By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department
of Neurology, Weill Cornell Medical College.
SYNOPSIS: In subjects with a syndrome associated with frontotemporal lobar degeneration, gamma aminobutyric acid and glutamate deficiency in the right inferior frontal gyrus was associated with greater degrees of impulsivity.
SOURCE: Murley AG, Rouse MA, Jones PS, et al. GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition. Brain 2020;143:3449-3462.
Behavioral disturbances such as disinhibition are common manifestations of syndromes associated with frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP). These behavioral symptoms not only are distressing to caregivers, but also are associated with increased loss of functional independence and increased mortality. Because there are no specific treatments for these behavioral symptoms, elucidating the underlying mechanisms is necessary to develop targeted therapies.
Previous studies, mainly in animal models, and postmortem human studies have found evidence for deficiency in gamma aminobutyric acid (GABA) and glutamate signaling in FTLD. However, there is limited evidence relating these neurotransmitters with the behavioral phenotype. Therefore, Murley et al examined whether changes in GABA and glutamate are seen in FTLD and whether changes in these neurotransmitters are associated with greater impulsivity.
Forty-four patients with FTLD carrying a clinical diagnosis of bvFTD or PSP (either PSP-Richard’s syndrome or PSP-Frontal syndrome) were recruited from the Cambridge Centre for Frontotemporal Dementia, Cambridge Centre for Parkinson-Plus, and the “Join Dementia Research” patient register. The researchers recruited 20 age- and sex-matched subjects with no history of a neurological or psychiatric illness as controls. All subjects underwent cognitive and neuropsychological assessments.
To measure impulsivity or response inhibition, a stop-signal type response inhibition task was used. To measure GABA and glutamate concentrations in the brain in vivo, all subjects underwent scanning with 7T 1H-magnetic resonance spectroscopy (MRS) targeting the right inferior frontal gyrus as the experimental region of interest and the right occipital lobe as a negative control. To compare gray and white matter volumes, voxel-based morphometry was conducted on T1-weighted MP2RAGE structural sequences.
Compared to control subjects, FTLD subjects had, as expected, reduced gray matter volumes in frontal lobes, including the right inferior frontal gyrus, temporal lobes, basal ganglia, thalamus, and cerebellum, with relative preservation in the occipital lobe. For the neurotransmitters, after correcting for age, sex, and partial volume, GABA concentrations were significantly reduced in the right inferior frontal gyrus but not the right occipital lobe in FTLD subjects, while glutamate concentrations were similar in both brain regions. For the behavior task, compared to control subjects, FTLD subjects exhibited greater impulsivity in the stop-signal reaction time, with nine FTLD subjects unable to complete the task. Finally, both glutamate and GABA concentrations in the right inferior frontal gyrus in FTLD subjects were inversely correlated with the stop-signal reaction time, which is consistent with loss of these neurotransmitters being associated with greater impulsivity or disinhibition.
COMMENTARY
A major strength of this study is the use of in vivo imaging to measure two neurotransmitters, glutamate and GABA, in the same individual and to correlate these neurotransmitters to a measure of impulsivity or disinhibition. The study results were consistent with earlier animal and postmortem human studies that found deficiencies in GABA and glutamate signaling in FTLD. Collectively, these studies suggest that restoration of GABA and glutamate signaling could improve behavioral symptoms in patients with FTLD.
However, the study had several limitations, including a relatively small study population, combining two potentially distinct diseases (bvFTD and PSP) as one FTLD group, and a relatively high number of FTLD subjects (nine, or 20% of total recruited) excluded from final analysis for being unable to complete the behavior task. Additionally, the MRS was restricted to prespecified regions of interest.
Although investigating the right inferior frontal gyrus was reasonable, other brain regions pertinent to the behavioral symptoms in FTLD may be involved. It is not clear if deficits in GABA and glutamate would be seen in other brain regions or if this is specific to the right inferior frontal gyrus. Classically, GABA is an inhibitory neurotransmitter, while glutamate is an excitatory neurotransmitter. At first glance, it would seem odd that deficiency in both an excitatory and inhibitory neurotransmitter in the same brain region would contribute to the same phenotype. Importantly, as the findings are correlative, GABA and glutamate deficiencies may not be the underlying culprit for the behavioral symptoms and instead simply may reflect neurodegeneration or loss of cells synthesizing or releasing these neurotransmitters in this brain region.
To determine any causative role for GABA and glutamate deficiency, longitudinal clinical studies and mechanistic studies in animal models would be essential. Furthermore, as mentioned by the study investigators, it may be too simplistic to assume that these are the only neurotransmitters involved, and others in this or other brain regions are likely to contribute to the behavioral phenotype.
Despite these limitations, this study lays the foundation for future studies that combine MRS with behavior or cognitive testing. By conducting similar studies in patients with neurodegenerative or other brain disorders, new insights into the relationship between neurotransmitters and the clinical phenotypes could be gained. This could lead to the future development of targeted therapies that ameliorate specific behavior impairment or cognitive deficits by restoring key neurotransmitter signaling in these disorders.
