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No efficacious interventions are available for HD, highlighting a major unmet medical need. The molecular mechanisms underlying HD are incompletely understood despite its monogenic aetiology. However, direct interactions between HTT and membrane lipids suggest that lipidomic perturbations may be implicated in the neuropathology of HD. In this study, we employed matrix\u2010assisted laser desorption\/ionisation imaging mass spectrometry (MALDI\u2013IMS) to generate a comprehensive, unbiased and spatially resolved lipidomic atlas of the caudate nucleus (CN) in human <jats:italic>post\u2010mortem<\/jats:italic> tissue from neurologically normal (<jats:italic>n<\/jats:italic>\u00a0=\u00a010) and HD (<jats:italic>n<\/jats:italic>\u00a0=\u00a013) subjects. Fourier transform\u2010ion cyclotron resonance mass spectrometry and liquid chromatography\u2013tandem mass spectrometry were used for lipid assignment. Lipidomic specialisation was observed in the grey and white matter constituents of the CN and these features were highly conserved between subjects. While the majority of lipid species were highly conserved in HD, compared to age\u2010matched controls, CN specimens from HD cases in our cohort spanning a range of neuropathological grades showed a lower focal abundance of the neuroprotective docosahexaenoic and adrenic acids, several cardiolipins, the ganglioside GM1 and glycerophospholipids with long polyunsaturated fatty acyls. HD cases showed a higher focal abundance of several sphingomyelins and glycerophospholipids with shorter monosaturated fatty acyls. Moreover, we demonstrate that MALDI\u2013IMS is tractable as a primary discovery modality comparing heterogeneous human brain tissue, provided that appropriate statistical approaches are adopted. Our findings support further investigation into the potential role of lipidomic aberrations in HD.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15325-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15325","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T15:21:19Z","timestamp":1613748079000},"page":"2158-2172","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["An imaging mass spectrometry atlas of lipids in the human neurologically normal and Huntington\u2019s disease caudate nucleus"],"prefix":"10.1111","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4803-7278","authenticated-orcid":false,"given":"Mandana","family":"Hunter","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology University of Auckland Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-9405","authenticated-orcid":false,"given":"Nicholas J.","family":"Demarais","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-9498","authenticated-orcid":false,"given":"Richard L. 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