Reduced norepinephrine transporter binding in Parkinson's disease with dopa responsive freezing gait

Freezing of gait (FOG) is a major cause of falling and leads to loss of independence in Parkinsons disease (PD). The pathophysiology of FOG is poorly understood - although there is a hypothesized link with NE systems. PD-FOG can present in levodopa-responsive and unresponsive forms. We examined NE transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[-(2-methoxyphenoxy)benzyl]morpholine) in N=52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize patients as non-freezing PD (NO-FOG, N=16), levodopa responsive freezing (OFF-FOG, N=10), levodopa-unresponsive freezing (ONOFF-FOG, N=21), and primary progressive freezing of gait (PP-FOG, N=5). Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P=0.021). Additional contrasts tested post-hoc identified trends toward increased NET expression in ONOFF-FOG vs. OFF-FOG ({approx}10%; P=0.123). Linear mixed models with interaction terms identified significantly reduced NET binding in right thalamus in the OFF-FOG group (P=0.038). A linear regression analysis identified an association between reduced NET binding and more severe NFOG-Q score only in the OFF-FOG group (P=0.022). This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.