GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition

Abstract

Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson’s syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.

Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes

“…This emphasises that frontal NAA and glutamate deficits are associated with clinically relevant cognitive impairment, building on earlier correlations with specific neuropsychological tasks. 20 Metabolites with lower loadings on the first canonical correlate were not statistically significant, as estimated by permutation testing, but may still be of interest. For example, myo-inositol, which is concentrated in glia and elevated with neuroinflammation, had a positive loading.…”

“…The hypotheses of this study were based on post mortem neurochemistry and pre-clinical evidence 23,24 , supported by later ultra-high field MRS. 20,25 We predicted an association in all FTLDassociated syndromes between glutamate concentration and clinically relevant carer-and clinicianmeasures of behavioral impairment. Pharmacological correction of such neurochemical deficits might be a tractable target for symptom treatment, especially where these have neurotransmitter functions in addition to metabolic roles.…”

“…Our study has several limitations. First, this study omits to report GABA concentrations, despite preclinical and ultra-high field MRS evidence of GABA deficits in bvFTD and PSP 20,[23][24][25] . This omission is because of the low sensitivity and inadequate spectral resolution for GABA using semi-LASER sequence at 3T.…”

“…The tissue correction method was the same as Murley at et (2020). 20 Factorial analysis of variance (ANOVA) was used to compare nineteen metabolite concentrations across three brain regions and between five groups. Dunnett’s post hoc test was used to explore differences between control participants and the FTLD syndrome subtypes.…”

Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes

“…We suggest that treating behavioural disturbance may delay the need for care home admission, with benefits to individual health and health economics. Potential strategies include restoration of neurotransmitter deficits associated with behavioural change [27][28][29][30] or motor impairment. 31 The relationship between cognitive impairment and prognosis is complex.…”