Neurocognitive Complications of HIV-Infection: Neuropathogenesis to Implications for Clinical Practice (Current Topics in Behavioral Neurosciences, 50)

Preface
	What´s Unique About This Volume
	The First Part
	The Second Part
	The Third Part
	The Fourth Part
	Our Sincerest Thanks
Contents
Part I: Neuropathogenesis and Biomarkers
New Potential Axes of HIV Neuropathogenesis with Relevance to Biomarkers and Treatment
	1 Introduction
	2 HAND Prevalence, Diagnosis, Prognosis and Treatment
		2.1 Treatment
	3 Risk Factors of HAND
	4 HAND Pathophysiology
		4.1 Natural HIV Infection of the CNS
		4.2 HAND Pathophysiology Following Viral Suppression with ART
	5 Mechanisms Driving HAND in Virally Suppressed Patients
		5.1 HIV Viral Presence/Replication in the CNS
		5.2 Host Cell and Epigenetic Factors
		5.3 Chronic Peripheral Inflammation
		5.4 ART Neurotoxicity
	6 Biomarkers of CNS Infection and HAND
		6.1 Measures of HIV Viremia and Viral Latency
		6.2 Neuronal Damage
		6.3 Cellular Activation
		6.4 Metabolic Dysfunction
		6.5 Novel Non-traditional Biomarkers
		6.6 Limitations of Biomarkers and Current Challenges
	7 Biomarkers of Neurocognitive Decline as Indicators of ART Success
	8 Where to from Here?
	References
Neurocognitive Impairment and Associated Genetic Aspects in HIV Infection
	1 Introduction
	2 HIV-Associated Neurocognitive Disorders
	3 Primary Host Genetic Variations in HAND: Immune-Related Genes
		3.1 C-C Chemokine Receptor Type 5 (CCR5)
		3.2 Macrophage Inflammatory Protein-1 Alpha (MIP-1α or CCL3)
		3.3 Stromal Cell-Derived Factor-1 (SDF-1 or CXCL12)
		3.4 Monocyte Chemoattractant Protein-1 (MCP-1 or CCL2)
		3.5 Mannose-Binding Lectin 2 (MBL2)
		3.6 Human Leukocyte Antigen (HLA) Alleles
		3.7 Tumor Necrosis Factor Alpha (TNF-α)
	4 Primary Host Genetic Variations in HAND: Genes Associated with Neurocognition
		4.1 Apolipoprotein E
		4.2 Dopamine-Related Genes
	5 Epigenetic Changes Associated with HAND
		5.1 MicroRNA (miRNA)
		5.2 Histone Modification
		5.3 Other Epigenetic Markers of Biological Aging
	6 Genetic Susceptibility to CNS Toxicity of Antiretroviral Drugs
		6.1 Limitations and Outlook
	References
Inflammatory Mechanisms and Cascades Contributing to Neurocognitive Impairment in HIV/AIDS
	1 Neurocognitive Impairment in HIV
		1.1 What Is Neurocognitive Impairment?
	2 Peripheral Inflammation Sets Up Processes That Lead to Neurocognitive Impairment
		2.1 Monocyte/Macrophage (M/Mphi) Activation
		2.2 CD14/16 Monocytes Facilitate BBB Crossing
		2.3 Chronic Interferon-α (IFN-α) Monocyte Phenotype
		2.4 Contribution of Lipopolysaccharide (LPS) to Inflammation Is Diminished
		2.5 Blood-Brain Barrier (BBB)
	3 Neuroinflammation: Transition of Inflammation from the Periphery to the CNS and the Consequences on Neurodegeneration
	4 HIV Proteins as Activators of Neuroinflammation
	5 Antiretrovirals Contribute to Neuroinflammation
		5.1 ART Drives Inflammation
		5.2 ART and Neuroinflammation
	6 Drugs of Abuse Contribute to Peripheral and Neuroinflammation
		6.1 Methamphetamine
		6.2 Opioids
		6.3 Cannabis
	7 Fluid Biomarkers of Neurocognitive Impairment Are Products of Inflammation
		7.1 Neurofilament Light Chain (NF-L)
		7.2 Soluble CD14 (sCD14)
		7.3 Soluble CD163 (sCD163)
		7.4 Exosomes as Fluid Biomarkers of Neuroinflammation
	8 Clinical Implications, Translational Aspects, and Future Directions
	References
Neuroimaging Advances in Diagnosis and Differentiation of HIV, Comorbidities, and Aging in the cART Era
	1 Neurological Consequences of HIV Infection (NeuroHIV)
	2 Mapping NeuroHIV and Neurological Disease with MR Based Imaging
		2.1 Mapping Anatomical Brain Morphometry
		2.2 Functional Brain MRI Studies of HIV
		2.3 Magnetic Resonance Spectroscopy Studies of HIV
		2.4 Brain Mapping with Diffusion-Weighted MRI
	3 HIV-Related Comorbidities and Aggregated Risk for Brain Dysfunction in Aging: The Role of Neuroimaging
		3.1 Aging with HIV Infection
		3.2 Risk Factors and Interactions Contributing to Complex Brain Disorders
		3.3 Effects of Viral Infection on the Pathogenesis of Neurodegenerative Disorders
		3.4 Effects of Alzheimer´s Disease Genetic Risk in the Context of HIV
	4 Advanced Imaging Methods to Identify Biomarkers of Aging, Alzheimer´s Disease and Related Dementias
		4.1 A Biomarker Approach to Diagnosing Alzheimer´s Disease
		4.2 Uncovering the Integrity of the Blood Brain Barrier with Dynamic Contrast-Enhanced MRI and Susceptibility Imaging
		4.3 Components of Brain Tissue Microstructure Assessed In Vivo with Multishell Diffusion MRI
		4.4 Neuroimaging and AI Methods to Assess Age-Related Decline and for Differential Diagnosis
	5 Heterogeneity Across HIV Studies and Discrepancies in Findings
	6 Future Directions in HIV and Aging Research and Clinical Implications
	References
Part II: Neurocognitive Impairments in Low-, Middle- and High-Income Countries - Incidence/Prevalence and Contexts
Neurocognitive Complications of Pediatric HIV Infections
	1 Neurocognitive and Neurologic Manifestations of Perinatal HIV Infection and Advances in Behavioral Interventions
		1.1 Extent and Nature of Cognitive Impairments in Perinatally HIV-Infected Children
		1.2 Preliminary Findings Using Diffusion Tensor Imaging (DTI) to Evaluate Neuronal Injury in Perinatal HIV
		1.3 Dynamic Versus Static Neuropsychological Assessment of Neurocognitive Function
		1.4 Brain Training and Neuroimaging Evidence Support the Need for Dynamic Assessment
		1.5 CCRT Positive Neuroplasticity Intervention Model
		1.6 Threats to Quality of Caregiving in African HIV-Affected Children
		1.7 Quality of Home Environment, Caregiving, and the Developmental Effects of HIV
		1.8 Caregiver Training Intervention to Enhance Early Childhood Development Affected by HIV
		1.9 A Brain/Behavior Model for the Benefits of MISC in Early Childhood Development
		1.10 Theoretical Foundation of MISC Training
	2 Cellular and Molecular Mechanisms of Inflammation and Neuronal Injury in Perinatal HIV and Implications for Therapeutics
		2.1 Viral Entry to the CNS
		2.2 Mediators of HIV Replication, Persistence, and Neuronal Injury in the CNS
		2.3 Brain as a Latent Reservoir in Perinatal HIV
		2.4 Virologic Factors Can Potentially Impact the Pathogenesis of the CNS
		2.5 Biomarkers for Immune Activation and Neuronal Injury in the CNS
		2.6 Developmental Differences in Monocyte Turnover and Function in the Neonatal Window and Implications for Perinatal HIV
	3 Conclusion: Multipronged Approaches for Optimizing Neurodevelopmental Outcomes in Perinatal HIV
		3.1 Mixed Evidence for Benefit of ART Alone
		3.2 New Treatment Strategies
		3.3 Concluding Remarks
	References
Neurocognitive Complications of HIV Infection in Women: Insights from the WIHS Cohort
	1 Are WLWH More Cognitively Vulnerable Than MLWH?
	2 Pattern of Cognitive Impairment Among Women Living with HIV
	3 Inflammatory Contributors to NCI Among WLWH
	4 Common Comorbidities Among WLWH and Cognitive Correlates
		4.1 Mental Health Comorbidities
		4.2 Substance Use Comorbidities
		4.3 Vascular and Metabolic Risk Factors
		4.4 Female-Specific Reproductive Risk Factors
		4.5 Coinfections and Liver Function
		4.6 Non-ARV Medications
		4.7 Genetic Markers
	5 Summary
	6 Future Directions
	References
Cultural Neuropsychology Considerations in the Diagnosis of HIV-Associated Neurocognitive Disorders
	1 Introduction
	2 Health Disparities in HIV
		2.1 African American/Black and Latinx Populations
		2.2 Asian/Native Hawaiian/Other Pacific Islanders
		2.3 American Indians/Alaskan Natives
		2.4 First Peoples of Australia
		2.5 Indigenous People of Canada
	3 HAND in Culturally Diverse Populations
		3.1 HAND Diagnosis
		3.2 Risk for Misdiagnosis of HAND in CALD Groups
	4 Sociocultural Assessment Considerations
		4.1 Quality of Education
		4.2 Acculturation
		4.3 Socioeconomic Status
		4.4 Discrimination and Social Adversity
		4.5 Language
		4.6 Qualitative Approach
	5 Regional to Global Considerations and Special Populations in HAND
		5.1 Urban vs. Rural Disparities in HIV
		5.2 Gender Inequalities and HAND
		5.3 Migration and HAND
	6 Clinical Implications, Translational Aspects, and Future Directions
	References
Neurocognitive Complications of HIV Infection in Low-Income Countries
	1 Introduction: Global Epidemiology of HIV and HIV-Associated Neurological Disorders
	2 Neurocognitive Complications of HIV-1 in the ART Era: Prevalence and Persistence in Resource-Limited Settings
	3 HAND in Low-Income Countries: Socioeconomic and Public Health Factors
		3.1 Low Linkage to Care and Poor Health Status
		3.2 Cognitive Reserve and Education Inequality
		3.3 Mental Health and HIV-Related Stigma in Vulnerable Populations
	4 Consequences of HAND: Productivity, Quality of Life, and Morbidity
	5 Advancing NeuroAIDS: Building an Infrastructure for Neurocognitive Testing in RLS
	6 Clinical Implications, Translational Aspects, and Future Directions
	7 Conclusion
	References
Deep Phenotyping of HIV Neurocognitive Complications Among Individuals Residing in High-Income Countries
	1 Introduction
	2 Variability in Viral-Host-Brain Dynamics Begins During Early Infection
	3 Neuropathological Signatures of HIV
	4 Neuroimaging Abnormalities of HIV
	5 The Neurocognitive Phenotype of HIV
	6 HIV Disease Correlates of Brain Injury
	7 Age-Related Mechanisms of HAND
	8 Application of the Frascati Criteria for HAND
	9 Research Opportunities Using Data Science Methods
	10 Clinical Implications
	References
Reliably Measuring Cognitive Change in the Era of Chronic HIV Infection and Chronic HIV-Associated Neurocognitive Disorders
	1 Introduction: People Living with HIV Infection (PLHIV) Have Different Starting Points for Their Life-Span Cognitive Health
	2 Existing Statistical Frameworks to Quantify Cognitive Change at the Group and at the Individual Levels
		2.1 The Advantage of Longitudinal Studies
		2.2 The Critical Importance of the Practice Effect and Its Correction Via Longitudinal Normative Data Strategies
		2.3 Other Neuropsychological Test Characteristics That Impact the Interpretation of Cognitive Change in Longitudinal Studies
		2.4 Assessing Cognitive Change Across Groups
		2.5 Assessing Cognitive Change in Individuals
	3 Longitudinal Studies in Early Treated HIV Infection
	4 Longitudinal Studies in Chronically Treated HIV Infection
	5 Conclusions, Clinical Implications, and Future Directions
	References
Part III: Comorbidities and Complications
Geriatric Syndromes in People Living with HIV Associated with Ageing and Increasing Comorbidities: Implications for Neurocogni...
	1 Introduction
		1.1 Epidemiology of Ageing in HIV
		1.2 Profile of Ageing People Living with HIV
		1.3 Assessment of Older Patients Living with HIV
	2 Geriatric Syndromes
		2.1 Polypharmacy
		2.2 Falls and Impaired Mobility
		2.3 Frailty
		2.4 Sarcopenia
		2.5 Sensory Impairment
			2.5.1 Visual Impairment
			2.5.2 Hearing Impairment
			2.5.3 Olfaction
			2.5.4 Peripheral Neuropathy
		2.6 Clinical Implications, Translational Aspects and Future Directions
			2.6.1 Clinical Implications
			2.6.2 Translational Aspects
		2.7 Future Directions in Terms of Basic Science/Health Services Delivery/Public Health
	3 Conclusions
	References
Conceptualizing and Assessing Everyday Functioning in the Context of HIV-Associated Neurocognitive Disorders
	1 Global Everyday Functioning
	2 Financial Management
	3 Automobile Driving
	4 Employment and Vocational Functioning
	5 Clinical Implications of Current Research
	References
Neuropsychiatric Disorders, Emotional Disturbances, and Their Associations with HIV-Associated Neurocognitive Disorder
	1 Introduction
	2 Epidemiology
	3 Connection to HAND and Relation to Cognitive Symptoms
		3.1 Depression
		3.2 Anxiety
		3.3 Apathy
		3.4 Alexithymia
		3.5 Emotional Processing
	4 Connection to Perceived Stress and Stressful Life Events
		4.1 Perceived Stress
		4.2 Stressful Life Events
	5 The Role of Coping
	6 Non-pharmacological Interventions
	7 Conclusions and Clinical Implications
	References
Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Di...
	1 Cardiovascular Diseases
		1.1 Atrial Fibrillation
		1.2 Hypertension
		1.3 Coronary Artery Disease
		1.4 Carotid Intima-Media Thickness (cIMT)
	2 Metabolic Syndrome
		2.1 Diabetes
		2.2 Obesity
		2.3 Dyslipidemia
	3 The Concept of Vascular Cognitive Impairment (VCI)
		3.1 Stroke
		3.2 Cerebral Small-Vessel Disease
		3.3 Clinical Implications for HAND Criteria
	4 Conclusion
	References
HIV-Associated Neurocognitive Disorder (HAND): Relative Risk Factors
	1 Neurodegeneration and Types of Dementia
	2 Non-modifiable Risk Factors
		2.1 The Aging Process
		2.2 Genetics
		2.3 Ethnicity and Gender
	3 Modifiable Risk Factors
		3.1 Cardiovascular Health
		3.2 Depressive and Substance Use Disorders
		3.3 Educational Level and Socioeconomic Status
	4 Risk Factors and Diagnosis for HAND and for All-Type Dementia
	5 Animal Models for Dementia
	6 Biological Measures to Detect All-Type Dementia Risk
		6.1 A Focus on FTD
		6.2 A Focus on DLB
	7 Clinical Implications, Translational Aspects, and Future Directions
	8 Summary
	References
Part IV: Screening, Interventions and Clinical Management
Screening for HIV-Associated Neurocognitive Disorders: Sensitivity and Specificity
	1 Screening for HAND: Needs Versus Practice
	2 Screening Tests for HAND
		2.1 Need for Functional Assessment
		2.2 Screening Test Psychometrics
	3 Global Perspective
	4 Future Directions
	5 Summary
	Appendix
	References
Behavioral and Physical Activity Interventions for HAND
	1 HIV-Associated Neurocognitive Disorders
	2 Physical Activity as a Behavioral Intervention for HAND
		2.1 Physical Activity Levels Among People Living with HIV
		2.2 Relationship Between Physical Activity and Neurocognition
		2.3 Underlying Biologic Mechanisms Linking Physical Activity and Neurocognition
		2.4 Interventions to Increase Physical Activity, Thereby Benefiting Neurocognition
	3 Diet as a Behavioral Intervention for HAND
		3.1 Diet and Neurocognitive Function in the General Population
		3.2 Diet and Nutrition Concerns in the Context of HIV
		3.3 Diet Interventions Specific to People Living with HIV
	4 Sleep as a Behavioral Intervention for HAND
		4.1 Sleep Disturbance in the Context of HIV
		4.2 Effect of Sleep Disturbance on Neurocognitive Function
		4.3 Behavioral Strategies to Improve Sleep Quality
	5 Promotion of Antiretroviral Therapy Adherence as a Behavioral Intervention for HAND
		5.1 Antiretroviral Therapy Adherence and Neurocognitive Performance
		5.2 Strategies to Promote Antiretroviral Therapy Adherence
	6 Clinical Implications
	7 Conclusion
	References
Targeting HIV-Related Neurocognitive Impairments with Cognitive Training Strategies: Insights from the Cognitive Aging Literat...
	1 Introduction
	2 Cognitive Training Across Aging Populations
	3 Cognitive Training in HIV
		3.1 Speed of Processing Training
		3.2 Changing the HAND Diagnosis
		3.3 Variations of Speed of Processing Training
	4 Clinical Implications
	5 Research Implications
	6 Conclusion
	References
Clinical Treatment Options and Randomized Clinical Trials for Neurocognitive Complications of HIV Infection: Combination Antir...
	1 NeuroHIV-Targeted Combination Antiretroviral Therapy
	2 Association Between CPE and HIV Suppression in the CSF
	3 Association Between CPE and Neurocognitive Improvement
	4 Adjuvant Therapies
	5 Reservoirs Eradication
	6 Conclusion
		6.1 Clinical Implications
		6.2 Further Perspectives
	References