Jean-Philippe Coutu

PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington 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.

Tract-based analysis of white matter degeneration in Alzheimer's disease.

Although much prior work has focused on the known cortical pathology that defines Alzheimers 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 microstructural 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 Alzheimers 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.

White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease.

White matter lesions are highly prevalent in individuals with Alzheimers disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimers Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.

Effects of insulin resistance on white matter microstructure in middle-aged and older adults.

Objective: To investigate the potential relationship between insulin resistance (IR) and white matter (WM) microstructure using diffusion tensor imaging in cognitively healthy middle-aged and older adults. Methods: Diffusion tensor imaging was acquired from 127 individuals (age range 41–86 years). IR was evaluated by the homeostasis model assessment of IR (HOMA-IR). Participants were divided into 2 groups based on HOMA-IR values: “high HOMA-IR” (≥2.5, n = 27) and “low HOMA-IR” (<2.5, n = 100). Cross-sectional voxel-based comparisons were performed using Tract-Based Spatial Statistics and anatomically defined regions of interest analysis. Results: The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity. Conclusions: In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults.

Differential associations between systemic markers of disease and cortical thickness in healthy middle-aged and older adults.

Abstract Aside from cortical damage associated with age, cerebrovascular and neurodegenerative diseases, its an outstanding question if factors of global health, including normal variation in blood markers of metabolic and systemic function, may also be associated with individual variation in brain structure. This cross‐sectional study included 138 individuals between 40 to 86 years old who were physically healthy and cognitively intact. Eleven markers (total cholesterol, HDL, LDL, triglycerides, insulin, fasting glucose, glycated hemoglobin, creatinine, blood urea nitrogen, albumin, total protein) and five derived indicators (estimated glomerular filtration rate, creatinine clearance rate, insulin‐resistance, average glucose, and cholesterol/HDL ratio) were obtained from blood sampling of all participants. T1‐weighted 3T MRI scans were used to evaluate gray matter cortical thickness. The markers were clustered into five factors, and factor scores were related to cortical thickness by general linear model. Two factors, one linked to insulin/metabolic health and the other to kidney function (KFF) showed regionally selective associations with cortical thickness including lateral and medial temporal, temporoparietal, and superior parietal regions for both factors and frontoparietal regions for KFF. An association between the increasing cholesterol and greater thickness in frontoparietal and occipital areas was also noted. Associations persisted independently of age, presence of cardiovascular risk factors and ApoE gene status. These findings may provide information on distinct mechanisms of inter‐individual cortical variation as well as factors contributing to trajectories of cortical thinning with advancing age. HighlightsCortical thickness was associated with blood markers in younger and older adults.Associations were present even within the “normal range” of blood markers.Lower cortical thickness was associated with higher levels of insulin and lipids.Lower regional cortical thickness was associated with decreasing kidney function.Higher levels of cholesterol were associated with higher cortical thickness.

Differential associations between systemic markers of disease and white matter tissue health in middle-aged and older adults.

Age-associated cerebrovascular disease impacts brain tissue integrity, but other factors, including normal variation in blood markers of systemic health, may also influence the structural integrity of the brain. This cross-sectional study included 139 individuals between 40 to 86 years old who were physically healthy and cognitively intact. Eleven markers (total-cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, insulin, fasting glucose, glycated hemoglobin, creatinine, blood urea nitrogen, albumin, total protein) and five derived indicators (estimated glomerular filtration rate, creatinine clearance rate, insulin-resistance, average glucose, and cholesterol/high-density lipoprotein ratio) were obtained from blood sampling. Diffusion tensor imaging was used to evaluate white matter tissue health. Blood markers were clustered into five factors. The first factor (defined as insulin/high-density lipoprotein factor) was associated with markers of integrity in the deep white matter and projection fiber systems, while the third factor (defined as kidney function factor) was associated with different markers of integrity in the periventricular and watershed white matter regions. Differential segregated associations for insulin and high-density lipoprotein levels and serum markers of kidney function may provide information about distinct mechanisms of brain changes across the lifespan. These results emphasize the need to determine whether therapeutic modulation of systemic health and organ function may prevent decline in brain structural integrity.

REGIONAL WHITE MATTER QUALITY CHANGES IN ALZHEIMER’S DISEASE

IC-P-165 REGIONALWHITE MATTER QUALITY CHANGES IN ALZHEIMER’S DISEASE Emily R. Lindemer, Jean-Philippe Coutu, Bruce Fischl, Douglas N. Greve, David H. Salat, MIT/HMS/MGH, Charlestown, MA, USA; MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 3 HMS/MGH, Charlestown, MA, USA. Contact e-mail: lindemer@mit.edu

HIGHER CHOLESTEROL AND LDL LEVELS ASSOCIATED WITH BETTER SPATIAL COGNITION IN GENERALLY HEALTHY MIDDLE-AGED AND OLDER ADULTS

(VRF) and cognitive decline in otherwise healthy and cognitively normal (CN) adults is not well understood. Within this context, the aim of this study was to identify whether the nature and magnitude of VRF affect the rate of cognitive change in CN older individuals from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Study of Ageing. Methods:768 CN adults (age 69.966.9 years, range 60-95, 331M/437F, and 27% APOE ε4+) were included in the study cohort. All underwent a comprehensive neuropsychological assessment at baseline, 18, 36 and 54 months. The sample was divided into subgroups of those with (n1⁄4606) and without (n1⁄4138) VRF. Participants in the VRF sub-group had at least one of the following risk factors: (1) hypertension, (2) diabetes, (3) dyslipidaemia, (4) BMI>30 kg/m, (5) chronic kidney disease, (6) smoking history and (7) hyperhomocysteinemia. The relationship between VRF and cognitive decline was examined using five cognitive composite factors which included both pencil-and-paper and computerised tasks, and assess: (1) language, (2) verbal and visual memory, (3) executive function and (4) visuospatial skills. Results: The cognitive composite factors were subjected to linear-mixed-model analyses adjusted for age, estimated IQ and APOE ε4 load. The results showed that relative to those individuals without VRF, those with VRF had a greater rate of cognitive decline in verbal (F (624.016, 1)1⁄47.2; p1⁄40.01) and visual (F (1775.533, 1)1⁄46.89; p1⁄40.01) memory, executive functions (F (1821.035, 1)1⁄44.48; p1⁄40.03) and visuospatial skills (F (1204.6, 1)1⁄41.055; p1⁄40.03). When participants were divided according to the number of VRFs (one point was given for each VRF present), those with high VRF burden displayed a greater magnitude of decline on the visual memory (Cohen’s d1⁄40.47), executive functions (Cohen’s d1⁄40.35) and visuospatial skills (Cohen’s d1⁄40.35) factors. Conclusions:VRF increase the rate of decline in memory, executive function and visuospatial skills in CN older adults. These cognitive domains are recognised for their complexity and widespread distributed networks, which could explain their higher vulnerability to VRF. The implication may be that individuals who suffer from high VRF burden might have an increased likelihood of cognitive difficulties being manifested early in the dementia process.