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           <jats:p>The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotemporal dementia (112 with chromosome 9 open reading frame 72 [C9orf72] expansion, 119 with granulin [GRN] mutations and 60 with microtubule-associated protein tau [MAPT] mutations) and 83 non-carriers (including 50 young and 33 old non-carriers). We computed the diffusion tensor image analysis along the perivascular space index by calculating diffusivities in the x-, y- and z-axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations. The diffusion tensor image analysis along the perivascular space index was lower in symptomatic frontotemporal dementia (estimated marginal mean \u00b1 standard error, 1.21 \u00b1 0.02) than in old non-carriers (1.29 \u00b1 0.03, P = 0.009) and presymptomatic mutation carriers (1.30 \u00b1 0.01, P &amp;lt; 0.001). In mutation carriers, lower diffusion tensor image analysis along the perivascular space was associated with worse disease severity (\u03b2 = \u22121.16, P &amp;lt; 0.001), and a trend towards a significant association between lower diffusion tensor image analysis along the perivascular space and higher plasma neurofilament light chain was reported (\u03b2 = \u22120.28, P = 0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low diffusion tensor image analysis along the perivascular space at baseline than in those with average (P = 0.009) or high (P = 0.006) diffusion tensor image analysis along the perivascular space index. Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic frontotemporal dementia. Such measures of the glymphatic system may elucidate pathophysiological processes in human frontotemporal dementia and facilitate early phase trials of genetic frontotemporal dementia.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae185","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T19:29:38Z","timestamp":1718393378000},"source":"Crossref","is-referenced-by-count":21,"title":["Impaired glymphatic system in genetic frontotemporal dementia: a GENFI study"],"prefix":"10.1093","volume":"6","author":[{"given":"Enrico","family":"Premi","sequence":"first","affiliation":[{"name":"Stroke Unit, ASST Spedali Civili Brescia , Brescia, 25123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Diano","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Torino , Turin, 10124 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mattioli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia , Brescia, 25123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia , Brescia, 25123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Cantoni","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia , Brescia, 25123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1814-5024","authenticated-orcid":false,"given":"Martina","family":"Bocchetta","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London, WC1N , UK"},{"name":"Centre for Cognitive and Clinical Neuroscience, Division of Psychology, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London , London, UB8 3PN , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Gasparotti","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, University of Brescia , Brescia, 25123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1356-9074","authenticated-orcid":false,"given":"Emanuele","family":"Buratti","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Enginneering and Biotechnology , Trieste, 34149 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Pengo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental 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