Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson’s disease into this case-control PET study. Patients with Parkinson’s disease were divided into 24 RBD-negative (PDRBD−) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD− and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10−13, ANOVA). When compared to the PDRBD− patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10−5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD− (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD− data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson’s disease.
Using ultrafiltration by centrifugation we have isolated the free, unbound fractions of insulin-like growth factor I and II (free IGF-I and IGF-II) in human serum. In thii way near in vivo conditions could be maintained before and during isolation. The recovery was 80 to 100% in the ultraliltrates, which contained no detectable amounts of IGF-binding proteins (IGFBPs) as measured by Western ligand blotting and IGFBP-I and IGFBP3 immunoassays. The concentration of free peptides was measured in two ultrasensitive non-competitive IGF-I and IGF-II time-resolved fluoroimmunoassays. We found that (i) equilib~um between free and prote~-~rnplex~ IGF was strongly dependent on re~s~biis~ent of in vivo conditions (temperature, pH, ionic milieu and dilution); (ii) metabolic events (glucose load and fasting) caused significant changes in free IGF-I and IGF-II levels without concomitant changes in total circulating levels of IGFs; (iii) in 49 healthy adult subjects (20 to above 60 years) free IGF-I was inversely related to age and ranged from 950 + 150 rig/l (mean z!z S.E.M.) (20-30 years) to 410 + 70 r&l (>60 years). The relative percentage was, however, unchanged, being 0.38 + 0.02% of total IGF-I. In contrast, free IGF-II was independent of age, being 1,480 k 80 rig/l (-0.20 f 0.01% of total IGF-II).
Background Obese subjects show major abnormalities in the growth hormone (GH)/insulin‐like growth factor (IGF) system. Furthermore, they are prone to develop Type 2 diabetes, but the impact of diabetes plus obesity on the GH/IGF system remains unknown. Methods We compared overnight fasting serum levels of free and total (extractable) IGF‐I and ‐II, IGF‐binding protein (IGFBP) ‐1, ‐2 and ‐3, and the high affinity GH‐binding protein (GHBP) in matched groups of lean subjects (n=26) and obese subjects without (n=24) and with (n=29) Type 2 diabetes. Two groups (n=7) of healthy and Type 1 diabetic subjects were also studied. Results Non‐diabetic obese subjects had increased free IGF‐I and ‐II, total IGF‐II, IGFBP‐3 and GHBP, reduced IGFBP‐1 and ‐2 (p<0.05), but normal total IGF‐I, when compared to lean subjects. In obese Type 2 diabetics free IGF‐I was insignificantly reduced by 9% (p=0.3), when compared to non‐diabetic obese subjects. However, the concentration was not significantly elevated when compared to that of lean controls (p=0.13). Also IGFBP‐1 and total IGF‐I were normal in obese Type 2 diabetics, whereas free and total IGF‐II and IGFBP‐3 remained elevated to a similar extent as in simple obesity (p<0.05). In contrast, GHBP was further increased and IGFBP‐2 further reduced in obese Type 2 diabetics (p<0.05). In Type 1 diabetics total IGF‐I and ‐II, and IGFBP‐3 were normal. In contrast, free IGF‐I and ‐II and GHBP were markedly reduced, whereas IGFBP‐1 and ‐2 were increased (p<0.05). Conclusions Simple obesity was associated with marked changes in the GH/IGF system. Many of these abnormalities were unaffected by the concomitant presence of Type 2 diabetes (total IGF‐I, free and total IGF‐II and IGFBP‐3). However, some changes became accentuated (GHBP and IGFBP‐2), while others (free IGF‐I and IGFBP‐1) were no longer present. Notably, the impact of Type 1 diabetes on the GH/IGF system was clearly different from that of Type 2 diabetes. Copyright © 1999 John Wiley & Sons, Ltd.
We tested the hypothesis that body composition is the major predictor of growth hormone (GH) secretion in nonobese adults. We measured lean and fat tissue distribution (computerized tomography and dual-energy X-ray absorptiometry scan) and physical fitness [maximal oxygen consumption (Vo2max)] in 42 healthy nonobese adults (22 women and 20 men, age range 27-59 yr, mean +/- SE body mass index = 24 +/- 0.5 kg/m2). Deconvolution analysis was used to estimate specific features of 24-h GH secretion and clearance. Approximate entropy was used to quantify the regularity of GH release. Older subjects exhibited decreased estimates of GH secretion compared with younger subjects. Females had higher estimates of GH secretion, a longer GH half-life, and displayed more irregularity in GH release than males. Mean 24-h serum GH concentrations correlated inversely with intra-abdominal fat and waist-to-hip ratio and positively with Vo2max. Multiple linear regression analysis revealed intra-abdominal fat as the dominant determinant of estimates of GH secretion. Vo2max was more important than sex and age in predicting GH secretion. We conclude that abdominal fat is the major determinant of GH secretion in healthy nonobese adults. Although the underlying mechanisms remain elusive, our findings extend the clinical implications of visceral adiposity to include hyposomatotropism.
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