Effects of Cardiovascular Disease and Related Risk Factors on Neurocognition

Cardiovascular disease (CVD) affects approximately 44 million American adults older than age 60 years and remains the leading cause of death in the United States, with approximately 610,000 each year. With improved survival from acute cardiac events, older adults are often faced with the prospect of living with CVD, which causes significant psychological, social, and economic hardship. The various disease processes that constitute CVD also exert a deleterious effect on neurocognitive functioning. Although existing knowledge of neurocognitive functioning in CVD and its subtypes is substantial, a review of these findings by CVD type and neurocognitive domain does not exist, despite the potential impact of this information for patients, health care providers, and clinical researchers. This chapter provides a resource for clinicians and researchers on the epidemiology, mechanisms, and neurocognitive effects of CVDs. This chapter includes a discussion of neurocognitive consequences of CVD subtypes by neuropsychological domain and recommendations for assessment. Overall, the CVD subtypes that have the most findings available on specific neurocognitive domains are heart failure, hypertension, and atrial fibrillation. Despite a large discrepancy between the number of available studies across CVD subtypes, existing literature on neurocognitive effects by domain is consistent with the literature on the neurocognitive sequelae of unspecified CVD. Specifically, the research literature suggests that cognitive processing speed, attention, executive functioning, and memory are the domains most frequently affected. Given the prevalence of CVDs, neuropsychological assessment of older adults should include instruments that allow consideration of these potential neurocognitive consequences of CVD.

Cancer and Cancer Treatment-Related Cognitive Impairment

As the population of cancer survivors has grown into the millions, there is increasing emphasis on understanding how late effects of treatment impact survivors’ ability return to work/school, ability to function and live independently, and overall quality of life. Cognitive changes are one of the most feared problems among cancer survivors. This chapter describes the growing literature examining cognitive changes associated with non-central nervous system cancer and cancer treatment. Typical elements of cancer treatment are discussed, followed by a description of clinical presentation, self-reported and objectively assessed cognitive findings, and results of structural and functional neuroimaging research. Genetic and other risk factors for cognitive decline following treatment are identified and discussed, together with biomarkers and animal models of treatment-related effects. This is followed by a discussion of behavioral and pharmacologic treatments. Finally, challenges and recommendations for future research are provided to help guide subsequent research and theoretical models.

Huntington Disease

Huntington disease (HD) is a autosomal dominant neurodegenerative disease caused by expansion of a trinucleotide repeat (cytosine, adenine, and guanine [CAG]) on the short arm of chromosome four. Average age of motor diagnosis is 39 years, and age at diagnosis is associated with the length of the CAG mutation. The prodrome of HD can be recognized 15 years prior to motor diagnosis and is characterized by subtle impairments in emotional recognition, smell identification, speed of processing, time estimation and production, and psychiatric abnormalities. HD shows particular vulnerability of the medium spiny neuron in the basal ganglia. Progressive brain dysfunction and neuron death lead to insidious loss of function in motor, cognitive, and behavioral control over 34 years (17 prodromal and 17 post-diagnosis). Treatment plans rely on genetic counseling, psychiatric symptom treatment as needed, physical therapy, and environmental modifications. There are two treatments for the reduction of chorea, but there are no disease-modifying therapies. Experimental therapeutics are rapidly emerging with multiple and various targets, however, and gene therapies to silence the mutant HD gene are currently ongoing. This chapter reviews clinical and neuropathological descriptions of HD and discusses potential underlying mechanisms and animal models, diagnostic and clinical assessments used to characterize and track the disease, treatment planning, and challenges for research to advance care.

HIV-Associated Neurocognitive Disorders

Human immunodeficiency virus enters the central nervous system (CNS) early after systemic infection, and may cause neural injury and associated neurocognitive impairment through multiple direct and indirect mechanisms. An international conference of multidisciplinary neuroAIDS experts convened in 2005 to propose operationalized research criteria for HIV-related cognitive and everyday functioning impairments. The resulting classification system, known as the Frascati criteria, defined three types of HIV-associated neurocognitive disorder (HAND): asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (HAD). Consideration of comorbid conditions that can influence neurocognitive performance, such as developmental disabilities, non-HIV forms of CNS compromise (neurological and systemic), severe psychiatric conditions, and substance use disorders, is essential to differential diagnosis. Since the introduction of combination antiretroviral therapy (ART), rates of severe HAND (i.e., HAD) have greatly declined, although the milder forms of HAND remain quite prevalent, even in virally suppressed people living with HIV (PLWH). Beyond ART, clinical management of HAND includes behavioral interventions focused on neurocognitive and functional improvements. This chapter covers a range of HAND-related topics, such as the neuropathological mechanisms of HIV-related CNS injury, assessment and diagnostic systems for neurocognitive and everyday functioning impairment in HIV, treatment and protective factors, aging with HIV, HAND in international settings, and ongoing challenges and controversies in the field. Future needs for progress with HAND include advances in early detection of mild cognitive deficits and associated functional impairment in PLWH; biomarkers that may be sensitive to its underlying pathogenesis; and differential diagnosis of HAND versus age-related, non-HIV-associated disorders.

The Spectrum of Cerebrovascular Disease and Associated Cognitive Decline

Throughout the lifespan, common variations in systemic health and illness contribute to alterations in vasculature structure and function throughout the body, significantly increasing risk for cardiovascular and cerebrovascular disease (CVD). CVD is a prevalent cause of mortality in late life; it also promotes brain alterations, contributing to cognitive decline and, when severe, vascular dementia. Even prior to diseased states, individual variation in CVD risk is associated with structural and functional brain alterations. Yet, how cumulative asymptomatic alterations in vessel structure and function contribute to more subtle changes in brain tissue integrity and function that emerge in late life is unclear. Finally, vascular risk factors are associated with the clinical progression of neurodegenerative diseases such as Alzheimer’s disease (AD); however, recent theory posits that vascular degeneration may serve a contributory role in these conditions. This chapter reviews how lifespan changes in vascular health contribute to degenerative changes in neural tissue and the subsequent development of cognitive impairment and/or vascular dementia. It first discusses associations between vascular risk factors and cognition and also how declining vascular health may lead to cognitive impairment and dementia. Next, it identifies basic aspects of cerebrovascular anatomy and physiology sustaining tissue health and discusses how vulnerabilities of this system contribute to neurodegenerative changes. Finally, it reviews evidence of vascular contributions to AD and presents ideas for future research to better understand the full spectrum of cerebrovascular contributions to brain aging, cognitive decline, and dementia.

Issues of Diversity in Cognitive Aging

Cognitive impairment associated with aging and Alzheimer’s disease (AD) is among the most common and debilitating conditions, and it poses a major public health problem. Projections indicate that the prevalence of cognitive impairment is expected to increase substantially in the next decade. This will be particularly true for minority populations, especially the older African American population, which is growing at an even more rapid pace than the older majority population. This chapter presents an overview of studies that have examined racial differences in cognitive aging. Studies have found consistent level differences in cognitive performance, with older African Americans tending to score lower on cognitive tests compared to similarly aged non-Hispanic Whites, even after adjusting for confounding factors such as education and socioeconomic status. Such findings have led to the proposal that African Americans are more likely to have cognitive impairment and are at greater risk of AD. The chapter presents critical challenges in comparing African Americans and Whites on cognitive function tests, and it discusses the utility of using longitudinal designs to compare the racial groups. It also discusses critical barriers to understanding of racial differences in the field and offers concrete actions that should be taken to move the field forward in this area.

Considerations for Translational Research in the Study of Adult Cognitive Disorders

Adult cognitive disorders exact a staggering burden on worldwide health care, with the need for efficacious and accessible treatments growing every day. The ability to probe questions relevant to normal or aberrant cognition in humans makes animal models indispensable tools in translational research. The use of animal models enables detailed investigation of complex interactions between genes, environment, and cognition that would be difficult or impossible in human subjects or populations. However, special consideration must be given to create specific, translatable models of human cognitive disorders. First, a model must prove statistically reliable, reproducible, and valid. Successful translational research requires thoughtful consideration and careful deployment of reliable, well-chosen animal models that are appropriately matched to their experimental purpose. In addition, to ensure specificity of a model to one disorder, it is prudent to focus on clusters of clinical features and disease-specific phenotypes in addition to environmental and genetic risk factors. Many neurological disorders share symptomatic elements in common, which drives the necessity for relevant cognitive domains to the disease in question to be carefully considered and replicated. Thoughtfully created animal models facilitate translational research aimed at understanding disease mechanisms and developing effective diagnostics, therapeutics, and preventive strategies to achieve better health care outcomes for people affected by cognitive disorders.

Alcohol Dementia, Wernicke’s Encephalopathy, and Korsakoff’s Syndrome

Chronic alcohol consumption has direct effects on the central nervous system and is among the leading causes of cognitive impairment and dementia. Alcohol-related dementia, Wernicke’s encephalopathy, and Korsakoff’s syndrome are among the most common forms of severe alcoholism-related neurological complications that are associated with widespread abnormalities in the brain, as well as impairments of multiple mental and emotional processes. Abnormalities have been consistently reported in association with Wernicke’s encephalopathy and Korsakoff’s syndrome, but alcohol-related dementia remains less well characterized. This chapter reviews the neurological and neuropsychological characteristics of these conditions, associated changes in the brain, potential molecular mechanisms involved, and some of the treatment or rehabilitation options. Future use of evidence-based diagnostic test-selection is advised to assist in refining differential diagnoses.

Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive, neurodegenerative tauopathy associated with exposure to repetitive head injury, including concussions and subconcussions. Clinical features of CTE consist of abnormalities in behavior, including explosivity, impulsivity, and suicidality; mood, including depressed mood and hopelessness; cognition, including executive dysfunction, memory loss, and dementia; and movement, including parkinsonism. Neuropathologically, there is often generalized cortical atrophy, which may be most severe in the frontal and temporal lobes; abnormalities of the septum pellucidum, such as cavum septum or fenestrations; enlargement of the lateral and third ventricles; atrophy of the diencephalon; and depigmentation of the substantia nigra and locus coeruleus. Microscopically, CTE is defined by the perivascular accumulation of hyperphosphorylated tau (p-tau) in neurons and neuronal processes as neurofibrillary tangles (NFTs) and disordered neurites and in astrocytes, irregularly distributed in the cerebral cortex, with a predilection for the sulcal depths. In the mildest forms of CTE, a few perivascular CTE lesions are found in the cortex; in advanced CTE, p-tau NFTs and neurites are widely distributed in other cortical regions, often in the superficial layers of cortex, as well as the hypothalamus, thalamus, and brainstem. Most of the knowledge about CTE has been gained from the careful clinical characterization and comprehensive postmortem pathological analysis of brain donors. Although these studies have been essential to understanding the clinicopathological features of CTE and its molecular pathogenesis, current tissue-based research efforts have expanded to include developing in vivo biomarkers and diagnostics, characterizing risk factors, and developing methods to prevent and treat CTE.

Adult Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common, symptomatically heterogeneous, neurodevelopmental disorder. It’s symptoms first appear early in life and evolve as the brain matures and reorganizes over the lifespan. Cognitive dysfunction is a key feature of adult ADHD and typically manifests as a dysregulation of executive control of attention, working memory, inhibitory control, and emotion regulation rather than as a defining deficit in a specific cognitive domain. The heterogeneity of presentation, changing clinical manifestations across development, and variability in functional impairment associated with ADHD contribute to the difficulty of obtaining a “snapshot” diagnosis using a single assessment or representative battery. Careful history-taking of information across raters and settings generally reveals a pattern of symptoms beginning in childhood. Manifested impairment required for diagnosis depends on a variety of supportive or mitigating versus contributory factors. In adulthood, persisted or untreated ADHD may predispose to a variety of other conditions, including low educational and/or academic attainment, decreased earning potential, substance use or abuse, parenting and marital problems, poor health practices, a variety of risky behaviors, and a variety of comorbid Axis I and Axis II psychiatric disorders. High-functioning adults who have not previously come to clinical attention may present for care because of academic underattainment, suboptimal performance in the workplace, or behavioral or mood dysregulation. In addition, ADHD may be discovered as part of a more comprehensive workup of other disorders. A range of psychosocial and psychopharmacological treatments are available; response is often good to excellent once the disorder is properly identified.