NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study.

BACKGROUND AND PURPOSE: The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive. MATERIALS AND METHODS: A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent 1H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry. RESULTS: Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis. CONCLUSIONS: This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

Prevalence of intimate partner violence perpetration among military populations: A systematic review and meta-analysis.

Intimate partner violence (IPV) is a global health issue that impacts both civilian and military populations. Factors associated with military service may result in increased risk of IPV perpetration among Veterans and Active Duty military personnel. Six bibliographic databases were searched to identify studies that estimated the prevalence of IPV perpetration among military populations by sociodemographic and military characteristics. Where possible, random effect meta-analyses were conducted to determine pooled prevalence estimates. 42 studies were eligible for inclusion in this systematic review. 28 of these studies met the requirements for inclusion in subsequent meta-analyses. Among studies that measured past-year physical IPV perpetration, the pooled prevalence was higher among men compared to women (26% and 20% respectively). Among Veterans, there were consistently higher prevalences compared to Active Duty samples. Similarly, higher prevalences were found among studies in general military settings compared to clinical settings. Further research that considers the impact of the act(s) of IPV perpetration on the victims is needed. This, along with the use of a consistent measurement tools across studies will help to develop a stronger evidence base to inform prevention and management programs for all types of IPV perpetration among military personnel.

Correction to 'An empirical measure of nonlinear strain for soft tissue indentation'.

[This corrects the article DOI: 10.1098/rsos.170894.].

Indentation of heterogeneous soft tissue: Local constitutive parameter mapping using an inverse method and an automated rig.

In the domain of soft tissue biomechanics, the development of numerical simulations has raised the experimental challenge of identifying local internal mechanical constitutive data of heterogeneous organs (e.g. brain tissue). In this context, this paper presents an ex-vivo alternative characterization method to full-field imaging techniques. It is based on automated, multiple indentations of an organ section using a custom-built rig, effectively allowing to map the viscoelastic and hyperelastic constitutive parameters of the tissue at the millimetre scale, under dynamic conditions. In this paper, this technique is described and used to map the constitutive data of three sections from porcine liver, kidney and brain tissues. The results of this mapping present strong evidence of correlation between the organ constituents (e.g. white/grey matter distribution) and the identified constitutive parameters. It was also found that brain and kidney tissues are highly heterogeneous in terms of identified properties, suggesting that such a technique is essential for fully characterizing their mechanical behaviour. This method opens the way to 3D mapping of constitutive parameters to feed finite element models of the organs with region-specific properties.

An empirical measure of nonlinear strain for soft tissue indentation.

Indentation is a primary tool in the investigation of the mechanical properties of very soft tissue such as the brain. However, the usual material characterization protocols are not applicable because the resulting deformation is inhomogeneous, with even the identification of the amount of strain ambiguous and uncertain. Focusing on spherical indentation only, a standard is needed to quantify the amount of strain in terms of the probe radius and displacement so that different indentation experiments can be compared and contrasted. It is shown here that the minimum axial value of the Eulerian logarithmic strain tensor has many desirable properties of such a standard, such as invariance under the choice of material model, and experimental conditions for a given probe displacement. The disadvantage of this measure is that sophisticated finite element techniques need to be used in its determination. An empirical relation is obtained between this strain and the probe radius and displacement to circumvent this problem, and it is shown that this relationship is an excellent predictor of the strain measure. Two essential features of this empirical measure for nonlinear strains are that the exact strain measure for the linear theory is recovered on restriction to infinitesimal deformations and that the simulations use models based on reliable and accurate indentation data obtained from freshly harvested murine brains using a bespoke micro-indentation device.

A new formulation of slight compressibility for arterial tissue and its Finite Element implementation.

In order to avoid the numerical difficulties in locally enforcing the incompressibility constraint using the displacement formulation of the Finite Element Method, slight compressibility is typically assumed when simulating the mechanical response of arterial tissue. The current standard method of accounting for slight compressibility of hyperelastic soft tissue assumes an additive decomposition of the strain-energy function into a volumetric and a deviatoric part. This has been shown, however, to be inconsistent with the linear theory and results in cubes retaining their cuboid shape under hydrostatic tension and compression, which seems at variance with the reinforcement of arterial tissue with two families of collagen fibres. A remedy for these defects is proposed here, a solution which generalises the current standard model of slight compressibility to include two additional terms, one of which is quadratic in the [Formula: see text] invariants and the other quadratic in [Formula: see text]. Experimental data are used to motivate typical values for the associated material constants of these additional terms. Some simulations are performed to allow contrasts and comparisons to be made between the current standard model of slight compressibility and its generalisation proposed here.

Finite element implementation of a new model of slight compressibility for transversely isotropic materials.

Modelling transversely isotropic materials in finite strain problems is a complex task in biomechanics, and is usually addressed by using finite element (FE) simulations. The standard method developed to account for the quasi-incompressible nature of soft tissues is to decompose the strain energy function (SEF) into volumetric and deviatoric parts. However, this decomposition is only valid for fully incompressible materials, and its use for slightly compressible materials yields an unphysical response during the simulation of hydrostatic tension/compression of a transversely isotropic material. This paper presents the FE implementation as subroutines of a new volumetric model solving this deficiency in two FE codes: Abaqus and FEBio. This model also has the specificity of restoring the compatibility with small strain theory. The stress and elasticity tensors are first derived for a general SEF. This is followed by a successful convergence check using a particular SEF and a suite of single-element tests showing that this new model does not only correct the hydrostatic deficiency but may also affect stresses during shear tests (Poynting effect) and lateral stretches during uniaxial tests (Poisson's effect). These FE subroutines have numerous applications including the modelling of tendons, ligaments, heart tissue, etc. The biomechanics community should be aware of specificities of the standard model, and the new model should be used when accurate FE results are desired in the case of compressible materials.

Dynamic mechanical properties of murine brain tissue using micro-indentation.

In the past 50 years significant advances have been made in determining the macro-scale properties of brain tissue in compression, tension, shear and indentation. There has also been significant work done at the nanoscale using the AFM method to characterise the properties of individual neurons. However, there has been little published work on the micro-scale properties of brain tissue using an appropriate indentation methodology to characterise the regional differences at dynamic strain rates. This paper presents the development and use of a novel micro-indentation device to measure the dynamic mechanical properties of brain tissue. The device is capable of applying up to 30/s strain rates with a maximum indentation area of 2500 µm(2). Indentation tests were carried out to determine the shear modulus of the cerebellum (2.11 ± 1.26 kPa, 3.15 ± 1.66 kPa, 3.71 ± 1.23 kPa) and cortex (4.06 ± 1.69 kPa, 6.14 ± 3.03 kPa, 7.05 ± 3.92 kPa) of murine brain tissue at 5, 15, and 30/s up to 14% strain. Numerical simulations were carried out to verify the experimentally measured force-displacement results.

Violent behaviour in U.K. military personnel returning home after deployment.

BACKGROUND: There is growing concern about an alleged rise in violent behaviour amongst military personnel returning from deployment to Iraq and Afghanistan. The aims of this study were to determine the prevalence of violence in a sample of U.K. military personnel following homecoming from deployment in Iraq and to examine the impact of deployment-related experiences, such as combat trauma, on violence, and the role of sociodemographics and pre-enlistment antisocial behaviour. METHOD: This study used baseline data from a cohort study of a large randomly selected sample of U.K. Armed Forces personnel in service at the time of the Iraq war (2003). Regular personnel (n=4928) who had been deployed to Iraq were included. Data, collected by questionnaire, included information on deployment experiences, sociodemographic and military characteristics, pre-enlistment antisocial behaviour, post-deployment health outcomes and a self-report measure of physical violence in the weeks following return from deployment. RESULTS: Prevalence of violence was 12.6%. This was strongly associated with pre-enlistment antisocial behaviour [adjusted odds ratio (aOR) 3.6, 95% confidence interval (CI) 2.9-4.4]. After controlling for pre-enlistment antisocial behaviour, sociodemographics and military factors, violence was still strongly associated with holding a combat role (aOR 2.0, 95% CI 1.6-2.5) and having experienced multiple traumatic events on deployment (aOR for four or more traumatic events 3.7, 95% CI 2.5-5.5). Violence on homecoming was also associated with mental health problems such as post-traumatic stress disorder (aOR 4.8, 95% CI 3.2-7.2) and alcohol misuse (aOR 3.1, 95% CI 2.5-3.9). CONCLUSIONS: Experiences of combat and trauma during deployment were significantly associated with violent behaviour following homecoming in U.K. military personnel. Post-deployment mental health problems and alcohol misuse are also associated with increased violence.

Movement abnormalities and psychotic-like experiences in childhood: markers of developing schizophrenia?

BACKGROUND: Both involuntary dyskinetic movements and psychotic-like experiences (PLEs) are reported to be antecedents of schizophrenia that may reflect dysfunctional dopaminergic activity in the striatum. The present study compared dyskinetic movement abnormalities displayed by children with multiple antecedents of schizophrenia (ASz), including speech and/or motor developmental lags or problems, internalising/externalising problems in the clinical range, and PLEs, with those displayed by children with no antecedents (noASz). METHOD: The sample included 21 ASz and 31 noASz children, aged 9-12 years old. None had taken psychotropic medication or had relatives with psychosis. The antecedents of schizophrenia were assessed using questionnaires completed by children and caregivers. A trained rater, blind to group status, coded dyskinetic movement abnormalities using a validated tool from videotapes of interviews with the children. RESULTS: ASz children reported, on average, 'certain experience' of 2.5 PLEs, while noASz children, by definition, reported none. The ASz children, as compared with noASz children, displayed significantly more dyskinetic movement abnormalities in total, and in the facial and the upper-body regions, after controlling for sex and age. Receiver operator characteristics analyses yielded high area under the curve values for the total score (0.94), facial score (0.91) and upper-body score (0.86), indicating that these scores distinguished between the ASz and noASz children with great accuracy. CONCLUSIONS: Brief questionnaires identified children with multiple antecedents of schizophrenia who displayed significantly more involuntary dyskinetic movement abnormalities than children without antecedents. The presence of PLEs and dyskinesias could reflect early disruption of striatal dopamine circuits.

BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis.

BG-12, an immunomodulatory agent, reduces frequency of new gadolinium-enhancing (Gd+) lesions in relapsing multiple sclerosis (MS). This study reports the effect of 240 mg BG-12 orally three times daily (tid) for 24 weeks on the evolution of new Gd+ lesions to T1-hypointense lesions. Brain magnetic resonance imaging (MRI) scans from patients in placebo and 240 mg BG-12 tid arms of a phase 2b study were examined retrospectively. Included patients had at least one new Gd+ lesion from weeks 4 to 12. Week 24 scans were analyzed for number and proportion of new Gd+ lesions that evolved to T1-hypointense lesions. Eighteen patients receiving BG-12 and 38 patients receiving placebo were included in the analysis. The analysis tracked 147 new Gd+ lesions in patients from the BG-12 group and 221 Gd+ lesions in patients from the placebo group. The percentage of Gd+ lesions that evolved to T1-hypointense lesions was 34% lower with BG-12 treatment versus placebo (29%, BG-12; 44%, placebo; odds ratio 0.51; 95% confidence interval 0.43, 0.61; p < 0.0001). In addition to reducing frequency of new Gd+ lesions, BG-12 significantly reduced probability of their evolution to T1-hypointense lesions in patients with MS compared with placebo.

Mental health and health service use among post-national service veterans: results from the 2007 Adult Psychiatric Morbidity Survey of England.

BACKGROUND: There is concern surrounding the psychological health and uptake of treatment services among veterans of the UK Armed Forces. METHOD: Data from a cross-sectional, nationally representative sample were used to compare health outcomes and treatment seeking among 257 post-national service veterans aged 16-64 years and 504 age and sex frequency-matched non-veterans living in the community in England. Early leavers (<4 years service) were compared with longer serving veterans. RESULTS: Male veterans reported more childhood adversity and were more likely to have experienced a major trauma in adulthood than non-veterans. There was no association between any measure of mental health and veteran status in males, except reporting more violent behaviours [adjusted odds ratio (aOR) 1.44, 95% confidence interval (CI) 1.01-2.06]. In females, a significant association was found between veteran status and ever having suicidal thoughts (aOR 2.82, 95% CI 1.13-7.03). No differences in treatment-seeking behaviour were identified between veterans and non-veterans with any mental disorder. Early service leavers were more likely to be heavy drinkers (aOR 4.16, 95% CI 1.08-16.00), to have had suicidal thoughts (aOR 2.37, 95% CI 1.21-4.66) and to have self-harmed (aOR 12.36, 95% CI 1.61-94.68) than longer serving veterans. CONCLUSIONS: The findings of this study do not suggest that being a veteran is associated with adversity in terms of mental health, social disadvantage or reluctance to seek treatment compared with the general population. Some evidence implies that early service leavers may experience more mental health problems than longer-serving veterans.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy.

OBJECTIVE: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. METHODS: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. RESULTS: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. CONCLUSION: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Measurement of shock wave unsteadiness using a high-speed schlieren system and digital image processing.

A new method to measure shock wave unsteadiness is presented. Time-resolved visualizations of the flow field under investigation are obtained using a high-speed schlieren optical system and the motion of the shock wave is determined by means of digital image processing. Information on the shock's unsteadiness is subsequently derived with Fourier analysis. A sample study on shock unsteadiness in a shock-wave/turbulent boundary-layer interaction with separation is included. The method presented enables a measure of shock unsteadiness at locations in the imaged flow field not accessible by intrusive methods.

Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects. MATERIALS AND METHODS: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored. RESULTS: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048). CONCLUSIONS: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS.

BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials.

Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.99(2) + (0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by approximately 56%, equating to a approximately 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

Increased rate of whole-brain atrophy over 6 months in early Huntington disease.

The authors measured the rate of whole-brain atrophy over 6 months in 13 patients with early Huntington disease (HD) and seven matched controls. Patients with early HD had significantly increased rates of whole-brain atrophy vs controls (mean [SD] HD, 1.10 [0.88]%/year; controls, 0.26 [0.54]%/year). The measurement of cerebral change over short time periods (e.g., 6 months) may be relevant for trials designed to assess effects on neurodegeneration or atrophy.

Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy.

INTRODUCTION: Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). METHODS: We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. RESULTS: One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). CONCLUSION: Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease.

MRS shows abnormalities before symptoms in familial Alzheimer disease.

BACKGROUND: Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset. METHODS: Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation. RESULTS: PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset. CONCLUSIONS: Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.