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    • noradrenaline This study has highlighted the complexity of o

    2018-10-30

    This study has highlighted the complexity of operationally defining compensation in neurodegenerative diseases such as HD. The previous literature in HD has thus far failed to address this issue, instead making assumptions of putative compensation based solely on increased activation or connectivity in high disease load groups compared to those with lower levels of disease or healthy controls and typically did not include performance level (Scheller et al., 2014). We cannot therefore differentiate between functional changes that are due to HD pathology and those that represent compensatory behavior. Here, we explicitly modeled the interaction between fMRI signals and structural disease load as a predictor of cognitive and motor performances taking into account both variability in structural disease load and performance. By explicitly considering the joint relationships between noradrenaline function, task performance and structural disease load, we have identified regions in which increased brain activity (or connectivity) in those closer to onset is associated with preserved performance. We contend that relatively preserved performance is an additional necessary component for demonstrations of neuronal compensation. This is a new study of neurodegenerative disease that has explicitly characterized and measured neural compensation using fMRI in combination with structural measures of disease load and markers of task performance. Despite the exploratory nature of our findings, they may have mechanistic implications for the future planned testing of potential disease modifying agents in the presymptomatic phases of neurodegenerative diseases such as HD, where it may be important to monitor for preservation of compensatory activity and connectivity.
    Role of the Funding Source This work was funded by the CHDI Foundation (TrackOn_RecID_A-4738), the Wellcome Trust (100227) (GR), and the Medical Research Council (MR/L012936/1) (SJT, MP). and supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). The main study sponsor (CHDI_Foundation) contributed to the conception of the study and the study design but was not responsible for data collection, data analysis, data interpretation, or writing of the report. BB, the sponsor\'s Science Director, also contributed to data interpretation and writing of the report.
    Author Contributions
    Conflict of Interest Disclosures
    Acknowledgments
    Introduction Alterations in the balance of excitatory-inhibitory neurotransmission might underlie the cognitive and learning deficits found in several neurodevelopmental conditions (Ramamoorthi and Lin, 2011). Neurofibromatosis type 1 (NF1) is a common single gene disease affecting the human nervous system, inherited in autosomal dominant manner (Friedman and Birch, 1997). Besides cutaneous and musculoskeletal manifestations, cognitive problems resulting in learning disabilities are the most challenging complication, impacting the quality of life of the affected individuals (Krab et al., 2008). In addition, NF1 patients exhibit motor skill impairments. Johnson and colleagues investigated motor proficiency in NF1 children (n=26, age=4–15years) using the Bruininks-Oseretsky Test (BOT 2) instrument. Patients presented significant impairments in a composite score including fine manual control, manual coordination, body coordination, strength and agility (Johnson et al., 2010). In a complementary study, Feldmann and colleagues showed in their cohort, which also covered adult NF1 patients (n=100, age=6–37years), impaired fine motor skills. Furthermore, patients with focal areas of high signal intensity on T2-weighted MRI scored worse in cognitive and fine motor performance (Feldmann et al., 2003). NF1 occurs by mutation of the Nf1-gene that encodes the Neurofibromin-protein, a negative regulator of the RAS signaling cascade. Animal studies have revealed that the Neurofibromin-protein modulates gamma-Aminobutyric acid(GABA)ergic neurotransmission leading to enhanced inhibitory activity directly affecting the induction of long-term potentiation (LTP) and learning (Costa et al., 2002). Recent studies using magnetic resonance spectroscopy measured the levels of GABA and glutamate + glutamine in the medial frontal cortex and the occipital cortex in NF1 patients. The GABA levels in patients were reduced in the medial frontal and occipital cortex when compared to controls. The glutamate + glutamine levels were normal, pointing to an abnormal inhibition/excitation balance in NF1. The medial frontal GABA levels correlates with intellectual abilities and inhibitory control. Interestingly, NF1 patients presented a reversed pattern, with higher GABA being associated with faster responses (Ribeiro et al., 2015). In this context, recent evidence supports the view that modulation of tonic GABA is essential for LTP-like plastic changes e.g., within the motor cortex (M1), (Stagg et al., 2011; Floyer-Lea et al., 2006) and further pharmacological studies demonstrated that GABA-agonist medication might suppress M1 plasticity and learning in healthy individuals (Butefisch et al., 2000).