Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

Florian Mainberger, Nikolai H Jung, Martin Zenker, Ute Wahlländer, Leonie Freudenberg, Susanne Langer, Steffen Berweck, Tobias Winkler, Andreas Straube, Florian Heinen, Sofia Granström, Victor-Felix Mautner, Karen Lidzba, Volker Mall, Florian Mainberger, Nikolai H Jung, Martin Zenker, Ute Wahlländer, Leonie Freudenberg, Susanne Langer, Steffen Berweck, Tobias Winkler, Andreas Straube, Florian Heinen, Sofia Granström, Victor-Felix Mautner, Karen Lidzba, Volker Mall

Abstract

Background: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin.

Methods: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed.

Results: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness.

Conclusions: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

Figures

Figure 1
Figure 1
Synaptic plasticity in patients with NF1 and controls. A) Depicted is the time course of MEP amplitudes after PAS in healthy controls and patients with NF1. PAS led to a significant MEP increase only in the control group. Abscissa pictures point in time and ordinate mean MEP amplitude. Asterisks indicate significant differences between two groups or points in time (p < 0.05, unpaired t test), error bars represent ± standard error of the mean. B) MEP amplitudes from two representative subjects of controls and NF1before and at POST 1 after PAS. Shown are averages of 20 MEP trials in each case.
Figure 2
Figure 2
SICI in healthy controls and patients with NF1 in on/off medication. Depicted are data of 10 patients of NF1 and healthy controls in on/off medication. Mean inhibition at 60% resting motor threshold (for more details see methods) of the conditioning stimulus was built for ISI of 2, 3, 5 ms and over all ISI. Here, a trend towards increased inhibition in patients with NF1 (treated with placebo but not with lovastatin) compared to healthy controls can be observed. Error bars represent ± standard error of the mean.
Figure 3
Figure 3
Reaction times of TAP in healthy controls and patients with NF1. Data of 10 patients with NF1 and healthy controls are plotted for Alertness, Go/NoGo, Visual Scanning and Incompatibility. Here patients with NF1 (treated with placebo but not with lovastatin) scored in lower ranges than healthy controls. The significance was set at a level of p < 0.05 and error bars represent ± standard error of the mean. Alertness: –WT (without warning tone), +WT (with warning tone); Visual Scanning: CS (critical stimulus), nCS (non critical stimulus); Incompartibility: CC (critical condition), nCC (non critical condition).
Figure 4
Figure 4
Time course of MEP amplitudes of patients with NF1 after PAS with and without lovastatin. A) Shown are data from the NF1 patients (n = 11). Abscissa depicts point in time and ordinate mean MEP amplitude. Administration of lovastatin 4 days before PAS led to a rescue of motor cortex plasticity in patients. Asterisks indicate significant differences between the two drug conditions (p < 0.05, paired t test) and error bars represent ± standard error of the mean. B) MEP amplitudes from one representative subject for placebo and lovastatin condition before and at POST 1 after PAS. Shown are averages of 20 MEP trials in each case.
Figure 5
Figure 5
Reaction times of TAP in patients with NF1 with placebo or lovastatin medication. Data of 10 patients with NF1 are plotted for Alertness, Go/NoGo, Visual Scanning and Incompatibility. For phasic alertness and Incompatibility (KB) patients with NF1 (treated with lovastatin) scored in lower ranges than patients treated with placebo. The significance was set at a level of p < 0.05 and error bars represent ± standard error of the mean. Alertness: –WT (without warning tone), +WT (with warning tone); Visual Scanning: CS (critical stimulus), nCS (non critical stimulus); Incompartibility: CC (critical condition), nCC (non critical condition).
Figure 6
Figure 6
Timeline of PAS experiment. We measured motor evoked potentials (MEP) amplitudes as well as resting motor threshold before and at three points in time after paired associative stimulation (PAS). PAS was performed with an interstimulus interval of 25 ms.

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