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Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioral variant frontotemporal dementia, 10 progressive supranuclear palsy) and 20 healthy age- and gender- matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10mg memantine, an uncompetitive NMDA-receptor antagonist. Ultrahigh-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. There was no overall effect of memantine on the magnitude of the mismatch negativity response in right frontotemporal cortex in patients, or controls. However, the change in right auditory cortex response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration, or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline-dependency in pharmacological restoration of neurotransmitter deficits, to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

My ABN fellowship focusses on the syndromes caused by frontotemporal lobar degeneration. Despite distinctive pathological causes, these highly heterogeneous syndromes overlap in clinical manifesta- tions and pathophysiology. This is both a challenge and an opportunity for future trials aimed at slowing the diseases or treating their symptoms. By modelling phenotypic data and long-term outcomes, I will determine the features of blood, brain and behaviour that predict survival. The “PIck’s disease and Pro- gressive supranuclear palsy Prevalence and INcidence” study (PiPPIN), has 440 participants from previous recruitment phases, of whom 318 have died. I have recruited 91 from an expected 220-250 patients in this 3rd phase. My initial analysis of existing samples will test the hypothesis that metabolic signatures dif- ferentiate disorders (PSP, FTD, controls). Preliminary results from N=269 samples confirm multiple metabolic differences between patients and controls, focussing within the lipid pathways. This will be analysed in relation to clinical severity, phenotype, and survival outcomes. Subsequent analysis will integrate cognitive/behavioural profiles, magnetic resonance imaging and spectroscopy, and blood biomarkers (including metabolites) in multivariate models of survival. Prediction of survival does not indicate causation but will generate hypotheses of promising targets for intervention and tools for risk-based stratification.