Supplementary Material for: Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

<p><b><i>Background and Objective:</i></b> Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene <i>(GRN)</i>. However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to <i>GRN </i>mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in <i>GRN</i>-negative FTD. <b><i>Methods:</i></b> Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for <i>GRN</i> mutations, yielding a target cohort of 34 patients without pathogenic mutations in <i>GRN</i> (<i>GRN</i>-negative cohort) and 3 <i>GRN</i> mutation carriers (2 LoF variants and 1 novel missense variant). <b><i>Results:</i></b> Not only the <i>GRN</i> mutation carriers but also the <i>GRN</i>-negative patients showed decreased CSF levels of progranulin (serum levels in<i> GRN</i>-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel <i>GRN</i> missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with <i>GRN</i> LoF mutations, suggesting a pathogenic effect of this missense variant. <b><i>Conclusions:</i></b> Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by <i>GRN</i> LoF mutations, but also contributes to the more common <i>GRN-</i>negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.</p><br>