Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models.

BACKGROUND: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free-water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. OBJECTIVES: To quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). METHOD: Multi-shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. RESULTS: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ 2 > 0.46). CONCLUSIONS: Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessing transmission risks and control strategy for monkeypox as an emerging zoonosis in a metropolitan area.

To model the spread of monkeypox (MPX) in a metropolitan area for assessing the risk of possible outbreaks, and identifying essential public health measures to contain the virus spread. The animal reservoir is the key element in the modeling of zoonotic disease. Using a One Health approach, we model the spread of the MPX virus in humans considering potential animal hosts such as rodents (e.g., rats, mice, squirrels, chipmunks, etc.) and emphasize their role and transmission of the virus in a high-risk group, including gay and bisexual men-who-have-sex-with-men (gbMSM). From model and sensitivity analysis, we identify key public health factors and present scenarios under different transmission assumptions. We find that the MPX virus may spill over from gbMSM high-risk groups to broader populations if the efficiency of transmission increases in the higher-risk group. However, the risk of outbreak can be greatly reduced if at least 65% of symptomatic cases can be isolated and their contacts traced and quarantined. In addition, infections in an animal reservoir will exacerbate MPX transmission risk in the human population. Regions or communities with a higher proportion of gbMSM individuals need greater public health attention. Tracing and quarantine (or "effective quarantine" by postexposure vaccination) of contacts with MPX cases in high-risk groups would have a significant effect on controlling the spreading. Also, monitoring for animal infections would be prudent.

Using seconds-resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time-varying physiology.

AIM: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench-top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours-scale, time-varying physiological processes. Given the recent advent of in vivo electrochemical aptamer-based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time-dense datasets to describe time-varying pharmacokinetic models with good statistical significance. METHODS: We used seconds-resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one- and two-compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. RESULTS: We found that a modified one-compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two-compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one-compartment, time-varying model was statistically preferred over the standard one-compartment model for 80% of our datasets. CONCLUSIONS: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high-time resolution EAB sensor measurements to identify such impacts.

Age-specific contribution of contacts to transmission of SARS-CoV-2 in Germany.

Current estimates of pandemic SARS-CoV-2 spread in Germany using infectious disease models often do not use age-specific infection parameters and are not always based on age-specific contact matrices of the population. They also do usually not include setting- or pandemic phase-based information from epidemiological studies of reported cases and do not account for age-specific underdetection of reported cases. Here, we report likely pandemic spread using an age-structured model to understand the age- and setting-specific contribution of contacts to transmission during different phases of the COVID-19 pandemic in Germany. We developed a deterministic SEIRS model using a pre-pandemic contact matrix. The model was optimized to fit age-specific SARS-CoV-2 incidences reported by the German National Public Health Institute (Robert Koch Institute), includes information on setting-specific reported cases in schools and integrates age- and pandemic period-specific parameters for underdetection of reported cases deduced from a large population-based seroprevalence studies. Taking age-specific underreporting into account, younger adults and teenagers were identified in the modeling study as relevant contributors to infections during the first three pandemic waves in Germany. For the fifth wave, the Delta to Omicron transition, only age-specific parametrization reproduces the observed relative and absolute increase in pediatric hospitalizations in Germany. Taking into account age-specific underdetection did not change considerably how much contacts in schools contributed to the total burden of infection in the population (up to 12% with open schools under hygiene measures in the third wave). Accounting for the pandemic phase and age-specific underreporting is important to correctly identify those groups of the population in which quarantine, testing, vaccination, and contact-reduction measures are likely to be most effective and efficient. Age-specific parametrization is also highly relevant to generate informative age-specific output for decision makers and resource planers.

Transfer of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) from oral exposure into cow's milk - part II: toxicokinetic predictive models for risk assessment.

Understanding the transfer of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as well as polychlorinated biphenyls (PCBs) from oral exposure into cow's milk is not purely an experimental endeavour, as it has produced a large corpus of theoretical work. This work consists of a variety of predictive toxicokinetic models in the realms of health and environmental risk assessment and risk management. Their purpose is to provide mathematical predictive tools to organise and integrate knowledge on the absorption, distribution, metabolism and excretion processes. Toxicokinetic models are based on more than 50 years of transfer studies summarised in part I of this review series. Here in part II, several of these models are described and systematically classified with a focus on their applicability to risk analysis as well as their limitations. This part of the review highlights the opportunities and challenges along the way towards accurate, congener-specific predictive models applicable to changing animal breeds and husbandry conditions.

Determination of Fat-Free Mass Density and its Components in Older Hispanic Adults by In Vivo Methods.

The densitometry method estimates body composition based on cadaver reference values, mainly the fat-free mass density value of 1.100 g/cm3. However, several changes in fat-free mass components by aging, ethnicity, and excess adiposity could influence their density and affect body composition estimations. The present study aimed to compare the mean fat-free mass component values in older Hispanic adults to cadaver reference values. This cross-sectional study included a sample of 420 subjects aged ≥60 yr from northern Mexico. Fat-free mass was determined by the four-compartment model using air displacement plethysmography, the deuterium dilution technique, and dual-energy X-ray absorptiometry for body density, aqueous and mineral fractions of body weight, respectively. A 1-sample t test was used to compare the fat-free mass density and aqueous, mineral, and residue fractions of fat-free mass from subjects in the study to the assumed cadaver reference values. The mean fat-free mass density value for the total sample of older Hispanic adults (1.096 ± 0.011 g/cm3) was significantly (p < 0.001) lower than the assumed value of 1.100 g/cm3, except in obese older men. The mean aqueous fraction of fat-free mass (74.8 ± 3.3%) was higher than the assumed value of 73.8%, and the mean residue fraction of fat-free mass value was lower (18.3 ± 3.4%) than the reference value of 19.4%. Indeed, only the mean mineral fraction of fat-free mass value (6.8 ± 0.8%) was similar to the reference value. In the total sample, all characteristic mean fat-free mass values in these older Hispanic adults differed from cadaver reference values, except the mineral fraction of fat-free mass value.

Five-component model validation of reference, laboratory and field methods of body composition assessment.

This study reports the validity of body fat percentage (BF%) estimates from several commonly employed techniques as compared with a five-component (5C) model criterion. Healthy adults (n 170) were assessed by dual-energy X-ray absorptiometry (DXA), air displacement plethysmography (ADP), multiple bioimpedance techniques and optical scanning. Output was also used to produce a criterion 5C model, multiple variants of three- and four-component models (3C; 4C) and anthropometry-based BF% estimates. Linear regression, Bland-Altman analysis and equivalence testing were performed alongside evaluation of the constant error (CE), total error (TE), se of the estimate (SEE) and coefficient of determination (R2). The major findings were (1) differences between 5C, 4C and 3C models utilising the same body volume (BV) and total body water (TBW) estimates are negligible (CE ≤ 0·2 %; SEE < 0·5 %; TE ≤ 0·5 %; R2 1·00; 95 % limits of agreement (LOA) ≤ 0·9 %); (2) moderate errors from alternate TBW or BV estimates in multi-component models were observed (CE ≤ 1·3 %; SEE ≤ 2·1 %; TE ≤ 2·2 %; R2 ≥ 0·95; 95 % LOA ≤ 4·2 %); (3) small differences between alternate DXA (i.e. tissue v. region) and ADP (i.e. Siri v. Brozek equations) estimates were observed, and both techniques generally performed well (CE < 3·0 %; SEE ≤ 2·3 %; TE ≤ 3·6 %; R2 ≥ 0·88; 95 % LOA ≤ 4·8 %); (4) bioimpedance technologies performed well but exhibited larger individual-level errors (CE < 1·0 %; SEE ≤ 3·1 %; TE ≤ 3·3 %; R2 ≥ 0·94; 95 % LOA ≤ 6·2 %) and (5) anthropometric equations generally performed poorly (CE 0·6- 5·7 %; SEE ≤ 5·1 %; TE ≤ 7·4 %; R2 ≥ 0·67; 95 % LOA ≤ 10·6 %). Collectively, the data presented in this manuscript can aid researchers and clinicians in selecting an appropriate body composition assessment method and understanding the associated errors when compared with a reference multi-component model.

Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments.

Compartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and further analysis of these systems. Transit compartment models are a popular semi-mechanistic approach for generalising simple PK models to allow for delayed kinetics, but computing exact solutions for multi-dosing inputs to transit compartment systems leading to different final compartments is nontrivial. Here, we find exact solutions for drug levels as functions of time throughout a linear transit compartment cascade followed by an absorption compartment and a central blood compartment, for the general case of n transit compartments and M equi-bolus doses to the first compartment. We further show the utility of exact solutions to PK ODE models in finding constraints on equi-dosing regimen parameters imposed by a prescribed therapeutic range. This leads to the construction of equi-dosing regimen regions (EDRRs), providing new, novel visualisations which summarise the safe and effective dosing parameter space. EDRRs are computed for classical and transit compartment models with two- and three-dimensional parameter spaces, and are proposed as useful graphical tools for informing drug dosing regimen design.

Residence time distribution (RTD) revisited.

Residence Time Distribution (RTD) theory is revisited and tracer technology discussed. The background of RTD following Danckwerts ideas is presented by introducing "distribution" functions for residence time, internal age and intensity function and how to experimentally obtain them with tracer techniques (curves C and F of Danckwerts). Compartment models to describe fluid flow in real reactors are reviewed and progressive modeling of chromatographic processes discussed in some detail. The shortcomings of Standard Dispersion Model (SDM) are addressed, the Taylor-Aris model discussed and the Wave Model of Westerterp's group introduced. The contribution of Computational Fluid Dynamics (CFD) is highlighted to calculate RTD from momentum and mass transport equations and to access spatial age distribution and degree of mixing. Finally smart RTD and future challenges are discussed.

What are the COVID-19 models modeling (philosophically speaking)?

COVID-19 epidemic models raise important questions for science and philosophy of science. Here I provide a brief preliminary exploration of three: what kinds of predictions do epidemic models make, are they causal models, and how do different kinds of epidemic models differ in terms of what they represent?

Higher-order diffusion MRI characterization of mesorectal lymph nodes in rectal cancer.

PURPOSE: Mesorectal lymph node staging plays an important role in treatment decision making. Here, we explore the benefit of higher-order diffusion MRI models accounting for non-Gaussian diffusion effects to classify mesorectal lymph nodes both 1) ex vivo at ultrahigh field correlated with histology and 2) in vivo in a clinical scanner upon patient staging. METHODS: The preclinical investigation included 54 mesorectal lymph nodes, which were scanned at 16.4 T with an extensive diffusion MRI acquisition. Eight diffusion models were compared in terms of goodness of fit, lymph node classification ability, and histology correlation. In the clinical part of this study, 10 rectal cancer patients were scanned with diffusion MRI at 1.5 T, and 72 lymph nodes were analyzed with Apparent Diffusion Coefficient (ADC), Intravoxel Incoherent Motion (IVIM), Kurtosis, and IVIM-Kurtosis. RESULTS: Compartment models including restricted and anisotropic diffusion improved the preclinical data fit, as well as the lymph node classification, compared to standard ADC. The comparison with histology revealed only moderate correlations, and the highest values were observed between diffusion anisotropy metrics and cell area fraction. In the clinical study, the diffusivity from IVIM-Kurtosis was the only metric showing significant differences between benign (0.80 ± 0.30 µm2 /ms) and malignant (1.02 ± 0.41 µm2 /ms, P = .03) nodes. IVIM-Kurtosis also yielded the largest area under the receiver operating characteristic curve (0.73) and significantly improved the node differentiation when added to the standard visual analysis by experts based on T2 -weighted imaging. CONCLUSION: Higher-order diffusion MRI models perform better than standard ADC and may be of added value for mesorectal lymph node classification in rectal cancer patients.

Development of a dual-energy X-ray absorptiometry-derived body volume equation in Hispanic adults for administering a four-compartment model.

The purpose of the present study was: (1) to develop a new dual-energy X-ray absorptiometry (DXA)-derived body volume (BV) equation with the GE-Lunar prodigy while utilising underwater weighing (UWW) as a criterion and (2) to cross-validate the novel DXA-derived BV equation (4C-DXANickerson), Wilson DXA-derived BV equation (4C-DXAWilson) and air displacement plethysmography (ADP)-derived BV (4C-ADP) in Hispanic adults. A total of 191 Hispanic adults (18-45 years) participated in the present study. The development sample consisted of 120 females and males (50 % females), whereas the cross-validation sample comprised of forty-one females and thirty males (n 71). Criterion body fat percentage (BF %) and fat-free mass (FFM) were determined using a four-compartment (4C) model with UWW as a criterion for BV (4C-UWW). 4C-DXANickerson, 4C-DXAWilson and 4C-ADP were compared against 4C-UWW in the cross-validation sample. 4C-DXANickerson, 4C-DXAWilson and 4C-ADP all produced similar validity statistics when compared with 4C-UWW in Hispanic males (all P > 0·05). 4C-DXANickerson also yielded similar BF % and FFM values as 4C-UWW when evaluating the mean differences (constant error (CE)) in Hispanic females (CE = -0·79 % and 0·38 kg; P = 0·060 and 0·174, respectively). However, 4C-DXAWilson produced significantly different BF % and FFM values (CE = 3·22 % and -2·20 kg, respectively; both P < 0·001). Additionally, 4C-DXAWilson yielded significant proportional bias when estimating BF % (P < 0·001), whereas 4C-ADP produced significant proportional bias for BF % and FFM (both P < 0·05) when evaluated in Hispanic females. The present study findings demonstrate that 4C-DXANickerson is a valid measure of BV in Hispanics and is recommended for use in clinics, where DXA is the main body composition assessment technique.

The computation of biomarkers in pharmacokinetics with the aid of singular perturbation methods.

In pharmacokinetics, exact solutions to one-compartment models with nonlinear elimination kinetics cannot be found analytically, if dosages are assumed to be administered repetitively through extravascular routes (Tang and Xiao in J Pharmacokinet Pharmacodyn 34(6):807-827, 2007). Hence, for the corresponding impulsed dynamical system, alternative methods need to be developed to find approximate solutions. The primary purpose of this paper is to use the method of matched asymptotic expansions (Holmes Introduction to Perturbation Methods, vol 20. Springer Science & Business Media, Berlin, 2012), a singular perturbation method (Holmes, Introduction to Perturbation Methods, vol 20. Springer Science & Business Media, Berlin, 2012; Keener Principles of Applied Mathematics, Addison-Wesley, Boston, 1988), to obtain approximate solutions. With this method, we are able to rigorously determine conditions under which there is a stable periodic solution of the model equations. Furthermore, typical important biomarkers that enable the design of practical, efficient and safe drug delivery protocols, such as the time the drug concentration reaches the peak and the peak concentrations, are theoretically estimated by the perturbation method we employ.

Modeling the pharmacokinetics and pharmacodynamics of sevoflurane using compartment models in children and adults.

BACKGROUND: Sevoflurane pharmacokinetics have been traditionally described using physiological models, while pharmacodynamics employed the use of minimal alveolar concentration. AIMS: The integrated pharmacokinetic-pharmacodynamic relationship of sevoflurane in both adults and children was reviewed using compartment models. We wished to delineate age-related changes in both pharmacokinetics and pharmacodynamics. METHODS: The bispectral index and sevoflurane endtidal concentration were continuously measured in 50 patients, aged 3-71 years, scheduled for minor surgery. During maintenance of anesthesia and after stable bispectral index values of 60-65 were obtained, the inspired concentration of sevoflurane was increased to 5 vol % for 5 minutes or until BIS 40 and then decreased. Data were analyzed using mammillary compartments with nonlinear mixed effects population modeling. The covariate effects of age and size were investigated. RESULTS: A three-compartment PK model adequately described sevoflurane pharmacokinetics. Size standardization using allometry explained clearance and volume changes with age. The equilibration half-time (1.48 minutes) increased with age, but could be predicted using allometry in those under 40 years. The effect site concentration eliciting half the maximum response at age 40 years was 1.3% (95%CI 1.22, 1.42) decreased with age from 1.6% at 3 years to 1.1% at 70 years. CONCLUSION: Pharmacokinetic compartment models offer an alternative method to describe inhalation anesthetic drug disposition and effects.

Transit and lifespan in neutrophil production: implications for drug intervention.

A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells. An overview of the well established linear chain technique, used to reformulate transit compartment models with constant transit rates as distributed delay differential equations (DDEs), is then given. A state-dependent time rescaling of the Quartino model is performed to apply the linear chain technique and rewrite the Quartino model as a distributed DDE, yielding a discrete DDE model in a certain parameter limit. Next, stability and bifurcation analyses are undertaken in an effort to situate such studies in a mathematical pharmacology context. We show that both the original Friberg and the Quartino extension models incorrectly define the mean maturation time, essentially treating the proliferative pool as an additional maturation compartment. This misspecification can have far reaching consequences on the development of future models of myelosuppression in PK/PD.

A distributed delay approach for modeling delayed outcomes in pharmacokinetics and pharmacodynamics studies.

A distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models). Real-life examples were given to demonstrate how to implement distributed delays in Phoenix® NLME™ 8.0, and to numerically show the advantages of the distributed delay approach over the traditional methods.

Robust and fast nonlinear optimization of diffusion MRI microstructure models.

Advances in biophysical multi-compartment modeling for diffusion MRI (dMRI) have gained popularity because of greater specificity than DTI in relating the dMRI signal to underlying cellular microstructure. A large range of these diffusion microstructure models have been developed and each of the popular models comes with its own, often different, optimization algorithm, noise model and initialization strategy to estimate its parameter maps. Since data fit, accuracy and precision is hard to verify, this creates additional challenges to comparability and generalization of results from diffusion microstructure models. In addition, non-linear optimization is computationally expensive leading to very long run times, which can be prohibitive in large group or population studies. In this technical note we investigate the performance of several optimization algorithms and initialization strategies over a few of the most popular diffusion microstructure models, including NODDI and CHARMED. We evaluate whether a single well performing optimization approach exists that could be applied to many models and would equate both run time and fit aspects. All models, algorithms and strategies were implemented on the Graphics Processing Unit (GPU) to remove run time constraints, with which we achieve whole brain dataset fits in seconds to minutes. We then evaluated fit, accuracy, precision and run time for different models of differing complexity against three common optimization algorithms and three parameter initialization strategies. Variability of the achieved quality of fit in actual data was evaluated on ten subjects of each of two population studies with a different acquisition protocol. We find that optimization algorithms and multi-step optimization approaches have a considerable influence on performance and stability over subjects and over acquisition protocols. The gradient-free Powell conjugate-direction algorithm was found to outperform other common algorithms in terms of run time, fit, accuracy and precision. Parameter initialization approaches were found to be relevant especially for more complex models, such as those involving several fiber orientations per voxel. For these, a fitting cascade initializing or fixing parameter values in a later optimization step from simpler models in an earlier optimization step further improved run time, fit, accuracy and precision compared to a single step fit. This establishes and makes available standards by which robust fit and accuracy can be achieved in shorter run times. This is especially relevant for the use of diffusion microstructure modeling in large group or population studies and in combining microstructure parameter maps with tractography results.

The muddle of ages, turnover, transit, and residence times in the carbon cycle.

Comparisons among ecosystem models or ecosystem dynamics along environmental gradients commonly rely on metrics that integrate different processes into a useful diagnostic. Terms such as age, turnover, residence, and transit times are often used for this purpose; however, these terms are variably defined in the literature and in many cases, calculations ignore assumptions implicit in their formulas. The aim of this opinion piece was i) to make evident these discrepancies and the incorrect use of formulas, ii) highlight recent results that simplify calculations and may help to avoid confusion, and iii) propose the adoption of simple and less ambiguous terms.

Biokinetic measurements and modelling of urinary excretion of cerium citrate in humans.

Tracer kinetics in healthy human volunteers was studied applying stable isotopes of cerium citrate to obtain biokinetic human data for the urinary excretion of cerium. These data were then used to compare and validate the biokinetic model for lanthanides (cerium) proposed by Taylor and Leggett (Radiat Prot Dosim 105:193-198, 2003), which is substantially improved and more realistic than the biokinetic model currently recommended by the International Commission on Radiological Protection (ICRP Publication 67, 1993); both models are primarily based on animal data. In the present study, 16 adults were investigated and two cerium tracers were simultaneously administered, both intravenously and/or orally. The cerium concentrations in urine were determined by inductively coupled plasma mass spectrometry. Ingested cerium citrate was poorly absorbed, and its low excretion was similar to the prediction of the biokinetic model of Taylor and Leggett. In contrast, after injection of cerium citrate its urinary excretion was rapidly increased, and the model underestimated the experimental results. These results suggest that urinary excretion of cerium may be dependent on the administered chemical form of cerium (speciation).

Information-based ranking of 10 compartment models of diffusion-weighted signal attenuation in fixed prostate tissue.

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.