Alterations in Multiple Measures of White Matter Integrity in Normal Women at High Risk for Alzheimer\u27s Disease

There is evidence that disruption of white matter (WM) microstructure is an early event in the course of Alzheimer\u27s disease (AD). However, the neurobiological bases of WM microstructural declines in presymptomatic AD are unknown. In the present study we address this issue using a multimodal imaging approach to the study of presymptomatic AD. Participants were 37 high-risk (both family history of dementia and one or more APOE4 alleles) women and 20 low-risk (neither family history nor APOE4) women. Groups were matched for age, education, neuropsychological performance, and vascular factors that could affect white matter. Whole-brain analyses of diffusion tensor imaging data [including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA) and radial diffusivity (DR)] and volumetric comparisons of medial temporal lobe (MTL) structures were conducted. Results indicated equivalent entorhinal cortex and hippocampal volumes between risk groups. Nevertheless, the high risk group showed decreased microstructural integrity in WM tracts with direct and secondary connections to the MTL. The predominant alteration in WM integrity in the high AD-risk group was decreased FA not solely driven by either DA or DR changes alone in regions where no MD changes were observed. A second pattern observed in a smaller number of regions involved decreased FA and increased DR. These results suggest that disconnection of MTL-neocortical fiber pathways represents a very early event in the course of AD and suggest that demyelination may represent one contributing mechanism

Whole-brain patterns of 1H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies

Acknowledgements We thank Craig Lambert for his help in processing the MRS data. The study was funded by the Sir Jules Thorn Charitable Trust (grant ref: 05/JTA) and was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University and the NIHR Biomedical Research Centre and Biomedical Research Unit in Dementia based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.Peer reviewedPublisher PD

Detecting and tracking early neurodegeneration in familial Alzheimer’s disease

Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, with initial deposition of extracellular amyloid and intracellular tau, followed by downstream neurodegeneration and cognitive decline. There is great interest in testing potential disease-modifying treatments for AD prior to the onset of symptoms, when minimal neuronal loss has occurred. To facilitate this, robust and sensitive methods are needed to identify at-risk individuals, stage their disease, and track progression. Familial Alzheimer’s disease (FAD) shares many features, clinically, radiologically, and neurophysiologically, with the more common sporadic form of disease. Carriers of autosomal dominantly inherited mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes have relatively predictable ages at symptom onset, based on family history. Study of FAD mutation carriers therefore provides the opportunity for the prospective study of asymptomatic individuals with known underlying AD pathology prior to the onset of clinical disease. The studies presented herein aim to improve the identification and characterization of early FAD neurodegenerative change and its earliest downstream cognitive effects. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals included. Chapter one provides an introduction to AD and methods for measuring early neurodegeneration. Chapter two then outlines the general methodological approach across the different studies. Chapters three and four present results of magnetic resonance imaging studies of macrostructural (cortical thickness) and microstructural (diffusion-weighted imaging) cortical change. Chapter five reports results for a new blood-based biomarker of neurodegeneration – serum neurofilamentlight. Chapter six investigates a novel approach to presymptomatic cognitive testing – 6 assessing accelerated long-term forgetting. In all studies, significant differences between mutation carriers and non-carrier controls are detectable during the presymptomatic period. The thesis draws together these different approaches and discusses how they advance our understanding of the neurobiology of AD and their potential utility in both clinical assessment and presymptomatic therapeutic trials

Understanding the Contributions of Alzheimer’s Disease & Cardiovascular Risks to Cerebral Small Vessel Disease Manifest as White Matter Hyperintensities on Magnetic Resonance Imaging (MRI)

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia. Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative association of age, AD (visualized as hippocampal atrophy) and cSVD (visualized as white matter hyperintensities; WMH) with global brain atrophy in experiment 1. In experiment 2, we analyzed cross-sectional MRI scans from 62 participants from the University of Kentucky Alzheimer’s Disease Center (UKADC) with available clinical data on cardiovascular risk and cerebrospinal fluid (CSF) beta-amyloid levels as a marker of AD. Voxel wise regression was used to examine the association of white matter hyperintensities with AD and/or cardiovascular risk (hypertension). Experiment 3, examined longitudinal MRI changes in WMH volumes in 377 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI 2). Subjects were categorized into three groups based on WMH volume change, including those that demonstrated regression (n=96; 25.5%), stability (n=72; 19.1%), and progression (n=209; 55.4%) of WMH volume over time. Differences in brain atrophy measures and cognitive testing among the three group were conducted. Results: In the first experiment, logistic regression analysis demonstrated that a 1-year increase in age was associated with global brain atrophy (OR = 1.04; p = .04), medial temporal lobe atrophy (MTA; a surrogate of AD) (OR = 3.7; p \u3c .001), and WMH as surrogate of cSVD (OR = 8.80; p \u3c .001). Both MTA and WMH were strongly associated with global brain atrophy in our study population, with WMH showing the strongest relationship after adjusting for age. In the second experiment, linear regression as well as mediation and moderation analyses demonstrated significant main effects of hypertension (HTN; the strongest risk factor associated with cSVD) and CSF Aβ 1-42 (a surrogate of AD) on WMH volume, but no significant HTN×CSF Aβ 1-42 interaction. Further exploration of the independence of HTN and Aβ using a voxelwise analysis approach, demonstrated unique patterns of WM alteration associated with either hypertension or CSF Aβ 1-42, confirming that both independently contribute to WMH previously classified as cSVD. Extending this work into a longitudinal model rather than focusing on purely cross-sectional associations, we demonstrated that spontaneous WMH regression is common, and that such regression is associated with a reduced rate of global brain atrophy (p = 0.012), and improvement in memory function over time (p = 0.003). Conclusion: These data demonstrate that both AD and cSVD frequently coexist in the same brain, contributing differentially to alterations in brain structure, subcortical white matter injury, and cognitive function. These effects can be disentangled using MRI, and while we currently lack therapeutic interventions to halt or reverse AD, the dynamic WMH change evident in our data clearly suggests that the ability to reverse cSVD exists today

Diffusion imaging markers of cerebral small vessel disease

Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients

Diffusion imaging markers of cerebral small vessel disease

Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients