Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.Peer Reviewe

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory

Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study

Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease

Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study

Background: In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design: This multi-center, prospective controlled study has a two-phase cohort design. Methods: Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD's outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes: Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients' quality of life and evaluation of care; and f) physicians' satisfaction with the innovative care approach. Conclusions: This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease