Fractal lacunarity of trabecular bone in vertebral MRI to predict osteoporotic fracture risk in over-fifties women. The LOTO study.

BACKGROUND: Osteoporotic fractures are a major cause of morbidity in the elderly. Menopausal women represent the population with the highest risk of early osteoporosis onset, often accompanied by vertebral fractures (VF). Bone mineral density (BMD) is commonly assessed by dual-energy X-ray absorptiometry (DXA) for osteoporosis diagnosis; however, BMD alone does not represent a significant predictor of fracture risk. Bone microarchitecture, instead, arises as a determinant of bone fragility independent of BMD. High-resolution magnetic resonance imaging (MRI) is an effective noninvasive/nonionizing tool for in vivo characterisation of trabecular bone microarchitecture (TBA). We have previously set up an MRI method able to characterise TBA changes in aging and osteoporosis by one parameter, trabecular bone lacunarity parameter ß (TBLß). Fractal lacunarity was used for TBA texture analysis as it describes discontinuity of bone network and size of bone marrow spaces, changes of which increase the risk of bone fracture. This study aims to assess the potential of TBLß method as a tool for osteoporotic fracture risk. METHODS: An observational, cross-sectional, and prospective study on over-50s women at risk for VF was designed. TBLß, our index of osteoporotic fracture risk, is the main outcome measure. It was calculated on lumbar vertebra axial images, acquired by 1.5 T MRI spin-echo technique, from 279 osteopenic/osteoporotic women with/without prior VF. Diagnostic power of TBLß method, by Receiver Operating Characteristics (ROC) curve and other diagnostic accuracy measurements were compared with lumbar spine DXA-BMD. RESULTS: Baseline results show that TBLß is able to discriminate patients with/without prevalent VF (p = 0.003). AUC (area under the curve from ROC) is 0.63 for TBLß, statistically higher (p = 0.012) than BMD one (0.53). Contribution of TBLß to prevalent VF is statistically higher (p < 0.001) than BMD (sensitivity: 66% vs. 52% respectively; OR: 3.20, p < 0.0001 for TBLß vs. 1.31, p = 0.297 for BMD). Preliminary 1-year prospective results suggest that TBA contribution to incident VF is even higher (sensitivity: 73% for TBLß vs. 55% for BMD; RR: 3.00, p = 0.002 for TBLß vs. 1.31, p = 0.380 for BMD). CONCLUSION: Results from this study further highlight the usefulness of TBLß as a biomarker of TBA degeneration and an index of osteoporotic fracture risk.

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson's Disease.

Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson's disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer's disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate between AD and aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter ß, from the hyperbola model function of our lacunarity method, was statistically different between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter ß is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and aging.

Measuring Drug Therapy Effect on Osteoporotic Fracture Risk by Trabecular Bone Lacunarity: The LOTO Study.

An MRI method providing one parameter (TBLß: trabecular-bone-lacunarity-parameter-ß) that is sensitive to trabecular bone architecture (TBA) changes with aging and osteoporosis is under study as a new tool in the early diagnosis of bone fragility fracture. A cross-sectional and prospective observational study (LOTO: Lacunarity Of Trabecular bone in Osteoporosis) on over-50s women, at risk for bone fragility fracture, was designed to validate the method. From the baseline data, we observed that in women with prevalent vertebral fractures (VF+), TBA was differently characterized by TBLß when osteoporosis treatment is considered. Here we verify the potential of TBLß as an index of osteoporosis treatment efficacy. Untreated (N = 156) and treated (N = 123) women were considered to assess differences in TBLß related to osteoporosis treatment. Prevalent VFs were found in 31% of subjects, 63% of which were under osteoporosis medications. The results show that TBLß discriminates between VF+ and VF- patients (p = 0.004). This result is mostly stressed in untreated subjects. Treatment, drug therapy in particular (89% Bisphosphonates), significantly counteracts the difference between VF+ and VF- within and between groups: TBLß values in treated patients are comparable to untreated VF- and statistically higher than untreated VF+ (p = 0.014) ones. These results highlight the potential role of TBLß as an index of treatment efficacy.

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer's Disease.

Alzheimer's disease (AD) represents one major health concern for our growing elderly population. It accounts for increasing impairment of cognitive capacity followed by loss of executive function in late stage. AD pathogenesis is multifaceted and difficult to pinpoint, and understanding AD etiology will be critical to effectively diagnose and treat the disease. An interesting hypothesis concerning AD development postulates a cause-effect relationship between accumulation of mitochondrial DNA (mtDNA) mutations and neurodegenerative changes associated with this pathology. Here we propose a computerized method for an easy and fast mtDNA mutations-based characterization of AD. The method has been built taking into account the complexity of living being and fractal properties of many anatomic and physiologic structures, including mtDNA. Dealing with mtDNA mutations as gaps in the nucleotide sequence, fractal lacunarity appears a suitable tool to differentiate between aging and AD. Therefore, Chaos Game Representation method has been used to display DNA fractal properties after adapting the algorithm to visualize also heteroplasmic mutations. Parameter ß from our fractal lacunarity method, based on hyperbola model function, has been measured to quantitatively characterize AD on the basis of mtDNA mutations. Results from this pilot study to develop the method show that fractal lacunarity parameter ß of mtDNA is statistically different in AD patients when compared to age-matched controls. Fractal lacunarity analysis represents a useful tool to analyze mtDNA mutations. Lacunarity parameter ß is able to characterize individual mutation profile of mitochondrial genome and appears a promising index to discriminate between AD and aging.

MR imaging and osteoporosis: fractal lacunarity analysis of trabecular bone.

We develop a method of magnetic resonance (MR) image analysis able to provide parameter(s) sensitive to bone microarchitecture changes in aging, and to osteoporosis onset and progression. The method has been built taking into account fractal properties of many anatomic and physiologic structures. Fractal lacunarity analysis has been used to determine relevant parameter(s) to differentiate among three types of trabecular bone structure (healthy young, healthy perimenopausal, and osteoporotic patients) from lumbar vertebra MR images. In particular, we propose to approximate the lacunarity function by a hyperbola model function that depends on three coefficients, alpha, beta, and gamma, and to compute these coefficients as the solution of a least squares problem. This triplet of coefficients provides a model function that better represents the variation of mass density of pixels in the image considered. Clinical application of this preliminary version of our method suggests that one of the three coefficients, beta, may represent a standard for the evaluation of trabecular bone architecture and a potentially useful parametric index for the early diagnosis of osteoporosis.

Fractal lacunarity of trabecular bone and magnetic resonance imaging: New perspectives for osteoporotic fracture risk assessment.

Osteoporosis represents one major health condition for our growing elderly population. It accounts for severe morbidity and increased mortality in postmenopausal women and it is becoming an emerging health concern even in aging men. Screening of the population at risk for bone degeneration and treatment assessment of osteoporotic patients to prevent bone fragility fractures represent useful tools to improve quality of life in the elderly and to lighten the related socio-economic impact. Bone mineral density (BMD) estimate by means of dual-energy X-ray absorptiometry is normally used in clinical practice for osteoporosis diagnosis. Nevertheless, BMD alone does not represent a good predictor of fracture risk. From a clinical point of view, bone microarchitecture seems to be an intriguing aspect to characterize bone alteration patterns in aging and pathology. The widening into clinical practice of medical imaging techniques and the impressive advances in information technologies together with enhanced capacity of power calculation have promoted proliferation of new methods to assess changes of trabecular bone architecture (TBA) during aging and osteoporosis. Magnetic resonance imaging (MRI) has recently arisen as a useful tool to measure bone structure in vivo. In particular, high-resolution MRI techniques have introduced new perspectives for TBA characterization by non-invasive non-ionizing methods. However, texture analysis methods have not found favor with clinicians as they produce quite a few parameters whose interpretation is difficult. The introduction in biomedical field of paradigms, such as theory of complexity, chaos, and fractals, suggests new approaches and provides innovative tools to develop computerized methods that, by producing a limited number of parameters sensitive to pathology onset and progression, would speed up their application into clinical practice. Complexity of living beings and fractality of several physio-anatomic structures suggest fractal analysis as a promising approach to quantify morpho-functional changes in both aging and pathology. In this particular context, fractal lacunarity seems to be the proper tool to characterize TBA texture as it is able to describe both discontinuity of bone network and sizes of bone marrow spaces, whose changes are an index of bone fracture risk. In this paper, an original method of MRI texture analysis, based on TBA fractal lacunarity is described and discussed in the light of new perspectives for early diagnosis of osteoporotic fractures.