The association of single-nucleotide polymorphism rs6265 of the brain-derived neurotrophic factor gene with clinical features in Parkinson’s disease

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OBJECTIVE

To evaluate the frequency and severity of various clinical symptoms of Parkinson’s disease (PD) depending on the BDNF rs6265 polymorphism.

MATERIAL AND METHODS

The study included 533 patients with PD. The stage of PD was assessed using the Hoehn and Yahr scale (1967), motor symptoms were evaluated with MDS-UPDRS. Assessment of non-motor symptoms (NMS) in PD was conducted using the Beck Depression Inventory II (BDI-II); the Hospital Anxiety and Depression Scale (HADS); the Apathy Scale; the Montreal Cognitive Assessment (MoCA test); the Questionnaire for Impulsive-Compulsive Disorders in PD -Rating Scale (QUIP-RS). Genotyping of the BDNF variant (rs6265) was performed using real-time PCR with TaqMan probes.

RESULTS

Most PD patients have a combination of NMS increasing as the disease progresses and is determined by molecular-genetic individual characteristics. There are significant differences in the severity of motor symptoms and NMS: individuals with the AA genotype showed significantly pronounced motor symptoms (p<0.0001); emotional-affective symptoms (p<0.0001); cognitive and impulsive behavioral disorders (p<0.0001).

CONCLUSION

The rs6265 BDNF allele A is associated with a wide range of NMS, increasing the risk of their development in patients with PD, thus playing the important role in the etiopathogenesis of this pathology.

Keywords:

Parkinson’s disease

non-motor symptoms

motor manifestations

apathy

anxiety

impulsive behavioral disorders

brain-derived neurotrophic factor

BDNF

rs6265

G196A

Val66Met

neurodegenerative diseases

Authors:

Nikitina M.A.

Siberian State Medical University

ORCID: 0000-0002-2614-207X

Bragina E.Yu.

Scientific Research Institute of Medical Genetics — Tomsk National Research Medical Center of the Russian Academy of Sciences

ORCID: 0000-0002-0673-4094

Nazarenko M.S.

Siberian State Medical University;
Scientific Research Institute of Medical Genetics — Tomsk National Research Medical Center of the Russian Academy of Sciences

ORCID: 0000-0002-0673-4094

Alifirova V.M.

Siberian State Medical University

SPIN RSCI: 3824-1016
Scopus AuthorID: 6507431329
ORCID: 0000-0002-4140-3223

Received:

19.01.2024

List of references:

Bonnet AM, Jutras MF, Czernecki V, et al. Nonmotor symptoms in Parkinson’s disease in 2012: relevant clinical aspects. Parkinsons Dis. 2012;2012:198316. https://doi.org/10.1155/2012/198316
Shipilova NN, Titova NV, Katunina EA. The problem of non-motor symptoms of Parkinson’s disease and the effect of dopaminergic therapy on their correction. RMJ. 2018;(4-II):85-90. (In Russ.).
Nikitina MA, Zhukova NG, Bragina EYu, et al. Heterogeneity of non-motor symptoms in patients with Parkinson’s disease in the Tomsk region. Yakut Medical Journal. 2019;3(67):70-74. (In Russ.). https://doi.org/10.25789/YMJ.2019.67.20
Scott BM, Eisinger RS, Burns MR, et al. Co-occurrence of apathy and impulse control disorders in Parkinson disease. Neurology. 2020;95(20):e2769-e2780. https://doi.org/10.1212/WNL.0000000000010965
Palasz E, Wysocka A, Gasiorowska A, et al. BDNF as a Promising Therapeutic Agent in Parkinson’s Disease. Int J Mol Sci. 2020;21(3):1170. https://doi.org/10.3390/ijms21031170
Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2001;63(1):71-124. https://doi.org/10.1016/s0301-0082(00)00014-9
Nguyen VT, Hill B, Sims N, et al. Brain-derived neurotrophic factor rs6265 (Val66Met) single nucleotide polymorphism as a master modifier of human pathophysiology. Neural Regen Res. 2023;18(1):102-106. https://doi.org/10.4103/1673-5374.343894
Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223-250. https://doi.org/10.1007/978-3-642-45106-5_9
Allen SJ, Watson JJ, Shoemark DK, et al. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther. 2013;138(2):155-175. https://doi.org/10.1016/j.pharmthera.2013.01.004
Chen ZY, Jing D, Bath KG, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314(5796):140-143. https://doi.org/10.1126/science.1129663
Nassan M, Veldic M, Winham S, et al. Methylation of Brain Derived Neurotrophic Factor (BDNF) Val66Met CpG site is associated with early onset bipolar disorder. J Affect Disord. 2020;267:96-102. https://doi.org/10.1016/j.jad.2020.02.002
Szarowicz CA, Steece-Collier K, Caulfield ME. New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism. Int J Mol Sci. 2022;23(14):8011. https://doi.org/10.3390/ijms23148011
Nikitina MA, Bragina EYu, Nazarenko MS, et al. The relationship between the rs6265 polymorphism of the BDNF gene and the level of serum neurotrophic factor in patients with Parkinson’s disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;124(1):114-120. (In Russ.). https://doi.org/10.17116/jnevro2024124011114
Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591-1601. https://doi.org/10.1002/mds.26424
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan. Movement Disorders. 2007;22(1):41-47. https://doi.org/10.1002/mds.21198
Beck C, Gable R. Postpartum Depression Screening Scale: Development and Psychometric Testing. Nursing Research. 2000;49(5):272-282. https://doi.org/10.1097/00006199-200009000-00006
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370. https://doi.org/10.1111/j.1600-0447.1983.tb09716.x
Starkstein SE, Mayberg HS, Preziosi TJ, et al. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1992;4(2):134-139. https://doi.org/10.1176/jnp.4.2.134
Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699. https://doi.org/10.1111/j.1532-5415.2005.53221.x
Evans AH, Okai D, Weintraub D, et al. Members of the International Parkinson and Movement Disorder Society (IPMDS) Rating Scales Review Committee. Scales to assess impulsive and compulsive behaviors in Parkinson’s disease: Critique and recommendations. Mov Disord. 2019;34(6):791-798. https://doi.org/10.1002/mds.27689
Sal’kov VN, Voronkov DN, Khacheva KK, et al. Clinical and morphological analysis of a caseof Parkinson’s disease. Russian Journal of Archive of Pathology. 2020;82(2):52-56. (In Russ.). https://doi.org/10.17116/patol20208202152
Gorzkowska A, Cholewa J, Cholewa J, et al. Risk Factors for Apathy in Polish Patients with Parkinson’s Disease. Int J Environ Res Public Health. 2021;18(19):10196. https://doi.org/10.3390/ijerph181910196
den Brok MG, van Dalen JW, van Gool WA, et al. Apathy in Parkinson’s disease: A systematic review and meta-analysis. Mov Disord. 2015;30(6):759-769. https://doi.org/10.1002/mds.26208
Kimura I, Revankar GS, Ogawa K, et al. Neural correlates of impulsive compulsive behaviors in Parkinson’s disease: A Japanese retrospective study. Neuroimage Clin. 2023;37:103307. https://doi.org/10.1016/j.nicl.2022.103307
Weintraub D, Simuni T, Caspell-Garcia C, et al. Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson’s disease. Mov Disord. 2015;30(7):919-927. https://doi.org/10.1002/mds.26170
Karlsson Linnér R, Biroli P, Kong E, et al. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat Genet. 2019;51(2):245-257. https://doi.org/10.1038/s41588-018-0309-3
Baselmans B, Hammerschlag AR, Noordijk S, et al. The Genetic and Neural Substrates of Externalizing Behavior. Biol Psychiatry Glob Open Sci. 2021;2(4):389-399. https://doi.org/10.1016/j.bpsgos.2021.09.007
Levchenko A, Malov S, Antonik A, et al. A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures. Biomedicines. 2022;10(12):3007. https://doi.org/10.3390/biomedicines10123007
Xu K, Li B, McGinnis KA, et al. Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals. Nat Commun. 2020;11(1):5302. https://doi.org/10.1038/s41467-020-18489-3
Erzurumluoglu AM, Liu M, Jackson VE, et al. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Mol Psychiatry. 2020;25(10):2392-2409. https://doi.org/10.1038/s41380-018-0313-0
Saunders GRB, Wang X, Chen F, et al. Genetic diversity fuels gene discovery for tobacco and alcohol use. Nature. 2022;612(7941):720-724. https://doi.org/10.1038/s41586-022-05477-4
Białecka M, Kurzawski M, Roszmann A, et al. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson’s disease. Neurosci Lett. 2014;561:86-90. https://doi.org/10.1016/j.neulet.2013.12.051
Altmann V, Schumacher-Schuh AF, Rieck M, et al. Val66Met BDNF polymorphism is associated with Parkinson’s disease cognitive impairment. Neurosci Lett. 2016;615:88-91. https://doi.org/10.1016/j.neulet.2016.01.030
Sampedro F, Marín-Lahoz J, Martínez-Horta S, et al. Pattern of cortical thinning associated with the BDNF Val66Met polymorphism in Parkinson’s disease. Behav Brain Res. 2019;372:112039. https://doi.org/10.1016/j.bbr.2019.112039
van der Kolk NM, Speelman AD, van Nimwegen M, et al. BDNF polymorphism associates with decline in set shifting in Parkinson’s disease. Neurobiol Aging. 2015;36(3):1605.e1-6. https://doi.org/10.1016/j.neurobiolaging.2014.08.023
Yin Y, Su X, Pan L, Li C. BDNF Val66Met polymorphism and cognitive impairment in Parkinson’s disease-a meta-analysis. Neurol Sci. 2019;40(9):1901-1907. https://doi.org/10.1007/s10072-019-03907-2
Gajewski PD, Hengstler JG, Golka K, et al. The Met-allele of the BDNF Val66Met polymorphism enhances task switching in elderly. Neurobiol Aging. 2011;32(12):2327.e7-19. https://doi.org/10.1016/j.neurobiolaging.2011.06.010
Fischer DL, Auinger P, Goudreau JL, et al. BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson’s Disease. Neurotherapeutics. 2020;17(4):1785-1795. https://doi.org/10.1007/s13311-020-00965-9
Приинята в печати 02.04.2024

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