Brain Blood Flow and Metabolism: Variable Relationships in Altered Metabolic States

Brain metabolism is usually thought of in terms of energy production. Decades of research has shown that the brain derives the majority of its energy from the oxidative phosphorylation of glucose transported from the blood into the brain. Because of this, cerebral blood flow (CBF), the cerebral metabolic rate of glucose consumption (CMRglc), and the cerebral metabolic rate of oxygen consumption (CMRO2) generally are tightly coupled. Indeed, the coupling between CBF, CMRglc, and CMRO2 is robust enough such that many investigators believe them to be equivalent measures of brain activity. Nevertheless, research over the last few decades has shown that cerebral metabolic coupling is not stoichiometrically exact. Perhaps the best example of metabolic uncoupling occurs during focal increases in brain activity. Sensory stimulation, for instance, increases CBF and CMRglc to a much greater extent than CMRO2. This response results in: 1) an increase in nonoxidative glucose consumption, and 2) an increase in oxygenated blood in the brain’s vasculature, the phenomenon which underlies blood oxygen dependent (BOLD) functional magnetic resonance imaging (fMRI). Importantly, metabolic uncoupling is not restricted to periods of increased neural activity. The primary goal of this thesis is to investigate other examples of uncoupling between CBF, CMRglc, and CMRO2. I performed four separate studies that all examine metabolic uncoupling from a different perspective. In the first study, I performed a meta-analysis of published papers to show that at rest, nearly 10% of the brain’s glucose consumption uses nonoxidative pathways that do not end in lactate efflux. If CMRglc and CMRO2 were completely coupled, then one would not expect to find any nonoxidative glucose consumption (NOglc). The second study expands upon the first by showing that there are regional differences in the amount of glucose consumed using nonoxidative pathways. In some brain regions, such as the precuneus and medial prefrontal cortex, NOglc accounts for nearly 20% of resting CMRglc. Conversely, there does not appear to by any NOglc in the cerebellum. The aim of the remaining two studies was to determine if changes in blood glucose concentration produce similar changes in CBF, CMRglc, and CMRO2. Although multiple studies have reported that hypoglycemia focally increases CBF in humans, it is not clear how it impacts regional CMRglc. Therefore, I examined both regional CBF and regional CMRglc during moderate hypoglycemia. Although hypoglycemia decreased CMRglc in every region of the brain, it only increased CBF significantly in the globus pallidus. This suggests that CBF does not increase during hypoglycemia to prevent a fall in CMRglc. Next, I examined regional changes in brain metabolism during hyperglycemia. Previous studies have established that acute hyperglycemia alters the topography of cerebral glucose metabolism. However, the impact of hyperglycemia on regional CBF and CMRO2 has not yet been determined. Therefore, I examined CBF, CMRglc, and CMRO2 in several brain regions during hyperglycemia. Hyperglycemia did not change CBF or CMRO2 in any brain region. However, hyperglycemia did increase CMRglc in white matter and in the brain stem by over 30%. CMRglc was not altered by hyperglycemia in any other region. Therefore, hyperglycemia appears to selectively increase NOglc in the brain stem and white matter. Taken together, the four studies that make up this thesis show that metabolic uncoupling, in particular NOglc, is an important part of brain metabolism. These results also highlight the need for future studies that can elucidate the mechanisms behind uncoupling in both health and disease

Metabolite-specific echo-planar imaging of hyperpolarized [1-- 13 C]pyruvate at 4.7 T

Although hyperpolarization (HP) greatly increases the sensitivity o

Prion disease induced alterations in gene expression in spleen and brain prior to clinical symptoms

Prion diseases are fatal neurodegenerative disorders that affect animals and humans. There is a need to gain understanding of prion disease pathogenesis and to develop diagnostic assays to detect prion diseases prior to the onset of clinical symptoms. The goal of this study was to identify genes that show altered expression early in the disease process in the spleen and brain of prion disease-infected mice. Using Affymetrix microarrays, we identified 67 genes that showed increased expression in the brains of prion disease-infected mice prior to the onset of clinical symptoms. These genes function in many cellular processes including immunity, the endosome/lysosome system, hormone activity, and the cytoskeleton. We confirmed a subset of these gene expression alterations using other methods and determined the time course in which these changes occur. We also identified 14 genes showing altered expression prior to the onset of clinical symptoms in spleens of prion disease infected mice. Interestingly, four genes, Atp1b1, Gh, Anp32a, and Grn, were altered at the very early time of 46 days post-infection. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as surrogate markers for the early detection and diagnosis of prion disease

Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer\u27s disease

Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. Keywords: Inflammation, White matter damage, Diffusion basis spectrum imaging, Neuro-inflammation imaging, Cerebrospinal fluid, Preclinical Alzheimer disease, Early symptomatic Alzheimer disease, Magnetic resonance imagin

Ic‐P‐204: The Relationship Between Tau Pet And Other Ad Biomarkers In Autosomal Dominant Alzheimer Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152660/1/alzjjalz2018062271.pd

Brain aerobic glycolysis and resilience in Alzheimer disease

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process

Quantitative analysis of PiB-PET with FreeSurfer ROIs

In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions