Objective: In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [18 F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset.Methods: Nine mutation carriers (age 51.5 6 13.5 years) and 11 noncarriers (age 52.7 6 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches.Results: Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 6 0.09 vs 0.92 6 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r 5 0.74; Functional Rating Scale r 5 20.73) but not age and years to estimated onset in mutation carriers. Conclusion:The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s-early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated. The multifaceted clinical syndrome of frontotemporal dementia (FTD) arises from degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration). Mutations in the gene encoding progranulin (GRN), discovered in 2006, 1,2 are found in 5%-20% of those with familial FTD (FTD-GRN).2,3 Despite the common haploinsufficiency mechanism 1 and transactive response DNA-binding protein M r 43 kD (TDP-43) neuropathology, 4 there is phenotypic variation in FTD-GRN, with behavioral variant FTD (bvFTD), progressive nonfluent aphasia (PNFA), and corticobasal syndrome.5 Mean age at onset is 59-65 years, but can range from 35 to 87 years. 6 In GRN mutation carriers with FTD, an asymmetric pattern of brain structural abnormalities is found, with severe gray matter loss involving frontal, anterior temporal, but also posterior temporal and inferior parietal regions. [7][8][9] There is only very limited evidence on brain

Risperidone, serotonin reuptake inhibitors as a class and dextromethorphan/quinidine demonstrated evidence of efficacy for agitation in dementia, although findings for dextromethorphan/quinidine were based on a single RCT. Our findings do not support prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability. The decision to prescribe should be based on comprehensive consideration of the benefits and risks, including those not evaluated in this meta-analysis.