Regional changes in the type 1 cannabinoid receptor are associated with cognitive dysfunction in Parkinson's disease

Purpose: The endocannabinoid system plays a regulatory role in a number of physiological functions, including motor control but also mood, emotion, and cognition. A number of preclinical studies in Parkinson's disease (PD) models demonstrated that modulating the type 1 cannabinoid receptor (CB₁R) may improve motor symptoms and components of cognitive processing. However, the relation between CB₁R, cognitive decline and behavioral symptoms has not been investigated in PD patients so far. The aim of this study was to examine whether CB₁R availability is associated with measures of cognitive and behavioral function in PD patients.

Methods: Thirty-eight PD patients and ten age- and gender-matched controls underwent a [¹⁸F]MK-9470 PET scan to assess CB₁R availability, as well as volumetric MR imaging. Neuropsychological symptoms were evaluated using an extensive cognitive and behavioral battery covering the five cognitive domains, depression, anxiety, apathy, and psychiatric complications, and were correlated to CB₁R availability using vowel-wise regression analysis (P < 0.05, corrected for familywise error).

Results: PD patients with poorer performance in episodic memory, executive functioning, speed and mental flexibility (range P 0.003-0.03) showed lower CB₁R availability in predominantly the midcingulate cortex and middle to superior frontal gyrus (T_peak-level > 4.0). Also, PD patients with more severe visuospatial dysfunction showed decreased CB₁R availability in the precuneus, midcingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (T_peak-level = 5.5). These correlations were not related to cortical gray matter atrophy. No relationship was found between CB₁R availability and mood or behavioral symptom scores.

Conclusions: Decreased CB₁R availability in the prefrontal and midcingulate cortex in PD patients is strongly correlated with disturbances in executive functioning, episodic memory, and visuospatial functioning. Further investigation of regional CB1R expression in groups of PD patients with mild cognitive impairment or dementia is warranted in order to further investigate the role of CB1R expression in different levels of cognitive impairment in PD.