Changes in circulating osteoblast lineage cells following PTH (1–34) therapy and correlation with changes in trabecular bone mass

Using flow-cytometry, we previously demonstrated a five-fold increase in circulating osteoblast progenitor cells in pubertal boys compared to adult males (NEJM 352:1959–1966). We recently further classified these osteocalcin (OCN) positive cells into two distinct populations: small, relatively agranular cells that co-stained for the stem cell marker, CD34 (OCNsmall, which may represent a less differentiated cell population), and larger, more granular cells that were CD34 negative (OCNgran, which may represent a more differentiated cell population) (Bone 40:1370–1377). To evaluate the effects of PTH therapy on these cells, we studied 8 women at baseline, 3 months and 12 months after starting 20 meg/day rh 1–34 PTH (Forteo). All 8 subjects completed the baseline and 3 month visit, and 7 of the 8 completed the 12 month visit. Panel A in the figure shows the changes in the OCNsmalland OCNgran cells. At 3 months, there was no significant change in the OCNsmall cells, but a trend for an increase (of 26%, P = 0.14) in the OCNgran cells. However, at 12 months, this pattern was reversed, with the OCNsmall cells showing a marked increase (of 64%, P = 0.016), and the OCNgran showing a decrease back to baseline levels. Interestingly, the percent change in OCNgran cells between 0 and 12 months was highly positively correlated (R = 0.82, P = 0.02) with changes in bone volume/tissue volume (BV/TV) as assessed by high resolution 3D-pQCT (Xtreme CT, Scanco) in these patients (Panel B). The mean (± SEM) increase in BV/TV in the subjects who had an increase in the OCNgran cells between baseline and 12 months was 10.8 ± 3.25% as compared to 1.7 ± 0.6% in the subjects who had a decrease in these cells (P = 0.066). To the extent that the OCNsmall cells and OCNsmall cells represent less as compared to more differentiated osteoprogenitor populations, respectively, our findings suggest that PTH initially expands the population of more mature osteoprogenitor cells, whereas over a longer period of time this effect wanes, and more immature cells are recruited along the osteoblast pathway. Sustained increases in the more differentiated cells appear to be predictive of larger gains in trabecular bone volume, although further studies characterizing the relative osteoblastic differentiation of the OCNsmall vs. OCNgran are needed to test this hypothesis

A novel MRI-biomarker candidate for Alzheimer's disease composed of regional brain volume and perfusion variables

Background: Earlier evidence indicates that regional cerebral volume (rVOL) and blood flow (rCBF) variables carry independent information on incipient and early Alzheimer's disease (AD) and combining these modalities may increase discriminant performance. We compared single variables and combinations regarding their power for optimizing diagnostic accuracy. Methods: Twelve cognitively normal elderly controls (CN), 30 subjects with mild cognitive impairment (MCI) and 15 with mild AD were examined by structural and perfusion-weighted magnetic resonance imaging (MRI) in single sessions at 1.5 Tesla. rVOLs were measured by manual volumetry, and rCBFs were calculated with a ROI-based co-localization technique. Results: Applying single MRI variables for the differentiation of AD versus CN, the area under curve (AUC) of receiver operating characteristic curves (ROCCs) was highest for rVOL variables (maximum of 0.972 for right amygdala). A composite marker selected and weighted by logistic regression containing left amygdalar rCBF, left hippocampal and right amygdalar rVOLs gave a diagnostic accuracy for AD versus CN of 100%. Internal cross-validation revealed a reliability of 88.9%. Conclusions: Whilst external revalidation is mandatory employing a naturalistic sample containing disease controls, our phase I/II findings demonstrate that deducing composite markers from multimodal MRI acquisitions can optimize diagnostic accuracy for AD

The relation of regional cerebral perfusion and atrophy in mild cognitive impairment (MCI) and early Alzheimer's dementia

The spatial and temporal relations between regional cerebral blood flow (rCBF) and brain volume (rVOL) changes in incipient and early Alzheimer's dementia (AD) are not fully understood. The participants comprised 30 subjects with mild cognitive impairment (MCI) and 15 with mild AD who were examined using structural and perfusion-weighted magnetic resonance imaging (MRI) at 1.5 Tesla. Hippocampus and amygdala volumes were measured by manual volumetry. A region-of-interest co-localisation method was used to calculate rCBF values. DNA samples were genotyped for apolipoprotein E (APO E). In comparisons of AD with MCI, rCBF was reduced in the posterior cingulum only, while profound rVOL reductions occurred in both right and left amygdala and in the right hippocampus, and as a trend, in the left hippocampus. Brain volumes of the hippocampus and the amygdala were uncorrelated with the respective rCBF variables in both MCI and AD. Hippocampal but not amygdalar volumes were associated with presence of one or two APOE epsilon4 alleles in MCI and mild AD, while there was no association of APOE epsilon4 allele with rCBF. These data support earlier indications that rCBF and rVOL changes are at least partly dissociated in the early pathogenesis of AD and heterogeneously associated with the APOE risk allele. The data also support the concept of functional compensatory brain activation and the diaschisis hypothesis as relevant in incipient and early AD