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

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Abstract

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 (Tpeak-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 (Tpeak-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.

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References

  1. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol Elsevier. 2006;5:525–35.

    Article  Google Scholar 

  2. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease. JAMA. 2014;311:1670.

    Article  CAS  PubMed  Google Scholar 

  3. Meireles J, Massano J. Cognitive impairment and dementia in Parkinson’s disease: clinical features, diagnosis, and management. Front Neurol. 2012;3:88.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tang Y, Ge J, Liu F, Wu P, Guo S, Liu Z, et al. Cerebral metabolic differences associated with cognitive impairment in Parkinson’s disease. PLoS One. 2016;11:e0152716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Broeders M, Velseboer DC, de Bie R, Speelman JD, Muslimovic D, Post B, et al. Cognitive change in newly-diagnosed patients with Parkinson’s disease: a 5-year follow-up study. J Int Neuropsychol Soc. 2013;19:695–708.

    Article  PubMed  Google Scholar 

  6. Muslimović D, Post B, Speelman JD, De Haan RJ, Schmand B. Cognitive decline in Parkinson’s disease: a prospective longitudinal study. J Int Neuropsychol Soc. 2009;15:426–37.

    Article  PubMed  Google Scholar 

  7. Schapira AHV, Olanow CW, Greenamyre JT, Bezard E. Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet. Elsevier. 2014:545–55.

  8. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature. 2007;445:643–7.

    Article  CAS  PubMed  Google Scholar 

  9. Ferrer B, Asbrock N, Kathuria S, Piomelli D, Giuffrida A. Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur J Neurosci. 2003;18:1607–14.

    Article  PubMed  Google Scholar 

  10. van der Stelt M, Fox SH, Hill M, Crossman AR, Petrosino S, Di Marzo V, et al. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease. FASEB J. 2005;19:1140–2.

    Article  CAS  PubMed  Google Scholar 

  11. Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci. 2002;22:6900–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Van Laere K, Casteels C, Lunskens S, Goffin K, Grachev ID, Bormans G, et al. Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol Aging. 2012;33:620.e1–8.

    Article  CAS  Google Scholar 

  13. van Vliet SAM, Vanwersch RAP, Jongsma MJ, Olivier B, Philippens IHCHM. Therapeutic effects of Δ9-THC and modafinil in a marmoset Parkinson model. Eur Neuropsychopharmacol. 2008;18:383–9.

    Article  CAS  PubMed  Google Scholar 

  14. Fernandez-Espejo E, Caraballo I, Rodriguez de Fonseca F, Ferrer B, El Banoua F, Flores JA, et al. Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function. Neuropsychopharmacology. 2004;29:1134–42.

    Article  CAS  PubMed  Google Scholar 

  15. Fernandez-Espejo E, Caraballo I, de Fonseca FR, El Banoua F, Ferrer B, Flores JA, et al. Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol Dis. 2005;18:591–601.

    Article  CAS  PubMed  Google Scholar 

  16. González S, Scorticati C, García-Arencibia M, de Miguel R, Ramos JA, Fernández-Ruiz J. Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson’s disease. Brain Res. 2006;1073–1074:209–19.

    Article  CAS  PubMed  Google Scholar 

  17. Zanettini C, Panlilio LV, Aliczki M, Goldberg SR, Haller J, Yasar S. Effects of endocannabinoid system modulation on cognitive and emotional behavior. Front Behav Neurosci. 2011;5:57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Varvel SA, Wise LE, Lichtman AH. Are CB1 receptor antagonists nootropic or cognitive impairing agents? Drug Dev Res. 2009;70:555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Riedel G, Davies SN. Cannabinoid function in learning, memory and plasticity. Handb Exp Pharmacol. 2005:445–77.

  20. Tan H, Lauzon NM, Bishop SF, Chi N, Bechard M, Laviolette SR. Cannabinoid transmission in the basolateral amygdala modulates fear memory formation via functional inputs to the prelimbic cortex. J Neurosci. 2011;31:5300–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, et al. A cannabinoid link between mitochondria and memory. Nature. 2016;539:555–9.

    Article  CAS  PubMed  Google Scholar 

  22. Akirav I. The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus. Front Behav Neurosci. 2011;5:34.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, et al. Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology. 2008;33:1113–26.

    Article  PubMed  Google Scholar 

  24. Schneider M, Schömig E, Leweke FM. Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict Biol. 2008;13:345–57.

    Article  CAS  PubMed  Google Scholar 

  25. Galanopoulos A, Polissidis A, Georgiadou G, Papadopoulou-Daifoti Z, Nomikos GG, Pitsikas N, et al. WIN55,212-2 impairs non-associative recognition and spatial memory in rats via CB1 receptor stimulation. Pharmacol Biochem Behav. 2014;124:58–66.

    Article  CAS  PubMed  Google Scholar 

  26. Basavarajappa BS, Subbanna S. CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations. Hippocampus. 2014;24:178–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ashton CH, Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand. 2011;124:250–61.

    Article  CAS  PubMed  Google Scholar 

  28. Katzman MA, MFLA. Targeting the endocannabinoid system in psychiatric illness. J Clin Psychopharmacol. 2016;36:691–703.

    Article  CAS  PubMed  Google Scholar 

  29. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25:2649–53.

    Article  Google Scholar 

  30. Van Laere K, Goffin K, Casteels C, Dupont P, Mortelmans L, de Hoon J, et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [18F]MK-9470 PET. Neuroimage. 2008;39:1533–41.

    Article  PubMed  Google Scholar 

  31. Burns HD, Van Laere K, Sanabria-Bohorquez S, Hamill TG, Bormans G, Eng W-S, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci. 2007;104:9800–5.

    Article  CAS  PubMed  Google Scholar 

  32. Sanabria-Bohórquez SM, Hamill TG, Goffin K, De Lepeleire I, Bormans G, Burns HD, et al. Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain. Eur J Nucl Med Mol Imaging. 2010;37:920–33.

    Article  CAS  PubMed  Google Scholar 

  33. Kempster PA, O’Sullivan SS, Holton JL, Revesz T, Lees AJ. Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain. 2010;133:1755–62.

    Article  PubMed  Google Scholar 

  34. Litvan I, Aarsland D, Adler CH, Goldman JG, Kulisevsky J, Mollenhauer B, et al. MDS task force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Mov Disord. 2011;26:1814–24.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13:217–31.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76:70–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008;7:438–55.

    Article  CAS  PubMed  Google Scholar 

  38. Volkow ND, Swanson JM, Evins AE, DeLisi LE, Meier MH, Gonzalez R, et al. Effects of Cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry. 2016;73:292.

    Article  Google Scholar 

  39. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19:833.

    Article  PubMed Central  Google Scholar 

  40. Wu L, Liu F-T, Ge J-J, Zhao J, Tang Y-L, Yu W-B, et al. Clinical characteristics of cognitive impairment in patients with Parkinson’s disease and its related pattern in 18 F-FDG PET imaging. Hum Brain Mapp. 2018;39(12):4652–62.

    Article  PubMed  Google Scholar 

  41. Firbank MJ, Yarnall AJ, Lawson RA, Duncan GW, Khoo TK, Petrides GS, et al. Cerebral glucose metabolism and cognition in newly diagnosed Parkinson’s disease: ICICLE-PD study. J Neurol Neurosurg Psychiatry. 2017;88:310–6.

    Article  CAS  PubMed  Google Scholar 

  42. Chung SJ, Yoo HS, Oh JS, Kim JS, Ye BS, Sohn YH, et al. Effect of striatal dopamine depletion on cognition in de novo Parkinson’s disease. Parkinsonism Relat Disord. 2018;51:43–8.

    Article  PubMed  Google Scholar 

  43. Ito K, Nagano-Saito A, Kato T, Arahata Y, Nakamura A, Kawasumi Y, et al. Striatal and extrastriatal dysfunction in Parkinson’s disease with dementia: a 6-[18F]fluoro-L-dopa PET study. Brain. 2002;125:1358–65.

    Article  PubMed  Google Scholar 

  44. Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, et al. Tau positron emission tomographic imaging in the Lewy body diseases. JAMA Neurol. 2016;73:1334.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Prell T. Structural and functional brain patterns of non-motor syndromes in Parkinson’s disease. Front Neurol. 2018;9:138.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Palermo S, Morese R, Zibetti M, Dematteis F, Sirgiovanni S, Stanziano M, et al. Impulse control disorder and response-inhibition alterations in Parkinson’s disease. A rare case of totally absent functionality of the medial-prefrontal cortex and review of literature. J Adv Res. 2017;8:713–6.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dörfel D, Werner A, Schaefer M, Von Kummer R, Karl A. Distinct brain networks in recognition memory share a defined region in the precuneus. Eur J Neurosci. 2009;30:1947–59.

    Article  PubMed  Google Scholar 

  48. Lundstrom BN, Petersson KM, Andersson J, Johansson M, Fransson P, Ingvar M. Isolating the retrieval of imagined pictures during episodic memory: activation of the left precuneus and left prefrontal cortex. Neuroimage. 2003;20:1934–43.

    Article  PubMed  Google Scholar 

  49. Lundstrom BN, Ingvar M, Petersson KM. The role of precuneus and left inferior frontal cortex during source memory episodic retrieval. Neuroimage. 2005;27:824–34.

    Article  PubMed  Google Scholar 

  50. Wenderoth N, Debaere F, Sunaert S, Swinnen SP. The role of anterior cingulate cortex and precuneus in the coordination of motor behaviour. Eur J Neurosci. 2005;22:235–46.

    Article  PubMed  Google Scholar 

  51. Ruiz-Contreras AE, Carrillo-Sánchez K, Ortega-Mora I, Barrera-Tlapa MA, Román-López TV, Rosas-Escobar CB, et al. Performance in working memory and attentional control is associated with the rs2180619 SNP in the CNR1 gene. Genes Brain Behav. 2014;13:173–8.

    Article  CAS  PubMed  Google Scholar 

  52. Ruiz-Contreras AE, Carrillo-Sánchez K, Gómez-López N, Vadillo-Ortega F, Hernández-Morales S, Carnevale-Cantoni A, et al. Working memory performance in young adults is associated to the AATn polymorphism of the CNR1 gene. Behav Brain Res. 2013;236:62–6.

    Article  CAS  PubMed  Google Scholar 

  53. Saravia R, Flores Á, Plaza-Zabala A, Busquets-Garcia A, Pastor A, de la Torre R, et al. CB1 cannabinoid receptors mediate cognitive deficits and structural plasticity changes during nicotine withdrawal. Biol Psychiatry. 2017;81:625–34.

    Article  CAS  PubMed  Google Scholar 

  54. Arguello PA, Jentsch JD. Cannabinoid CB1 receptor-mediated impairment of visuospatial attention in the rat. Psychopharmacology (Berl). 2004;177:141–50.

    Article  CAS  Google Scholar 

  55. Colizzi M, Fazio L, Ferranti L, Porcelli A, Masellis R, Marvulli D, et al. Functional genetic variation of the cannabinoid receptor 1 and Cannabis use interact on prefrontal connectivity and related working memory behavior. Neuropsychopharmacology. 2015;40:640–9.

    Article  CAS  PubMed  Google Scholar 

  56. Malak ALSB, Vasconcellos LF, Pereira JS, Greca DV, Cruz M, Alves HVD, et al. Symptoms of depression in patients with mild cognitive impairment in Parkinson’s disease. Dement Neuropsychol. 2017;11:145–53.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lewis MM, Du G, Lee E-Y, Nasralah Z, Sterling NW, Zhang L, et al. The pattern of gray matter atrophy in Parkinson’s disease differs in cortical and subcortical regions. J Neurol. 2016;263:68–75.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Beyer MK, Janvin CC, Larsen JP, Aarsland D. A magnetic resonance imaging study of patients with Parkinson’s disease with mild cognitive impairment and dementia using voxel-based morphometry. J Neurol Neurosurg Psychiatry. 2007;78:254–9.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the participants for their willingness to participate in this study. The authors also extend their gratitude to the PET radiopharmacy, research technologists (Kwinten Porters and Jef Van Loock) and radiology team of UZ Leuven for their skilled support. Jenny Ceccarini is a postdoctoral fellow of the Research Foundation Flanders (FWO). Wim Vandenberghe and Koen Van Laere are Senior Clinical Investigators of the FWO and have received a FWO research grant for this work (FWO/G0493.10).

Funding

This study was funded by the Research Foundation Flanders (FWO/G0493.10). Jenny Ceccarini is a FWO postdoctoral fellow of the. Wim Vandenberghe, Mathieu Vandenbulcke and Koen Van Laere are Senior Clinical Investigators of the FWO.

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Authors and Affiliations

  1. Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Jenny Ceccarini, Cindy Casteels, Rawaha Ahmad, Melissa Crabbé, Heleen Vanhaute & Koen Van Laere

  2. Department of Imaging and Pathology, KU Leuven, Leuven, Belgium

    Jenny Ceccarini, Cindy Casteels, Rawaha Ahmad, Melissa Crabbé, Heleen Vanhaute & Koen Van Laere

  3. Department of Old Age Psychiatry, University Psychiatric Centre, KU Leuven, Leuven, Belgium

    Laura Van de Vliet, Heleen Vanhaute & Mathieu Vandenbulcke

  4. Department of Neurosciences, KU Leuven, Leuven, Belgium

    Laura Van de Vliet, Mathieu Vandenbulcke & Wim Vandenberghe

  5. Department of Neurology, University Hospitals Leuven, Leuven, Belgium

    Wim Vandenberghe

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  1. Jenny Ceccarini
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Correspondence to Jenny Ceccarini.

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Ceccarini, J., Casteels, C., Ahmad, R. et al. Regional changes in the type 1 cannabinoid receptor are associated with cognitive dysfunction in Parkinson’s disease. Eur J Nucl Med Mol Imaging 46, 2348–2357 (2019). https://doi.org/10.1007/s00259-019-04445-x

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