Roger I. Price

Amyloid imaging results, from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimers Disease Neuroimaging Initiative (ADNI), performed (11)C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimers disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-epsilon4 carriers vs 21% in noncarriers) and increased with age, most strongly in epsilon4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in epsilon4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Abeta) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline.

Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study.

BACKGROUND Osteoporosis research has focused on vertebral fractures and trabecular bone loss. However, non-vertebral fractures at predominantly cortical sites account for 80% of all fractures and most fracture-related morbidity and mortality in old age. We aimed to re-examine cortical bone as a source of bone loss in the appendicular skeleton. METHODS In this cross-sectional study, we used high-resolution peripheral CT to quantify and compare cortical and trabecular bone loss from the distal radius of adult women, and measured porosity using scanning electron microscopy. Exclusion criteria were diseases or prescribed drugs affecting bone metabolism. We also measured bone mineral density of post-mortem hip specimens from female cadavers using densitometry. Age-related differences in total, cortical, and trabecular bone mass, trabecular bone of cortical origin, and cortical and trabecular densities were calculated. FINDINGS We investigated 122 white women with a mean age of 62.8 (range 27-98) years. Between ages 50 and 80 years (n=89), 72.1 mg (95% CI 67.7-76.4) hydroxyapatite (68%) of 106.5 mg hydroxyapatite of bone lost at the distal radius was cortical and 34.3 mg (30.5-37.8) hydroxyapatite (32%) was trabecular; 17.1 mg (11.7-22.5) hydroxyapatite (16%) of total bone loss occurred between ages 50 and 64 years (n=34) and 89.4 mg (83.7-101.1) hydroxyapatite (84%) after age 65 years (n=55). Remodelling within cortex adjacent to the marrow accounted for 49.9 mg (45.4-53.7) hydroxyapatite (47%) of bone loss. Between ages 50-64 years (n=34) and 80 years and older (n=33), cortical density decreased by 127.8 mg (93.1-162.1) hydroxyapatite per cm(3) (15%, p<0.0001) before porosity trabecularising the cortex was included, but 374.3 mg (318.2-429.5) hydroxyapatite per cm(3) (43%, p<0.0001) after; trabecular density decreased by 18.2 mg (-1.4 to 38.2) hydroxyapatite per cm(3) (14%, p=0.06) before cortical remnants were excluded, but 68.7 mg (37.7-90.4) hydroxyapatite per cm(3) (52%, p<0.0001) after. INTERPRETATION Accurate assessment of bone structure, especially porosity producing cortical remnants, could improve identification of individuals at high and low risk of fracture and therefore assist targeting of treatment. FUNDING Australia National Health and Medical Research Council.

An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.

Prediction of thoracic and lumbar vertebral body compressive strength: correlations with bone mineral density and vertebral region.

The bone density of thoracolumbar vertebral columns (T1 to L5) from 18 individuals was measured using quantitative computed tomography and dual energy x-ray absorptiometry. Three hundred six isolated vertebral bodies were tested in a materials test device to determine their compressive strength. Between T1 and L5 the mean segmental increase in bone mineral content was 0.3 g, while the corresponding mean decrease in trabecular density was 4.7 HU. Midvertebral body cross-sectional area increased by an average of 46 mm2 per segment and the mean segmental increase in compressive strength was 0.17 kN. Compressive strength was significantly correlated with bone mineral density measured with dual energy x-ray absorptiometry (r = 0.86). Vertebral trabecular density samples measured with quantitative computed tomography were poorly correlated with compressive strength (r = 0.28); however, this was improved when the trabecular density was multiplied by the midvertebral body cross-sectional area (r = 0.83). This study provides information concerning the relationships between density and mechanical properties of all thoracic and lumbar vertebral bodies across a wide age range. While the load-bearing capacity of the vertebral bodies is largely dependent on their geometry and bone density, this relationship has been only extensively tested for the lumbar spine. This study extends these observations over the lumbar and thoracic regions to provide a comprehensive analysis of the strength characteristics of each vertebral body. This is particularly important given the paucity of data on the thoracic spine where age-related vertebral fractures predominate. These data provide a basis for the development of models to predict the potential for thoracolumbar fractures in the elderly vertebral column.

Predicting Alzheimer disease with β-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing

Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β‐amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E ε4 status in nondemented, older individuals.

The efficiency of intestinal calcium absorption is increased in late pregnancy but not in established lactation

SummaryThe fractional absorption of calcium (FA-Ca) was measured using a dual non-radioactive Ca isotope technique in 26 control women, 49 women in the last triimester (36 weeks) of pregnancy and 31 of these women in established (20 weeks) lactation. The ratio of the two non-radioactive Ca isotopes was measured, by high precision thermal ionisation mass spectrometry, in urine 12–24 hours after administration and was used to calculate Fa-Ca. This is the first study to clearly show that FA-Ca is significantly elevated in late pregnancy but not in established lactation, when compared with control women.

Ex vivo estimation of thoracolumbar vertebral body compressive strength : The relative contributions of bone densitometry and vertebral morphometry

The estimation of vertebral fracture risk in individuals with suspected osteopenia is commonly based on measurements of lumbar spine bone density. The efficacy of vertebral size and deformity, as assessed by vertebral morphometry, in the prediction of fractures has been less studied. In an ex vivo investigation the regional relationships between vertebral size, vertebral deformity, bone density and compressive strength throughout the thoracolumbar spine were examined. In 16 vertebral columns (T1–L5) the bone mineral content (BMC) and bone mineral density (BMD) of each segment were measured using lateral projection dual-energy X-ray absorptiometry, and the vertebral cancellous density (VCD) and mid-vertebral cross-sectional area (CSA) measured using quantitative computed tomography. Vertebral body heights were determined from mid-sagittal CT scans, and vertical height ratios calculated for each segment. The failure load and failure stress of the isolated vertebral bodies were determined using a material testing device. Separate analyses were performed for the upper (T1–4), middle (T5–8) and lower (T9–12) thoracic, and lumbar (L1–5) segments. In all regions, failure load was strongly correlated with BMD (r=0.82–0.86), moderately correlated with VCD (r=0.60–0.71) and vertebral height (r=0.22–0.49), and poorly correlated with the height ratios (r=0.04–0.33). Failure stress was best predicted by BMD (r=0.73–0.78) and VCD (r=0.70–0.78) but was poorly correlated with all morphometric variables (r=0.01–0.33). The segmental correlations between BMD and VCD ranged fromr=0.49 tor=0.79. For all regions, BMD and VCD were included in the stepwise regression models for predicting failure load and failure stress. Either the mid-vertebral height or CSA were included in all the failure load models, while mid-vertebral height was included in only one of the failure stress models. The results suggest that vertebral deformity and size (as assessed by vertebral morphometry) make only a minor contribution to the prediction of vertebral strength additional to that provided by bone densitometry alone. The consistent regional relationships between variables appear to support the practice of global fracture risk assessment based on lumbar spine densitometry.

The relative influence of vertebral body and intervertebral disc shape on thoracic kyphosis

OBJECTIVE The aim of this study was to quantify the morphology or shape of thoracic vertebral bodies and intervertebral discs, and to examine the ex vivo association of thoracic kyphosis with these shape parameters. DESIGN A quantitative, retrospective study design was applied to define vertebral body and disc influences on thoracic kyphosis. BACKGROUND Age-related progression of thoracic kyphosis is a well-defined process that is influenced by the morphology of vertebral bodies. However, little is known about the contribution of intervertebral disc shape to the thoracic curvature. METHODS Vertebral and disc morphology, as represented by antero-posterior height ratios, were quantified in 93 lateral spine radiographs and midsagittal computed tomography films of ex vivo spines. Kyphosis was indicated by the Cobb angle. Linear and stepwise regression were applied to examine relationships for cumulative (T1-T12) and regional (T4-T9) analyses. RESULTS Vertebral morphology was highly predictive of thoracic curvature, while a poorer association was noted for disc morphology. The combined influence of both accounted for >85% of the variability in kyphosis. There was a trend for a more pronounced anterior wedge configuration of the midthoracic vertebral bodies and discs. Higher associations between variables were also noted in this region. CONCLUSIONS The normal kyphosis of the thoracic spine reflects the morphological adaptation of both the vertebral bodies and intervertebral discs. RELEVANCE This study contributes new data on the thoracic spine, particularly the characteristics of thoracic discs and their contribution to kyphosis genesis. Future directions for morphology studies should encompass more detailed examination of the thoracic discs and greater emphasis on the midthoracic segments, considering the prevalence of osteoporosis related fractures and subsequent deformity at these levels.

Topographical variation within the articular cartilage and subchondral bone of the normal ovine knee joint: a histological approach.

Topographical variation in the articular cartilage and subchondral bone of the normal ovine knee was examined using histological techniques. The articular cartilage was examined grossly, then histological sections were cut and the cartilage thickness and chondrocyte density were measured. Bone mineral density, thickness of the subchondral bone plate (SBP) and volume and surface histomorphometrical parameters and mineral apposition rate were calculated for the subchondral bone. It was found that the articular cartilage on the tibial plateaux was thicker, less cellular, and overlay a thicker SBP than that on the femoral condyles. Similarly, the cartilage in the medial joint compartments was thicker, less cellular and overlying a thicker less dense SBP than that in the lateral joint compartments. There was no variation in bone histomorphometric parameters or mineral apposition rate between regions. Biomechanical testing has shown that loading is not uniform throughout the normal human knee joint. The present results suggest that loading within the ovine knee is also nonuniform, with the central regions of the tibial plateaux bearing greater loads than the femoral condyles, and the medial joint compartment being loaded more than the lateral one. The articular cartilage and subchondral bone have adapted in order to best withstand these variations in loading. These histological findings, plus the topographical variations in cartilage biochemistry reported by Read et al. (Topographical variation in composition, PG-biosynthesis and swelling pressure of cartilages of loaded tibio-femoral joints (Abstract). Proceedings of the Combined Meeting of the Orthopaedic Research Societies of USA, Japan and Canada.(ABSTRACT TRUNCATED AT 250 WORDS)

Formalin fixation effects on vertebral bone density and failure mechanics: an in-vitro study of human and sheep vertebrae.

Vertebral bone density of two human vertebral specimens was evaluated using dual-anergy X-ray absorptiometry and single-energy quantitative computed tomography immediately before and after 4 weeks of fixation. The repeated QCT assessment of these segments produced a mean rate of change of 1.17 HU/month, while for DXA the mean rate of change was -0.002 g/month for BMC and -0.0004 g/cm(2)/month for BMD. Ten fresh and 10 fixed sheep lumbar spines underwent absorptiometry before being sectioned into units comprising a central vertebra and adjacent intervertebral discs, plus 1 cm of the flanking vertebral end-plate for embedding into bone cement. The fixed sheep spines underwent a repeat scan after 4 weeks in 10% formalin. Mechanical testing produced a significantly lower average failure load for unfixed specimens (9.3 kN) than for the fixed material (10.8 kN). Failure strain was not significantly different between groups. Linear regression showed a high correlation of BMC values before and after 4 weeks of formalin fixation, while the slopes of the regression for BMD and failure load of both fresh and fixed groups were not significantly different. While formalin fixation may result in a slight increase in compressive strength this does not appear to be associated with a systematic change in mineral density.