Heterozygous TREM2 Mutation in Semantic Variant of Primary Progressive Aphasia

Dear Editor, Triggering receptor expressed on myeloid cells 2 (TREM2) protein, which is expressed on the membranes of a subset of myeloid cells, regulates immune responses in the brain.1 Genetic variants of TREM2 are associated with increased risks of developing Alzheimer’s disease (AD) and frontotemporal dementia (FTD). 2,3 In this study we identified a semantic variant in a primary progressive aphasia (svPPA) patient with one heterozygous TREM2 mutation. The 50-year-old right-handed male presented with a 10-year history of progressive anomia and comprehension difficulty. He also exhibited irritable and aggressive behaviors as well as alcohol and gambling addictions. Neuropsychological testing revealed poor performance in most tasks, but his visuospatial function was relatively spared (84.37th percentile). His language function assessed using the Western Aphasia Battery was indicative of Wernicke’s aphasia. As shown in Fig. 1A, which was adapted from our previous report,4 MRI revealed atrophy in the bilateral anterior temporal lobes (left>right), while [18F]THK5351 positron emission tomography (PET) revealed greater [18F]THK5351 retention in the anteroinferior temporal regions. [18F]FDG PET showed hypometabolism in the bilateral anterior temporal areas (left>right) (Supplementary Material, Supplementary Fig. 1 in the online-only Data Supplement). He was diagnosed with svPPA based on the results of the neuropsychological testing and neuroimaging findings.5 The family history (Fig. 1B) showed that the proband’s father (I-2) and half-brother (II-1) also reportedly exhibited aggressive and violent behaviors as well as alcohol addiction that required interventions from hospitalization to institutionalization in an asylum, while the proband’s mother (I-3) and sisters (II-2 and II-3) had no history of neurological or psychiatric diseases. Whole-exome sequencing identified one heterozygous TREM2 variant in the proband: c.574G>A, p.Ala192Thr (NM_018965). Sanger sequencing for the proband (II-4) and additional unaffected family members (I-3, II-2, and II-3) (Fig. 1C) confirmed that the variant segregated with the phenotype in the family. Moreover, there was neither any gene mutation associated with FTD (e.g., TARDP, MAPT, GRN, C9orf72, VCP, CHMP2B, FUS, ITM2B, TBK1, and TBP) nor any gene mutation that is not commonly linked to FTD (e.g., PSEN1). The heterozygous rare variants of TREM2 including R47H, D87N, and Q33X reportedly increase the risk of AD.2 Additionally, TREM2 variants such as R47H, R62H, and T66M have been associated with a predisposition to FTD.3 Meanwhile, recent studies have identified the A192T variant in a Chinese individual with late-onset AD6 and a Korean patient with earlyonset AD.7 This study was subject to some limitations. First, since the patient did not undergo amyloid PET, and so we could not exclude the possibility of amyloid pathology being present. However, the [18F]FDG PET findings indicated that the possibility of AD would be low, even if it were. Second, we presumed that the proband had a family history of this neurological disease because his father and half-brother had similar clinical phenotypes. However, we could Min-Jin Ji Sungwon Jung Ha-Eun Seo Sang-Young Kim Woo-Ram Kim Sora Kim Jin Sook Lee Young Noh