Memantine in Autism Using Magnetic Resonance Spectroscopy

Background and Rationale

Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental disorder
characterized by early childhood onset of marked deficiencies in social and communication
skills and presence of restrictive, repetitive behaviors. Its phenotypic heterogeneity makes
studying ASD and its treatment a challenging task. Currently, only two FDA approved drugs,
risperidone and aripiprazole, are available to treat ASD that manage irritability associated
with the disorder. None have shown conclusive benefit for core features of social and
communication deficits.

Research indicates that a disrupted balance between excitation (glutamate) and inhibition
(gamma amino-butyric acid, GABA) is likely to be one of the underlying mechanisms of ASD.
This hypothesis is supported by a number of magnetic resonance spectroscopy studies that
report an excess of glutamatergic excitation and/or a reduction in GABAergic inhibition
observed in different brain regions including the limbic system and the anterior cingulate
cortex. Similar findings have also been reported in post mortem studies of the ASD
brain.Thus, it is expected that drugs targeting this imbalance could be beneficial. For
example, the GABAB agonist, arbaclofen, was tested in ASD for this reason and showed
promising results but a large trial failed to show improvement on the primary endpoints of
lethargy and social withdrawal.

Memantine, a moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, is known to
improve communication in patients with Alzheimer's disease and is an FDA approved treatment
for that disease. Examination of the efficacy of memantine in treating ASD has also been
driven by the excitatory (glutamate) - inhibitory (gamma amino-butyric acid, GABA) imbalance
hypothesis of ASD pathology. Memantine binds to the glutamatergic NMDA receptors and
attenuates glutamatergic excitation. This reduction in excessive glutamatergic activation is
thought to decrease the "noise" in the neural network system and facilitate learning and
memory. A few small studies have shown effectiveness for memantine in the treatment of social
and communication aspects of ASD spectrum disorder (ASD) as well. However, one large clinical
trial using memantine in ASD reported a failure to respond. These discrepancies in results
could possibly be due to the heterogeneity in the excitatory-inhibitory imbalance between ASD
patients thereby causing a variation in response. In such a scenario, having a biomarker to
predict an individual's treatment response would be invaluable.

MR Spectroscopy is a non-invasive tool used to examine the biochemical profile of brain
tissue associated with different psychiatric and neurological conditions including ASD.
Specifically, 1H-MRS studies in ASD demonstrated the excitatory-inhibitory imbalance in
various cortical and subcortical regions of the brain, a finding also reported in post mortem
brain tissue studies. The use of this technique to determine if Glutamate/GABA concentrations
in certain regions of the brain can predict response to treatment with memantine would be an
innovative breakthrough in providing more effective individualized treatment for patients
since very little research has been done to explore this possibility.

A similar approach has been adopted in a recent ongoing study that uses proton MR
spectroscopy to map changes in glutamate and GABA following use of riluzole in ASD. Riluzole
is a drug commonly used in amyotrophic lateral sclerosis (ALS) and is a glutamate antagonist
that works by blocking presynaptic glutamate release and noncompetitive inhibition of NMDA
receptors. However, riluzole is not clinically used in the treatment of ASD. To our
knowledge, only one study so far (apart from the ongoing study mentioned) has examined the
effects of riluzole in ASD, but as an adjunct to risperidone. The primary outcomes of the
Ghaleiha et al. study were irritability and repetitive motor behaviors and not core social
and communication deficits as in the present proposal. The purpose of riluzole in this MR
spectroscopy study is a proof of principle for its effects on spectroscopy based on its
glutamate antagonistic effects. By contrast, memantine, which will be studied in the present
proposal, has some documented evidence from small studies of being beneficial in treating
social and communication deficits associated with ASD in clinical settings, despite the
failure of the larger trial.

The investigator's lab has previously utilized MR spectroscopy techniques to map these
different compounds in a group of 14 subjects with ASD and identify glutamate and GABA
alterations in the cerebellum, discovering a relationship to cerebrocerebellar connectivity
and behavioral outcomes in individuals with ASD.

Specific Aims:

Specific Aim 1: The investigator proposes a pilot, exploratory, clinical follow-on study
using proton magnetic resonance spectroscopy (1H-MRS) to examine whether the following
measures can be used to predict treatment response to memantine in ASD:

1. Glx and/or GABA and the Glx/GABA ratio in the anterior cingulate cortex,

2. Glx levels in the dorsolateral prefrontal cortex and the cerebellum

3. Markers of neuronal integrity, N-acetyl aspartate (NAA), myo-inositol, choline and
creatine/phosphocreatine levels in the anterior cingulate, dorsolateral prefrontal
cortex and cerebellum

Specific Aim 2: To examine whether resting state functional connectivity between the
dorsolateral prefrontal cortex, anterior cingulate and the cerebellum, holds predictive value
for treatment response to memantine in ASD.

The anterior cingulate cortex, dorsolateral prefrontal cortex and the cerebellum have been
have been chosen as regions of interest (ROIs) due to known atypical glutamate and GABAergic
profiles in these regions associated with ASD. The approach of limiting to selected ROIs has
been adopted in order to ensure patient comfort during the imaging process by reducing the
time spent in the scanner. Since altered levels for markers of neuronal integrity, such as
NAA, choline, creatine/phosphocreatine and myoinositol have also been reported in ASD, we
will be mapping these biochemicals as well in order to explore their effect on treatment
response. Resting state functional connectivity will also be analyzed for possible
association with treatment outcome prediction since as mentioned before, a previous study
from the investigator's has shown a link between alterations in resting state
cerebrocerebellar connectivity, excitatory-inhibitory ratio in the cerebellum and behavioral
outcome in ASD using MR spectroscopy.

Inclusion Criteria:

- Potential participants will be asked to take part in this study because he/she:

1. has autism spectrum disorder

2. is starting memantine off label for managing their autism symptoms

3. is deemed safe to enter the MR environment using the attached screening form, and

4. is capable of lying still for approximately 1.5 hour.

Exclusion Criteria:

- Subjects would be excluded if:

1. they have certain types of metallic implants, risk of exposure to metallic
foreign bodies, pacemakers, magnetically sensitive implants that cannot be
removed or are not securely attached,

2. pregnancy

3. claustrophobia

4. memantine intolerance

5. known hypersensitivity to memantine hydrochloride or

6. inability to lie still for approximately 90 minutes.