David H. Salat - US grants

Understanding changes in the brain and changes in cognition with healthy aging is useful for defining neural substrates of cognition. fMRI is a potentially useful technique for the early diagnosis neurodegenerative conditions such as AD and the development of therapies to ameliorate cognitive decline in both healthy aging and AD. Still, it is unclear how to compare activation data in individual subjects or groups of subjects that differ in cortical morphology. Thus, the research proposed will examine appropriate ways of comparing functional activation between younger and older subjects using a task of working memory (WM), a cognitive ability that depends critically on prefrontal function and declines with aging. The overall goals of this research proposal are to: Specific Aim number 1: To investigate patterns of age-related regional cortical degeneration and morphological alteration using high resolution 3D MRI images and corticals surface-based morphological analyses in young and older adults. Specific Aim number 2: To examine methods of combining structural and functional data in the study of age-related attenuation of (WM) with fMRI in young and older subjects performing the N-Back task of WM. To do this, structural data from Aim number 1 will be used to determine how age-related degeneration is related to functional activation. Specific Aim number 3: To use structure/function methods developed in Aim number 1 and Aim number 2 and N-Back task variants to examine the contribution of inhibitory processes and speed of mental processing to the attenuation of WM with aging. It is expected that the proposed studies will demonstrate that correcting functional activation for regional tissue measurements is useful in the examination of neural changes with healthy aging. Additionally, it is expected that WM deficits in older subjects will be greatly due to decline in inhibitory processes and slower cognitive processing as opposed to a decline in WM storage (span) or updating abilities.

DESCRIPTION (provided by applicant): Diffusion Tensor Imaging of White Matter Change in AD. This Career Development application describes an integrated research and training period with two primary goals: (1) the development of the candidate into a strong and independent researcher in the study of the neuropathology of Alzheimer's disease (AD) through the application of advanced neuroimaging techniques and complementary neuropathology studies and (2) to determine the unique contribution of white matter (WM) degeneration in AD to the clinical profile of patients. The candidate is enthusiastic to continue AD-related research and to add new training to this research program. Immediate training goals will focus on three domains of study: (1) the application of novel neuroimaging data acquisition techniques to study neuropathology, (2) neuropathological assessment of AD and quantitative neuropathology techniques, and (3) advanced statistical analysis procedures for clinical research and multivariate data. The Mentors/Advisors on this proposal and the training environment of the Athinoula A. Martinos Center for Biomedical Imaging and the Massachusetts Alzheimer's Disease Research Center (MADRC) will assure superb instruction in the three fields. The candidate expects to apply the foundation in advanced imaging protocols and neuropathology of AD to develop a strong research program aimed at fully integrating these disparate domains to better understand AD pathophysioiogy. The proposed research will integrate novel diffusion tensor imaging (DTI) measures of WM microstructure with advanced methods for measuring morphological properties of gray matter to determine whether WM degeneration differs in AD compared to normal aging, and whether WM degeneration contributes to specific aspects of AD symptomology when controlling for gray matter degeneration. Patients will be recruited through the MADRC. Imaging data will be related to cognitive and clinical measures (including memory and dementia severity). The Specific Aims of this research are to: Aim 1. Identify differences in the patterns of WM degeneration in AD compared to normal aging. Aim 2. Identify the relation between WM degeneration and gray matter degeneration. Aim 3. Identify the unique contribution of WM degeneration to the patient's clinical profile. Thus, the proposed integrated training and research program could lead to novel insights about the unique contribution of WM degeneration to the clinical sequel of AD.

DESCRIPTION (provided by applicant): The proposed work aims to identify direct mechanisms by which vascular health influences neural integrity, and in turn, cognitive fitness in older adults as well as to determine how risk for Alzheimer's disease (AD) contributes to a neural environment in which degenerative processes are disproportionately facilitated due to enhanced vulnerability to limits in blood supply. We propose that age-associated decline in specific aspects of vascular health promotes progressive degenerative changes in white matter tissue structure and that this deterioration is a primary mechanism of cognitive decline. More advanced decline in vascular health compounded with risk for AD contributes to breakdown of the blood brain barrier, deterioration of the cerebral cortex and subcortical gray matter, and to a more generalized cognitive deficit. The Specific Aims of this continuation are: (1) to determine whether regions of reduced blood flow and altered flow regulation co-localize with white matter lesions and predict future lesion formation. We expect that white matter bordering the end zones of the long penetrating arteries and watershed areas will be most vulnerable to microstructural damage, and this damage will be directly associated with functional neuroimaging metrics of white matter perfusion and vascular autoregulation. (2) To characterize the regional profile of white matter damage and quantify the degree of tissue damage within white matter lesions. We hypothesize that taking quantitative information into account when characterizing white matter lesions will provide greater sensitivity to detect cognitive decline and other clinically relevant phenomena. (3) To determine whether breakdown of the blood brain barrier with risk for AD promotes white matter lesion formation. We hypothesize that individuals with risk for AD have a greater incidence of systemic inflammation and that this is associated with deterioration of the blood brain barrier, augmenting degenerative processes due to vascular risk. Taken together, these studies would demonstrate that regions of the cerebral white matter with spatial proximity to particular portions of the vascular tree are most susceptible to preclinical cerebral blood flow dysregulation and lesion formation. This initial pathway leads to the standard pattern of non-demented age-associated cognitive decline. Progressive decline in vascular function coupled with an AD-associated inflammatory response contributes to a breakdown of the blood brain barrier and additional degenerative changes predictive of subsequent cognitive decline. Data generated here could provide important and very practical insights for individualized clinical management and would identify mechanistic targets for future clinical intervention.

Abstract. Three major principles are at the forefront of current understanding about the pathology and potential therapeutic approach to addressing the massive public health burden of Alzheimer?s disease (AD). First, the clinical symptoms and functional dependence resulting from this disease are known to occur after potentially decades of degenerative brain changes linked to amyloid plaque and neurofibrillary tangle cortical pathologies; second, prevalent comorbid pathologies, particularly cerebrovascular dysfunction, contribute to a hastening of disease processes and clinical decline; third, any therapeutic intervention targeting either of these pathologic domains would need to be implemented at the earliest time possible, prior to evidence of cognitive decline given that dementia is only apparent after substantial irrecoverable neurodegeneration has transpired. Functional magnetic resonance imaging (fMRI) is used to measure brain activity and previously contributed extensively to the characterization of AD progression. Individuals at genetic risk of AD show altered fMRI indicators even prior to expression of cognitive impairment, and thus, fMRI has provided critical insights into pathophysiology of preclinical AD. The fMRI signal is an indirect correlate of neural activity based on the phenomenon of ?functional hyperemia? in which metabolic activity in the brain is followed by a nutritive increase in cerebral blood flow and this hemodynamic response can be measured through the blood oxygenation level dependent (BOLD) contrast mechanism. A critical barrier in the application of fMRI to the study of AD is the intricate entanglement of neural and vascular physiology at the basis of the BOLD signal resulting in an inability to differentiate between the effects of neural dysfunction and comorbid vascular pathology. The goal of this NIH R21 research proposal is to decouple neurophysiological from vasculo-physiological components of the fMRI BOLD signal and to apply this new technology to the study of brain pathology, associated with the genetic risk of AD, before any evidence of cognitive and functional decline. To this end, we will implement a cutting-edge scanning and analysis paradigm in cognitively healthy older participants at different levels of genetic risk of AD by [1] simultaneous recording of combinations between fMRI, electro-encephalographic, and magnetoencephalographic data, [2] quantifying transient intrinsic neurophysiological states of brain networks, and [3] using these states to anchor measurement of the neurally induced hemo-dynamic response. We emphasize that the R21 mechanism is exploratory/developmental, and in this spirit, we propose to explore optimal parameters to advance this novel technology. Successful implementation of this approach would provide novel insight into how genetic vulnerabilities are linked to distinct neural and vascular dysfunctions, which have been suggested to influence the plaque and tangle pathology in AD. Targeting specific neural and vascular pathophysiology by novel, alternative therapies in preclinical AD holds promise to make prevention and early intervention, to thwart or slow down progressive neurodegeneration, possible.

Abstract of the funded parent award. Three major principles are at the forefront of current understanding about the pathology and potential therapeutic approach to addressing the massive public health burden of Alzheimer?s disease (AD). First, the clinical symptoms and functional dependence resulting from this disease are known to occur after potentially decades of degenerative brain changes linked to amyloid plaque and neurofibrillary tangle cortical pathologies; second, prevalent comorbid pathologies, particularly cerebrovascular dysfunction, contribute to a hastening of disease processes and clinical decline; third, any therapeutic intervention targeting either of these pathologic domains would need to be implemented at the earliest time possible, prior to evidence of cognitive decline given that dementia is only apparent after substantial irrecoverable neurodegeneration has transpired. Functional magnetic resonance imaging (fMRI) is used to measure brain activity and previously contributed extensively to the characterization of AD progression. Individuals at genetic risk of AD show altered fMRI indicators even prior to expression of cognitive impairment, and thus, fMRI has provided critical insights into pathophysiology of preclinical AD. The fMRI signal is an indirect correlate of neural activity based on the phenomenon of ?functional hyperemia? in which metabolic activity in the brain is followed by a nutritive increase in cerebral blood flow and this hemodynamic response can be measured through the blood oxygenation level dependent (BOLD) contrast mechanism. A critical barrier in the application of fMRI to the study of AD is the intricate entanglement of neural and vascular physiology at the basis of the BOLD signal resulting in an inability to differentiate between the effects of neural dysfunction and comorbid vascular pathology. The goal of this NIH R21 research proposal is to decouple neurophysiological from vasculo-physiological components of the fMRI BOLD signal and to apply this new technology to the study of brain pathology, associated with the genetic risk of AD, before any evidence of cognitive and functional decline. To this end, we will implement a cutting-edge scanning and analysis paradigm in cognitively healthy older participants at different levels of genetic risk of AD by [1] simultaneous recording of combinations between fMRI, electro-encephalographic, and magnetoencephalographic data, [2] quantifying transient intrinsic neurophysiological states of brain networks, and [3] using these states to anchor measurement of the neurally induced hemo-dynamic response. We emphasize that the R21 mechanism is exploratory/developmental, and in this spirit, we propose to explore optimal parameters to advance this novel technology. Successful implementation of this approach would provide novel insight into how genetic vulnerabilities are linked to distinct neural and vascular dysfunctions, which have been suggested to influence the plaque and tangle pathology in AD. Targeting specific neural and vascular pathophysiology by novel, alternative therapies in preclinical AD holds promise to make prevention and early intervention, to thwart or slow down progressive neurodegeneration, possible.

Abstract. It has become increasingly clear that the cerebrovascular system is under assault in many individuals infected with COVID-19. In recent studies, patients with hypertension were found at a two-fold increased risk of dying from COVID-19 infection, and 100% of infected patients who received a magnetic resonance imaging (MRI) exam showed reduced CBF with 23% showing evidence indicative of ischemic stroke. The cerebrovascular dysregulation due to COVID-19 may add to the already enormous burden of stroke and dementia associated with age-related vascular deterioration. The pathogen SARS-CoV-2, causing COVID-19 illness, is now known to reduce function of an enzyme termed ACE2 that is a major regulator in the Renin- Angiotensin system (RAS) that controls blood pressure and cerebral blood flow (CBF). This SARS-CoV-2 pathophysiology might lead to excessive stimulation of type 1 angiotensin receptor (AT1R) but reduced stimulation of type 2 angiotensin receptor (AT2R), which is likely to both exacerbate hypertension and disrupt CBF autoregulation and neurovascular coupling. Fortunately, two classes of currently available antihypertensive medications are designed to regulate RAS by inhibiting AT1R. However, there may be a critical difference between these two classes. Angiotensin II receptor blockers (ARBs) are protective of the pro-CBF activity on the AT2R, and thus may be more effective at preventing the cerebrovascular dysregulation than the other class, inhibitors of an enzyme termed ACE (ACEIs), which inhibit AT2R activity. The goal of this R21 research proposal is to compare the effectiveness of ARB and ACEI antihypertensive medicines in preventing long-term cerebrovascular dysregulation in hypertensive patients infected with COVID- 19. Two novel imaging methods recently developed in our lab will be leveraged to assess CBF autoregulation and neurovascular coupling (NVC) at least 1 year after the severe infection. First, we will conduct noninvasive optimized arterial spin labeling (ASL) MRI and respiratory challenge-weighted blood oxygenation level- dependent (BOLD) MRI to measure baseline CBF and autoregulatory capacity in combination with novel analyses that decouple the magnitude of vascular signal from contamination due to timing-related differences. Second, we will acquire simultaneous resting-state electroencephalogram and BOLD MRI to estimate the body?s capacity to adjust vascular energy delivery in response to changes in the demand from neural electrophysiological activity. We will quantify this NVC with cutting-edge mathematical analysis that detects transient states of network activity in EEG and models the time-concordant local BOLD MRI responses. Successful implementation of this approach would offer sensitive measurement of CBF regulation in hypertensive COVID-19 survivors and would indicate that one class of antihypertensive medication may be more effective in CBF management in the face of COVID-19-related dysregulation, demonstrating urgency of clinical trials of RAS inhibitors in hypertensive patients with COVID-19 to optimize future clinical care.

Project Summary/Abstract. It is now understood that cerebrovascular dysfunction contributes to a host of neurocognitive disorders including the reduction in cognitive capacity with typical aging as well as the more serious impairments resulting from vascular disease and dementia. Cerebrovascular pathology is also highly prevalent in patients with Alzheimer?s disease (AD) and is an important factor contributing to the conversion from an independent state of mild cognitive impairment to the functional dependence associated with Alzheimer?s dementia. Thus, vascular health and disease are important mechanisms contributing to heterogeneity in cognitive aging and progression to vascular and Alzheimer?s dementias. Unlike the proteinopathies of AD and other neurodegenerative conditions, vascular health is immediately modifiable through behavioral and lifestyle factors, as well as a range of pharmacological and device related interventions. Thus, it is critical to develop methods for quantitative tracking of metrics of cerebrovascular health that could be used to detect the earliest stages of abnormalities that may require intervention. Optimally, such technology would be wireless, mobile/web interfacing and would be very low cost allowing for accessibility to traditionally medically underserved populations. We have designed and prototyped such a device that would permit widespread cerebrovascular monitoring in older adults. The goal of this R21 proposal is to complete the development of, and to validate this novel low-cost cerebral oximeter that can be used to screen for cerebrovascular disorders that contribute to cognitive impairment and increase risk for the development of AD. To do so, we will aim to Specific Aim 1: 1a) complete the design and casing and programming of our existing developed device; 1b) to optimize the design for high performance and reliable physiological signal detection; Aim 2: 2a) to validate performance of the low-cost mobile oximeter relative to gold standard high grade cerebral oximeter; 2b) to validate performance of the low-cost mobile oximeter relative to cerebral physiology measurements obtained by magnetic resonance imaging. The proposed sensor would promote widespread cerebrovascular monitoring in individuals at risk for vascular dysfunction and neurocognitive disorders. Ultimately, in the future, we aim for this sensor to be translated for use in clinical practice for generalized primary care as well as specialty clinical use.

PROJECT SUMMARY Alzheimer?s disease (AD) currently affects 5.6 million Americans aged 65 years and older, with a projected increase to 13.8 million by 2050. Beta-amyloid plaques and neurofibrillary tangles are characteristic of AD pathology, but white matter lesions (WMLs) indicative of cerebral small vessel disease have also been shown to be an independent contributor to cognitive decline in AD patients. Possession of an ?4 allele of the apolipoprotein E gene (APOE) is considered the strongest risk factor for developing late-onset AD. In addition, APOE-?4 also represents a major risk factor for cerebrovascular disease, and APOE-?4 carriers are known to exhibit a greater burden and faster progression of WMLs compared with non-carriers. However, the physiological mechanisms through which APOE-?4 leads to tissue hypoxia and the formation of these lesions remain incompletely understood. The overall goal of this study is to elucidate differences in microvascular physiology between APOE- ?4 carriers and non-carriers that may indicate potential mechanisms for the pathological effects of APOE-?4 on vascular function. Such hemodynamic impairment could be caused by mechanisms associated with abnormal tissue perfusion. However, prior studies that have examined effects of APOE-?4 on cerebral perfusion have reported conflicting results on whether perfusion is reduced or elevated APOE-?4 carriers versus non-carriers, indicating that differences in blood flow alone may not fully explain the extent of hemodynamic compromise. Hemodynamic impairment may also result from inefficiencies in oxygen exchange from vasculature into tissue due to flow disturbances at the capillary level, which have previously been shown to be related to heterogeneities in capillary flow patterns. Recently, we have characterized venous hyperintense signal (VHS) on cerebral blood flow (CBF)-weighted images acquired using arterial spin labeling magnetic resonance imaging (MRI) as a marker of capillary-level flow disturbances and oxygen exchange inefficiency. In this work, we propose to apply noninvasive MRI methods and this novel construct to elucidate associations between tissue-level hemodynamic physiology and WML burden in older APOE-?4 carriers and non-carriers. Specifically, we will (i) study the effect of microvascular flow disturbances on oxygen exchange efficiency, (ii) investigate the association between microvascular dysfunction and CBF according to APOE genotype, and (iii) identify differences in associations between microvascular physiology and WML burden between APOE-?4 carriers and non-carriers. Successful completion of this work will determine the degree to which the observed higher burden of WMLs in older adults with APOE-?4 is associated with mechanisms involving oxygen exchange inefficiency, which are indicated by VHS, versus impaired CBF. These findings could have implications for the titration of different therapeutic approaches for preventing vascular-related cognitive decline in older adults with versus without APOE-?4.

Project Summary/Abstract. Advanced biomarker mapping has led to the current understanding that Alzheimer?s disease (AD) is an extremely complex neurodegenerative disorder, with substantial heterogeneity in temporal and spatial characteristics of the classical amyloid and tau pathologies and resultant neurodegeneration among patients (as described by the amyloid-tau-neurodegeneration, ?A-T-N? biological framework that is the new standard for characterizing the neuropathology of AD). This complexity is a major barrier to clinical care and to the development of effective therapies, highlighting the importance of integrated biomarker neuromapping for understanding AD. However, substantial challenges remain in the neuropathologic characterization of patients. Current procedures for mapping the neurodegenerative component (N) of AD are limited in sensitivity to early pathology. Additionally, the specific biomarkers of the amyloid- and tau-based primary AD neuropathologies are only available through relatively invasive and/or expensive positron emission tomography (PET) and lumbar puncture (LP) cerebrospinal fluid (CSF) procedures in specialized laboratories and clinics. We aim here to advance AD neuropathology mapping on multiple levels: 1) we will implement a novel multi-scale structural mapping (MSSM) MRI procedure for sensitive quantification of the neurodegeneration component of AD; 2) we will use the MSSM procedure to differentially predict amyloid and/or tau positivity in symptomatic and asymptomatic individuals, providing a highly accessible method for pathology detection when advanced biomarkers are not available; 3) we will create individualized ?A-T-N? brainmaps through the integration of the MSSM metrics with existing PET amyloid and tau data; and 4) we will use MSSM features for the regional prediction of amyloid and tau pathology for use when PET data are not available. Our Specific Aims are: Aim 1. To test the accuracy of a novel MSSM procedure for probabilistic classification of symptomatic and asymptomatic individuals as being amyloid ?positive? or tau ?positive.? Hypothesis 1a (H1a). We hypothesize that MSSM ?N? metric can be used with a high level of sensitivity to predict whether an individual is A+ measured via PET using standard thresholds and/or T+ measured via PET using standard thresholds, or both. H1b. MSSM will provide better separation of individuals as N+ vs. N- than conventional MRI-based atrophy measures, validated through concordance with molecular pathology and clinical progression. Aim 2. To utilize the novel MSSM features for synthesis of PET-like maps of AD neuropathologic change. H2a. MSSM features will provide accurate spatial prediction of specific regional neuropathologic changes. Prediction accuracy will be measured against independent in vivo datasets including a subset with autopsy confirmation and regional quantification of plaques, tangles, and neuronal loss. Successful MSSM implementation would greatly advance the ability to screen for early and complex AD neuropathology. Successful MSSM implementation would greatly advance the ability to screen for AD neuropathology.