Objective: To investigate if the vulnerability of Parkinson’s Disease (PD) can be reflected in the neuroanatomical structure in different MAPT haplotype carriers.

Background: It has been demonstrated that MAPT haplotypes can influence the risk of tauopathies and synucleinopathies such as Parkinson’s disease (PD)¹. Among people with PD,  carriers of the MAPT haplotype H1 have a higher risk of accelerated progression to dementia, poor cognitive performance and more severe non-tremor dominant phenotype than MAPT haplotype H2 carriers^2,3,4. In addition, neuroimaging studies of PD have shown that there is significant loss of volume in cortical and subcortical regions compared with healthy controls.⁵

Method: MAPT haplotypes and neuroimaging data were derived from UK Biobank (UKBB) and the Adolescent Brain Cognitive Development (ABCD)^6,7.  30716 unrelated European older adults in UKBB and 4403 adolescent individuals in ABCD were included in the analysis. We performed a haplotype analysis of MAPT, where H1 and H2 haplotypes were derived by the genotype of SNP rs1052553⁸. We then compared haplotype status with structural MRI data including cortical thickness, cortical surface area and subcortical volume by fitting multiple general linear models for each region, while considering a regional measurement as the dependent and MAPT haplotype as the independent variable.

Results: An increased total cortical surface area, a reduced global cortical thickness and a decreased putamen volume were significantly associated with the presence of the MAPT haplotype H1.

We next investigated if there was a MAPT-expression-specific distribution of the haplotype effect: significant correlations were found between PD DBM atrophy progression and t values obtained from the models fitted by subcortical volumes and MAPT haplotypes.

The haplotype analyses described above were replicated in ABCD. Significant associations were also detected in many regions.

Conclusion: The results from UKBB suggested that MAPT H1 carriers which has a higher risk in PD tend to have a thinner cortex increased cortical surface area in several brain regions, and a smaller putamen in both hemispheres. In ABCD, significant association of a reduced thickness and volume in several cortical regions and putamen respectively with MAPT H1 carriers implies that the influence of MAPT haplotype starts before adolescence.

References: 1. Zhang, Cheng-Cheng et al. “The Role of MAPT in Neurodegenerative Diseases: Genetics, Mechanisms and Therapy.” Molecular neurobiology vol. 53,7 (2016): 4893-904. doi:10.1007/s12035-015-9415-8
2. Setó-Salvia, Núria et al. “Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes.” Archives of neurology vol. 68,3 (2011): 359-64. doi:10.1001/archneurol.2011.17
3. Morley, James F et al. “Genetic influences on cognitive decline in Parkinson’s disease.” Movement disorders : official journal of the Movement Disorder Society vol. 27,4 (2012): 512-8. doi:10.1002/mds.24946
4. Di Battista, Maria Elena et al. “Clinical subtypes in Parkinson’s disease: the impact of MAPT haplotypes.” Journal of neural transmission (Vienna, Austria : 1996) vol. 121,4 (2014): 353-6. doi:10.1007/s00702-013-1117-7
5. Laansma, Max A et al. “International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson’s Disease.” Movement disorders : official journal of the Movement Disorder Society vol. 36,11 (2021): 2583-2594. doi:10.1002/mds.28706
6. Sudlow, Cathie et al. “UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.” PLoS medicine vol. 12,3 e1001779. 31 Mar. 2015, doi:10.1371/journal.pmed.1001779
7. Casey, B J et al. “The Adolescent Brain Cognitive Development (ABCD) study: Imaging acquisition across 21 sites.” Developmental cognitive neuroscience vol. 32 (2018): 43-54. doi:10.1016/j.dcn.2018.03.001
8. Wider, C et al. “Association of the MAPT locus with Parkinson’s disease.” European journal of neurology vol. 17,3 (2010): 483-6. doi:10.1111/j.1468-1331.2009.02847.x

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigate-the-association-of-mapt-haplotype-and-neuroanatomical-structure-and-its-influence-on-the-risk-of-parkinsons-disease/