Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration—Insights into disease mechanisms and current therapeutic approaches

Abstract

Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of fatal neurodegenerative diseases and, to date, no validated diagnostic or prognostic biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. Current treatment strategies rely on the off-label use of medications for symptomatic treatment. Changes in several neurotransmitter systems including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems have been reported in FTLD spectrum disease patients. Many FTLD-related clinical and neuropsychiatric symptoms such as aggressive and compulsive behaviour, agitation, as well as altered eating habits and hyperorality can be explained by disturbances in these neurotransmitter systems, suggesting that their targeting might possibly offer new therapeutic options for treating patients with FTLD. This review summarizes the present knowledge on neurotransmitter system deficits and synaptic dysfunction in model systems and patients harbouring the most common genetic causes of FTLD, the hexanucleotide repeat expansion in C9orf72 and mutations in the granulin (GRN) and microtubule-associated protein tau (MAPT) genes. We also describe the current pharmacological treatment options for FLTD that target different neurotransmitter systems.

Relationship of serum beta‐synuclein with blood biomarkers and brain atrophy

“…Synaptic alterations have also been observed in other types of dementia including syndromes of the frontotemporal lobar degeneration (FTLD) spectrum of diseases ). 5 Fluid biomarkers offer the opportunity to characterize synaptic alterations in patients during the lifetime, are capable of uncovering differences between neurological diseases, and can be measured longitudinally to mirror the neuropathology and pathophysiology. They are also in the center of interest to support clinical (differential) diagnosis and to evaluate treatment effects in clinical trials.…”

“…Synaptic degeneration is an early hallmark of Alzheimer's disease (AD), 4 the most common form of dementia. Synaptic alterations have also been observed in other types of dementia including syndromes of the frontotemporal lobar degeneration (FTLD) spectrum of diseases (i.e., behavioral variant frontotemporal dementia [bvFTD], semantic variant of primary progressive aphasia [svPPA], non‐fluent variant of PPA [nfvPPA], progressive supranuclear palsy [PSP], and corticobasal syndrome [CBS]) 5 . Fluid biomarkers offer the opportunity to characterize synaptic alterations in patients during the lifetime, are capable of uncovering differences between neurological diseases, and can be measured longitudinally to mirror the neuropathology and pathophysiology.…”

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

“…Indeed, cortical sensory areas in the mismatch network have previously been implicated in bvFTD [ 9 , 10 ], Schizophrenia [ 9 , 10 ] and are sensitive to modulation by other drugs used to treat dementia [ 16 ]. A potential approach for a priori selection of regions for outcome variables is to use the information on neurotransmitter receptor distributions across the cortex [ 103 ], derived, for example, from PET receptor maps [ 104 ] or a transcriptomic atlas. Regions preferentially targeted by the drug are most likely to show drug-induced changes and perhaps even exhibit within-patient heterogeneity.…”

Wszystko na swoim miejscu – rola receptorów VPS10P w komórkowej segregacji białek

“…frontotemporal lobar degeneration, FTLD) to ogólna nazwa zespołu chorób neurodegeneracyjnych, związanych z postępującą atrofią płatów czołowych i skroniowych, prowadzących do powstania drastycznych zmian osobowości oraz postępujących zaburzeń mowy. FTLD uważa się za drugą, tuż po AD, najpowszechniejszą przyczynę demencji u osób między 45 a 60 rokiem życia, przy czym około 40% przypadków ma podłoże genetyczne [94][95][96]. Postępująca podczas rozwoju choroby neurodegeneracja w wielu przypadkach spowodowana jest mutacjami w genie GRN kodującym progranulinę [97][98][99].…”