Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ−) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
•Study cohort of preclinical subjects (N = 139) at risk for Alzheimer's disease•Examination of four DTI metrics in three groups based on global amyloid load•Greater amyloid load was associated with higher fractional anisotropy.•Diffusivity was negatively associated with amyloid in fronto-lateral gray matter.•DTI metrics were not correlated with cognition at this early disease stage.
DTI, Diffusion Tensor Imaging; PIB, Pittsburgh compound B; WRAP, Wisconsin Registry for Alzheimer's Prevention; FA, fractional anisotropy; MD, mean diffusivity; Da, axial diffusivity; Dr, radial diffusivity; APOE4, apolipoprotein E gene ε4; FH, (parental) family history; WM, white matter; GM, gray matter; Aβ+, amyloid positive; Aβi, amyloid indeterminate; Aβ−, amyloid negative; SPM, Statistical Parametric Mapping; FSL, FMRIB Software Library; PRELUDE, phase region expanding labeler for unwrapping discrete estimates; FUGUE, FMRIB's utility for geometrically unwarping EPIs; BET, Brain Extraction Tool; DTI-TK, Diffusion Tensor Imaging Toolkit; HARDI, high angular resolution diffusion imaging; DVR, distribution volume ratio; ICBM, International Consortium for Brain Mapping; ANTs, Advanced Normalization Tools; Cingulum–CC, cingulum adjacent to corpus callosum; Cingulum–HC, hippocampal cingulum (projecting to medial temporal lobe); PCC, posterior cingulate cortex; RAVLT, Rey Auditory Verbal Learning Test; TMT, Trail Making Test; ANCOVA, Analysis of Covariance; FWE, family wise error; WASI, Wechsler Abbreviated Scale of Intelligence; WRAT, Wide Range Achievement Test; Alzheimer's disease; Amyloid imaging; AD risk; White matter
Although [18F]fluoro-L-dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.
Fluorodopa; motor control; Parkinson's disease; positron emission tomography; ageing; Tongue/*physiopathology; Facial Muscles/*physiopathology
Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.
HDL; cholesterol; brain; gray; matter; volume; Alzheimer's; dementia
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in humans is associated with brain differences including decreased number of activated microglia. In animals, NSAIDs are associated with reduced microglia, decreased amyloid burden, and neuronal preservation. Several studies suggest NSAIDs protect brain regions affected in the earliest stages of AD, including hippocampal and parahippocampal regions. In this cross-sectional study, we examined the protective effect of NSAID use on gray matter volume in a group of middle-aged and older NSAID users (n = 25) compared to non-user controls (n = 50). All participants underwent neuropsychological testing and T1-weighted magnetic resonance imaging. Non-user controls showed smaller volume in portions of the left hippocampus compared to NSAID users. Age-related loss of volume differed between groups, with controls showing greater medial temporal lobe volume loss with age compared to NSAID users. These results should be considered preliminary, but support previous reports that NSAIDs may modulate age-related loss of brain volume.
Alzheimer's disease; aging; risk factors; volumetric MRI; NSAIDs