Age-associated white matter degeneration has been well-documented and is likely an important mechanism contributing to cognitive decline in older adults. Recent work has explored a range of noninvasive neuroimaging procedures to differentially highlight alterations in the tissue microenvironment. Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI) that accounts for non-Gaussian water diffusion and can reflect alterations in the distribution and diffusion properties of tissue compartments. We used DKI to produce whole-brain voxel-based maps of mean, axial and radial diffusional kurtoses (MK, AK and RK, respectively), quantitative indices of the tissue microstructure’s diffusional heterogeneity, in 111 participants ranging from 33 to 91 years of age. As suggested from prior DTI studies, greater age was associated with alterations in white-matter tissue microstructure, which was reflected by a reduction in all three DKI metrics. Prominent effects were found in prefrontal and association white matter compared to relatively preserved primary motor and visual areas. Although DKI metrics co-varied with DTI metrics on a global level, DKI provided unique regional sensitivity to the effects of age not available with DTI. DKI metrics were additionally useful in combination with DTI metrics for the classification of regions according to their multivariate ‘diffusion footprint’, or pattern of relative age effect sizes. It is possible that the specific multivariate patterns of age-associated changes measured are representative of different types of microstructural pathology. These results suggest that DKI provides important complementary indices of brain microstructure for the study of brain aging and neurological disease.

Objective: To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers.Methods: Sixty-four eligible consenting participants were randomly allocated (1:1) to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers.Results: Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months. Conclusion:We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers. Classification of evidence:This study provides Class I evidence that high-dose creatine is safe and tolerable. Neurology ® 2014;82:850-857 GLOSSARY AD 5 axial diffusivity; HC 5 healthy control; HD 5 Huntington disease; PHD 5 premanifest Huntington disease; PRECREST 5 Creatine Safety and Tolerability in Premanifest HD.Huntington disease (HD) is a progressive autosomal dominant inherited disorder that typically manifests clinically in the third to fifth decades. Genetic testing enables the unambiguous identification of those destined to develop HD and the possibility of initiating preventive treatments during the disease prodrome. Emerging neuroprotective therapies have set the stage for secondary prevention trials with the goal of delaying the onset of symptoms. Demonstrating prevention is a major challenge because very large trials are necessary to demonstrate reduced rates of clinical onset. Furthermore, while subtle cognitive and motor dysfunction and changes on neuroimaging measures occur as early as 2 decades before symptoms, 1,2 reliable markers of prodromal progression remain elusive. PRECREST (Creatine Safety and Tolerability in Premanifest HD) is a secondary prevention trial using up to 30 g daily of creatine monohydrate, a high-energy phosphate buffer that restores adenosine triphosphate from adenosine diphosphate. We used a novel study design that included asymptomatic individuals who were either 50% at risk on the basis of an affected first-degree relative but not wishi...

Although much prior work has focused on the known cortical pathology that defines Alzheimer’s disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated physiological differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that 1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and 2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.