Functional genetic variation in the serotonin 5-HTTLPR modulates brain damage in frontotemporal dementia

In frontotemporal dementia (FTD), nonmodifiable (genetic background) and modifiable (cognitive reserve [CR]) factors might interact in affecting frontotemporal damage. Serotoninergic dysfunction has been suggested as a key factor in FTD pathogenesis. 5-HTTLPR polymorphism on SCLA4 gene modulates the serotoninergic transmission. To evaluate the impact of 5-HTTLPR polymorphism on regional cerebral blood flow (rCBF) and its possible interaction with CR, 76 FTD patients with a 5-HTTLPR genotyping were recruited. All subjects underwent neuropsychological assessment and single-photon emission computed tomography imaging. Reserve index (RI) was computed from educational and occupational attainments, as proxy measure of CR. 5-HTTLPR analysis evidenced 14 S/S, 24 L/L, and 38 S/L carriers. No neuropsychological/behavioral differences were present. At the same disease stage, L/L carriers have a greater bilateral frontal rCBF decrease. Patients with higher RI had greater damage in right frontal and temporal regions. The additive effect of 5-HTTLPR polymorphism and RI was characterized by greater frontal rCBF deficit. 5-HTTLPR and CR act together to counteract brain pathology in FTD. Further studies are warranted to test the serotonin role in monogenic forms of FTD.