Aberrant type 2 dopamine receptor availability in violent offenders with psychopathy.

Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aß deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aß-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aß pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

In-target production of [11C]CH4 from a nitrogen/hydrogen gas target as a function of beam current, irradiation time, and target temperature.

BACKGROUND: Production of [11C]CH4 from gas targets is notorious for weak performance with respect to yield, especially when using high beam currents. Post-target conversion of [11C]CO2 to [11C]CH4 is a widely used roundabout method in 11C-radiochemistry, but the added complexity increase the challenge to control carrier carbon. Thus in-target-produced [11C]CH4 is superior with respect to molar activity. We studied the in-target production of [11C]CO2 and [11C]CH4 from nitrogen gas targets as a function of beam current, irradiation time, and target temperature. RESULTS: [11C]CO2 production was practically unchanged across the range of varied parameters, but the [11C]CH4 yield, presented in terms of saturation yield YSAT(11CH4), had a negative correlation with beam current and a positive correlation with target chamber temperature. A formulated model equation indicates behavior where the [11C]CH4 formation follows a parabolic graph as a function of beam current. The negative square term, i.e., the yield loss, is postulated to arise from Haber-Bosch-like NH3 formation: N2 + 3H2 → 2NH3. The studied conditions suggest that the NH3 (liq.) would be condensed on the target chamber walls, thus depleting the hydrogen reserve needed for the conversion of nascent 11C to [11C]CH4. CONCLUSIONS: [11C]CH4 production can be improved by increasing the target chamber temperature, which is presented in a mathematical formula. Our observations have implications for targetry design (geometry, gas volume and composition, pressure) and irradiation conditions, providing specific knowledge to enhance [11C]CH4 production at high beam currents. Increased [11C]CH4 radioactivity is an obvious benefit in radiosynthesis in terms of product yield and molar radioactivity.

Cognitively healthy APOE4/4 carriers show white matter impairment associated with serum NfL and amyloid-PET.

Except for aging, carrying the APOE ε4 allele (APOE4) is the most important risk factor for sporadic Alzheimer's disease. APOE4 carriers may have reduced capacity to recycle lipids, resulting in white matter microstructural abnormalities. In this study, we evaluated whether white matter impairment measured by diffusion tensor imaging (DTI) differs between healthy individuals with a different number of APOE4 alleles, and whether white matter impairment associates with brain beta-amyloid (Aß) load and serum levels of neurofilament light chain (NfL). We studied 96 participants (APOE3/3, N = 37; APOE3/4, N = 39; APOE4/4, N = 20; mean age 70.7 (SD 5.22) years, 63% females) with a brain MRI including a DTI sequence (N = 96), Aß-PET (N = 89) and a venous blood sample for the serum NfL concentration measurement (N = 88). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) in six a priori-selected white matter regions-of-interest (ROIs) were compared between the groups using ANCOVA, with sex and age as covariates. A voxel-weighted average of FA, MD, RD and AxD was calculated for each subject, and correlations with Aß-PET and NfL levels were evaluated. APOE4/4 carriers exhibited a higher MD and a higher RD in the body of corpus callosum than APOE3/4 (p = 0.0053 and p = 0.0049, respectively) and APOE3/3 (p = 0.026 and p = 0.042). APOE4/4 carriers had a higher AxD than APOE3/4 (p = 0.012) and APOE3/3 (p = 0.040) in the right cingulum adjacent to cingulate cortex. In the total sample, composite MD, RD and AxD positively correlated with the cortical Aß load (r = 0.26 to 0.33, p < 0.013 for all) and with serum NfL concentrations (r = 0.31 to 0.36, p < 0.0028 for all). In conclusion, increased local diffusivity was detected in cognitively unimpaired APOE4/4 homozygotes compared to APOE3/4 and APOE3/3 carriers, and increased diffusivity correlated with biomarkers of Alzheimer's disease and neurodegeneration. White matter impairment seems to be an early phenomenon in the Alzheimer's disease pathologic process in APOE4/4 homozygotes.

Midlife insulin resistance, APOE genotype, and change in late-life brain beta-amyloid accumulation - A 5-year follow-up [11C]PIB-PET study.

We studied if midlife insulin resistance (IR) and APOE genotype would predict brain beta-amyloid (Aß) accumulation and Aß change in late-life in 5-year follow-up [11C]PIB-PET study. 43 dementia-free participants were scanned twice with [11C]PIB-PET in their late-life (mean age at follow-up 75.4 years). Participants were recruited from the Finnish Health2000 study according to their HOMA-IR values measured in midlife (mean age at midlife 55.4 years; IR+ group, HOMA-IR > 2.17; IR- group, HOMA-IR <1.25), and their APOEε4 genotype. At late-life follow-up, [11C]PIB-PET composite SUVr was significantly higher in IR+ group than IR- group (median 2.3 (interquartile range 1.7-3.3) vs. 1.7 (1.5-2.4), p = 0.03). There was no difference between IR- and IR+ groups in [11C]PIB-PET SUVr 5-year change, but the change was significantly higher in IR+/APOEε4+ group (median change 0.8 (0.60-1.0)) than in IR-/APOEε4- (0.28 (0.14-0.47), p = 0.02) and in IR+/APOEε4- group (0.24 (0.06-0.40), p = 0.046). These results suggest that APOEε4 carriers with midlife IR are at increased risk for late-life Aß accumulation.