Neuroinflammation in Vascular Dementia

By Gary Rosenberg

Neuroinflammation in Vascular Dementia describes the molecular mechanisms that drive this transition to mixed pathology, along with the newer lifestyle and pharmacological approaches that can reduce the incidence of dementia. The book describes the practical aspects of neuroimaging methods, along with novel neuroimaging methods, using MRI, that are becoming important clinically. The author also discusses how the diagnosis of dementias will be greatly aided by biomarkers from neuroimaging, blood and CSF biochemistry and neuropsychological testing in the future. This information will be used in precision medicine to design treatment strategies based on the most likely causes of the disease.

Dementia research has undergone dramatic growth driven by current and projected increases in the aging of the population, and thus leading to a larger number of patients with dementia by 2050. Hence, advances in neuroimaging, brain chemistry, and genetics have accelerated our understanding of diseases that lead to cognitive decline.

• Reviews the clinical aspects and subtypes of dementia
• Explains molecular pathways involved in brain inflammation
• Includes the role of CSF and blood in diagnosis
• Covers established and novel neuroimaging methods
• Discusses established and developing treatment strategies
• Identifies future directions, such as machine learning and precision medicine

• Language: English
• Publisher: Academic Press
• Release date: Sep 7, 2022
• ISBN: 9780128234563

Gary Rosenberg

Gary Rosenberg, MD is a Professor of Neurology with joint appointments in Departments of Neuroscience, Cell Biology and Physiology, and Mathematics and Statistics at the University of New Mexico. He was Chairman of Neurology before becoming director of the UNM Center for Memory and Aging. He is a leading authority in dementia secondary to vascular disease. He discovered the role of the matrix metalloproteinases in the brain and was the first to describe the important role they played in disruption of the blood-brain barrier. He is an expert in neuroimaging and was one of the first investigators to use dynamic contrast-enhanced MRI to measure blood-brain barrier permeability in humans. He is currently principal investigator of one of centers in the NIH MarkVCID consortium for the study of biomarkers in vascular cognitive impairment and the impact of vascular disease on Alzheimer’s disease. He has published over 160 peer-reviewed papers and two books on brain fluids and metabolism.

Book preview

Chapter 1

Clinical aspects of diagnosis in dementia

Abstract

Dementia is a dynamic disease process with progressive loss of intellect. Many medical and neurological diseases cause dementia. Aging is a major contributor to dementia. The two major forms of dementia, neuronal cell death due to abnormal protein build-up and vascular injury to the white matter (WM). The major pathological changes were described at the end of the 19th century by Alois Alzheimer in the gray matter and Otto Binswanger in the WM. Very little new information was added to the original reports until the 1970s when neuroimaging with computed tomography and magnetic resonance imaging (MRI) permitted visualization of the brain during life. Alzheimer’s disease (AD) is the major form of dementia and is characterized by relentless memory loss. Binswanger’s disease involves the WM primarily due to the small vessel disease. Pathological studies show that a combination of Alzheimer pathology with vascular disease—mixed dementia—is the most common form. Amyloid plaques and neuronal tangles are the hallmark of AD, while changes in the WM on MRI is the hallmark of Binswanger’s disease. Other types of abnormal proteins are found in other forms of dementia, including α-synuclein in dementia of Parkinson’s disease and Lewy body dementia. Tau accumulates in frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy. As a consequence of accumulation of misfolded proteins, there is an inflammatory response that accelerates the dementia. Biomarkers in the cerebrospinal fluid (CSF), plasma, and on MRI are showing the presence of brain pathology at an earlier stage that will facilitate clinical trials.

Keywords

Diffusion tensor imaging (DTI); Alzheimer’s disease research centers (ADRCs); vascular cognitive impairment and dementia (VCID); fluid attenuated inversion recovery (FLAIR); single molecule assay (SIMOA) system; frontotemporal dementia

Introduction

The incidence of dementia has increased worldwide, paralleling the increase in the numbers of elderly individuals referred to as a silver tsunami. While there are a number of factors involved in this increase in people with dementia, the major one is a demographic shift related to the aging of populations worldwide. Sixty-five has been universally accepted as the age of retirement since the 1800s, when Bismarck (1815–98) set the age to a time beyond the lifespan of the average citizen in Germany so that social benefits would be given to only a few people. However, this age is no longer considered old, and many people are living into their 90s and 100s. Because dementia is a disease of old age, there is a dramatic increase in the number of people with cognitive problems. The main driver of this increase is the aging of populations in both the developed and developing countries. The percentage of people living to be over 100 is high in a number of countries, particularly in Japan, Italy, and France (Fig. 1.1). Senescence is the major factor involved in the incidence of dementia with the chances of being demented increasing drastically after age 80. While age is not a risk factor that can be avoided, there are ways to slow the progress of dementia related to changes in lifestyle; slowing of the age of onset of dementia is possible with a reduction in vascular risk factors, primarily lowering blood pressure, treating diabetes, reducing lipids, controlling sleep apnea, and increasing exercise: this along with adherence to a healthy diet and regular exercise has been proven to slow the onset of cognitive decline.

Figure 1.1 Places with the highest percentage of the total population over the age of 100 as of 2020. Only countries with more than 1000 centenarians are included. Countries where 100 is the new 80 permission requested from UN 11–24–21.

The increase in elderly, particularly in developed countries, has raised concerns that the cost of caring for those with cognitive impairment will overwhelm the available resources and that many countries will be unable to cope with this marked increase in medical and social services required. In spite of an influx of younger individuals through immigration, which has slowed the aging of the population in the United States, the government has become alarmed and has greatly increased the funds allocated through the National Institutes of Health (NIH) for research into treatments for Alzheimer’s disease (AD) and related dementia. As treatments have improved for medical conditions, primarily heart disease and cancer, there has been an increase in the number of people developing cognitive impairment. It is currently estimated that there are 6 million people with dementia and that number will double by 2050. Due to the reduced birth rate and increased longevity in developed countries, fewer people will be available to care for those with dementia, compounding the problem will be a reduced number of geriatricians. To meet these needs, the United States government has increased spending to expand planning and to implement plans for long-term care and research into diseases of the elderly. While the focus of this effort has been primarily on AD, there has been a growing awareness of a number of other diseases that are important causes of dementia.

The interest in neurodegenerative diseases of the brain is relatively recent. There was little interest in dementia, with most cognitive loss thought to be due to hardening of the arteries, and memory loss was considered part of the aging process. Few autopsies were done on older people leaving uncertain the numbers and causes of dementia. The original case report of a patient with early onset dementia by Alois Alzheimer was over 100 years ago; since autopsies on elderly patients with dementia were uncommon, there was little progress in our understanding of the pathological basis of diseases of the elderly. Two major events caused a paradigm shift in the 1970s: the first was a letter to the editor of a neurological journal by Dr. Robert Katzman expressing concern that many patients with dementia were being missed, and the numbers were much larger than thought. The other event were advances in neuroimaging that started with the discovery of computed tomography (CT) by Dr. Housefield in England, leading to the rapid growth in neuroimaging, first with x-ray-based CT and shortly thereafter with magnetic resonance imaging (MRI). These revolutionary changes in the ability to watch pathology develop during life stimulated a major increase in interest in dementia. Concomitant with the growth of imaging, there were major advances in the understanding of the molecular mechanisms, such as the role of amyloid and other abnormal proteins that accumulated in the brain with aging and were important in the pathological damage. The support of the NIH was crucial in the rapid growth in information that has continued over the past 50 years; the first center devoted to understanding and developing treatments for AD was started in a nursing home in the Bronx, New York, by Dr. Katzman. From that humble start, the number of AD research centers (ADRCs) has grown to 34. These centers are at the forefront in building knowledge of the pathophysiology not only of AD, but of all the causes of dementia in the elderly.

A major achievement of the research into the etiology of dementia over the past 30 years has been the recognition of the role of misfolded proteins that are accumulating in the brain and leading to cell death: the two main proteins are amyloid and tau (Long & Holtzman, 2019). Following that discovery, a number of treatments were developed to remove these abnormal proteins. In spite of intensive study with these promising agents, the results have been disappointing, and no disease modifying agent has been discovered although several are being tested. As a result of this failure to find a cure, a number of new research directions are now being explored. One of the most important is due to the recognition that abnormal proteins, many of which are misfolded proteins, stimulate an inflammatory response; this sterile inflammation is due to innate immunity. Other proteins besides amyloid and tau can accumulate in the brain, causing inflammation, and leading to cell damage. These proteins are found in forms of dementia that are less prevalent, including frontotemporal dementia (FTD), Parkinson’s disease with dementia, and the recently discovered transactive response DNA-binding protein 43 (TDP-43).

In addition to the deposition of abnormal proteins in the brain, aging results in an increase in damage to blood vessels related to vascular risk factors. This increase in vascular damage parallels the deposition of abnormal proteins and the combined effect is to accelerate cell death and cognitive loss. Blood vessel injury interacts with the deposition of abnormal proteins to accelerate the cognitive decline by hastening neuronal death (Tomimoto, 2011). Alois Alzheimer identified neuronal death in the cortex, while Otto Binswanger, a neuropathologist who was a colleague of Alzheimer’s, described the role of pathological damage to the white matter (WM) as a result of arteriolosclerosis/vascular damage as a cause of dementia. Alzheimer showed damage to neurons through the newly developed silver staining and the accumulation of plaques, while Binswanger showed that WM injury resulted from arteriolosclerosis in the penetrating blood vessels feeding the deeper parts of the brain, depriving them of nutrients. These initial observations at the turn of the century formed the basis for the concepts that are still prevalent today. Interest in diseases of old age that result in impaired cognition waned because of the paucity of neuropathological studies and the misconception that loss of memory was a normal accompaniment of aging or, as it was called at that time, senility, leading to therapeutic nihilism. Another major factor for the lack of advancement in our understanding of dementia was that few people lived past the age of 70.

In the late 1970s, computed axial tomography (CAT or CT) was developed in England, making it possible to view images of the brain during life that previously had required autopsy. The mathematical formulas that were developed to form tomographic images with x-rays were rapidly applied to other imaging modalities, including magnetic resonance (MR) and positron emission tomography (PET). With the ability to see inside the skull for the first time, the need for pathological verification increased. In the 1980s, another major leap occurred in our understanding of dementia as the methods of molecular biology showed the pathways involved in brain pathology and studies in genetics revealed the genes involved in the familiar forms of dementia. This powerful combination of imaging and molecular science produced the diagnostic tools that are now unraveling disease mechanisms. As these tools have become available to the neurologist and can be used in everyday practice, they have not only improved diagnosis but have also guided attempts at treatment.

Determining the etiology of cognitive decline

The term dementia is descriptive rather than diagnostic. This is the case in most circumstances except for its use in AD where it refers to a late stage where severe symptoms are present. The term dementia is derived from the Latin term, dementare, which means to make insane; it is defined in Thomas (1985) as an irreversible deterioration with absence or reduction of intellectual faculties due to an organic brain disease. The progressive nature of dementia separates it from the static processes, such as mental retardation or the results of brain injuries. While there are significant causes of dementia in children, including some vascular diseases, dementia is mainly a disease of older adults except in hereditary forms of AD. Severe hypertension can begin in mid-life with vascular dementia in later life. In the early stages, the term mild cognitive impairment (MCI) is used. Most people with dementia have the late onset form rather than an hereditary form.

While primary brain disorders are the major causes of dementia, there are a number of other medical conditions that are accompanied by a decline in intellect; these fall into two categories; those that are potentially treatable and those that are irreversible. One of the primary aims of the clinician prior to initiating a search for neurological causes is to eliminate the medical causes. Vascular risk factors are potentially treatable, and it is particularly important to identify them early before serious damage has occurred. The main risk factor is hypertension; the WM is vulnerable to long-standing hypertension. Treating hypertension reduces the risk of stroke and dementia. Until recently, the guidelines were to lower blood pressure to 140/90. A new study, SPRINT, suggests that the guidelines should be 120/80 (Yang & Williamson, 2019). Mid-life hypertension identified in participants in the long-term Framingham study showed that those individuals with a blood pressure of 140/90 had an increased risk of WM damage on MRI later in life, but the impact on cognition was not determined (Maillard et al., 2012). Studies such as these emphasize the importance of early identification and aggressive treatment of vascular diseases.

Diabetes is an example of a treatable cause of dementia that is common, and increasing in prevalence, particularly type 2. Diabetes has been linked to cognitive loss with insulin resistance being suspected as the cause. Insulin is important in a number of pathways of brain metabolism, including processing of amyloid and tau. Insulin resistance in the periphery leads to complex changes in the brain. Insulin crosses the blood–brain barrier, suggesting that insulin treatment may help in dementia. However, a trial of nasally administered insulin failed to improve dementia (Kellar & Craft, 2020). Small vessel disease is a common finding in both diabetes and hypertension. MRI shows brain atrophy and reduced cerebral blood flow in diabetes, paralleling the changes observable in the vasculature of the retina. Biomarkers of inflammation and blood–brain barrier disruption are found in patients with type 2 diabetes. Given that obesity and type 2 diabetes are increasingly prevalent in younger age groups, further work is needed to understand long-term effects on the underlying pathophysiology and how these relate to the risk and clinical trajectory of dementia. Other vascular risk factors are suspected to be implicated in the development of dementia, but the studies to show this are equivocal: these include elevated lipids and obesity. Many medical conditions can produce a clinical syndrome similar to degenerative dementia, but are potentially reversible with appropriate treatment. Frequently, patients with endocrinological and vitamin deficiencies have alterations in thinking; low levels of thyroid hormone and vitamin B12 are causes of cognitive loss and should be tested for routinely. Collagen-vascular diseases can impair cognition; primarily lupus erythematosus. There are other medical conditions that interfere with thinking, but these are rarely encountered during a work-up for dementia since they are generally detected by the