Neurotransmitter deficits from frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration causes a spectrum of complex degenerative disorders including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, each of which is associated with changes in the principal neurotransmitter systems. We review the evidence for these neurochemical changes and propose that they contribute to symptomatology of frontotemporal lobar degeneration, over and above neuronal loss and atrophy. Despite the development of disease-modifying therapies, aiming to slow neuropathological progression, it remains important to advance symptomatic treatments to reduce the disease burden and improve patients' and carers' quality of life. We propose that targeting the selective deficiencies in neurotransmitter systems, including dopamine, noradrenaline, serotonin, acetylcholine, glutamate and gamma-aminobutyric acid is an important strategy towards this goal. We summarize the current evidence-base for pharmacological treatments and suggest strategies to improve the development of new, effective pharmacological treatments.

Figure 1

Dopamine deficits in FTD. (A) Schematic illustration of dopaminergic pathways. (B) Ioflupane SPECT scan showing loss of pre-synaptic dopaminergic neurons in the striatum of FTD compared with normal scan. (C) Loss of dopaminergic neurons in the putamen (measured by ¹¹C-CFT-PET) correlates with severity of extra-pyramidal motor symptoms (Unified Parkinson’s Disease Rating Scale motor score). From Rinne et al. (2002). Reprinted with permission from Wolter Kluwer. (D) Dopamine levels are reduced in the caudate, putamen and globus pallidus. Graph of data from Kanazawa et al. (1988). Reprinted with permission from Elsevier. (E) There is loss of D2 dopamine receptors in the frontal lobes (as measured by ¹²³I-IBZM-PET). Graph of data from Frisoni et al. (1994). Reprinted with permission from Elsevier. (F) CSF DOPAC levels (3,4-dihydroxyphenylacetic acid, a dopamine metabolite) correlate with behavioural disturbance. From Engelborghs et al. (2008). Reprinted with permission from Elsevier.

Figure 2

Dopamine deficits in PSP and CBS. (A) Ioflupane SPECT scan showing reduced pre-synaptic dopaminergic neurons in the striatum of PSP and CBS compared to a normal scan. (B) Post-mortem dopamine receptor levels (measured by spiperone binding) are reduced in the frontal cortex in PSP. Graph of data from Ruberg et al. (1985). Reprinted with permission from Wiley. (C) Dopamine levels are reduced in the caudate nucleus and putamen in PSP. Graph of data from Ruberg et al. (1985). (D) D2 dopamine receptor levels (measured by ¹²³I-iodobenzofuran SPECT) are reduced in the striatum of PSP when compared with healthy controls and Parkinson’s disease. From Oyanagi (2002). Reprinted with permission from Wiley.

Figure 3

Noradrenergic deficits in FTD and PSP. (A) Schematic illustration of noradrenergic pathways. (B) MHPG/noradrenaline ratios, indicative of catabolic noradrenergic turnover, are reduced in Brodmann areas 11, 22, 24 and 46 in FTD. From Vermeiren et al. (2016). Reprinted with permission from the authors and IOS Press. The publication is available at IOS Press through http://dx.doi.org/10.3233/JAD-160320. (C) Post-mortem brainstem tissue from control and PSP brains. There is a paler locus coeruleus suggesting loss of melatonin-containing noradrenergic neurons. Courtesy of Kieran Allison, Cambridge Brain Bank. (D) Noradrenaline levels are reduced in the caudate (CN), putamen (PUT), hippocampus (HTH) and parolfactory cortex (PAROLF). Serotonin levels are reduced in those areas as well as in the subthalamic nucleus (SN). Dopamine levels are reduced in those areas as well as the globus pallidus externa (GPe) and interna (GPi). From Hornykiewicz and Shannak (1994). Reprinted with permission from Springer.

Figure 4

Serotonergic deficits in FTD and PSP. (A) Schematic illustration of serotonin pathways. (B) 5-HT1 and 2A receptor density is reduced in the frontal and temporal lobe in FTD. Graph of data from Bowen et al. (2008). Reprinted with permission of the authors and Springer. (C) Effect of 5-HTTLPR genotype on brain perfusion in FTD patients. Comparison of long (L/L) versus short (S/S) carriers at the same disease stage showing reduced perfusion of some areas of the frontal lobe in L/L carriers. From Premi et al. (2015). Reprinted with permission from Elsevier. (D) Presynaptic serotonergic neurons (measured by citalopram binding to post-mortem tissue) are reduced in the frontal and insular cortices in PSP. Graph of data from Chinaclia and Landwehrmeyer (1993). Reprinted with permission from Elsevier. (E) 5-HT2A receptor PET binding is increased bilaterally in the striatum and substantia nigra compared with controls. In the same study (F) disease severity positively correlated with 5-HT2A binding potential in the striatum. From Stamelou et al. (2009). Reprinted with permission from Wiley.

Figure 5

Cholinergic deficits in FTD, PSP and CBS. (A) Schematic illustration of cholinergic pathways. (B and C) ¹¹C-MP4A PET, a measure of acetylcholinesterase activity, in healthy controls, CBS, PSP and FTD. Cortical k₃ (a measure of PET ligand binding) is reduced in CBS and PSP but not FTD. Thalamic mean k₃ is reduced in PSP but not CBS or FTD. From Hirano et al. (2010). Reprinted with permission from Oxford University Press. (D) Quantitative estimation of choline acetyltransferase (ChAT) positivity rate (%) in the nucleus basalis of Meynert (nBM), laterodorsal tegmental (LdtgN) and pedunculopontine tegmental (PptgN) nuclei. From Kasashima and Oda (2003). Reprinted with permission of Springer. (E) SPECT of acetylcholine transporter. MNI = MRI template; HS = healthy subject. Specific binding in the striatum, thalamus and pedunculopontine nucleus extracted by subtracting reference from region of interest binding. Binding is lower in the thalamus and pedunculopontine nucleus. From Mazere et al. (2012). Reproduced with permission from the Radiological Society of North America. (F) Autoradiogram of brain tissue from a healthy control (NC) and PSP. ³H-vesamicol binding to acetylcholine transporter (VAChT). There is reduction in binding in the putamen (Put) and substantia nigra pars compacta (SNc). Rn = red nucleus. Image intensity converted to pseudocolour representation according to key. From Suzuki et al. (2002). Reproduced with permission from Wolters Kluwer.

Figure 6

Glutamate and GABA deficits in FTD and PSP. (A) Mean metabolite concentrations using magnetic resonance spectroscopy. Glutamine–glutamate concentrations are reduced in the frontal cortex of FTD. Graph of data from Ernst et al. (1997). Reprinted with permission from the authors and the Radiological Society of North America. (B) Post-mortem glutamatergic receptor binding in FTD. Binding to NMDA and AMPA receptors is reduced in the frontal and temporal lobes. From Procter et al. (1999). Reprinted with permission from S. Karger AG. (C) Neuron number in two thalamic nuclei [parafascicular (Pf) and centromedian (CM)] that contain glutamatergic neurons is reduced in PSP compared with controls. Adapted from Henderson et al. (2000), with permission from the authors and Oxford University Press. (D) Numbers of GABAergic neurons (measured by glutamic acid decarboxylase mRNA expression) in the striatum and pallidum in controls and PSP patients. There is significant reduction in striatal GABAergic neurons in patients. Graph of data from Levy et al. (1995), reprinted with permission from the authors and Wolters Kluwer. (E) Calbindin immunohistochemistry of GABAergic cells in the frontal cortex of FTD and control brains. From Ferrer (1999). Reproduced with permission from Karger. (F) ¹¹C-flumazenil PET binding to benzodiazepine receptors in healthy controls (N), PSP and the group difference in cortical and subcortical areas. From Foster et al. (2000). Reproduced with permission from Wolters Kluwer.