The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia.
The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR-s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD), a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2) of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03) and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01). These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Jennifer S
JS
Yokoyama
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Luke W
LW
Bonham
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Virginia E
VE
Sturm
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Babu
B
Adhimoolam
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Anna
A
Karydas
Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
Giovanni
G
Coppola
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Bruce L
BL
Miller
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Katherine P
KP
Rankin
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000209:etiology*; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013223:Statistics as Topic
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
Amygdala; Emotion; Frontotemporal dementia; Neurodegeneration; Serotonin transporter gene; Structural MRI