It has been suggested that monogenic frontotemporal lobar degeneration (FTLD) due to Granulin (GRN) mutations might present a specific pattern of atrophy, as compared with FTLD GRN-negative disease. Recent literature has suggested that the study of functional neural networks, rather than regional structural damage, might better elucidate the pathogenic mechanisms, showing complex relationships among structural alterations observed with conventional neuroimaging. The aim of this study was to evaluate effective brain connectivity in FTLD patients carrying GRN mutations (GRN1), compared with FTLD patients without pathogenetic GRN mutations (GRN2) and healthy controls (HCs). Methods: Twenty-six FTLD patients (13 GRN1 and 13 GRN2 matched for age, sex, and phenotype) and 13 age-and sex-matched HCs underwent brain perfusion SPECT. Brain regions involved in FTLD (dorsolateral, anterior cingulate, orbitofrontal, posterior temporal, temporal pole, and parietal) were used as regions of interest to identify functionally interconnected areas. An effective connectivity (path) analysis was defined with a PC algorithm (named after its inventors Peter Spirtes and Clark Glymour) search procedure and structural equation fitting. Statistically significant differences among the 3 groups were determined. Results: The best-fitting model was obtained by the data-driven approach, and brain connectivity pathways resembling state-of-the-art anatomic knowledge were obtained. When GRN1 and GRN2 groups were considered, the former presented a selective bilateral parietotemporal disconnection, compared with GRN2 patients. Furthermore, in FTLD GRN1 patients an increased compensative connectivity of the temporal regions (temporal pole and posterior temporal cortices) was observed. Conclusion: The present work suggests that impairment of effective functional connectivity of the parietotemporal regions is the hallmark of GRNrelated FTLD. However, compensative mechanisms-which should be further investigated-may occur.Key Words: frontotemporal dementia; frontotemporal lobar degeneration; granulin; mutation; SPECT; path analysis Fr ontotemporal lobar degeneration (FTLD) is a common cause of young onset neurodegenerative dementia (1,2). FTLD is clinically and pathologically heterogeneous (3), and genetic factors play a significant role, with a genetic basis implicated in up to 40% of cases (4).Discovery of disease-causing mutations in the Granulin (GRN) and microtubule-associated protein t-(MAPT) genes and the expanded hexanucleotide repeat insertion within C9orf72 have allowed a giant step forward in the knowledge of causative mechanisms of FTLD. Accordingly, recent literature has carefully detailed the peculiar features of these genetic forms, with the attempt to facilitate early and accurate diagnosis.Autosomal-dominant inherited GRN disease has been associated with a varied clinical spectrum, ranging from behavioral variant frontotemporal dementia (bvFTD) to nonfluent/aggramatic subtypes of primary progressive aphasia (nfvPPA), and with a widespre...