Abstract
Objective:HTT is a gene containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. HTT genes with <35 repeats are not associated with HD. The biological function of CAG repeat expansion below the non-pathological threshold is not well understood. In fact higher number of repeats in HTT confer advantageous changes in brain structure and general intelligence, but several studies focused on establishing the association between CAG expansions and susceptibility to psychiatric disturbances and to other neurodegenerative disease than HD. We hypothesized that HTT CAG repeat length below the pathological threshold might influence mood and personality traits in a longitudinal sample of individuals with Subjective Cognitive Decline.MethodsWe included 54 patients with SCD. All patients underwent an extensive neuropsychological battery at baseline, APOE genotyping and analysis of HTT alleles. We used the Big Five Factors Questionnaire (BFFQ) and Hamilton Depression Rating Scale (HDRS), respectively, to assess personality traits of patients and depression at baseline. Patients who did not progress to Mild Cognitive Impairment (MCI) had at least 5-year follow-up time.ResultsIn the whole sample, CAG repeat number in the shorter HTT allele was inversely correlated with conscientiousness (Pearson = −0.364, p = 0.007). There was no correlation between HDRS and CAG repeats. During the follow-up, 14 patients [25.93% (95% C.I. = 14.24–37.61)] progressed to MCI (MCI+) and 40 [74.07% (95% C.I. = 62.39–85.76)] did not (MCI−). When we performed the same analysis in the MCI+ group we found that: CAG repeat length on the shorter allele was inversely correlated with energy (Pearson = 0.639, p = 0.014) and conscientiousness (Pearson = −0.695, p = 0.006). CAG repeat length on the longer allele was inversely correlated with conscientiousness (Pearson = −0.901, p < 0.001) and directly correlated with emotional stability (Pearson = 0.639, p = 0.014). These associations were confirmed also by multivariate analysis. We found no correlations between BFFQ parameters and CAG repeats in the MCI− group.DiscussionPersonality traits and CAG repeat length in the intermediate range have been associated with progression of cognitive decline and neuropathological findings consistent with AD. We showed that CAG repeat lengths in the HTT gene within the non-pathological range influence personality traits.
Highlights
Huntingtin (HTT) is a gene coding for a soluble peptide which is widely expressed during development, being essential for embryogenesis [1], and plays crucial roles in axonal trafficking, regulation of gene transcription, and cell survival in post developmental life [2]
Six out of 54 patients [11.11%] were carriers of intermediate alleles of HTT gene (IAs+)
There was no significant difference in disease duration, family history of Alzheimer’s disease (AD), sex, years of education, TIB, MMSE, HDRS and Big Five Factors Questionnaire (BFFQ) score between IAs− and IAs+
Summary
Huntingtin (HTT) is a gene coding for a soluble peptide which is widely expressed during development, being essential for embryogenesis [1], and plays crucial roles in axonal trafficking, regulation of gene transcription, and cell survival in post developmental life [2]. The expansion of CAG triplet beyond 40 repeats leads to the dysfunction and death of neurons in the striatum and in other brain regions, causing Huntington’s disease (HD) [4], a neurodegenerative disorder characterized by cognitive, motor and psychiatric disturbance [5]. Several studies showed that carriers of HTT CAG repeats in the pathological range (HD carriers) had a defined personality profile, characterized by higher conscientiousness, lower emotional stability [6] and lower social cognition [7] as compared to controls. There are only a few studies exploring the effect of CAG repeats in the non-pathological range on personality traits and mood. IA proportion has been reported to be significantly increased in AD patients [8] as compared to healthy controls and HTT levels were increased in neuronal cells in the hippocampus of AD cases [11]. A recent work by our group found that HTT CAG expansions influence neuropsychological functions in individuals experiencing Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) [14]
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