What is it about?
This study supports the hypothesis that an individual’s background genetic constitution impacts the manifestation of neurodegenerative illness. Specifically, this research provides evidence that non-wild type DRD4 polymorphisms associated with blunted neuronal signaling predict brain atrophy in disease-specific regions of frontotemporal dementia (FTD) in frontal and limbic structures. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD and results covaried with frontoinsular cortical atrophy. In Alzheimer's disease subjects and controls, genotype did not impact brain atrophy or behavior.
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Why is it important?
The substantial anatomical and clinical heterogeneity within dementia syndromes influences diagnostic certainty and prognosis. Identifying sources of patient-level variation is important to clarify disease mechanisms and suggest possible targets for patient-tailored disease-modifying therapies. This study adds evidence to the the claim that genotype can shape the spatial landscape of degeneration and associated cognitive and behavioral profiles. The findings could serve as motivation for exploring the influence of manipulating dopamine signaling on FTD-related neurodegeneration in model organisms.
Perspectives
The localization of D4 receptors to limbic and cortical systems of the anterior more than posterior forebrain might explain why patients with FTD but not AD dementia were susceptible to aggravated neurodegeneration in these regions. In other words, the neuronal milieu may be threatened most in regions of neuroanatomical overlap between typical sites of neurodegeneration and circuits richly innervated by D4 receptors.
Monroe Butler
University of California San Francisco
Read the Original
This page is a summary of: Dopamine receptor D4 (DRD) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia, NeuroImage Clinical, January 2019, Elsevier,
DOI: 10.1016/j.nicl.2019.101822.
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Resources
COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures
This related study sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.
Novelty-seeking DRD4 polymorphisms are associated with human migration distance out-of-Africa after controlling for neutral population gene structure.
The reason why certain dopamine system genes are highly polymorphic in humans compared to other phylogenetically related species in unclear. One hypothesis is that evolutionary selective pressures may have driven variation of dopamine signaling genetics, which impacted migration behavior ~50,000 years ago. Certain dopamine receptor D4 (DRD4) polymorphisms are associated with low neuronal reactivity and increased exploratory behavior, novelty seeking, and risk taking. We propose that this rapid migration into new habitats selected for individuals with low reactivity to novel stressors. In this study we account for neutral genetic structure by modeling the nonindependence of neutral allele frequencies between human populations. We conclude there is an association between migratory distance and DRD4 polymorphisms associated with novelty seeking behavior (e.g. exon III 2R, 7R alleles) that cannot be accounted for by neutral genetic processes alone.
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